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1
Cafer’s Antidepressants:
Visualize to Memorize
TM
First Edition, 2020
Author: Jason Cafer, MD
Editor: Julianna Link, PA-C
Cafer’s Psychopharmacology | cafermed.com 1

2 Cafer’s Antidepressants: Visualize to Memorize
First Edition
Copyright 2020, CaferMed LLC
Author: Jason Cafer, MD
Editor: Julianna Link, PA-C
Illustrations: Coccus from 99Designs
Cover design: BengsWorks from 99Designs
Licensed images: Shutterstock and Wikimedia Commons
ISBN: 978-1-7350901-3-9
Contact: jasoncafer@gmail.com
The scope of drug interaction information is limited to what can be digested and applied to routine clinical practice. There
are countless unmentioned drug-drug interactions that could be relevant for some patients but are omitted because the
amount of material would be overwhelming.
This book is focused on medications, not overarching psychiatric care. Although chemicals are necessary for treatment of
mania or acute psychosis, pharmacologic treatment of depression/anxiety/insomnia/etc is not always the best medicine.
Always consider interventions including cognitive behavioral therapy, diet, exercise, mindfulness, sleep hygiene, etc.
Dosing recommendations are for healthy adults, and may differ from FDA prescribing guidelines. Refer to other sources for
treatment of children, older adults, pregnancy/breastfeeding and renal/hepatic insufficiency.
Every effort has been made to provide accurate and up-to-date information. Author/editors/publisher/reviewers disclaim all
liability for direct or consequential damages resulting from the use of this material. Readers are encouraged to confirm
information with other sources before incorporating it into your prescribing practice. Information should be compared with
official instructions from the drug manufacturer.
2 Cafer’s Psychopharmacology | cafermed.com

3
Table of Contents Milnacipran (Savella)
SNRIs / atypical antidepressants …....... 46
is an SNRI approved
for fibromyalgia, not Duloxetine (Cymbalta) ……………..…… 47
for depression.
Chapter 1 Venlafaxine (Effexor) ………...…………. 48
Fluvoxamine (Luvox)
is a strong 1A2 Interactions ………...……....…. 5 Desvenlafaxine (Pristiq, Khedezla) ……. 49
Trazodone is
inhibitor.
CYP1A2 …………………………….………10 commonly prescribed Milnacipran (Savella) ………………..….. 50
10
at low dose for
CYP2B6 …………………….………………12 Levomilnacipran (Fetzima) …………….. 51
insomnia, rarely
Citalopram, CYP2C9 ……………………….……………13 prescribed at full Trazodone (Desyrel, Oleptro) ………….. 52
escitalopram, and antidepressant
sertraline are SSRIs CYP2C19 …………………….……………. 14 Nefazodone (Serzone) ………….......….. 53
strength.
metabolized by 2C19. CYP2D6 …………………….………...…… 15 Mirtazapine (Remeron) …………………. 54
CYP3A4 ………………………………….…16 Mirtazapine California Rocket Fuel ………………….. 55
(Remeron) is great
Fluoxetine, Meds with minimal interactions ………..... 17 Vortioxetine (Trintellix) ………………..… 56
paroxetine, for promoting sleep
bupropion, and Interaction table ……………………………19 and stimulating Vilazodone (Viibryd) …………………….. 57
duloxetine are 2D6 appetite.
Serotonin discontinuation syndrome ….. 58
inhibitors.
NRIs, NDRIs, DNRIs ……………………. 59
Atomoxetine
Atomoxetine (Strattera) ……………........ 60
(Strattera) is
approved for ADHD, Bupropion (Wellbutrin) ……………….…. 61
Chapter 2 not for depression.
Solriamfetol (Sunosi)……………...….…. 62
Most antidepressants Intro to Antidepressants ....... 21
are serotonergic.
Neurotransmitters ………….…...………... 21
Sexual side effects ……………...……….. 24 Chapter 5
Except for tricyclics, MAOIs .................................... 63
QT prolongation is Anticholinergic burden scale …...……….. 24
rarely dangerous with Isocarboxazid (Marplan) ………..…....… 64
Serotonin syndrome ……...……….......…. 25
antidepressants.
QT prolongation ………………….…..…… 28 Esketamine nasal
Phenelzine (Nardil) ………..…..………... 65
spray is for Tranylcypromine (Parnate) ……...…..…. 65
Some TCAs are treatment-resistant
anxiety-reducing, depression. Selegiline transdermal (EMSAM) …....… 66
while others are
drive-enhancing. All
are 2D6 substrates.
Chapter 6
Chapter 3
Others for depression ..…...... 67
Amitriptyline is Tricyclics (TCAs) .............…... 29
strongly serotonergic L-methylfolate (Deplin) ………….....…… 67
Amitriptyline (Elavil) ………………………. 30
84
and anticholinergic.
Ketamine (Ketalar) ………….…..…...…. 68
Nortriptyline (Pamelor) …………..………..31
85 Brexanolone is an
Esketamine (Spravato) ………….……… 69
Doxepin (Sinequan, Silenor) ………..…… 32
86 intravenous
neurosteroid Brexanolone (Zulresso) ………….…..….. 70
Imipramine (Tofranil) ………………….….. 33
87 approved for post-
partum depression. St John’s Wort (SJW) …………….…..… 71
Clomipramine (Anafranil) ……..…….…….. 34
88
Desipramine (Norpramin) ………………... 35
Several
noradrenergic TCAs
Protriptyline (Vivactil) …………………….. 35
89 Chapter 7
have so little Amoxapine (Asendin) ……….…………….36 Other serotonergics ……........ 73
serotonergic activity
Maprotiline (Ludiomil) …………………..…37 Flibanserin (Addyi) …………...........…… 73
that they could be
safely combined with Trimipramine (Surmontil) .…….…...…..… 37 Buspirone (Buspar)……….…..……...…. 74
an MAOI.
Toxicity of antidepressant overdose ……. 38 Meperidine (Demerol) ………….……… 75
Some opioids can
contribute to Methadone (Dolophine) ………….…..….. 76
Sertraline is the serotonin syndrome
preferred Fentanyl (Duragesic) …………….…...… 76
antidepressant during Tramadol (Ultram) …………............…… 77
pregnancy.
Sumatriptan (Imitrex) ……….…..…...…. 78
Chapter 4
Rizatriptan (Maxalt) ………….……….… 78
Modern Antidepressants ...… 39
Metaxalone (Skelaxin) ………….……… 79
SSRIs …………………………………....… 39
Cyclobenzaprine (Flexeril) …...………... 80
Sertraline (Zoloft) …………………….…… 40
94
Dextromethorphan ……………………... 81
Escitalopram (Lexapro) ………………….. 41
Fluvoxamine is LSD .……….…..……………………...…. 82
Citalopram (Celexa) ……………………… 42 Cyproheptadine is an
approved for OCD,
antihistamine that
not for depression. Fluoxetine (Prozac) ………………………. 43
blocks 5-HT2
Paroxetine (Paxil) ………………………… 44 serotonin receptors. It Chapter 8
is used off-label for
Fluvoxamine (Luvox) …………………….. 45 nightmares and to
Antiserotonergics ………........ 73
stimulate appetite. Ondansetron (ZOFRAN) ………....…..... 73
Cyproheptadine (PERIACTIN) ……....… 74

Medication Monographs
#40 most prescribed (U.S.) Chemical structure Generic Name (TRADE NAME) ❖ Class of medication
100
1993 200
pronunciation ❖ Mechanism of action
$4–$250 400
mnemonic phrase mg
Year the drug was Monographs focus on the unique aspects of the individual drug, to
introduced to the be considered in context of the medication class. Most of the
U.S. market medications in this book are psychotropic, i.e., capable of affecting
the mind, emotions and behavior.
Price range for a month’s supply of A representative pill of the underlined

the generic (if available) version of strength, either a branded or generic
the drug. The price is generally version. The main purpose is to show
applicable to the most commonly whether we’re talking capsules or tablets.
dispensed prescription, which would For tablets, we try to show the side with
be #30 for drugs usually dosed QD, score lines. If no score lines are shown,
#60 for those dosed BID, and #90 assume that the pill is not intended to be
for those usually dosed TID. The split. For any splittable psychotropic
applicable milligram strength (200 medication, giving a half dose for the first
mg in this example) is the number two days may be a good idea, depending
underlined in the upper righthand on acuity of symptoms. Cutting tablets in
corner. half can cut prescription cost in half
because a 20 mg tab is usually no more
The bottom dollar value is the expensive than a 10 mg tab.
lowest GoodRx price, available with
a coupon at select pharmacies. The Dosing: When provided, dosing
high dollar value is the average recommendations are applicable to
retail price circa 2019–2020. The healthy adults. Refer to other sources for
wide cost differential between pediatric recommendations. Older adults
pharmacies underscores the should generally be given lower doses.
importance of checking GoodRx Each monograph features a mascot designed Doses may need to be modified when
before filling a script for cash. For to pair the drug’s generic name with the most considering kinetic/dynamic interactions,
instance, #30 of olanzapine 20 mg common U.S. trade name. pharmacogenetics, body weight, and
was $843 at Walgreens ($276 with renal/hepatic insufficiency. ePocrates.com
coupon) but only $9 at Walmart and the free ePocrates app provide
(Sept 2020). provide renal/hepatic dosing info.
Boxes like this contain contextual

information about the drug. The box with rounded corners contains a visual
hybrid of the mascot and CYP interaction
mnemonic(s). Over half of prescription drugs are
A link to a page with metabolized by 3A4, so there are plenty of fish.
relevant content looks page
# 3A4 substrate
like this:
Recurring Visuals
Antidepressant (rain cloud) QT interval-prolonging

medication
Anticholinergic with CNS effects

Tricyclic antidepressant (TCA)
(Mad as a hatter)
MAOI inhibitor (Chairman MAO) Antihistamine (push pin)

- “anti-hiss-tamine”

-
Chapter 1 – Interactions 5
5
PHARMACODYNAMICS VS PHARMACOKINETICS PHARMACOKINETIC INTERACTIONS

Drug-drug interactions fall into two main categories: Kinetics involves the rate at which a drug gets into or out of the body or
pharmacokinetic and pharmacodynamic. brain.
Pharmacodynamics is what a drug does to the body. Drug-drug Interactions involving absorption are generally straightforward.
Pharmacodynamic interactions are based on the drugs’ mechanisms For instance, anticholinergics slow gut motility and delay gastrointestinal
of action and do not involve alteration in blood levels of either absorption of other medications.
interacting drug.
Kinetic interactions involving rate of elimination from the body are
Pharmacokinetics is what the body does to a drug. Kinetic derives challenging to learn and daunting to memorize. It is important to consider
from the Greek verb kinein, "to move”. In this case we’re talking these interactions to avoid underdosing or overdosing certain
movement into and out of the body, for instance absorbing the medications. The Visualize to Memorize series tackles these tricky
chemical from the gut and processing it for excretion in urine or elimination interactions by illustrating:
feces. Pharmacokinetic (PK) interactions are generally manifested by
alteration of blood levels of one of the interacting drugs. ❖ Phase I metabolism involving the six most important cytochrome P450
(CYP450) enzymes - relevant to most antidepressants
For simplicity’s sake, let’s drop the pharmaco- prefix and refer to
these concepts as kinetic interactions and dynamic interactions. ❖ Phase II metabolism involving UGT enzymes, as applicable to
lamotrigine (Cafer’s Mood Stabilizers book)
- not applicable to antidepressants
PHARMACODYNAMIC INTERACTIONS ❖ Renal clearance of lithium (Cafer’s Mood Stabilizers book)
- not applicable to antidepressants
Dynamic interactions are intuitive if you understand how the
interacting drugs work. Although dynamic interactions are A mysterious type of kinetic interaction involves drugs getting across the
understandable without silly pictures, here are a couple anyhow. blood-brain barrier, as is necessary for a psychiatric medication to take
effect. If such an interaction is occurring, the effect will not be detectable
Dynamic interactions can be additive/synergistic, with enhanced in serum drug levels. This will be discussed in the context of
effects brought about by combining medications with similar or P-glycoprotein (page 9) - applicable to some antidepressants
complementary effects.
CYTOCHROME P450 ENZYMES
In the liver, kinetic interactions predominantly involve CYtochrome P450

Like-minded “dynos” ganging up to reduce blood pressure, enzymes, CYP enzymes for short, which can be pronounced “sip”.
which is an additive/synergistic effect. Instead of concerning yourself with the origin of P450 nomenclature, take
a moment to contemplate this picture of Ken (kinetic) taking a “sip”
Clonidine (CYP).
Amitriptyline
(Catapres) (Elavil)
CYP
“Sip” (CYP) enzyme interactions are
(pharmaco) “Ken-etic”
antihypertensive orthostasis as side effect
Other dynamic interactions are antagonistic, for instance combining CYP enzymes, which reside primarily in the liver, make chemicals less
a dopaminergic such as pramipexole (for restless legs) with an lipid-soluble so they can be more easily excreted in urine or bile. Of over
antidopaminergic like haloperidol (antipsychotic). Here’s another 50 CYP enzymes, six play a major role in the biotransformation of
example: medications: 1A2, 2B6, 2C9, 2C19, 2D6 and 3A4. Our visual mnemonics
will be built on the following phraseology:
Fighting “dynos” involved in an antagonistic interaction. 1A2 - One Axe To (grind)
Escitalopram Cyproheptadine
CYP
2B6 - Tube Socks
(Lexapro) (Periactin)
2C9 - To See Nice(ly)
2C19 - To See Nice Things
2D6 - Too Darn Sexy
3A4 - Three A’s For (fishing)
serotonergic antihistamine with

antidepressant anti-serotonergic effects
The three most important CYPs are 1A2, 2D6 and 3A4. For psychiatrists,
2C19 can be important, while 2B6 and 2C9 are rarely significant.

SUBSTRATES
Increased concentration of -
A drug that is biotransformed by a particular enzyme is referred to substrate (and increased ratio of
as a substrate of that enzyme. When the substrate is serum substrate:metabolite)
biotransformed (metabolized) it is then referred to as a metabolite.
H for High and Hurried, within 2–4
hours, although the effect may not
be clinically evident for 2–4 days
inHibitor
biotransformation
InHibitors of CYP enzymes will be represented by:
substrate metabolite
Unspecified inHibitor
Each CYP enzyme can metabolize several substrates and most

substrates can be metabolized by several CYP enzymes. Substrates
are the “victims” of the interactions described in this chapter. 1A2 inhibitor - Axe body spray
Throughout this book we use the following visuals for CYP
substrates:
2B6 inhibitor - thick calf

Unspecified substrate - sub
2C9 inhibitor - monocle
1A2 substrate - tree 2C19 inhibitor - watering can
2D6 inhibitor - air pump

2B6 substrate - sock
2C9 substrate - eyeball 3A4 inhibitor - fishing hook & bobber

“3 A’s for
fishing”
2C19 substrate - flower
2D6 substrate - beach ball
Some substrates are also competitive inHibitors of the same CYP

enzyme, for instance duloxetine (Cymbalta), which is represented as a
3A4 substrate - fish both a pump and a beach ball on page 15.
The magnitude to which an inHibitor increases the serum concentration

of a specific substrate depends on the number of alternative pathways
“Aggressor” medications affect how long victim substrates linger in available to metabolize the substrate. If the drug is a substrate of, e.g.,
the blood, and the relative serum concentration of parent drug 1A2, 2D6 and 3A4, then inhibiting one of the three pathways should be of
(substrate) to metabolite. For a given enzyme, interfering no consequence. Such substrates may be described as multi-CYP.
medications (aggressors) are either inDucers or inHibitors. InDucers
stimulate (inDuce) production of metabolic enzymes. InHibitors For a substrate metabolized by a single pathway, the effect of inhibition
interfere with an enzyme’s ability to metabolize other medications. (and induction) will be dramatic. An example is lurasidone (Latuda),
which is contraindicated with strong 3A4 inhibitors or inducers.
ENZYME INHIBITION
Some inhibitors are stronger than others. In general, expect blood levels
InHibition of an enzyme occurs when one drug (the inHibitor) binds of susceptible substrates to increase in the ballpark of:
more tightly to the enzyme than the victim substrate binds. The
inHibitor itself may be metabolized by the enzyme, or act as a ❖ mild inhibitor ~ 25% - 50% increase
non-competitive inhibitor. When an inhibitor is bound to an enzyme, ❖ moderate inhibitor ~ 50% - 100% increase
the victim substrate must find another enzyme to metabolize it, or ❖ strong inhibitor > 100% increase
hope that it can eventually be excreted unchanged. Strong inhibitors
may cause the victim substrate to linger longer, prolonging the Expect these numbers to vary widely between substrates and individuals,
victim’s half-life and elevating its concentration in the blood. For often unpredictably. Note that magnitude of inhibition tends to be
victim substrates that cross the blood brain barrier (as is necessary dose-related over the dosage range of the inhibitor.
to be psychoactive), inhibition leads to increased drug concentration
in the central nervous system.
The “fluffers” – notorious strong inHibitors:
Why is H being emphasized? Well, when an inHibitor is added to an
individual’s medication regimen, levels of victim drugs can escalate ❖ fluvoxamine (Luvox) - SSRI
(H for High). InHibition takes effect quickly, within Hours (H for ❖ fluoxetine (Prozac) - SSRI
Hurried), although the effect may not be clinically evident for 2 to 4 ❖ fluconazole (Diflucan) - antifungal
days, as the victim substrate accumulates. ❖ ketoconazole (Nizoral) - antifungal
The last two are “cone”-azole antifungals.

ENZYME INDUCTION Can shredding be problematic even if the patient is not taking a victim
- 7 medication? Consider this: 7
The opposite of inHibition is inDuction. InDuction occurs when an
inDucer stimulates the liver to produce extra enzymes, leading to
enhanced metabolism and quicker clearance of victim drugs.
The D is for Down, i.e., Decreased serum concentrations of victim

substrates. Unlike inHibition (H for Hurried), inDuction is Delayed, not Long-term use of a shredder
taking full effect for 2 to 4 weeks while we… leads to decreased bone mineral
wait for the liver to ramp up enzyme production. density. This is presumably due to
inDuction of enzymes that
inactivate 25(OH) vitamin D.
inDucer
D for Down and Delayed (2–4 weeks) bone shredding machine
REVERSAL OF INHIBITION/INDUCTION
Decreased serum concentration of
substrate (and decreased serum ratio All things being equal, it is best to avoid prescribing strong inducers or
of substrate:metabolite) inhibitors. Even if there is no problematic interaction at the time, having a
strong inhibitor or inducer on board may complicate future medication
management.
InDucers will be depicted by: Consider an individual on an established medication regimen who stops
taking an inducer or inhibitor. The serum concentration of victim
substrate(s) will change due to the reversal of induction/inhibition.
Unspecified inDucer After an inDucer is withdrawn, the concentration of a victim substrate will
increase gradually (D for Delayed) over a few weeks because the extra
CYP enzymes are degraded without being replenished.
1A2 inducer - axe When an inHibitor is stopped, levels of a victim substrate will decrease
as soon as the aggressor exits the body. “Hurriedly” does not mean
immediately, because it takes about five half-lives for the inhibitor to be
completely cleared.
2B6 inducer - lighter
For a patient on several psychotropic medications, reversal of inhibition
or induction can really throw things out of whack.
2C9 inducer - eyepatch
2C19 inducer - shears While ePrescribe systems may warn the doctor
when starting an interacting medication, there will
be no warning when stopping a medication will
2D6 inducer - N/A (2D6 is not subject to inDuction) lead to a reversal situation.
3A4 inducer - anvil “3 A’s for

For an example of reversal of inHibition, consider a patient taking
fishing”
alprazolam (Xanax, 3A4 substrate) who suddenly stops fluvoxamine
(Luvox, 3A4 inHibitor). In absence of the inhibitor, alprazolam levels drop
(from double) to normal. Since fluvoxamine has a short elimination
More often than not, an inducer is itself a substrate of the enzyme. half-life of 15 hours, it should be out of the body at 75 hours (15 hr x 5).
So, you would expect the patient on Xanax to become more anxious 3
days after stopping Luvox. It may be difficult to discern whether the
THE SHREDDERS patient’s emerging distress is due to serotonin withdrawal or decreased
alprazolam levels.
An example of reversal of inDuction involves tobacco, which is a 1A2

The “shredders” are four strong inDucers of several CYPs, inDucer. A patient taking clozapine (1A2 substrate) stops smoking,
which cause countless chemicals to be quickly expelled from reversing inDuction and causing clozapine levels to potentially double
the body: over the first week (which is faster than occurs with other inducers). The
individual may become obtunded, hypotensive, or even have a seizure.
❖ carbamazepine (Tegretol) - antiepileptic To avoid this, the recommendation is to decrease clozapine dose by 10%
❖ phenobarbital (Luminal) - barbiturate daily over the first four days upon smoking cessation, and to check
❖ phenytoin (Dilantin) - antiepileptic clozapine blood levels before and after the dose adjustment. Note that
❖ rifampin (Rifadin) - antimicrobial nicotine products (gum, patches, e-cigs) do not induce 1A2.
Although reversal of inHibition is typically faster than reversal of

Dr. Jonathan Heldt refers to the shredders as “Carb & Barb” induction, this does not apply to inhibitors with extremely long half-lives.
in his book Memorable Psychopharmacology. For instance, fluoxetine (Prozac) has a long elimination half-life of about
7 days, keeping itself around for about 35 days (7 days x 5). Consider a
patient with schizophrenia on aripiprazole (Abilify, 2D6 substrate) who
stops Prozac (2D6 inHibitor). The patient is doing well at one month, but
St John’s Wort (herbal antidepressant) also inDuces several CYPs, becomes paranoid two months out. Unless the prescriber anticipated this
but does so with less potency than the four shredders. possibility, no one will realize what happened.

PRODRUGS -
Phase I metabolism typically involves biotransformation of an active

drug to an inactive (or less active) chemical.
Phase I Phase II
Phase I Phase II glucuronic

substrate substrate acid
biotransformation
* The responsible enzyme is UDP-glucuronosyltransferase, abbreviated
UGT, as in “U Got Tagged” with glucuronic acid.
active substrate inactive metabolite
Medications metabolized primarily by Phase II are relatively immune to
* Note the lack of a propeller. drug interactions.
RENAL CLEARANCE
For a few medications, the parent drug has low therapeutic activity
until it is biotransformed by a CYP enzyme. In such cases, the A few medications are excreted in urine without being metabolised. Such
substrate is called a prodrug, and the biotransformation process can drugs are not subject to Phase I or II interactions, but may be victims of
be referred to as bioactivation. kinetic interactions. Renal “aggressors” act by slowing or hastening the
rate of excretion of the victim drug in urine.
Interactions affecting renal clearance of

victim drugs are also considered
* bioactivation (pharmaco)“Ken”etic.
inactive substrate active metabolite
(prodrug)
The aggressor in a renal interaction is not referred to as an inducer or
inhibitor, because no enzyme is involved. Nor is the victim called a
substrate, because it is not being biotransformed.
For most medications (active parent drug to inactive metabolite)
inDuction decreases (D for Down) effect of the drug and inHibition (H Lithium, excreted unchanged in urine, is subject to victimization as
for High) amplifies the therapeutic effect and/or side effects. illustrated in the book Cafer’s Mood Stabilizers and Antiepileptics.
With prodrugs, the opposite effect is observed clinically. Induction

increases and inhibition decreases the medication’s effect(s). CYP GENETIC PROFILES
Don’t let prodrugs confuse you. InHibitors increase and InDucers Genetic polymorphisms can influence an individual’s medication kinetics,
decrease the levels of substrate regardless of whether the parent which is most relevant for 2D6 and 2C19. Let’s talk about 2D6, arguably
drug is pharmacologically active. the most consequential example. Most antidepressants are 2D6
substrates and some SSRIs are 2C19 substrates.
Most individuals are genetically equipped with 2D6 genes that produce
normal 2D6 enzymes that metabolize 2D6 substrates at the usual rate.
The following are prodrugs activated by 2D6:
These normal individuals are said to have a 2D6 extensive metabolizer
(EM) genotype, resulting in a 2D6 EM phenotype.
❖ Codeine - metabolized to morphine
❖ Tramadol (Ultram) - weak opioid
❖ Tamoxifen - anti-estrogen for breast cancer
The bowling ball is explained on page 15. Here is a cute representation of how a normal
individual, i.e., 2D6 extensive metabolizer
(EM), processes 2D6 substrates. The air
inside the beach ball represents the substrate,
which is being expelled from the ball as
PHASE II METABOLISM metabolite at the usual rate. 2D6 substrates EM
will have typical elimination half-lives.
Phase II interactions are not clinically relevant for
antidepressants, but are described here to provide context.
About 5% of the population have extra copies of 2D6 genes, resulting in

an ultrarapid metabolizer (UM) phenotype. These individuals clear 2D6
Phase II metabolism occurs in substrates quickly.
the liver and is subject to
kinetic interactions. CYP
enzymes are not involved.
For 2D6 ultrarapid metabolizers (UM), the
Two Kens without a air (2D6 substrate) flows out of the ball
bottle to “CYP” (sip) quickly as metabolite. 2D6 substrates could
be ineffective for these individuals (with the
exception of 2D6 prodrugs, which could be UM
Phase II reactions typically involve conjugation of a substrate with be too strong).
glucuronic acid. This makes the drug water-soluble and prepped
for renal excretion.

- 9 About 10% of individuals have defective 2D6 enzymes resulting in a THE NATURE OF THIS INFORMATION 9
2D6 poor metabolizer (PM) phenotype. This condition may be found
on a diagnosis list as “Cytochrome P450 2D6 enzyme deficiency”. The information presented in the remainder of this chapter is a synthesis
of sources including the OpeRational ClassificAtion (ORCA) system (as
presented in The Top 100 Drug Interactions by Hansten & Horn, 2019),
For 2D6 “POOR Lexicomp, DrugBank, Flockhart Table, ePocrates, Carlat Medication Fact
ME”tabolizers (PM), air Book, Stahl’s Essential Psychopharmacology, The Medical Letter,
accumulates, resulting in Current Psychiatry, GeneSight, Genecept, various research papers and
unexpectedly long half-lives FDA prescribing information for the individual drugs.
for 2D6 substrates. These Poor me!
individuals are more likely to Reputable sources are often at odds with each other regarding the
report side effects. strength of specific inducers/inhibitors, the vulnerability of specific
PM
substrates to induction/inhibition, or even which CYPs are relevant to a
specific medication. CYP interactions are continuously being discovered
and clarified. Even with the freshest information and full knowledge of a
patient’s genotype, the magnitude of a specific CYP interaction is difficult
An individual taking a strong as if! to predict.
2D6 inHibitor (pump as
POOR
illustrated on page 15) will HOW TO APPLY THIS INFORMATION
metabolize 2D6 substrates
as if the individual had a
Refer to the tables on pages 19 and 20. Medications featured in this
2D6 PM genotype.
book are highlighted for you. First acquaint yourself with the inDucers
because the list is short. Memorize the bolded inducers (shredders).
After you know the inducers, move to the inHibitor column. Memorize the
bolded inhibitors (fluffers) and your highlighted medications.
In summary, genetic testing of CYP polymorphisms will interpret the
individual’s metabolizer profile for a given enzyme as either: When it comes to substrates, memorization is less important. Substrates
❖ Extensive metabolizer (EM) - normal are only relevant when an inducer or inhibitor is on board, or if the patient
❖ Ultrarapid metabolizer (UM) - fast clearance of substrates has a special metabolizer genotype. Of the medications you prescribe,
❖ Poor metabolizer (PM) - slow clearance of substrates be aware of the more susceptible substrates.
A genetic test result of intermediate metabolizer (IM) means that Consider running an interaction check whenever a patient is taking a
enzyme activity is likely to be a bit lower than that of an EM, i.e., an shredder, fluffer, systemic antifungal, HIV medication, or cancer
intermediate between EM and PM. Generally, IM individuals can be medication. ePocrates.com and the ePocrates app are adequate, and
clinically managed normally, like an EM individual. free.
Standalone 2D6 genotyping costs at least $200. GeneSight or Keep things simple. When choosing new medications, avoid major
Genecept panels cost about $4,000 and report the six relevant CYPs inducers and inhibitors if suitable alternatives are available. For the
and two UGT enzymes (UGT1A4 and UGT2B15). 23andMe ($199) complicated psychiatric patient on several medications, try to avoid
reports 1A2, 2C9, and 2C19, among 100s of other genes. 23andMe carbamazepine (shredder inducer) and the fluffer SSRIs (fluoxetine and
does not report the most relevant CYP genotype, 2D6, because the fluvoxamine). Among SSRIs, escitalopram (Lexapro) and sertraline
genetics of 2D6 metabolism is more complicated. (Zoloft) are good choices—they are 2C19 substrates but do not affect the
metabolism of other medications.
Genotyping may be useful when choosing which medication to
prescribe an individual patient. With GeneSight, about 1 in 5 patients Also think about choosing less vulnerable substrates. Each drug mascot
have a genetic variation relevant to their treatment. For an individual on pages 17 and 18 is depicted in box/bubble because it is generally not
already established on a medication, serum drug levels may be more involved in clinically significant kinetic interactions (although dynamic
useful than genotyping. interactions almost always apply). You don’t have to worry much about
benzodiazepine interactions if you stick to the “LOT”
benzos—lorazepam, oxazepam and temazepam. Most antipsychotics
are susceptible substrates, but not so much for ziprasidone, loxapine and
Therapeutic serum ranges are defined for
paliperidone.
three tricyclic antidepressants (TCAs):
desipramine, imipramine and nortriptyline
This book uses picture association as a memorization technique. Pages
—“mosquitos DINe on your blood”.
10 through 16 establish a visual mnemonic framework for various kinetic
interactions that will be reinforced by a mascot for each medication. The
mascots serve a double purpose of helping you remember US trade
name/generic name pairings.
P-GLYCOPROTEIN
Since you probably won’t be mentioning CYP nomenclature in casual
P-glycoprotein (P-gp) is a gatekeeper at the gut lumen and the conversation, you might want to bypass the technical naming system
blood-brain barrier. P-gp pumps P-gp substrates out of the altogether. Instead of keeping a list of “3A4 substrates” in your memory
brain—“Pumpers gonna pump”. Sertraline (Zoloft) and paroxetine bank, you could just learn the school of “fish”.
(Paxil) are two antidepressants shown to inhibit P-gp.
I hope this book empowers you to understand and memorize topics that
are otherwise daunting, so you can to use your knowledge to improve
patient care. Without further ado, let’s start our journey to becoming a
superhero of psychotropic medication management.
“Pumpers
gonna pump”
P-gp substrates P-gp
out of the brain substrate
An example of a relevant P-gp interaction involves the OTC opioid

antidiarrheal loperamide (Imodium). Loperamide does not cause
central opioid effects under normal circumstances. If the individual
takes a potent P-gp inhibitor, megadose loperamide can stay in the
brain long enough to cause euphoria.
1A2 accounts for 10–15% of Cytochrome P450 1A2 (CYP1A2) 52% of individuals are 1A2
CYP activity in the liver
ultrarapid metabolizers; -
“One Axe to Grind; One Axe to Grow” < 1% are poor metabolizers
“1 Axe to 2 Grind” “1 Axe 2 Grow”

inHibitor = High
inDucer = Down Increased substrate
1A2 Substrate
levels
1A2 Decreased
2 substrate levels 1A2
r 1A Substrate inHibition happens
uce within Hours = Hurried
ind induction onsets and reverses as soon
2 and reverses
1A as the inhibitor is
slowly = cleared from the body
1A2
Delayed * Inhibitor (five half-lives of the
inhibitor)
Hydrocarbons from smoked herbs such as tobacco and cannabis are
moderate potency 1A2 inducers. All other 1A2 inducers are weak. Fluvoxamine (Luvox) is the only strong 1A2 inhibitor.
weak strong
ma zepine) 1A2 inhibitor
TEGRETOL (Carba
r inducer o
mood stabilize cannabis als
antiepileptic,
moderate
1A2
Tobacco inducer SSRI
tch or gum For
not nicotine pa 1A2 OCD
LUVOX
weak
in) Fluvoxamine
DILANTIN (Phenyto 1A2
antiepileptic inducer
* Induction by smoking takes about 3 days to
start—notice the axe has no spinning wheel
1A2 1A2 1A2 moderate
like the other axes. Upon cessation of inhibitor
smoking, induction reverses over the first
CIPRO
week. This is much faster than with other ciprofloxacin
weak
inducers. 10 cigarettes daily is sufficient for 1A2
1A2
maximum induction effect.
St John’s Wort inducer quinolone
antibiotic
First Generation Antipsychotics Second Generation Antipsychotics “-pine” trees Antidepressant
NAVANE HALDOL STELAZINE

Thiothixene Haloperidol Trifluoperazine
ZYPREXA CLOZARIL SAPHRIS
Olanzapine Clozapine Asenapine
minor
minor minor ~ 50% increase 3-fold increase negligible decrease CYMBALTA
by Luvox by Luvox by smoking Duloxetine
Melatonin agonists Methylxanthines Spasmolytic
ROZEREM HETLIOZ NOURIANZ ZANAFLEX

Melatonin Theophylline Caffeine
Ramelteon Tasimelteon Istradefylline Tizanidine
“TREE
-ophylline”
up to 100-fold 3-fold increase > 10-fold increase

increase by Luvox by Luvox by Luvox
Contraindicated with Luvox
Contraindicated with Luvox or Cipro
Conclusion: Keep in mind that 52% of individuals have a 1A2 ultrarapid

Tobacco metabolizer genotype, and everyone who smokes has an ultrarapid
Decreases metabolizer phenotype. Smokers may need to take higher doses of 1A2
blood levels of substrates. The effect of smoking on olanzapine and clozapine is worthy
co Clozapine
b ac or these two of memorization. Memorization of other 1A2 substrates is of lower priority,
To Olanzapine 50% as long as you remember to run an interaction check on any medication
”pine trees”
by about 50%. regimen that includes Luvox. Consider keeping Luvox out of the mix
entirely—it is nonessential for treatment of OCD because other SSRIs are
equally effective at high doses (page 34).

- CYP1A2 inHibition Examples 1
Ciprofloxacin, a
moderate 1A2
inHibitor, increases
clozapine levels
about 2-fold.
1A2
Clozapine
CIPRO Clozapine
ciprofloxacin
quinolone
antibiotic
Fluvoxamine, a strong 1A2

inHibitor (“Fluffer”) increases
clozapine levels 3-fold on
average, but up to 10-fold in
some cases.
75% clozapine
60% cloz
40% norcloz
25% norclozapine
ROZEREM
ramelteon
LUVOX
Fluvoxamine
Kinetic interactions can be more complicated than simply

increasing/decreasing concentrations of victim substrates. sleep medication
Combining clozapine and fluvoxamine is hazardous, but can potentially be

used for therapeutic advantage. Close monitoring of serum clozapine
1A2
levels would be required.
Norclozapine is the main metabolite of clozapine, formed by 1A2

metabolism. When clozapine blood levels are reported, clozapine and
metabolite (norclozapine) levels are provided separately. Through 1A2
inHibition, Luvox increases the serum clozapine:norclozapine ratio. A
Higher serum clozapine:norclozapine ratio is generally considered
desirable*. Norclozapine provides little antipsychotic benefit and causes
weight gain, diabetes, seizures, and neutropenia.
Patients given clozapine 100 mg + Luvox 50 mg daily (compared to

clozapine 300 mg monotherapy) demonstrated more improvement with
less weight gain and less drooling. Clozapine levels were similar for both
groups with, as expected, lower norclozapine levels for those taking
Luvox.
(Lu ML et al, 2018; randomized controlled trial, N=85).
Fluvoxamine and ramelteon
*The negative aspect of a Higher clozapine:norclozapine is greater anticholinergic should not be prescribed
burden. Clozapine is anticholinergic, whereas norclozapine is cholinergic. concomitantly because
Consequently, clozapine causes constipation, while norclozapine does not. The ramelteon levels will be
anticholinergic properties of clozapine may impair cognition, whereas norclozapine increased up to 100-fold!
may provide cognitive benefits such as enhanced working memory.
Certain physiologic states may increase levels

of olanzapine and clozapine up to 2-fold.
“Pine”
trees
Clozapine
Clozapine
or ROZEREM
or
Olanzapine Olanzapine ramelteon
❖ Major inflammations
❖ Infections with fever
❖ Female gender (estrogen)
❖ 1A2 poor metabolizer genotype
LUVOX
(< 1% of population)
Fluvoxamine
For a patient with efficacy or tolerability issues, consider monitoring serum
levels of the antipsychotic. The author checks clozapine levels routinely,
and olanzapine levels in some cases.
3% of individuals are 2B6
2 Cytochrome P450 2B6 (CYP2B6) ultrarapid metabolizers;
-
“Tube Socks” 7% are poor metabolizers
inHibition
stretched sock = High
2B6 substrate
Increased substrate levels inHibition happens
2B
within Hours =
6i
r inDuction = Down
nh
e Hurried and reverses
uc
ibi
d as soon as the
t
in Decreased substrate levels
or
6 inhibitor is cleared
2B 2B6
sub from the body (five
induction onsets and reverses stra half-lives of the
slowly, over 2–4 weeks = te
inhibitor)
Delayed
There are no strong 2B6 inducers. There are no strong 2B6 inhibitors.
moderate
inducer moderate moderate
inducer Orp inhibitor
epine NO hena
Carbamaz
RF d
Rifampin
L
TEGRETO LEX rine
RIFADIN
tuberculosis antibiotic
weak spasmolytic
inducer
in moderate
Phenyto inducers
DILANTIN
HIV meds Clo weak
rals
antiretrovi p
PLA idogr inhibitor
weak VIX el
inducer - Efavirenz
bital - Nevirapine
Phenobar - Ritonavir
LUMINAL antiplatelet
Opioid
Methadone
DOLOPHINE
SSRI
Alkylating Drugs for Cancer

MAOI
Cyclophosphamide
CYTOXAN
Selegiline
ELDEPRYL, EMSAM
Ifosfamide
IFEX
Ketamine NNRTIs for HIV

KETALAR Zoloft
SERTRALINE
NMDA antagonist Efavirenz
(anaesthetic) SUSTIVA
NDRI antidepressant Nevirapine

VIRAMUNE
Esketamine
SPRAVATO
Anaesthetic
NMDA antagonist Bupropion
(intranasal for depression) WELLBUTRIN Propofol
DIPRIVAN
Conclusion: Fortunately, there are no strong inhibitors or inducers of 2B6. For psychiatrists, 2B6 is of minimal significance, unless methadone
is being prescribed. You will want to run an interaction check (e.g., ePocrates or Lexicomp) whenever a medication regimen includes a
shredder, cancer medication, HIV medication, or systemic antifungal.
For psychiatry, 2C9 interactions are of little Cytochrome P450 2C9 (CYP2C9) 0% of individuals are 2C9
- clinical significance. Paroxetine (Paxil) is the ultrarapid metabolizers;
only antidepressant on this page. “To See Nice(ly)” 5% are poor metabolizers
13
inHibition = High
2C9 inDuction = Down 2C9 Increased substrate
2C9 inhibitor levels
Decreased substrate
inducer levels
inHibition happens
substrate within Hours = Hurried
induction onsets and
reverses slowly, over
Inhibition reverses as
2–4 weeks = Delayed
soon as the inhibitor is
cleared from the body
(five half-lives of the
There are no strong 2C9 inducers. There are no strong 2C9 inhibitors inhibitor)
Enzalutamide Rifampin
(antibiotic) DIFLUCAN Tamoxifen PAXIL
(prostate cancer)
Fluconazole SERM for breast Paroxetine
cancer SSRI
antifungal
moderate inducer moderate inducer

moderate weak weak
inhibitor inhibitor inhibitor
LUMINAL
Phenobarbital
weak inducer
Antiepileptics Sulfonylureas for DM ARB for HTN NSAID
DILANTIN MICRONASE COZAAR FELDENE

“d-EYE-lantin; “glybur-EYED”
“Coz-EYEr” “p-EYE-roxicam”
phen-EYE-toin”
Phenytoin Glyburide Losartan Piroxicam
Also 2C19 Also 3A4
AMARYL
DEPAKOTE “glimepir-EYED” Lipid lowering COX-2 inhibitor
“Dep-EYE-
kote” Glimepiride LESCOL CELEBREX
Valproate “fluv-EYE- “cel-EYE-brex”
statin”
2C9 contributes only 25% Fluvastatin Celecoxib

GLUCOTROL
to the metabolism of VPA
“Glipiz-EYED”
Anticoagulant Glipizide Libido enhancer Conclusion: Consider

checking valproic acid (VPA)
ADDYI levels more often if the patient
COUMADIN
is taking or stops taking
“coum- ORINASE enzalutamide, rifampin, or
“Add-EYE”
EYE-din” diflucan; but don’t expect
“tolbutam-EYED” Flibanserin much variance from baseline.
Warfarin
Consider avoiding paroxetine
Tolbutamide entirely (page 44).
Also 2C19

Cytochrome P450 2C19 (CYP2C19) 10% of individuals are 2C19
ultrarapid metabolizers;
“To See Nice Things (grow)” 5% are poor metabolizers
inHibition = High
inDuction = Down 2
in C1 Increased substrate levels
2C19 hi 9
bi
to
inducer Decreased substrate levels r inHibition happens
within Hours = Hurried
2C19 induction onsets and
substrate reverses slowly, over Inhibition reverses as soon
2C19
2–4 weeks = Delayed as the inhibitor is cleared
substrate
from the body (five
half-lives of the inhibitor)
SSRI
RIFADIN
Rifampin
TB antibiotic DIFLUCAN LUVOX
strong
Fluconazole Fluvoxamine
ERLEADA strong moderate
Apalutamide “Fluffers”
- fluconazole
prostate cancer strong - fluvoxamine TCA s
TRICYCLICS PPIs ADDYI
- fluoxetine PROTON Flibanserin
TRICYCLICS PUMP
SSRI INHIBITORS
LUMINAL CBD amitriptyline omeprazole libido enhancer

doxepin esomeprazole
Phenobarbital PROZAC
clomipramine lansoprazole
barbiturate Cannabidiol Fluoxetine imipramine pantoprazole
moderate
trimipramine
strong moderate
SSRI antidepressants Sedative/Antiepileptic Anticoagulant
ZOLOFT LEXAPRO CELEXA SOMA LUMINAL DILANTIN VALIUM ONFI COUMADIN

Sertraline Escitalopram Citalopram Cariso- Pheno- Phenytoin Diazepam Clobazam Warfarin
prodol barbital
SSRI SSRI SSRI spasmolytic barbiturate antiepileptic BZD BZD Vitamin K

“antagonist”
2C19 poor metabolizers (PM) Poor me! 2C19 ultrarapid

Poor me! metabolizers (UM)
Individuals with a 2C19 PM genotype
clear 2C19 substrates slowly, leading to 2C19 UM individuals clear
Higher blood levels (as if they were taking 2C19 substrates quickly,
a 2C19 inHibitor). Standard doses of leading to low blood levels.
2C19 substrates may be too strong. These individuals are more
likely to be non-responders
2C19 poor metabolizers should not exceed
to 2C19 substrates at
20 mg of citalopram (QT prolongation). 2C19
2C19 standard doses.
UM
PM 10% of population
5% of population (20% of Asians)
Conclusion: 2C19 genotyping is not typically ordered as a standalone test, but if titrated the old-fashioned way, according to response and side effects. In
2C19 metabolizer genotype is known (e.g., from GeneSight or Genecept), the any event, avoid prescribing Soma, Valium, or phenobarbital for anxiety due
information can be put to good use when dosing (es)citalopram and sertraline. to their particularly high risk of abuse and dependence. Avoid St. John’s
Knowledge of metabolizer status is not essential because these SSRIs can be Wort due to interactions, and because it only works for mild depression.
titrated
2D6 metabolizes ~ 12% of prescription Cytochrome P450 2D6 (CYP2D6) 5% of individuals are 2D6 ultrarapid
- drugs. Notice how all of the -oxetine’s are metabolizers (UM). 1
2D6 inhibitors and/or substrates. “Too Darn Sexy” 10% are poor metabolizers (PM).
5
inHibition = High Prodrugs are substrates that are less potent than their
You’re inflating metabolites. Ordinary substrates (beach balls) are deactivated by
These balls are 2D6. Prodrugs (bowling balls) are activated by 2D6. In the
my ego! Increased substrate
2 Darn 6’y presence of an inhibitor prodrugs are less effective.
levels
inHibition happens It’s your

2D6 inhibitor 2D6
within Hours = Hurried Aw, snap! fault I
substrate
can’t roll
Inhibition reverses as pro-drug
hibitor
cleared from the body 2D6 in prodrug
(five half-lives of the
2D6 enzymes cannot be induced. inhibitor)
Quinid
antiarr ine
hythm
strong ic
mod/ also q
PROZAC PAXIL strong WELLBUTRIN strong CYMBALTA mod uinine strong
Fluoxetine paroxetine Bupropion Duloxetine
Antidepressants VMAT inhibitors Antitussive Anti-HTN

NRI for
SPARI ADHD
SNRI
AUSTEDO LOPRESSOR
deutetra- metoprolol
benazine
TRINTELLIX CYMBALTA OH-bupropion Tricyclic STRATTERA also tetrabenazine dextro- beta blocker
vortioxetine duloxetine active metabolite of antidepressants atomoxetine methorphan

bupropion (Wellbutrin)
“Cym-BALL-ta”
First Generation Antipsychotics (FGA) Second Generation Antipsychotics (SGA)
HALDOL TRILAFON MELLARIL ORAP ABILIFY FANAPT REXULTI

haloperidol perphenazine thioridazine pimozide aripiprazole iloperidone brexpiprazole
2D6 genotyping required also 3A4 substrate
Prodrugs
2D6 poor metabolizers have
defective 2D6 enzymes. Substrates are as if !
cleared slowly (by other pathways) or
are unmetabolized leading to Higher POOR
Codeine Tramadol Tamoxifen blood levels, as if the patient were
taking an inHibitor.
2D6 genotyping is recommended prior to starting these medications, which

metabolized to weak opioid are increased 3--4-fold in 2D6 PMs. Mellaril is contraindicated for 2D6 PMs.
morphine and SNRI breast cancer
50% dose reduction is recommended for 2D6 poor metabolizers.
According to the label, use 75% of Abilify dose if the individual is a 2D6 PM.
2D6 extensive 2D6 ultrarapid metabolizers Use 50% Abilify dose if 2D6 PM and taking a 3A4 inhibitor.
metabolizers clear 2D6 substrates quickly. These
have the typical individuals are more likely to be
genotype and process non-responders to 2D6 substrates
2D6 substrates as (excluding 2D6 prodrugs, which may be
too strong). This genotype is relatively Poor me!
expected
common among those with Middle Eastern
or North African heritage.
2D6 PM
10% of population
Conclusion: 2D6 interactions need to be understood by prescribers of
antidepressants and antipsychotics. To avoid 2D6 interactions, use Lexapro or
Zoloft instead of Prozac/Paxil.
Among the CYP genetic assays, 2D6 is the most useful. The test is about $200 as
a standalone, and is recommended prior to starting Trilafon, Mellaril, or
Orap—three antipsychotics that psychiatrists rarely prescribe. For the other 2D6
2D6 EM 2D6 UM substrates, serum drug levels may be more useful than genotyping. The author
checks blood levels of haloperidol, risperidone and aripiprazole when there are
85% of population 5% of
2D6 UM 5%population
of population issues with efficacy or tolerability.

> 50% of prescription drugs are 3A4 Cytochrome P450 3A4 (CYP3A4) 0% of individuals are 3A4
16
substrates—plenty of fish! ultrarapid metabolizers; -
“3 A’s For (fishing)” < 1% are poor metabolizers
inHibition Macrolide Antibiotics (-mycins) Systemic Antifungals (-conazoles)

= High
3A4 Increased
substrate
Inhibitor levels BIAXIN E-MYCIN NIZORAL SPORANOX DIFLUCAN
Clarithro- Erythro- Keto- Itra- Flu-
Three inHibition mycin mycin conazole conazole conazole
letter A’s happens
within Hours
= Hurried strong moderate strong strong moderate
3A4
substrate not Azithromycin (ZITHROMAX) not Terbinafine (LAMISIL) 2D6
Inhibition reverses as
cleared from the body (five Antidepressant HIV meds (-avirs) Calcium Channel Blockers
half-lives of the inhibitor)
inDuction = Down
Grapefruit Protease
SERZONE Inhibitors CARDIZEM CALAN
Decreased Juice
Nefazodone HIV meds Diltiazem Verapamil
substrate levels 33A
A44
induction inDdU
IN moderate
darunavir (mod)
strong moderate moderate
onsets and uCcEeR ritonavir (strong)
r atazanavir (strong)
reverses
etc
slowly, over
2–4 weeks 3A4
substra
= Delayed te
Benzodiazepines Antipsychotics DILANTIN
strong
** **
LATUDA *
SEROQUEL
Phenytoin
XANAX Lurasidone
PDE-5 Quetiapine
Alprazolam
TEGRETOL
**
inhibitors
Lurasidone is metabolized
strong
Quetiapine levels are
ADDYI exclusively by 3A4 and is increased 6-fold by strong Carbamazepine
Viagra, etc Flibanserin contraindicated with potent 3A4 inhibitors and decreased
3A4 inhibitors or inducers. 6-fold by strong inducers.
LIBRIUM LUMINAL
* Chlordiazepoxide
strong
Contra-
ceptives
*
ABILIFY
**
CAPLYTA Phenobarbital
Aripiprazole Lumateperone primidone also
VIIBRYD
Estrogens, progestins also 2D6
Vilazodone RIFAMPIN
KLONOPIN strong
*
Clonazepam
*
INGREZZA SUBOXONE
REXULTI *
VRAYLAR
antibiotic
Brexpiprazole Cariprazine
Valbenazine Buprenorphine
also: EFAVIRENZ
Diazepam (Valium) strong
Estazolam (Prosom)
** HIV med
Midazolam (Versed)
**
**
Triazolam (Halcion)
Clorazepate(Tranxene)
**
ORAP** *
NUPLAZID
nevirapine also
DAYVIGO Pimavanserin
not: Pimozide
Lemborexant
also
* Lorazepam (Ativan)
Oxazepam (Serax) also 2D6
mod
suvorexant BUSPAR Temazepam (Restoril)
(Belsomra), Clobazam (Onfi) 2C19
to a lesser extent Buspirone minor 3A4 substrates: not:
Chlorpromazine Asenapine (Saphris) 1A2
St John’s Wort
(Thorazine) Fluphenazine (Prolixin) 2D6
Clozapine (Clozaril) Molindone (Moban) PROVIGIL
There is risk of
**
rhabdomyolysis not: Haloperidol (Haldol) Olanzapine (Zyprexa) 1A2 mod
when HMG-CoA Pravastatin (Pravachol) Iloperidone (Fanapt) Paliperidone (Invega)
reductase inhibitors STATINS Rosuvastatin (Crestor) Loxapine (Loxitane) Promethazine (Phenergan) Modafinil
(statins) are Fluvastatin (Lescol) Prochlorperazine Thiothixene (Navane) 1A2
weaker: Nuvigil (armodafinil)
combined with 3A4 Perphenazine (Trilafon) Trifluoperazine (Stelazine)
inHibitors. simvastatin Risperidone (Risperdal) 1A2
atorvastatin Ziprasidone (Geodon)
* Dosing
defined
adjustments
Conclusion: 3A4 is the workhorse of CYP metabolism, accounting for 30% of hepatic CYP activity and 70% of CYP activity
in the gut. Since > 50% of drugs are 3A4 substrates, think twice before prescribing strong 3A4 inhibitors or inducers. ** Has contraindications
related to kinetic
interactions
Non-participants For a substrate metabolized through multiple pathways, serum levels
18 -
are not significantly affected by inHibition of a single CYP. For
page instance, over half of prescription drugs are 3A4 substrates, but will
Medications that do not become 5 not be depicted as fish (page 16) if they are multi-CYP substrates.
significantly involved in kinetic Multi-CYP substrates are depicted in a box (not a bubble) because
interactions are depicted “in a interactions do occur but are unlikely to matter much.
bubble”.
A multi-CYP substrate is more likely to be victimized by an inDucer
than by an inHibitor. It is worthwhile to run an interaction check on a
Some of these medications are “in a
patient’s medication list if they are taking a “shredder” inDucer (page
box” (with a hole in it) to indicate that
7), even for the boxed medications.
kinetic interactions exist, but usually do
not need be taken into consideration A bubble/box certifies the medication is:
when prescribing the medication. ❖ No more than a weak CYP inducer or inducer, and...
❖ Either a multi-CYP substrate or a substrate not metabolized
Dynamic interactions still apply to by any CYP
bubbled/boxed medications.
A bubble does not imply that a medication does not participate in
dynamic interactions, because almost all drugs do. Acamprosate
(Campral) and N-acetylcysteine (NAC) are rare exceptions, depicted
We will display medications “in a bubble” or “in a box” if they are not in a double bubble.
expected to serve as clinically significant substrates, inducers or
inhibitors. There is a hole at the top of the boxes to suggest some This book contains medication monographs with mascots designed to
degree of vulnerability to relevant kinetic interactions, but not to an help you pair antidepressant trade names with generic names, and
extent prescribers need to routinely worry about. In general, remember kinetic interactions. Medications featured in this book are
medications that are renally cleared have relatively few drug–drug highlighted. Refer to Cafer’s Psychopharmacology for all of the
interactions because their metabolism does not rely on CYP enzymes. mascots, 270 in total.
Dynamic interactions: “Bubbled” or “boxed” medications are unlikely to be involved in clinically significant kinetic interactions:
Not applicable to every
drug in class
Antipsychotics
❖ Extrapyramidal effects LOXITANE MOBAN COMPAZINE
❖ Sedation
❖ Weight gain
❖ Hyperglycemia
❖ QT prolongation
INVEGA GEODON
❖ Myelosuppression
❖ Anticholinergic Paliperidone Ziprasidone Loxapine Molindone Prochlorperazine
❖ Proconvulsant
Antidepressants
❖ Serotonergic
EFFEXOR PRISTIQ SAVELLA
❖ QT prolongation DESYREL REMERON
❖ Sedation
❖ Weight gain
❖ Hyponatremia
❖ Antiplatelet
❖ Hypo/hypertension
Trazodone Mirtazapine Venlafaxine Desvenlafaxine Milnacipran
❖ Anticholinergic
Antiepileptics
❖ Sedation KEPPRA LYRICA VIMPAT
❖ Stevens-Johnson
Syndrome
❖ Hyponatremia
SABRIL
❖ Acidosis NEURONTIN
❖ Myelosuppression
Gabapentin Levetiracetam Pregabalin Lacosamide Vigabatrin
Sedatives
ATIVAN ZULRESSO
❖ Sedation SERAX RESTORIL
❖ Respiratory depression
XYREM
GHB
Lorazepam Oxazepam Temazepam Brexanolone Sodium Oxybate

The 3 “LOT” benzos—No CYP interactions but levels may
double with VPA (Depakote) due to UGT2B15 inHibition
Dynamic interactions: “Bubbled” or “boxed” medications are unlikely to be involved in clinically significant kinetic interactions:
Not applicable to every
antiserotonergic 19
drug in class
BENADRYL VISTARIL
Antihistamines
PERIACTIN
❖ Anticholinergic
⁃ constipation
⁃ urinary retention
⁃ cognitive impairment UNISOM ANTIVERT
❖ Sedation
Diphenhydramine Doxylamine Hydroxyzine Meclizine Cyproheptadine
COGENTIN ARTANE ROBINUL

Anticholinergics
❖ Anticholinergic
⁃ constipation
⁃ urinary retention BENTYL
⁃ cognitive impairment SYMMETREL
❖ Sedation
Benztropine Trihexyphenidyl Amantadine Dicyclomine Glycopyrrolate
Cognitive Enhancers EXELON RAZADYNE

NAMENDA NICORETTE The hydrocarbons
❖ Cholinergic in smoked tobacco
❖ Lowers seizure inDuce 1A2.
threshold Nicotine itself does
not.
Rivastigmine Galantamine Memantine Nicotine
Addiction Medicine ReVIA NARCAN CAMPRAL

For some, dynamic Double bubble:
interactions are part of acamprosate
their mechanism of action, has no known
e.g., opioid antagonism by kinetic or
naltrexone and naloxone. dynamic
CHANTIX interactions.
Varenicline Naltrexone Naloxone Acamprosate
Sympatholytics PRECEDEX
INDERAL
❖ Hypotension
❖ Bradycardia
❖ Sedation / fatigue
CATAPRES MINIPRESS
Clonidine Prazosin Propranolol Dexmedetomidine
serotonergic
Spasmolytics
ROBAXIN LIORESAL
❖ Sedative SKELAXIN
❖ Hypotensive
❖ Anticholinergics
❖ Lowers seizure
threshold
Methocarbamol Baclofen Metaxalone
Stimulants Supplements DEPLIN

NAC
❖ Hypertensive Double bubble:
❖ Dopaminergic NAC has no
❖ Noradrenergic known kinetic
or dynamic
❖ Lowers seizure interactions.
threshold RITALIN SUNOSI
Methylphenidate Solriamfetol N-acetylcysteine L-Methylfolate

2
19 RELEVANT PHARMACOKINETIC INTERACTIONS, general overview with included medications highlighted -
INDUCERS INHIBITORS SUBSTRATES

InDuction Decreases substrates InHibition increases substrate “Victims” of inducers
slowly, over 2 to 4 weeks levels (High), happening within and inhibitors
(Delayed). With smoked Hours (Hurried). Inhibition reverses
tobacco, induction (1A2) starts in as soon as the inhibitor is cleared
3 days and reverses in about 1 week. from the body (five half-lives of the inhibitor).
1A2 inducers 1A2 inhibitors 1A2 substrates

Ψ Tobacco/Cannabis Ψ Fluvoxamine Ψ Asenapine Ψ Olanzapine
(faster on/off) Ciprofloxacin Ψ Clozapine Ψ Ramelteon
Ψ Carbamazepine Ψ Duloxetine Ψ Thiothixene
Ψ Phenytoin
2B6 inducers 2B6 inhibitors 2B6 substrates

Ψ Carbamazepine Ψ Orphenadrine (Norflex) HIV MEDS Ψ Methadone
Rifampin CANCER MEDS Ψ Selegiline
HIV MEDS Ψ Bupropion
Ψ Ketamine
2C9 inducers 2C9 inhibitors 2C9 substrates

Rifampin Fluconazole Ψ Valproate (VPA)
Ψ St John’s Wort
2C19 inducers 2C19 inhibitors 2C19 substrates

Ψ Phenobarbital Ψ Cannabidiol (CBD) Ψ Citalopram
Rifampin Fluconazole Ψ Diazepam
Apalutamide Ψ Fluoxetine Ψ Escitalopram
Ψ Fluvoxamine Ψ Phenobarbital
Ψ Phenytoin
Ψ Sertraline
Ultrarapid Poor metabolizer Ψ Methadone
metabolizer (UM) (PM) genotype Warfarin
genotype (10% of population)
(10% of population)
2D6 inducers 2D6 inhibitors Ψ Paroxetine 2D6 substrates

None Ψ Bupropion Quinidine Ψ Tricyclics (TCAs) Ψ Haloperidol
Ψ Duloxetine Ψ Aripiprazole Ψ Iloperidone
Ψ Fluoxetine Ψ Atomoxetine Ψ Perphenazine
Ψ Brexpiprazole Ψ Pimozide
Ψ Bupropion-OH Ψ Risperidone
Ψ Codeine *PRODRUG* Tamoxifen *PRODRUG*
Ultrarapid
Poor metabolizer Ψ Deutetrabenazine Ψ Tetrabenazine
Metabolizer (UM)
(PM) genotype Ψ Dextromethorphan Ψ Thioridazine
genotype
(10% of population) Ψ Duloxetine Ψ Tramadol *PRODRUG*
(5% of population)
Ψ Vortioxetine
3A4 inducers 3A4 inhibitors 3A4 substrates

Ψ Carbamazepine Protease Inhibitors (HIV) Immunosuppressants Ψ Fentanyl
Ψ Modafinil Clarithromycin Progestins Ψ Flibanserin
Ψ Phenobarbital Diltiazem Ψ Alprazolam Ψ Lemborexant
Ψ Phenytoin Grapefruit juice Ψ Aripiprazole Ψ Lumateperone
Rifampin Ketoconazole Ψ Brexpiprazole Ψ Lurasidone
Ψ St John’s Wort Itraconazole Ψ Buprenorphine Ψ Pimavanserin Tadalafil
Ψ Nefazodone Ψ Buspirone Ψ Pimozide Ψ Valbenazine
Verapamil Ψ Carbamazepine Ψ Quetiapine Ψ Vilazodone
Ψ Cariprazine Sildenafil
Ψ Chlordiazepoxide Simvastatin
Ψ Clonazepam Ψ Suvorexant
UGT inducers UGT inhibitors UGT substrates

Ψ Carbamazepine Ψ Valproate (VPA) Ψ Lamotrigine
Estrogens Ψ Lumateperone
Ψ Phenobarbital
Ψ Phenytoin
Rifampin
Lithium Decreased by: Increased by: NSAIDS: ACE Inhibitors “-prils”

levels Acetazolamide ⁃ Celebrex
Thiazides: ARBs "-sartans"
Ψ Caffeine ⁃ Ibuprofen
Ψ Topiramate ⁃ HCTZ ⁃ Indomethacin Antimicrobials:
Mannitol
Ψ Zonisamide ⁃ Chlorthalidone ⁃ Naproxen ⁃ Tetracyclines
Theophylline
⁃ Diclofenac ⁃ Metronidazole
UGT and lithium visual mnemonics are explained in the Visualize to Memorize Ψ = CNS meds (psychoactive)
edition Cafer’s Mood Stabilizers & Antiepileptics
Pharmacokinetic Drug-Drug Interactions with included medications highlighted
21
INDUCERS INHIBITORS SUBSTRATES In general, substrates that are metabolized through only one
InDuction decreases InHibition increases “Victims” of pathway are more vulnerable to drug interactions. For drugs
(Down) substrates substrate levels (High). inducers metabolized by multiple CYPs, strong inDuction of a single
slowly, over 2 to 4 Inhibition happens and inhibitors CYP is likely to reduce substrate levels, but inHibition of one
weeks* (Delayed). within Hours (Hurried). CYP is unlikely to significantly increase substrate levels.
Amiodarone (2C9, 2D6, 3A4) Apixaban 3A4 Losartan 2C9, 3A4

Ψ Armodafinil (3A4) weak
Ψ Asenapine (2D6) weak Atazanavir (HIV) 3A4 Ψ Loxapine (1A2, 2D6,3A4)
Ψ Bupropion 2D6 Ψ Alprazolam 3A4 Ψ Lumateperone 3A4, UGT-1A
Apalutamide 2C19, 3A4
Ψ Cannabidiol 2C19, UGT Ψ Amitriptyline 2D6, 2C19 Ψ Lurasidone *contraind* 3A4
(prostate cancer) & (2C9)
Cimetidine (multi) weak Amlodipine 3A4 Medroxyprogesterone 3A4
Ciprofloxacin 1A2, (3A4) Ψ Amoxapine 2D6 Meloxicam 2C9, (3A4)
Ψ Cannabis 1A2 fast
Clarithromycin 3A4 Ψ Amphetamine salts (2D6) Ψ Meperidine Black Box 3A4
Clopidogrel (2B6) Ψ Aripiprazole 2D6, 3A4 Ψ Methadone 3A4, 2B6, (etc)
Chargrilled meat 1A2
Darunavir (HIV) 3A4, (2D6) Ψ Armodafinil 3A4 Ψ Methamphetamine 2D6
Diltiazem 3A4, (2D6) Ψ Asenapine (1A2) Metoprolol 2D6, (2C19)
Ψ Carbamazepine 3A4, 2B6
Ψ Duloxetine 2D6 Ψ Atomoxetine 2D6, (2C19) Mexiletine 1A2, 2D6
(Tegretol) & (1A2)
Efavirenz (HIV) 2C9, 2C19 Atorvastatin 3A4 Ψ Midazolam 3A4, (2B6)
Erythromycin 3A4 Avanafil 3A4 Ψ Mirtazapine 2D6, 3A4, 1A2
Efavirenz (HIV) 3A4, 2B6
Esomeprazole (2C19) weak Ψ Modafinil 3A4 (2D6)
Fluconazole 2C9, 2C19, 3A4 Ψ Brexpiprazole 2D6, 3A4
Enzalutamide 3A4, 2C9
Ψ Fluoxetine 2D6, 2C19 Ψ Buprenorphine 3A4 Nevirapine 3A4 (2B6, 2D6)
(prostate cancer) & 2C19
Ψ Bupropion 2B6; 2D6 (OH-) Ψ Nefazodone 3A4; 2D6 mCPP
Ψ Fluvoxamine 1A2, 2C19, Ψ Buspirone 3A4, (2D6) Nifedipine 3A4, (2D6)
Estradiol UGT
(Luvox) & (3A4, 2C9) Ψ Caffeine 1A2 (etc) Norethindrone 3A4
Ψ Modafinil Ψ Carbamazepine 3A4 Ψ Nortriptyline 2D6 (etc)
3A4
Grapefruit juice 3A4 Ψ Cariprazine 3A4, (2D6) Ψ Olanzapine 1A2; (2D6)
Isoniazid (3A4) weak Ψ Carisoprodol 2C19 Omeprazole 2C19 (etc)
Nevirapine 2B6 (3A4)
Indinavir 3A4 Carvedilol 2D6 (etc) Ψ Oxazepam UGT-2B (VPA)
Itraconazole 3A4 Celecoxib 2C9, (3A4) Ψ Oxycodone 3A4, (2D6)
Ψ Phenobarbital 3A4 (1A2),
Ketoconazole 3A4, (2C19) Ψ Chlordiazepoxide 3A4 Pantoprazole 2C19,(2D6, 3A4)
(Luminal) (2B6, 2C9)
Ψ Methadone (2D6) weak Ψ Chlorpromazine 2D6, (1A2, 3A4) Ψ Paroxetine 2D6
& UGT
Ψ Modafinil (2C19) weak Ψ Citalopram 2C19, (3A4,2D6) Ψ Perphenazine 2D6 (etc)
Nelfinavir 3A4 Clarithromycin 3A4 Ψ Phenobarbital 2C19,(2C9)
Ψ Phenytoin 3A4 (1A2),
Omeprazole 2C19 Ψ Clomipramine 2D6, 2C19, 1A2 Ψ Phenytoin 2C9, 2C19,(3A4)
(Dilantin) (2B6), UGT
Ψ Clonazepam 3A4 Ψ Pimavanserin 3A4
Ψ Nefazodone 3A4 Clopidogrel 2C19, (3A4) Ψ Pimozide 2D6, 3A4 (1A2)
Ψ Primidone 3A4 (1A2),
Ψ Orphenadrine 2B6 Ψ Clozapine 1A2 (2D6, etc) Piroxicam 2C9
(Mysoline) (2B6, 2C9)
Ψ Paroxetine 2D6 Ψ Codeine *2D6 prodrug *2D6, (3A4) Ψ Promethazine (2B6, 2D6)
metab to phenobarb & UGT
Quinidine 2D6, (3A4) Ψ Cyclobenzaprine 1A2, (2D6, 3A4) Propafenone 2D6, (1A2, 3A4)
Ritonavir 3A4 Black Box Cyclophosphamide 2B6, 2C19 Ψ Propofol 2B6 (etc)
Rifampin 2C19,
Ψ Sertraline ≥150mg (2D6) Cyclosporine 3A4 (etc) Ψ Propranolol 2D6, 1A2,(2C19)
(Rifadin) 3A4, 2B6,
Terbinafine 2D6 Ψ Protriptyline 2D6
2C9 (1A2)
Ψ Thioridazine 2D6 Ψ Desipramine 2D6, (1A2)
& UGT
Ψ Valproate (VPA) UGT-1A & -2B Ψ Deutetrabenazine 2D6 Ψ Quetiapine 3A4, (2D6)
Voriconazole 3A4,2C19,(2C9) Ψ Dextromethorphan 2D6 (etc) Ψ Ramelteon 1A2 (3A4,2C19)
Ritonavir (HIV) 2B6 (2C19)
Verapamil 3A4, (1A2) Ψ Diazepam 2C19, 3A4 Ψ Risperidone 2D6, (3A4)
(1A2, 2C9)
Diclofenac multi Rivaroxaban 3A4
Ψ St John’s Wort Diltiazem 3A4 (2C19,3A4) Ψ Selegiline 2B6 (etc)
1A2, 2C9 InHibition is reversed as soon as Ψ Doxepin 2D6, 2C19 (etc) Ψ Sertraline 2C19 (2B6,2D6)
& 3A4 the inhibitor is cleared, which will Ψ Donepezil (2D6, 3A4) Sildenafil 3A4, (etc)
be about 5 half-lives after it is Ψ Duloxetine 2D6, 1A2
Ψ Tobacco 1A2 fast Simvastatin 3A4
discontinued. Efavirenz (HIV) 2B6, 3A4 Ψ Suvorexant 3A4
Ψ Topiramate Ψ Escitalopram 2C19, (3A4,2D6) Tacrolimus 3A4
(3A4)
≥200 mg Esomeprazole 2C19, (3A4) Tadalafil 3A4
UGT & UGT-1A refer to UGT1A4. Estradiol 1A2, 2C9, 3A4 Tamoxifen *2D6 prodrug *2D6, 3A4, 2C9
UGT-2B refers to UGT2B15. Ψ Eszopiclone 3A4 Ψ Tasimelteon 1A2, 3A4
inDuction reverses gradually
over a few weeks* after the Ψ Temazepam UGT-2B (VPA)
( ) = weak inducer/inhibitor; less Ψ Fentanyl 3A4 Black Box 3A4 (etc) Ψ Tetrabenazine 2D6
inducer is discontinued.
susceptible substrate Flecainide 2D6, 1A2 Theophylline 1A2, (3A4)
Ψ Flibanserin 3A4 Black Box 3A4, 2C9, 2C19 Ψ Thioridazine 2D6, (2C19)
*With smoking (tobacco or
Ψ = CNS medication Ψ Fluoxetine 2D6, 2C9 (etc) Ψ Thiothixene 1A2
cannabis), induction is faster
(psychoactive) Ψ Fluphenazine 2D6 Ψ Tiagabine 3A4
(a few days).
Ψ Flurazepam 3A4 Ψ Tizanidine 1A2
Fluvastatin 2C9 (2B6, 3A4)
Ψ Fluvoxamine 2D6, 1A2 Tolbutamide 2C9, (2C19)
Lithium levels Decreased by: Ψ Galantamine (2D6, 3A4) Ψ Tramadol *2D6 prodrug* 3A4,(2D6*; 2B6)
Glimepiride 2C9 Ψ Trazodone 3A4 (2D6 mCPP)
Acetazolamide Theophylline
Glipizide 2C9 Ψ Triazolam 3A4
Ψ Caffeine Ψ Topiramate
Glyburide 2C9 Ψ Trifluoperazine 1A2
Mannitol Ψ Zonisamide (weak)
Ψ Guanfacine 3A4 Ψ Trimipramine 2D6, 2C19, 3A4
Ψ Valproate (VPA) (multi); Aspirin*
Increased by: Ψ Haloperidol 2D6, 3A4, (1A2) Ψ Valbenazine 3A4 (2D6)
Etodolac Losartan Ψ Hydrocodone Black Box 3A4 Vardenafil 3A4
Benazepril HCTZ Metronidazole Ifosfamide 2B6 (& others) Ψ Venlafaxine 2D6, 3A4,(2C19)
Celecoxib Ibuprofen Minocycline Ψ Iloperidone 2D6, (3A4) Ψ Vilazodone 3A4,(2C19,2D6)
Chlorthalidone Indomethacin Naproxen Ψ Imipramine 2D6, 2C19 (etc) Vincristine 3A4
Diclofenac Irbesartan Lisinopril Olmesartan Ψ Ketamine 2B6, 2C9, 3A4 Voriconazole 2C9, 2C19, 3A4
Doxycycline Tetracycline Ramipril Ψ Lamotrigine UGT Ψ Vortioxetine 2D6, 3A4, etc
Enalapril Valsartan Lansoprazole 2C19, 3A4 Warfarin 2C9, 2C19,(3A4)
Ψ Lemborexant 3A4 Ψ Zaleplon (3A4)
Ψ Levomilnacipran 3A4, (2D6) Ψ Zolpidem 3A4 (etc)
With high-dose aspirin, Depakote (VPA) will be stronger Ψ Lorazepam UGT-2B (VPA)
than suggested by total VPA level because aspirin (highly
protein-bound) bumps VPA off of albumin.

[ Chapter 2 – Introduction to Antidepressants ]
Neurotransmitters
Here is a simplified overview of neurotransmitters in the brain that For an in-depth explanation of how neurotransmitters influence
are relevant to antidepressants. Serotonin, norepinephrine, mood and how drugs affect neurotransmitters. I recommend
dopamine, and histamine are referred to as monoamine Stahl's Essential Psychopharmacology:Neuroscientific Basis and
neurotransmitters because they contain a single amine group Practical Applications. Dr. Stahl’s book is a classic—great for
(—NH2). The monoamine neurotransmitters serotonin and visual learners. Prescriber's Guide: Stahl's Essential
dopamine are implicated in most psychiatric disorders. Psychopharmacology is also required reading.
Neurotransmitter Abbrev Normal activity Low activity High activity Comments

Serotonin 5-HT “Serenity” Depression Sexual dysfunction, Most antidepressants are
(5-hydroxytryptamine) Calmness Anxiety muscle twitching, serotonergic, i.e., enhance
Satisfaction OCD hyperreflexia, dilated 5-HT neurotransmission.
Euthymic mood pupils, restlessness,
Normal sleep gastrointestinal
distress/nausea,
serotonin syndrome,
hallucinations (LSD)
Norepinephrine NE Energy, motivation, Fatigue Insomnia, anxiety, NE is also known as
ability to focus and Inattention nausea, loss of appetite, noradrenaline. Stimulants
respond to stress Sexual dysfunction hypertension, seizure, increase noradrenergic (NE)
Hypotension dilated pupils activity. Some
antidepressants are
noradrenergic.
Dopamine DA Motivation, ability Anhedonia, inattention, Mania, euphoria, Think pleasure, passion,
to experience sexual dysfunction, agitation, anger, paranoia. Drugs of abuse,
pleasure and parkinsonism, akathisia, aggression, chemical colloquially known as “dope”,
strong emotions dystonia, neuroleptic “high”, paranoia, auditory cause euphoria by spiking DA
malignant syndrome hallucinations, in the nucleus accumbens.
(NMS), restless legs compulsive behaviors, Many stimulants and
syndrome, antiemetic hypersexuality, insomnia, Parkinson’s disease
nausea, dilated pupils medications are
dopaminergic.Only a few
antidepressants are
dopaminergic.
Acetylcholine ACh “Rest and digest” “Dry as a bone” - “SLUDGE” - Acetylcholine acts on
parasympathetic Constipation, urinary salivation, lacrimation, muscarinic and nicotinic
activity, normal retention, dry mouth; “Mad urination, diaphoresis, GI receptors. What are
cognitive function as a hatter” - confusion, upset (including diarrhea), commonly described as
delirium with visual emesis; constricted pupils “anticholinergic” effects would
hallucinations; dilated be more accurately termed
pupils, tachycardia “antimuscarinic”.
Histamine H Alertness Sedation Allergic reaction, pruritus, H1 antihistamines are used
Weight gain excessive gastric acid for sleep and allergies; H2
secretion antihistamines (ranitidine, etc)
reduce stomach acid; The H3
antihistamine pitolisant
(Wakix) promotes
wakefulness.
Selective serotonin reuptake inhibitors

Norepinephrine Serotonin (SSRIs) block 5-HT transporters without
significantly blocking DA or NE
transporters. Serotonin-norepinephrine
Energy Anxiety Serenity
Alertness vs reuptake inhibitors (SNRIs) block 5-HT
Contentment
Concentration Relaxation Sadness and NE transporters. The monoamine
“Fight or flight” Suicidality oxidase inhibitors (MAOIs) block the
breakdown of all monoamine
Mood neurotransmitters, which is why MAOIs are
Emotion more powerful antidepressants.
Cognition Sex
Attention Aggression
Motivation Obsessions Serotonin & Dopamine
Compulsions
"Technically, the only
two things you enjoy"
Pleasure / euphoria / mania
Drive / reward / addiction
Auditory hallucinations
Paranoia Most tricyclic antidepressants (TCAs)
contribute anticholinergic (antimuscarinic)
and antihistaminergic side effects.
Dopamine
Antidepressants and Related Medications
Class Abbrev Antidepressant $/mo Comments
Tricyclic Antidepressant TCA Amitriptyline (ELAVIL) metabolized $10 TCAs are older antidepressants, rarely used for
Nortriptyline (PAMELOR) to $10 depression today. They are prescribed at low
Imipramine (TOFRANIL) $10 dose for insomnia and migraine prevention. TCAs
Desipramine (NORPRAMIN) $20 are famous for anticholinergic side effects
Clomipramine (ANAFRANIL) for OCD $200 (constipation, dry mouth, urinary retention,
Doxepin 10 mg (generic) for sleep $10 confusion), orthostatic hypertension, weight gain,
Doxepin 3 mg, 6 mg (SILENOR) for $400 sedation, and sexual dysfunction. Not good for
sleep the elderly. Fatal in overdose due to disruption of
Protriptyline (VIVACTIL) $75 cardiac conduction. There are significant
Maprotiline (LUDIOMIL) $50 differences between members of the TCA class—
Amoxapine (ASENDIN) $25 some are sedating, while others are energizing.
Trimipramine (SURMONTIL) $100 Weight gain may be large.
Selective Serotonin Reuptake SSRI Sertraline (ZOLOFT) $5 SSRIs are considered first-line treatment for
Inhibitor Escitalopram (LEXAPRO) $5 depression and anxiety disorders. Side effects
Citalopram (CELEXA) $5 include sexual dysfunction, GI distress (nausea,
Fluoxetine (PROZAC) $5 diarrhea), headache, and fatigue. Possibility of
Paroxetine (PAXIL) $5 modest weight gain with long term use. Risk of
Fluvoxamine (LUVOX) for OCD $25 hyponatremia and impaired platelet functioning
Serotonin (5-HT) & Norepinephrine SNRI Duloxetine (CYMBALTA) $20 SNRIs are better for pain than are SSRIs. SNRIs
(NE) Reuptake Inhibitor Venlafaxine ER (EFFEXOR XR) $10 may cause a dose-dependent increase in blood
Desvenlafaxine (PRISTIQ) $40 pressure due to noradrenergic (NE) activity.
Levomilnacipran (FETZIMA) $350 Compared to SSRIs, SNRIs are less likely to
Milnacipran (SAVELLA) for fibromyalgia $350 cause weight gain with long-term.
Norepinephrine Reuptake Inhibitor NRI Atomoxetine (STRATTERA) for ADHD $300 For ADHD; Not considered an antidepressant.
Rare risk of serious hepatic injury
Norepinephrine & Dopamine NDRI Bupropion (WELLBUTRIN) TID $30 Stimulating. Modest weight loss and decreased
(DA) Reuptake Inhibitor Bupropion SR (WELLBUTRIN SR) $20 urge to smoke. Improved sexual functioning. Risk
Bupropion XL (WELLBUTRIN XL) $20 of seizures at high dose.
“Atypical Antidepressants”
Solriamfetol (SUNOSI) for somnolence $700
Noradrenergic & Specific NaSSA Mirtazapine (REMERON) $10 Great for sleep and stimulation of appetite. At
Serotonergic higher dose, noradrenergic (NE) activity is more
Antidepressant prominent (stimulating). Weight gain is common,
but less prominent than with amitriptyline.
Serotonin Antagonist & SARI Trazodone (DESYREL) $5 Trazodone is widely prescribed at low dose as a
Reuptake Inhibitor Nefazodone (SERZONE) $75 sleep medication. Nefazodone, rarely prescribed,
is less sedating.
Serotonin Modulator & SMS Vilazodone (VIIBRYD) $200 Less likely to cause weight gain or sexual
Stimulator Vortioxetine (TRINTELLIX) $300 dysfunction than SSRIs. Both off-patent in 2022
Monoamine Oxidase Inhibitor MAOI Phenelzine (NARDIL) $50 Potentially fatal if combined with tyramine rich
(non-selective) Tranylcypromine (PARNATE) $250 foods (hypertensive crisis) or other serotonergic
Isocarboxazid (MARPLAN) $750 medications (serotonin syndrome). Effective for
treatment-resistant depression
Selective MAO-B Inhibitor MAOI Selegiline transdermal (EMSAM) $1600 OK to combine with tyramine-rich foods with the
(transdermal) patch for depression lowest dose (6 mg) patch.
NMDA Receptor Antagonist Ketamine (KETALAR) - intravenous $10 Schedule III controlled anesthetic, rapidly
Esketamine (SPRAVATO) - nasal $5000 effective for treatment-resistant depression
Neurosteroid Brexanolone (ZULRESSO) $34000 Approved for postpartum depression. Given as an
IV infusion over 60 hours. Excessive sedation is
possible.
Medical food L-Methylfolate (DEPLIN) $200 Active form of folate, add-on to an antidepressant
Herbal SJW St John’s Wort $25 For mild depression only. Inducer of several CYP
enzymes
The asterisk means the medication is considered (or can be properly

This rain cloud indicates the * referred to as) an antidepressant, but is not typically prescribed for
depression. Examples include clomipramine for OCD, fluvoxamine (Luvox)
medication is an antidepressant.
for OCD, trazodone (Desyrel) for insomnia, and milnacipran (Savella) for
fibromyalgia.
Some medications have mechanisms resembling depression medication but are not
Not an antidepressant properly referred to as “antidepressants”. Examples include the NRI atomoxetine
(Strattera) and the NDRI solriamfetol (Sunosi).

[ Treatment of Depression ]
With an antidepressant, improvement of mood can occur within the first switching to another antidepressant (Bschor et al, 2018). There is no
two weeks, but it will take 4 to 6 weeks to achieve maximal benefit. About disadvantage to switching antidepressants at 2 weeks either, so if the
60% of individuals experiencing a major depressive episode will respond patient insists, go for it. Following resolution of a single depressive
to their first antidepressant. If no benefit is seen by 2 weeks, stay the episode, the antidepressant should generally be continued for a year to
course (if no side effects) because there is no advantage in consolidate recovery. For recurrent depressive episodes, long-term
PLACEHOLDER maintenance treatment may be indicated.
For adults, reasonable first-line antidepressants include:

First-line Class Choose when Sexual ~ Cost/ Comments
antidepressant dysfunction month
Escitalopram SSRI Depression with anxious distress Yes $5 Start 10 mg once daily (AM or PM). Usual maintenance dose is
(LEXAPRO) 10 to 20 mg. FDA max is 20 mg, but can go up to 60 mg for OCD
(Stahl 2016). Always superior to citalopram (Celexa)
Sertraline SSRI Depression with anxious distress Yes $5 Start 50 mg once daily (AM or PM). FDA max is 200 mg, but can
(ZOLOFT) go up to 400 mg for OCD (Stahl, 2016). More likely to cause
nausea and diarrhea than Lexapro.
Bupropion NDRI Depression with fatigue and No $20 For XL formulation, start 150 mg AM; Max is 450 mg. For SR
(WELLBUTRIN) oversleeping; comorbid ADHD or formulation, start 100 mg BID; Max 200 mg BID. The IR
tobacco use disorder formulation (TID) is not recommended due to risk of seizure.
Mirtazapine NaSSA Depression with insomnia and loss No $10 Start 15 mg HS. FDA max is 45 mg, although 60 mg is safe.
(REMERON) of appetite Higher doses are less sedating.
For first-episode depression, it is customary to start with an SSRI. For as effective as placebo (Zhou et al, 2015). Lithium (0.5–0.8 mmol/L)
adults, no SSRI is clearly more effective than others, although and aripiprazole (Abilify) 5–15 mg are the top choices for
escitalopram (Lexapro) has a slight advantage over the others for augmentation. Other proven options include quetiapine (Seroquel)
tolerability, and possibly for efficacy. For children, fluoxetine (Prozac) has 100–300 mg HS, risperidone (Risperdal) 0.5–3 mg HS and liothyronine
the best evidence. For adults, escitalopram and sertraline (Zoloft) are (Cytomel, T3 thyroid hormone) 50 mcg. There is moderate evidence for
preferred because they have fewer drug-drug interactions compared to adding olanzapine (Zyprexa) 5–15 mg or buspirone (Buspar) 5–15 mg
fluoxetine or paroxetine (Paxil). Although quite safe, citalopram (Celexa) BID–TID. About 50% of TRD cases are actually bipolar disorder
is a bit riskier than the other SSRIs due to mild QT prolongation, for (Francesca et al, 2014), for which lithium or lamotrigine (Lamictal) are
which FDA lowered the recommended maximum from 60 mg to 40 mg. superior to antidepressants in preventing the next depressive episode.
There is no reason to choose citalopram over escitalopram.
Intravenous ketamine or intranasal esketamine are quickly effective for
If the patient is not eating or sleeping, consider starting with mirtazapine TRD. Electroconvulsive therapy (ECT) has the highest rate of response
(Remeron). If insomnia is prominent but weight gain is not desired, and remission of any form of antidepressant treatment.
consider choosing an SSRI plus trazodone (Desyrel) 50 mg at bedtime,
PRN or scheduled ($4). The FDA max for trazodone is 400 mg, but All antidepressants have a black box warning of increased suicidal
prescribed doses rarely exceed 200 mg. thoughts and behavior in children, adolescents and young adults.
Increased risk of completed suicide has not been established. For
For depressed patients with fibromyalgia or other types of chronic pain, adults beyond age 24, incidence of suicidal thoughts does not exceed
an SNRI like venlafaxine (Effexor) or duloxetine (Cymbalta) would be a placebo. For those age 65 and older, antidepressants decrease
reasonable first-line choice. Effexor XR is dosed 75–225 mg QD. suicidal thoughts. In reduction of suicide risk, lithium is superior to
Cymbalta is 30–60 mg QD (FDA max 120 mg). antidepressants.
Treatment-resistant depression (TRD) is defined as failure of two For children and adolescents, antidepressants (SSRIs, SNRIs) show
6-week antidepressant trials. For TRD, trying a third antidepressant is no more prominent benefit for anxiety than for depression (Locher et al,
more effective than placebo. Augmenting the antidepressant is twice 2017).
PLACEHOLDER
All antidepressants have the potential to induce a “switch” to mania,
usually in the context of undiagnosed bipolar disorder. Patients with
page
known bipolar disorder suffering a depressive episode may be treated
Almost all with an antidepressant combined with a mood stabilizer or an
15
antidepressants are antipsychotic. Upon successful treatment of a bipolar depressive
metabolized, at least in episode, consider tapering off the antidepressant after a few months to
part, by CYP2D6. For
avoid destabilization of mood over the long term.
patients with a 2D6
ultrarapid metabolizer Following a Mediterranean diet can improve acute depression and
(UM) genotype (3%), prevent future depressive episodes (Jacka et al 2017; Parletta et al,
2D6 Ultrarapid
non-response to a wide 2D6 metabolizer (UM) 2017). 30–60 minutes of light therapy every morning can produce
range of antidepressants substrate
(at standard doses) is
benefits comparable to medication for seasonal and non-seasonal
3% of population depression (Penders et al, 2016). All depressed patients should be
possible.
screened for hypothyroidism—ordering a serum TSH level is sufficient.
10% of population page

2D6 Poor For the 10% of individuals who
15 The antidepressants not metabolized by 2D6:
metabolizer are 2D6 poor metabolizers (PM),
(PM) antidepressant levels may be ► Desvenlafaxine (Pristiq)
Poor me! higher than expected, possibly ► Selegiline (EMSAM patch)
leading to side effects. For a
known 2D6 PM, it is
recommended to dose the Other antidepressants unlikely to be significantly
following at half-strength: affected by 2D6 interactions include citalopram
tricyclics (TCAs), vortioxetine (Celexa), escitalopram (Lexapro), sertraline (Zoloft),
(Trintellix), and atomoxetine levomilnacipran (Fetzima), and vilazodone (Viibryd).
(Strattera).

62 Antidepressant-Associated Sexual Dysfunction -
Serotonergic medications commonly decrease sexual desire, About half of individuals taking antipsychotics also experience sexual
disrupt the sexual pleasure response, and increase latency to dysfunction, particularly with antipsychotics that elevate prolactin like
orgasm. Here are some drugs ranked (approximately) from worst haloperidol (Haldol), risperidone (Risperdal), and paliperidone (Invega).
to best in regard to sexual dysfunction: Among antipsychotics, aripiprazole (Abilify) is the least likely to cause
sexual dysfunction, followed by ziprasidone (Geodon), and quetiapine
❖ Paroxetine (Paxil) - the worst, > 70% of patients (Seroquel). Mood stabilizers are generally unlikely to cause sexual
❖ Sertraline (Zoloft) > 60% - “so soft” dysfunction. Lamotrigine (Lamictal) does not have sexual side effects.
❖ Escitalopram (Lexapro) and citalopram (Celexa) ~ 60%
❖ Fluoxetine (Prozac) ~ 60%
❖ Venlafaxine (Effexor) ~ 60%
❖ Fluvoxamine (Luvox) - least among the SSRIs but still > 50%
Dapoxetine is a short acting SSRI
❖ Duloxetine (Cymbalta) - least among the SNRIs
available in over 50 countries (but not
❖ Vortioxetine (Trintellix) - minimal at 10 mg (44% at > 10 mg)
the US) for PRN treatment of
❖ Vilazodone (Viibryd) - slightly more than placebo
premature ejaculation. Paxil could be
❖ Placebo - up to 30% sexual dysfunction
used PRN for this purpose, off-label.
❖ Trazodone - possible enhancement (and risk of priapism)
Also, the OTC cough suppressant
❖ Nortriptyline and Desipramine (TCAs without serotonergic effects)
dextromethorphan (DXM) can be used
❖ Nefazodone (Serzone) - possible enhancement
to delay orgasms via serotonergic
❖ Mirtazapine (Remeron) - possible enhancement
mechanism.
❖ Bupropion (Wellbutrin) - enhances sexual functioning (female > male)
❖ Buspirone (BuSpar) - enhances sexual functioning (female > male)
Anticholinergic Burden Scale (Risk of CNS impairment/dementia) – “mad as a hatter”

Anticholinergic load should be minimized with older adults. Dose should be taken into consideration when estimating risk.
3 Points (worst) 2 points 1 point (mild) 0 points

TCA Amitriptyline, Clomipramine, Desipramine (Norpramin) Amoxapine (Asendin) Doxepin ≤ 6 mg (Silenor)
Antidepressants Doxepin ≥ 50 mg, Doxepin ≤ 25 mg (Sinequan) Doxepin ≤ 10 mg (Sinequan)
Imipramine, Maprotiline, Nortriptyline (Pamelor)
Protriptyline, Trimipramine
Other N/A Paroxetine (Paxil) Citalopram (Celexa) SNRIs, Other SSRIs,
Antidepressants Fluoxetine (Prozac) Bupropion (Wellbutrin),
- “Paxil packs it in” (constipation MAOIs Trazodone, Nefazodone,
as a peripheral anticholinergic Mirtazapine (Remeron) Vilazodone (Viibryd),
effect) Vortioxetine (Trintellix)
Antipsychotics Low potency FGAs: Intermediate potency FGAs: High potency FGAs: SGAs:
(and other D2 Chlorpromazine (Thorazine) Loxapine (Loxitane) Fluphenazine (Prolixin) Aripiprazole (Abilify)
blockers) Promethazine (Phenergan) Molindone (Moban) Haloperidol (Haldol) Asenapine (Saphris)
Thioridazine (Mellaril) Perphenazine (Trilafon) Pimozide (Orap) Brexpiprazole (Rexulti)
Prochlorperazine (Compazine) Cariprazine (Vraylar)
SGAs: Thiothixene (Navane) Iloperidone (Fanapt)
Clozapine (Clozaril) Trifluoperazine (Stelazine) Lurasidone (Latuda)
Olanzapine (Zyprexa) SGAs: Paliperidone (Invega)
Pimavanserin (Nuplazid) Risperidone (Risperdal)
Quetiapine (Seroquel) Ziprasidone (Geodon)
Antihistamines Cyproheptadine (Periactin) Chlorpheniramine Cetirizine (Zyrtec) Levocetirizine (Xyzal)
Diphenhydramine (Benadryl) (Chlor-Trimeton), Cimetidine (Tagamet)
Doxylamine (Unisom) Fexofenadine (Allegra)
Meclizine (Antivert) Loratadine (Claritin)
Hydroxyzine (Vistaril) Ranitidine (Zantac)
Anticholinergics Oxybutynin (Ditropan) Tolterodine (Detrol) Fesoterodine (Toviaz) Darifenacin (Enablex)
for OAB Solifenacin (Vesicare) Trospium (Sanctura)
Other Atropine (injected) Amantadine (Symmetrel) Ipratropium inhaler (Atrovent) Glycopyrrolate (Robinul)*
Anticholinergics Benztropine (Cogentin) Atropine eye drops
Dicyclomine (Bentyl) Note that ipratropium is like an *Strong anticholinergic but does
Hyoscyamine (Levsin) inhaled form of atropine (the not cross blood-brain barrier;
Scopolamine (Transderm Scōp) strongest anticholinergic) Therefore it causes constipation
Trihexyphenidyl (Artane) but not cognitive problems.
Muscle relaxants Carisoprodol (Soma) Cyclobenzaprine (Flexeril) Methocarbamol (Robaxin) Metaxalone (Skelaxin)
Orphenadrine (Norflex) Baclofen (Lioresal) Tizanidine (Zanaflex)
Sedatives See antihistamines See antihistamines Diazepam (Valium) **Other benzodiazepines
Temazepam (Restoril) Z-drugs; barbiturates; melatonin
Mood stabilizers; N/A Carbamazepine (Tegretol) Lithium Other anticonvulsants
Antiepileptics Oxcarbazepine (Trileptal)
Other N/A Cimetidine (Tagamet) Buspirone (Buspar) Antihypertensives, cognitive
Codeine Pramipexole (Mirapex) enhancers and ADHD
Metoclopramide (Reglan) stimulants;
Pseudoephedrine (Sudafed) atomoxetine, ondansetron,
tramadol, ropinirole
Compiled from many sources. There are at least 10 published anticholinergic risk/burden scales (including **These sedatives may impair cognition,
Beers criteria) which differ substantially in the estimation of anticholinergic load for certain medications. but not by anticholinergic effect.

[ Serotonin Syndrome (5-HT Toxicity)
]
Serotonin syndrome, better understood as serotonin toxicity, is a rare “Twitchy frog”

condition that can occur when serotonergic drugs are combined,
especially with monoamine oxidase inhibitors (MAOIs). The mechanism
involves serotonin overload in the brain stem. 50% of cases onset within 5-HT
2 hours of adding the offending serotonergic. Only 25% of cases persist
longer than 24 hours. 70% of cases resolve within 24 hours.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6141939/
15% of SSRI overdoses lead to serotonin toxicity. Overdoses of a

combination of a SSRI plus a MAOI have a 50% likelihood of causing
serotonin syndrome.
Hyperreflexia
Although it may rarely progress to multi-organ failure and death,
serotonin syndrome is not as dangerous as the Neuroleptic Malignant
Syndrome (NMS) caused by antipsychotic medications. Refer to pages Antidepressant Combinations
26–27 for a head-to-head comparison of 5-HT toxicity and NMS.
Reasonable combos (although not necessarily effective):
The diagnosis of 5-HT Syndrome is defined by the Hunter Serotonin ► Antidepressant + lithium
Toxicity Criteria with 84% sensitivity and 97% specificity. The criteria
focus on clonus, ocular clonus, and hyperreflexia. ► Antidepressant (excluding nefazodone)
+ quetiapine (Seroquel)
On physical exam, the sufferer of 5-HT toxicity may appear ► Escitalopram or sertraline
uncomfortable and twitchy. Deep tendon reflexes may be very brisk. Try + aripiprazole (Abilify) or risperidone (Risperdal)
to elicit clonus by flexing the patient’s foot and watching for rhythmic
contractions of the ankle. Assess for ataxia through observation of gait, ► SSRI + buspirone (Buspar)
Romberg testing, and point-to-point testing.
► Trazodone + other antidepressant
(excluding nefazodone)
Be careful if combining antidepressants with other medications that have
serotonergic properties: ► Trazodone + doxepin for sleep
❖ dextromethorphan (DXM) – cough suppressant ► Fluoxetine + olanzapine (Zyprexa)
❖ tramadol (Ultram) – pain medication (SNRI + weak opioid)
❖ methadone – opioid ► SSRI + bupropion (Wellbutrin)
❖ fentanyl – opioid ► Nortriptyline + escitalopram or sertraline
❖ meperidine (Demerol) – opioid
❖ metaxalone (Skelaxin) – muscle relaxant, MAOI activity ► SNRI + mirtazapine (Remeron) -
❖ cyclobenzaprine (Flexeril) – tricyclic muscle relaxant (unlikely) “California Rocket Fuel” (page 55)
❖ St. John’s wort – herbal antidepressant ► MAOI + TCA without serotonergic activity—
❖ LSD (“acid”) – hallucinogen nortriptyline, desipramine, maprotiline, trimipramine =
❖ MDMA (ecstasy) – a common cause of serotonin toxicity “Non-Disparaged MAOI Tagalongs”
❖ linezolid (Zyvox) – an antimicrobial with MAOI activity
❖ methylene blue (Urelle) – urinary tract antiseptic
“Bad” combinations
Mascots of ❖ red medications are featured in Chapter 7 - Serotonergics. ► 2 SSRIs
Despite an FDA warning, the risk of serotonin syndrome with a triptan ► 2 SNRIs
migraine medication (Imitrex, Maxalt, etc) is miniscule, if not nonexistent.
► SSRI + SNRI
Orlova et al (2018) estimated the risk at about 1 in 10,000 person-years
of exposure to a triptan plus an SSRI/SNRI. Serotonin syndrome is ► 2 TCAs
hypothesized to involve 5-HT2A and 5-HT1A receptors, while triptans are
agonists at 5-HT1B and 5-HT1D receptors. ► SNRI + TCA
► Fluoxetine or paroxetine (strong 2D6 inhibitors)
Combining SSRIs, combining SNRIs, or combining an SSRI with an
with 2D6 substrates (including all TCAs)
SNRI makes no sense therapeutically, but is unlikely to cause serotonin
toxicity at standard doses. Switching between SSRIs and SNRIs can ► Bupropion + noradrenergic TCA or SNRI
generally be done without a washout period. Since fluoxetine (Prozac) ► Antidepressant + St John’s wort
has a long half-life, consider waiting a few days after stopping it before
starting the replacement serotonergic antidepressant. ► SSRI or SNRI + tramadol (Ultram)
► Mirtazapine + clonidine or guanfacine
Treatment of 5-HT toxicity involves stopping the offending agent and ► Atomoxetine + SNRI, bupropion, fluoxetine or paroxetine
aggressive cooling of high fever. In some cases, medications with
anti-serotonergic activity may be helpful, such as the antihistamine
cyproheptadine (Periactin) or the antipsychotic chlorpromazine Dangerous combinations
(Thorazine). ► MAOI + other antidepressants, excluding those without
serotonergic effects (trazodone, bupropion, nortriptyline,
desipramine, maprotiline, trimipramine)
History lesson: A high-profile case of serotonin syndrome Her father, an attorney, believed her death was the result of
occurred in 1984. Libby Zion, an 18-year-old college freshman overworked resident physicians. In 1989 New York state
taking the MAOI phenelzine presented to the ER and was treated adopted the “Libby Zion Law” which limited medical
with meperidine (Demerol) to control “strange jerking movements” residents to 80 hours per week. In 2003 all accredited
(think twitchy frog). She was hospitalized, developed a fever of medical training institutions adopted a similar regulation,
107°F, and died of a heart attack within hours. limiting residents to 80 hours per week and 24 consecutive
hours.

Serotonin Syndrome -vs- Neuroleptic Malignant Syndrome (NMS)
Serotonin (5-HT) Syndrome and Neuroleptic Malignant Syndrome are NMS - “can’t Bend(er)”
rare psychiatric emergencies. These syndromes should be
considered when an individual taking several psychotropic
medications becomes acutely ill. Since some symptoms overlap, here
is a head-to-head comparison.
NMS
5-HT “twitchy frog” syndrome Mental status
changes
Agitation
Dilated pupils 30%
Lead pipe
+
Autonomic
rigidity instability
- can’t bend
‘er limbs
Sweating
Hyperreflexia
Fever 45% High fever Sweating
Bender from Futurama
Serotonin Syndrome Neuroleptic Malignant Syndrome (NMS)

Mechanism Serotonin (5-HT) overload in the brain stem Dopamine blockade in the hypothalamus (fever)
and nigrostriatal pathway (rigidity)
Usual onset Within 24 hours of combining antidepressants (or other Within 30 days of starting or increasing an antipsychotic
serotonergics) (anti-dopaminergic) or stopping a dopaminergic drug
Cardinal features Myoclonic jerks > 50% High fever 100% by definition
Hyperreflexia > 50% Rigidity 100% by definition
Mental status changes > 50% Mental status changes 99%
Shivering > 50% Elevated or labile BP most
Fever 45% Yes; Temp > 40°C (104°F) in 40% of cases
Autonomic instability 35% tachycardia 99% overall

35% HTN 88% tachycardia
15% hypotension 70% labile BP
Mental status change 51% confusion Confusion is the first symptom to present in 82% of cases, and
50% restlessness/hyperactivity/agitation may evolve to mutism, profound encephalopathy and coma.
29% unresponsiveness (may evolve to coma)
Muscle rigidity 51% and less severe than with NMS 100% by definition; “lead pipe rigidity”
Motor activity Hyperkinesia (restlessness/hyperactivity) Bradykinesia (slowness of movement)
Hyperreflexia 52% No
Clonus 23% - Examine for repetitive dorsiflexion of the ankle in No

response to one forcible dorsiflexion. Go to
cafermed.com/clonus to see how its done.
Tremor 43% You could clone us (clonus) Less prominent
Ataxia 40% Uncommon
Shivering > 50% Uncommon
...with chattering teeth 15%

or bruxism No
Sweating (diaphoresis) Common Common
Sialorrhea Often prominent < 15%

(hypersalivation)
Eyes 30% dilated pupils; 20% unreactive pupils; Usually not affected; Go to cafermed.com/crisis to see oculogyric
Ocular clonus is possible as seen on cafermed.com/clonus. crisis, a manifestation of dystonia which may co-occur with
NMS.
continued...
Serotonin Syndrome Neuroleptic Malignant Syndrome (NMS)
Nature of Can be referred to as serotonin toxicity because it is a true An idiosyncratic reaction, not a toxidrome; All cases of NMS are serious.
syndrome toxidrome, caused by excess serotonin in a Partial, early, or aborted presentations of NMS cases were described as
concentration-dependent way; Some cases are mild. forme fruste, especially with low potency antipsychotics. Rigidity may be
absent or milder with clozapine.
Typical Rapid onset; First: Mental status changes (confusion, mutism, catatonia);
evolution May have prodrome of nausea and diarrhea; Second: Rigidity;
Serotonin toxicity may be mild to severe. Third: Fever and BP lability;
Peak severity in as little as 3 days
Mortality 1% mortality if treated; When fatal, it is usually due to extreme Fatal if untreated; 10% mortality when treated; Renal failure from
fever, leading to the same complications as seen with NMS. rhabdomyolysis, heart attack, respiratory failure (from chest wall rigidity),
DVT/pulmonary embolism, dehydration, electrolyte imbalance,
disseminated intravascular coagulation (DIC), liver failure, seizures
Resolution 70% of cases completely resolve within 24 hours. If not fatal, NMS typically resolves slowly over 1 to 2 weeks.
Most likely 15% of SSRI overdoses lead to 5-HT toxicity; High potency 1st gen antipsychotics (FGAs); Haldol is responsible for 44%
culprits 50% incidence when overdosing on combo SSRI + MAOI; of cases. Long-acting injectable FGAs—haloperidol decanoate (Haldol D)
Clomipramine, imipramine are most likely among TCAs. and fluphenazine decanoate (Prolixin D)—pose an even higher risk.
Non- LSD (“Acid”) St. John’s Wort Antiemetics that are D2 blockers: Dopamine depleting agents
antidepressant/ MDMA (Ecstasy) Tramadol (Ultram) - Metoclopramide (Reglan) - Reserpine (Serpasil)
antipsychotic Dextromethorphan (DXM) Meperidine (Demerol) - Prochlorperazine (Compazine) - Tetrabenazine (Xenazine)
culprits
L-Tryptophan Fentanyl (Duragesic) - Promethazine (Phenergan) - Deutetrabenazine (Austedo)
Metaxalone (Skelaxin) Methadone (Dolophine) - Trimethobenzamide (Tigan) - Valbenazine (Ingrezza)
Linezolid (Zyvox) Buspirone (Buspar) - unlikely
Triptans (Imitrex, Maxalt, etc) TCA that blocks D2 receptors:
Methylene blue (Urelle)
- highly unlikely - Amoxapine (Asendin)
Lithium? Lithium may contribute to 5-HT syndrome, although unlikely Lithium may contribute to NMS.
Caused by N/A Stopping a dopaminergic antiparkinson medication (e.g., levodopa) can

stopping... induce NMS. This variety of NMS is referred to as
parkinsonism-hyperpyrexia syndrome or “withdrawal-emergent
hyperpyrexia and confusion”.
Relatively low Rarely caused by a lone antidepressant. Not caused by Low potency 1st gen antipsychotics—chlorpromazine (Thorazine) and
risk buspirone or triptans. Highly unlikely to be caused by thioridazine (Mellaril); 2nd gen antipsychotics—clozapine (Clozaril),
medications mirtazapine, trazodone, cyclobenzaprine or lithium. quetiapine (Seroquel), olanzapine (Zyprexa)
Leukocytosis Less prominent > 75% of cases have WBC > 12,000
Creatinine Less prominent 90% show creatine kinase (CK) over 3x upper limit of normal (ULN). CK
kinase (CK) of over 5x ULM is diagnostic of rhabdomyolysis (skeletal muscle
elevation breakdown), which can lead to renal failure and disseminated
intravascular coagulation (DIC). The normal range of CK is 22 to 198
units/Liter. CK is also called creatine phosphokinase (CPK).
Management Discontinue the contributing medication(s). ICU admission, rapid cooling and hydration. Stop the antipsychotic or
Aim to normalize vital signs. restart the dopaminergic med.
Potentially Benzodiazepines for agitation Bromocriptine (DA agonist)

helpful meds Cyproheptadine (anti-serotonergic antihistamine) Amantadine (DA agonist, NMDA antagonist)
Methysergide (anti-serotonergic migraine medication) Dantrolene (direct acting muscle relaxant)
Risk factors Combinations of serotonergics, use of street drugs Iron deficiency, dehydration, catatonia, Lewy body dementia, genetically
reduced function of D2 receptors, rapid dose escalation, males under age
40
Incidence Severe 5-HT toxicity is rare. Mild toxicity is more common. Quite rare - About 1 in 5,000 on antipsychotics
Sequelae None, although delirium may persist for a few days Memory problems (although usually temporary)
Differential Serotonin discontinuation syndrome (withdrawal) in the context Alcohol withdrawal, thyrotoxicosis, sepsis, heat stroke, tetanus, acute
diagnosis of cross-tapering/titrating antidepressants. hydrocephalus, status epilepticus
Anticholinergic toxicity, which manifests as dry, flushed skin
(“dry as a bone, red as a beet”) rather than diaphoresis.
Formal Google Hunter criteria, which focuses on clonus (spontaneous Defined by DSM 5; Severe rigidity and high fever are both necessary to
diagnosis or inducible), ocular clonus, and hyperreflexia make the diagnosis.
Notes Some experts prefer the term serotonin toxicity to more Neuroleptic, a synonym of antipsychotic, refers to something that “grabs
accurately reflect the condition as a dose-dependent form of ahold of nerves”. Idiopathic NMS (with no identifiable culprit drug) is
5-HT poisoning. called malignant catatonia.
Thanks to Ahmed Eid Elaghoury MD for contributing to this content.

QT prolongation
]
“Cutie heart”
The risk of torsades is the highest within the first few days of
initiating treatment with a QT prolonger. For most drugs that prolong
In this book, an ECG QT, the risk of torsades is so low that routine ECG screening is
tracing like the one on this unnecessary. Although combining QT prolonging medications does
candy heart means that prolong QT interval, the magnitude of the effect is likely to be tiny,
the medication prolongs with a very low probability of clinical consequences (Carlat Report,
QT interval. March 2018). However, it is prudent to check an ECG for patients
taking high doses of multiple QT prolonging medications, or
individuals with these risk factors:
On electrocardiogram (ECG), the QT interval, measured from the Risk factors for QT prolongation
beginning of the QRS complex to the end of the T-wave, reflects ► Hypokalemia (low K+)
the rate of electrical conduction through the ventricles as they ► Hypomagnesemia (low Mg+)
contract and relax. The useful number for our purposes is the QTc ► Bradycardia
interval, which is QT corrected for heart rate, which takes into ► Left ventricular hypertrophy
account that QT interval is naturally longer at slower heart rate.
Patients with congenital long QT syndrome should not be given QT
prolonging medications. Do not add a QT prolonging medication
ECG of Normal Sinus Rhythm when QTc is near 500 msec.
QT prolongation by psychotropic medications:
Risk Medication Class

Highest Thioridazine (Mellaril) Antipsychotic
High Pimozide (Orap) Antipsychotic
Ziprasidone (Geodon) Antipsychotic
Moderate Iloperidone (Fanapt) Antipsychotic
Chlorpromazine (Thorazine) Antipsychotic
Haloperidol (Haldol)* Antipsychotic
Amitriptyline (Elavil) TCA
Desipramine (Norpramin) TCA
Imipramine (Tofranil) TCA
Maprotiline (Ludiomil) TCA
Citalopram (Celexa) SSRI
Methadone (Dolophine) Opioid
Pitolisant (Wakix) H3 antihistamine
QT interval
Low risk Most antidepressants
except in Most antipsychotics
combination
or overdose
Normal:
*Intravenous haloperidol poses high risk of QT prolongation.
Due to the extent of QT prolongation caused by thioridazine

(Mellaril), most psychiatrists avoid prescribing it. For healthy
QT prolongation: patients taking ziprasidone (Geodon), the author checks an ECG
before exceeding the FDA maximum dose of ziprasidone (80 mg
BID) or when combining 3 or more medications known to prolong
QT interval. Check an ECG if a patient taking QT prolonging
QT prolongation is a delay in cardiac conduction that can trigger medications experiences palpitations or syncope/presyncope.
Torsades de pointes (French “twisting of points”). This may
precede sudden death.
Other medications that prolong QT interval:
Torsades (twisting) Class Medication
Antiarrhythmic Amiodarone (Cordarone)
Flecainide (Tambocor)
Quinidine (Cardioquin)
Sotalol (Betapace)
Antimicrobial Azithromycin (Zithromax)
Many psychotropic medications prolong QT interval, including most Ciprofloxacin (Cipro)
antidepressants and antipsychotics. In overdose scenarios involving Clarithromycin (Biaxin)
antidepressants or antipsychotics, QT interval is usually long, Erythromycin (Erythrocin)
necessitating a trip to the ICU. As you will see in the next chapter, Fluconazole (Diflucan)
tricyclic antidepressants (TCAs) are particularly deadly in overdose Hydroxychloroquine (Plaquenil)
due to disruption of cardiac conduction manifested by, among other Levofloxacin (Levaquin)
measures, prolonged QT. Other Cocaine
Opioids (most) - generally mild except methadone
Roughly speaking, QTc > 460 milliseconds is long and QTc > 500 Ondansetron (Zofran) - antiemetic (IV route)
msec can be dangerous. An increase in QTc > 60 msec caused by a Propofol (Diprivan) - anesthetic
medication would be of concern.
page
Chapter 7 – Tricyclic Antidepressants 28
[ Chapter 3 – Tricyclic Antidepressants

]
Tricyclic Antidepressants (TCAs)

[ tri SIC lic ] including the -triptylines [ -trip ta LEEN ]
“Tricycles tripped a line”
page
28
pag
Think of QT 82
If QT interval
prolongation as a is too long,
A tricyclic stretching out of the Torsades de
about to ECG tracing. pointes may
“trip a line” result.
The TCAs are older antidepressants, derived from the three-ringed Clomipramine is highly serotonergic, whereas four TCAs have so
chemical (imipramine) shown above. They work by inhibiting little serotonergic activity that they could be safely coadministered
reuptake of serotonin (5-HT) and/or norepinephrine (NE). TCAs differ with an MAOI— nortriptyline, desipramine, maprotiline, trimipramine
from newer SSRIs and SNRIs in that TCAs are “dirty drugs”, non- = “Non-Disparaged MAOI Tagalongs”.
selectively affecting several other neurotransmitter systems. Most
TCAs are antihistaminic (sedation and weight gain) and TCAs are deadly in overdose, some more dangerous than others.
anticholinergic (dry mouth, constipation, urinary retention, and Overdose on a ten-day supply of a TCA can be life-threatening owing
confusion). They also block alpha-1 adrenergic (NE) receptors, which to disturbance of cardiac conduction. This is seen on EKG as
may lead to orthostatic hypotension. prolongation of the QT interval and other forms of conduction delay.
The exception is clomipramine, which is relatively benign in
Mechanistically, the prototypical TCA is like a combination of overdose.
venlafaxine (SNRI), diphenhydramine (antihistamine and
anticholinergic) and prazosin (alpha-1 blocker). This does not apply Compared to SSRIs, TCAs are less likely to contribute to serotonin
to all TCAs, which are a diverse bunch. Amitriptyline and imipramine syndrome, with clomipramine as an exception.
are prototypical TCAs.
Although TCAs are not addictive or abusable, they are reported on
TCAs were largely replaced by SSRIs, which are cleaner (selective), the basic urine drug screen (UDS). False positive tricyclic screens
without the antihistaminic and anticholinergic baggage. Unlike the can be caused by carbamazepine (Tegretol), oxcarbazepine
diverse TCAs, SSRIs are pretty much homogenous, with similar (Trileptal), cyclobenzaprine (Flexeril), quetiapine (Seroquel),
efficacy and side effects. The main difference between members of chlorpromazine (Thorazine), thioridazine (Mellaril), and at toxic
the SSRI class are half-life and potential for kinetic interactions. doses, diphenhydramine (Benadryl).
This chapter highlights the differences between members of the TCA The muscle relaxant cyclobenzaprine (Flexeril) is a tricyclic by
class. Some TCAs are anxiety-reducing (amitriptyline, doxepin), structure. Single-drug overdose on cyclobenzaprine is less
while others can be energizing (nortriptyline, desipramine). dangerous than overdose on a prototypical TCA.
Rx TCA Cost Sed Wt ACh NE 5-HT Comments
#1 Amitriptyline (ELAVIL) $10 Calming (as opposed to drive-enhancing). The most weight gain
+++ +++ +++ ++ +++ among TCAs. Highly anticholinergic so not good for the elderly.
metabolized to
#2 Nortriptyline (PAMELOR) $10 Drive-enhancing. The least orthostatic hypotension of TCAs.

+ + + ++++ - Active metabolite of amitriptyline.
#3 Doxepin (SILENOR) $10 Highly antihistaminic. Effective for sleep at very low dose.
($450) +++ ++ +++ ++ +++ 3 mg and 6 mg tablets are expensive. 10 mg capsules are cheap.
#4 Imipramine (TOFRANIL) $15 ++ ++ ++ ++ +++ 1st antidepressant approved in US. Metabolized to desipramine.
#5 Clomipramine (ANAFRANIL) $380 +++ ++ +++ - ++++ Highly serotonergic, for OCD only. The safest TCA in overdose.
#6 Desipramine (NORPRAMIN) $15 Energizing with minimal side effects. Exceptionally fatal in
+/- +/- + ++++ - overdose. The only TCA likely to cause hypertension.
#7 Protriptyline (VIVACTIL) $81 - +/- +++ ++++ +/- Energizing / drive-enhancing
#8 Maprotiline (LUDIOMIL) $68 ++ ++ + ++++ - Tetracyclic structure. Risk of inducing seizures.
#9 Amoxapine (ASENDIN) $25 + ++ +/- +++ ++ Tetracyclic. Weak antipsychotic with potential to cause EPS.
#10 Trimipramine (SURMONTIL) $88 Highly sedating. Not a significant 5-HT or NE reuptake inhibitor.
+++ ++ ++ - - Antihistamine and 5-HT2A antagonist.
Rx – sales rank; Cost – month’s supply (see GoodRx.com); Sed – sedation; Wt – weight gain;
ACh – anticholinergic; NE – noradrenergic (norepinephrine); 5-HT – serotonergic

❖ Tricyclic Antidepressant (TCA) 10 mg
]
#88 Amitriptyline (ELAVIL) ❖ Serotonin and norepinephrine 25
reuptake inhibitor (SNRI) 50
1961 am i TRIP ta leen / EL a vil
❖ 5-HT2 receptor antagonist 75
$4–$16
“Am I trippin’ (off the) Elevator?” ❖ 5-HT > NE
100
150
FDA-approved for:
❖ Depression
Used off-label for:

❖ Neuropathic pain
❖ Migraine prevention
❖ Fibromyalgia
❖ Postherpetic neuralgia
❖ Insomnia
Risk of falls for
the elderly
“Elavil elevates your mood”. Introduced in 1961, overdosing on pills. Of 33,219 single-drug exposures to
amitriptyline (Elavil) was heavily prescribed prior to the amitriptyline reported to Poison Control, there were 145
arrival of SSRIs. Amitriptyline remains the most prescribed deaths (Nelson & Spyker, 2017). This equates to a
TCA, and is the #88 most prescribed drug in the US. It mortality risk of 1 in 229. Multi-drug overdoses including
appears to be more effective than newer antidepressants amitriptyline are much more dangerous.
(Cipriani et al, 2018). Off-label uses include headache
prevention, fibromyalgia, and insomnia. Amitriptyline is metabolized to nortriptyline, which has
fewer side effects and fewer interactions. So, why are more
Amitriptyline is anxiety-reducing (as opposed to scripts written for amitriptyline than for nortriptyline?
drive-enhancing). Amitriptyline is not recommended for the Possibly because the side effect of sedation is not a bug,
elderly because it is more anticholinergic and antihistaminic it’s a feature—amitriptyline is often intended to double as a
than the average TCA. This can lead to falls. Of the sleep medication.
tricyclics, it is the most likely to cause weight gain,
averaging about 15 pounds over 6 months—“Am I fat Dosing: For depression start 10 or 25 mg HS and titrate
now?” slowly due to sedative effects. The usual maintenance
dose for depression is 50–150 mg HS. Maximum is 300 mg
Amitriptyline is highly anticholinergic. Dry mouth (an HS for depression and 150 mg for other uses. The target
anticholinergic effect) occurs in almost everyone who takes dose range for migraine prophylaxis is 10–100 mg HS. For
50 mg or more nightly. neuropathic pain, consider dispensing a bottle of 10 mg
tabs and instruct the patient to take 10 mg HS for one week
Although amitriptyline is not the deadliest TCA, it is the and increase the dose by 10 mg weekly until pain is
most prescribed. As a result, over 40% of all improved, up to 50 mg HS while they wait for their
antidepressant fatalities are caused by amitriptyline. It follow-up visit. Taper gradually to discontinue. Consider
should not be prescribed to patients with a history of dispensing less than a 30-day supply if the patient is at risk
PLACEHOLDER of overdosing.
amitriptyline nortriptyline imipramine desipramine
metabolized to
metabolized to
Serotonergic; Noradrenergic; Serotonergic; Noradrenergic;

Tertiary amine Secondary amine Tertiary amine Secondary amine
page
page 14
Dynamic interactions: page
24
15
❖ Serotonergic
❖ Sedation/CNS depression
Amitriptyline is highly
❖ Weight gain (worst of TCAs)
anticholinergic
❖ QT prolongation (moderate)
❖ Anticholinergic (strong)
❖ Lowers seizure threshold (moderate)
“Mad as a ❖ Hyponatremia
hatter” ❖ Hypotension TCA
Kinetic interactions:
❖ 2D6 substrate (major) All TCAs are
❖ 2C19 substrate 2D6 substrates. 2C19 substrate

[ Nortriptyline (PAMELOR) 10 ]
#192 ❖ Tricyclic Antidepressant (TCA) 25
1963 nor TRIP ta leen / PAM e lor ❖ Norepinephrine reuptake 50
$4–$15 inhibitor (NRI)
“North-tripping Pam” 75
mg
FDA-approved for:
❖ Depression
Used off-label for:

❖ Migraine prevention
❖ Smoking cessation
❖ ADHD
❖ Fibromyalgia
❖ Postherpetic neuralgia
Nortriptyline (Pamelor) is the major active Not all TCAs combine well with SSRIs, but Think twice before prescribing nortriptyline
metabolite of amitriptyline. Sometimes nortriptyline plus sertraline (Zoloft) or to anyone at risk of overdosing on pills.
nortriptyline is referred to as a second escitalopram (Lexapro) is considered a Risk of mortality in single-drug overdose is
generation TCA (amitriptyline being the first favorable pairing. Nortriptyline has been only slightly less than with amitriptyline.
generation). Nortriptyline is a shown more effective than escitalopram for
norepinephrine reuptake inhibitor (NRI) depression in individuals with high Initial milligram dose for nortriptyline is the
with no significant serotonergic activity. It is C-reactive protein, which is a general same as amitriptyline and imipramine,
similar to bupropion (Wellbutrin), although marker of inflammation (Uher et al, 2014). although the FDA max for nortriptyline (150
with more side effects and greater toxicity mg) is lower than for
in overdose. Because it is not serotonergic, Sedation from nortriptyline is by amitriptyline/imipramine (300 mg).
nortriptyline could be safely combined with antihistamine effect. The label instructs to
an MAOI for refractory depression (Thomas give nortriptyline at bedtime. Considering Dosing: According to the label, the target
& Shin et al, 2015). its stimulating properties, AM dosing may dose for depression is 50–150 mg HS;
be more appropriate for some patients. Start: 25–50 mg HS and increase by 25–50
Nortriptyline is arguably underutilized mg/day q 2–3 days; Max dose is 150
because it is superior to other TCAs in Nortriptyline has been used off-label for mg/day; May give in divided doses, or in
terms of safety and tolerability (Gillman, smoking cessation and ADHD, which is AM; Use lower dose for elderly patients.
2007). It has a relatively wide margin reasonable because its mechanism of Taper dose gradually to stop. Therapeutic
between therapeutic effects and side action resembles that of atomoxetine serum range is about 50–150 ng/mL, which
effects/toxicity. Nortriptyline causes the (approved for ADHD) and bupropion is easy to remember since the
least orthostatic hypotension among the (approved for smoking, used off-label for recommended dose range is 50–150 mg.
TCAs, so the individual is less likely to ADHD). Serum level does not necessarily correlate
become lightheaded and fall—Pamelor with clinical efficacy.
“keeps Pam’s head pointed North”. It can
be effective for SSRI non-responders. It is
one of two antidepressants (citalopram)
with demonstrated benefit for post-stroke
depression.
metabolized to metabolized to

page
Dynamic interactions:
Therapeutic serum ranges 15
❖ QT prolongation (mild)
are defined for desipramine,
❖ Anticholinergic (moderate)
imipramine and nortriptyline
—“mosquitos DINe on your
blood”.
Serum level does not
necessarily correlate with ❖ 2D6 substrate (major)
clinical efficacy. - 2D6 ultra-rapid metabolizers may have All TCAs are
undetectable serum levels of nortriptyline 2D6 substrates.

#239 Doxepin (SILENOR) ❖ Tricyclic Antidepressant (TCA)
10
25
]
1969 ❖ NE & 5-HT reuptake inhibitor 50 3
$10–$21 caps
DOX e pin / SIGH len or ❖ 5-HT2 receptor antagonist 6
75 mg
$450–$550 tabs “Box pins (for a) Silent night” ❖ Antihistamine (sedating)
Cheap
100
Expensive
150
FDA-approved for: Doxepin (Sinequan) was released in 1969 as a tricyclic antidepressant (TCA). It is
❖ Depression (150–300 mg HS) an incredibly strong antihistamine. It is available as a topical cream for pruritus.
❖ Anxiety (150–300 mg HS)
❖ Insomnia (3–6 mg, branded Silenor) Doxepin is rarely prescribed at antidepressant strength (150–300 mg capsules) but
❖ Pruritus (topical cream) is commonly used at 10 mg for insomnia. The advantage of doxepin over other
antihistamines for sleep is doxepin has minimal anticholinergic activity at a low dose.
Used off-label for: Traditional antihistamines such as diphenhydramine (Benadryl) and doxylamine
(Unisom) are highly anticholinergic, as are the other sedating TCAs such as
❖ Insomnia (10–25 mg generic Sinequan)
amitriptyline (Elavil) and clomipramine (Anafranil). In most circumstances,
anticholinergic effects are undesirable. Anticholinergics constipate, cause
xerostomia, impair cognition (“mad as a hatter”) and increase risk of dementia with
long-term use. Doxepin’s advantage is lost at a high dose where it becomes highly
anticholinergic.
Overdosing on a bottle of any full-strength TCA can be fatal, However, low dose
Doxepin is safe to prescribe, even for patients at risk for suicidal overdose for whom
you would never prescribe most TCAs. A 30-day supply of Doxepin 10 mg is only
300 mg, which would not kill a patient downing the full bottle (although 300 mg could
theoretically be contributory to a fatal multidrug overdose).
The original trade name of the (now generic) doxepin capsule is Sinequan. A tiny
dose doxepin tablet was released in 2017, branded as Silenor, available in 3 mg and
6 mg strengths. Generic 3 mg or 6 mg pills do not exist. Branded Sillenor costs about
$15 per tablet, which is about $450 monthly. Compare this to 10 mg generic doxepin
capsules, which are only $0.33 per capsule (about $10 monthly).
Generic doxepin (Sinequan) carries the same black box warning as all other
antidepressants regarding suicidal thoughts and behaviors in children and young
adults. Silenor (3 mg, 6 mg) does not have the boxed warning
Dosing: For depression or anxiety the target

dose is 150–300 mg HS, starting at 25–75 mg
HS; Max is 300 mg; May divide doses; Taper
Doxepin is a strong antihistamine
gradually to stop; For insomnia use 10 mg
capsule HS; Max for insomnia is 50 mg, although
if you stick with 10–20 mg then overdose on a
30-day supply will not be fatal; Avoid the 3 mg
and 6 mg tabs (Silenor brand) due to cost.
Doxepin 5% cream is approved as a topical

antihistamine for pruritus, branded as
Zonalon, priced at $300–$660 per tube. The
$11– Doxepin (SINEQUAN) cream may cause systemic symptoms
$21 DOX e pin / SIN e qwan including sedation and anticholinergic effects,
caps especially if applied to > 10% of body surface.
“Box pin Sine wave” “Anti-HISSed-amine” The cream is intended for no longer than 8
days of treatment.
The original brand name of doxepin

capsule was Sinequan, approved for
depression and anxiety in the
page
maintenance dose range of 150–300 14
mg HS. Dynamic interactions: page
❖ Serotonergic 15
❖ Sedation/CNS depression (strong)
❖ Anticholinergic (strong > 50 mg)
❖ Hyponatremia
❖ Hypotension
TCA
❖ 2C19 substrate
❖ 2D6 substrate All TCAs are
sine wave 2C19 substrate 2D6 substrates.

[ Imipramine (TOFRANIL) ❖ Tricyclic Antidepressant (TCA)
]
10
1957 im IP ra meen / TOE fra nil ❖ 5-HT > NE reuptake inhibitor 25
$21–$78 (SNRI) 50
“I’m stopping it! (with) toffee” ❖ Antihistamine mg
FDA-approved for:
❖ Depression
❖ Enuresis (bedwetting)
Used off-label for:

the oldest bicycle,
❖ Generalized anxiety disorder representing
❖ Panic disorder he oldest
❖ Chronic pain antidepressant
❖ Sleepwalking
❖ Sleep terrors
❖ Confusional arousals
“I’m stopping it” due to side effects.
In 1957 imipramine (Tofranil) was released to the US market was added to venlafaxine. In other words, imipramine was
Page as the first antidepressant. It was widely prescribed prior to shown to outperform “California Rocket Fuel” (page 55).
109 the arrival of better tolerated antidepressants. It is still
prescribed for refractory depression. Imipramine and clomipramine are the TCAs established as
effective for panic disorder.
Imipramine was originally synthesized in 1951 by tweaking
the molecule of the antipsychotic chlorpromazine (Thorazine). Imipramine was used to treat nocturnal enuresis because it
At the time, these chemicals were classified as shortens the duration of deep sleep, when bedwetting occurs.
antihistamines. The antipsychotic effect of Thorazine was Other TCAs can be effective for enuresis, but imipramine is the
discovered in 1952. Imipramine was then tested as an only psychotropic medication FDA-approved for this indication.
antipsychotic but was ineffective for psychosis. The other medication approved for enuresis is desmopressin
Serendipitously, imipramine was found to relieve severe (DDAVP), an antidiuretic derived from vasopressin.
depression.
The liver converts imipramine into desipramine
Imipramine is an example of a “dirty” chemical, i.e., it affects (desmethyl-imipramine) as a metabolite. Desipramine
many neurotransmitter systems indiscriminately. It highly (Norpramin) is a “cleaner” drug, affecting fewer
anticholinergic. Many patients report lightheadedness related neurotransmitter systems and causing fewer side effects. In
to antagonism of alpha-1 adrenergic receptors, which causes terms of tolerability, “desipramine is more desirable than
orthostatic hypotension. Imipramine is a very poor choice for imipramine”.
elderly patients who are at risk for falls.
Dosing: Dosing for imipramine is the same as for amitriptyline.
Imipramine is considered a powerful antidepressant, more For depression start at 10 or 25 mg HS and titrate slowly due
likely than others to lead to “switching” to mania when used to sedative effects. The usual maintenance dose for depression
for bipolar depression. Navarro et al (2019) found that 72% of is 50–150 mg HS. Maximum is 300 mg HS (100 mg max for
nonresponders to venlafaxine (Effexor) showed remission of elderly patients); Taper gradually to stop. Therapeutic serum
depression when changed to imipramine. By comparison, level is 150–300 ng/mL of combined imipramine plus
remission rate was only 39% when mirtazapine (Remeron) desipramine.
PLACEHOLDER
metabolized to
metabolized to

page
Therapeutic serum ranges 14
are defined for desipramine, Dynamic interactions: page
imipramine and nortriptyline ❖ Serotonergic (strong) 15
—“mosquitos DINe on your ❖ Sedation/CNS depression (moderate)
blood”. ❖ QT prolongation (mild)
Serum level does not
necessarily correlate with
❖ Hyponatremia (5-HT)
clinical efficacy.
❖ Hypotension (strong)
TCA
❖ 2C19 substrate
2C19 substrate 2D6 substrates.

Clomipramine (ANAFRANIL) ❖ Tricyclic Antidepressant (TCA) 25
]
1990 ❖ 5-HT > NE reuptake 50
kloe MIP ra meen / an AF ra nil
$84–$239 inhibitor (SNRI) 75
“Anne Frank's Clompulsion” ❖ Antihistamine mg
FDA-approved for: Used off-label for:

❖ Obsessive-compulsive
disorder (OCD)
❖ Cataplexy (in narcolepsy)
❖ Confusional arousals
❖ Sleep terrors
*
❖ Sleepwalking Obsessive-“Clompulsive”
behavior of aligning
tricycles
Clomipramine (Anafranil) was engineered Due to side effects, clomipramine is

from imipramine in the early 1960s. It was considered a third-line OCD treatment after
Clomipramine is one of four
approved for treatment of depression in two trials of high-dose SSRIs have failed
antidepressants (maprotiline,
Europe in 1970, but not available in the (Robert Hudak, MD). It may be somewhat
amoxapine, and bupropion IR)
US until 1990. This delay was because more effective than SSRIs for OCD.
known to significantly lower seizure
the FDA considered it just a “me too” drug
threshold, i.e., may predispose the
of imipramine. Eventually, the FDA Clomipramine may be the safest TCA. Of
individual to having a seizure. The
approved it for obsessive-compulsive 680 single-drug exposures to clomipramine
risk is dose-dependent.
disorder (OCD). reported to Poison Control, there were no
deaths and only 44 major serious outcomes
* Clomipramine is the only available
TCA not approved for depression. It has
(Nelson & Spyker, 2017). Protriptyline
(Vivactil) may be safer, but the sample size
been established as effective for panic was small (77 exposures).
disorder, off-label.
Dosing: For OCD start 25 mg QD, increase
Clomipramine was considered the gold by 25 mg QD every 4–7 days for maximum of
standard for treatment of OCD due to 200 mg in the first 2 weeks, then to FDA
potent serotonergic activity. The other maximum maintenance dose of 250 mg. Give
medication approved for OCD but not for in divided doses with food during initial
depression is the SSRI fluvoxamine titration. Taper gradually to discontinue.
(Luvox), which is also highly serotonergic.
page page page

25
Kinetic interactions: 14 15
❖ Serotonergic (very strong) Multi-CYP
❖ Sedation/CNS depression ❖ 2C19 substrate
❖ Weight gain (moderate) ❖ 2D6 substrate
❖ QT prolongation (mild) ❖ 1A2 substrate page
❖ Anticholinergic (strong) ❖ 3A4 substrate 81
❖ Lowers seizure threshold (strong) Clomipramine poses a TCA
❖ Hyponatremia (5-HT) particularly high risk of Multi-CYP substrates
❖ Antiplatelet effects (5-HT) serotonin toxicity if are less likely to be
combined with another involved in clinically All TCAs are
serotonergic drug. significant interactions. 2C19 substrate 2D6 substrates.
Serotonergic medications need to be dosed high to effectively treat

obsessive-compulsive disorder. Citalopram (Celexa) is not a suitable SSRI for
OCD due to QT prolongation at high dose.
Serotonergic medication Class FDA Maximum for OCD

Maximum (Stahl, 2016)
Clomipramine (Anafranil) TCA 250 mg 250 mg
Fluvoxamine (Luvox) SSRI 300 mg 450 mg
Escitalopram (Lexapro)* SSRI 20 mg 60 mg

Fluoxetine (Prozac) SSRI 80 mg 120 mg
Paroxetine (Paxil) SSRI 60 mg 100 mg
Sertraline (Zoloft) SSRI 200 mg 400 mg
*Off-label
[ 10
]
1963
Desipramine (NORPRAMIN) ❖ Tricyclic Antidepressant (TCA)
25
50
des IP ra meen / NOR pra min ❖ Norepinephrine reuptake 75
$17– $50
inhibitor (NRI) 100
“Deceased (No prayin’, man)” 150
mg
FDA-approved for: Desipramine has the weakest antihistamine activity of all TCAs,
❖ Depression making it non-sedating. While other TCAs are useful for treating
insomnia, desipramine can cause insomnia. Recommended
dosing is once daily in the morning. Unlike most other TCAs,
Used off-label for: DECEASED desipramine causes no weight gain, sexual dysfunction, or
❖ REM sleep behavior No prayin’, man orthostatic hypotension. It is the only TCA that can cause
disorder hypertension.
❖ ADHD
The observation that desipramine helped ADHD was the basis
for development of the NRI atomoxetine (Strattera).
The main disadvantage of desipramine is risk of mortality in
single-dose overdose, which appears to be higher than any
Released in 1963, desipramine (Norpramin) was once commonly other antidepressant. Out of 680 single-drug overdoses, there
prescribed, but is rarely used today. It is exceptionally fatal in overdose. were 11 deaths, and 52 had major serious outcomes (Nelson &
Desipramine is an active metabolite of imipramine. In regard to side Spyker, 2017).
effects, “desipramine is more desirable than imipramine”.
Therapeutic serum ranges are defined for desipramine,
Desipramine (and nortriptyline) have been referred to as second imipramine and nortriptyline—“mosquitos DINe on your blood”.
generation TCAs, making imipramine (and amitriptyline) first generations. On drug screens, desipramine can cause a false positive for
amphetamine or LSD.
Desipramine is “drive enhancing” (stimulating), as opposed to “anxiety
reducing”. It can be described as a relatively selective Dosing: Start 25–50 mg q AM and increase by 25–50 mg
norepinephrinereuptake inhibitor (NRI). The trade name Norpramin is intervals every 2–3 days to target of 150–200 mg QD; Max is
fitting because it is the most potent noradrenergic TCA. Don’t confuse 300 mg; Taper gradually to stop. Therapeutic serum level is
Norpramin with nortriptyline, which is also noradrenergic. 150–300 ng/mL.
page
Dynamic interactions: 15
amitriptyline nortriptyline imipramine desipramine ❖ QT prolongation (moderate)
❖ Lowers seizure threshold
metabolized metabolized (moderate)
to to ❖ Hypertensive (unlike other TCAs)
Serotonergic; Noradrenergic; Serotonergic; Noradrenergic; Kinetic interactions:
Tertiary amine Secondary amine Tertiary amine Secondary amine ❖ 2D6 substrate All TCAs are
2D6 substrates.
1966
Protriptyline (VIVACTIL) ❖ Tricyclic Antidepressant (TCA) 5
$68–$181 pro TRIP ta leen / viv ACT il ❖ Norepinephrine reuptake 10
inhibitor (NRI) mg
“Vivactil the pterodactyl’s Pro tip (to lean)”
FDA-approved for: Used off-label for: As the trade name suggests, protriptyline (Vivactil) is a stimulating TCA. It is so
❖ Depression ❖ ADHD energizing that it has been used to treat ADHD and to promote daytime
❖ Narcolepsy (wakefulness wakefulness with narcolepsy. Protriptyline is safe to use with sleep apnea because
promoter) it is a respiratory stimulant (the same can be said for fluoxetine, a relatively
❖ Migraine prophylaxis stimulating SSRI). Potential for weight gain is minimal. It appears to be less toxic in
❖ Chronic pain overdose than other TCAs, although sample size is small. Of 77 single-drug
I’m Vivactil the ❖ Smoking cessation overdoses, there were no deaths and only 2 major serious outcomes.
Pterodactyl. My
pro tip is to lean
Available since 1966, protriptyline is rarely prescribed, ranked #7 of 10 in TCA
like this.
sales. Since 2000 it has been unavailable in several countries including the UK and
Australia. Protriptyline is the only TCA given in TID–QID divided doses, but it could
be dosed less frequently given its long half-life of about 80 hours.
Dosing: Protriptyline has uniquely

low dosing among TCAs due to its Dynamic interactions: page
❖ QT prolongation (moderate) 15
long half-life of about 80 hours.
Protriptyline’s dose range is 15 to ❖ Anticholinergic (strong)
40 mg/day (divided TID–QID)
(moderate)
compared to the usual TCA range
❖ Hypotensive (moderate)
of 25–300 mg/day. Therapeutic
serum range for protriptyline is Kinetic interactions:
about 70–250 ng/mL is similar to ❖ 2D6 substrate All TCAs are
other TCAs. 2D6 substrates.

Amoxapine (ASENDIN) ❖ Tricyclic Antidepressant (TCA) 25 ]
❖ Norepinephrine & Serotonin 50
1992
a MOX a peen / a SEND in Reuptake inhibitor 100
$19– $28
❖ NE > 5-HT
“Ammo to Ascend” ❖ D2 antagonist (weak)
150
mg
FDA-approved for:
❖ Depression
“I’m-a-sendin’ ammo”
Although grouped with the tricyclic antidepressants (TCAs), amoxapine

(Asendin) is actually a tetracyclic antidepressant (TeCA) by structure with
four hydrocarbon rings. Amoxapine is rarely prescribed. It is the least
anticholinergic of all TCAs.
Amoxapine is one of two antidepressants (trimipramine) that block D2

dopamine receptors. Dopamine antagonism gives amoxapine weak
antipsychotic properties as well as risk of extrapyramidal symptoms (EPS)
and prolactin elevation. The first generation antipsychotic (FGA) loxapine
(Loxitane) is metabolized to amoxapine. Note that other drugs with the -pine
suffix are antipsychotics (olanzapine, quetiapine, clozapine, asenapine, etc).
loxapine amoxapine
Out of 71 single-drug exposures reported to Poison Control, there 7 major (antipsychotic) (antidepressant)
serious outcomes including 1 death (Nelson & Spyker, 2017). This is a high
mortality index, but due to small sample size it is undetermined whether
amoxapine is actually more dangerous than the average TCA. Regardless, a
bottle of amoxapine may provide the suicidal patient “ammo to ascend” to
heaven. metabolized
to
Dosing: Target dose for depression is 200–300 mg HS or in divided doses;
The label recommends starting at 50 mg BID–TID; Max is 400 mg/day if
outpatient (600 mg/day if inpatient); Divide doses > 300 mg daily; Taper
gradually to stop.
page
Amoxapine has a high risk of inducing ❖ Serotonergic
seizures. ❖ Lowers seizure threshold
(high risk)
Risk of seizures: ❖ Extrapyramidal effects
#1 Maprotiline (LUDIOMIL) highest risk (D2 blocker)
#2 Amoxapine (ASENDIN) high risk ❖ QT prolongation (mild)
#3 Clomipramine (ANAFRANIL) 1–3% risk ❖ Anticholinergic (mild)
#4 Bupropion (WELLBUTRIN) IR 1–2% risk ❖ Hypotensive (moderate)
❖ Hyponatremia (5-HT)
In general, antidepressants (other than All TCAs are
TCAs) have a slight antiepileptic effect at Kinetic interactions:
2D6 substrates.
therapeutic dose. ❖ 2D6 substrate

[ Maprotiline (LUDIOMIL) ❖ Tricyclic 25
]
1976 Antidepressant (TCA) 50
ma PRO ti leen / LU dee o mil
$45–$84 ❖ Norepinephrine reuptake 75
“Map telling Lude milf” inhibitor (NRI) mg
FDA-approved for:
Maprotiline (Ludiomil) is a tetracyclic antidepressant commonly classified
❖ Depression as a TCA. It is a drive-enhancing norepinephrine reuptake inhibitor (NRI)
without serotonergic effects.
I’m the Map Of all available antidepressants, maprotiline is the most likely to cause a
telling this seizure, although risk is less than 1 in 1,000 at standard dose assuming
Lude milf she no other risk factors. Seizure risk can be minimized by slow titration. Since
could have there is also a risk of bone marrow suppression, nortriptyline or
a seizure! desipramine is a better choice if you are looking for NRI tricyclic.
Dosing: Target dose for depression is 75–150 mg HS or in divided doses;

Start 75 mg HS, may increase by 25 mg daily in 2-week intervals; Max is
150 mg for outpatient use (225 mg max for inpatient); Max for elderly is 75
mg; The label instructs a faster inpatient titration, though seizure risk will
be higher; Taper gradually to stop.
Noradrenergic (NE) activity among TCAs:

Most: Least:
Desipramine (NORPRAMIN) Clomipramine (ANAFRANIL)
Protriptyline (VIVACTIL) Trimipramine (SURMONTIL)z
Maprotiline (LUDIOMIL)

Antidepressants that lower seizure threshold: 15
(worst among antidepressants)
#1 Maprotiline (LUDIOMIL) - highest risk of seizure ❖ QT prolongation (moderate)
#2 Amoxapine (ASENDIN) - TCA ❖ Anticholinergic (moderate)
#3 Clomipramine (ANAFRANIL) - TCA
#4 Bupropion IR (immediate-release WELLBUTRIN) Kinetic interactions:
❖ 2D6 substrate
All TCAs are 2D6 substrates.
❖ Tricyclic Antidepressant (TCA)

1979
Trimipramine (SURMONTIL) ❖ 5-HT antagonist
25
2A 50
try MIP ra meen / SUR mon til ❖ Antihistamine (sedating)
$42 - $128 100
“Sermon ‘til trimming” ❖ D2 antagonist (antipsychotic) mg
FDA-approved for:
❖ Depression
Sermon ‘til
trimming! Trimipramine (Surmontil) is the least prescribed of the TCAs available in the US.
You’ll probably never see it in the wild.
Trimipramine’s mechanism differs from other TCAs. It is not a significant 5-HT or

NE reuptake inhibitor. It is mainly an antihistamine and 5-HT2A receptor
antagonist. It is also one of two antidepressants (amoxapine) that block D2
dopamine receptors This gives it antipsychotic properties and the potential to
cause extrapyramidal symptoms (EPS) and elevate prolactin. Trimipramine has
a receptor binding profile similar to the antipsychotic clozapine (Clozaril).
Trimipramine can be highly sedating, which is an H1 antihistaminic effect.
page page
Dynamic interactions: 14 15
Dosing: Target dose for depression is 50–150 mg HS ❖ Sedation/CNS depression
or in divided doses; Max is 200 mg/day for outpatients ❖ Extrapyramidal effects
(300 mg/day for inpatients); Max for elderly patients is (D2 blocker)
100 mg; Taper gradually to stop. ❖ Hypotension
TCA
❖ 2C19 substrate
2C19 substrate 2D6 substrates.

Toxicity of psychotropic medication in overdose ]
Listed from highest to lowest risk (approximate) of fatality in single-drug overdose:
Class Medication Mortality Index

TCA Antidepressant Desipramine (Norpramin) — 11 deaths from 680 overdoses 141
TCA Antidepressant Amoxapine (Asendin)* — 1 death from 71 overdoses 124
Combo Perphenazine + amitriptyline (Triavil) 74
TCA Antidepressant Amitriptyline (Elavil), doxepin (Sinequan), imipramine (Tofranil) ~ 40
MAOI Antidepressant Phenelzine (Nardil), tranylcypromine (Parnate) ~ 35
Other Aspirin ~35
TCA Antidepressant Nortriptyline (Pamelor) ~ 30
Other Acetaminophen (Tylenol) ~25
Combo Olanzapine + fluoxetine (Symbyax) ~25
SNRI Antidepressant Venlafaxine (Effexor) 9.7
AED Mood stabilizer Valproate (Depakote, Depakene) 8.1
NDRI Antidepressant Bupropion (Wellbutrin) 7.5
SGA Antipsychotic Olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon) ~ 6–7
AED Antiepileptic Gabapentin (Neurontin) 5.8
AED Mood stabilizer Carbamazepine (Tegretol) ~5
SNRI Antidepressant Desvenlafaxine (Pristiq) ~5
OTC Antihistamine Diphenhydramine (Benadryl) ~5 It is important for prescribers to have a
SSRI Antidepressant Citalopram (Celexa), fluvoxamine (Luvox) ~4 general awareness of relative risk
Benzo Anxiolytic Benzodiazepines (alprazolam, clonazepam, lorazepam, etc) 3.4 among medications and select drugs
NaSSA Antidepressant Mirtazapine (Remeron) ~3 accordingly. Multi-drug overdoses are
SARI Antidepressant Nefazodone (Serzone) ~3
more serious. Certain drugs that are
SGA Antipsychotic Risperidone (Risperdal) 2.5
AED Mood stabilizer Lamotrigine (Lamictal) 2.2
relatively benign in single-drug
SNRI Antidepressant Duloxetine (Cymbalta) 2 overdoses (e.g., benzodiazepines,
SSRI Antidepressant Paroxetine (Paxil) 1.4 quetiapine, gabapentin) are more
TCA Antidepressant Clomipramine (Anafranil), protriptyline (Vivactil)* 0–1 dangerous when combined with or
SNRI Antidepressant Levomilnacipran (Fetzima)*, milnacipran (Savella) 0–1 drugs or alcohol.
SARI Antidepressant Trazodone (Desyrel) 0–1
SMS Antidepressant Vilazodone (Viibryd), vortioxetine (Trintellix)* 0–1 Patients presenting to the emergency
SSRI Antidepressant Escitalopram (Lexapro), fluoxetine (Prozac), sertraline (Zoloft) 0–1 department with a single-drug
SGA Antipsychotic Aripiprazole (Abilify), lurasidone (Latuda) 0–1 overdose on a drug with mortality
AED Antiepileptic Oxcarbazepine (Trileptal), pregabalin (Lyrica) 0–1 index < 3 could probably be admitted
SRA Anxiolytic Buspirone (Buspar) — No deaths from 9,081 overdoses 0–1 directly to the behavioral health unit if
there are no major mental status
changes and ECG shows no cardiac
Mortality index = deaths per 10,000 single-drug exposures reported to Poison Control (about half of conduction delay. Otherwise, most
which were suicide attempts). overdose patients should be admitted
to the intensive care unit (ICU).
*Small sample size. Mortality index numbers are from Nelson & Spyker, 2017.
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Psychopharmacology: EMBIGGEN

Chapter 8 – Modern Antidepressants and Related Medications
[ Chapter 4 – Modern Antidepressants and Related Medications ]
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are the mainstay of treatment for depression, generalized serotonin. 5HT receptors are located on the far end of the
1A
anxiety disorder, panic disorder, and obsessive-compulsive disorder presynaptic neuron (not shown, a mile above this page). As
(OCD). By blocking serotonin transporters (SERT), SSRIs keep desensitization occurs, serotonin stops inhibiting its own release, so
serotonin in the extracellular space where it can continue to bind serotonin flows more freely from the end of the presynaptic neuron
serotonin receptors. Although an SSRI blocks SERT immediately, shown below. 5HT1A receptor desensitization takes a few weeks, which
antidepressant effects are generally not seen until 2 to 4 weeks of correlates with onset of therapeutic effect. Anti-inflammatory effects of
continuous treatment. Over time, increased extracellular availability of SSRIs may also contribute. Refer to Stahl’s Essential
serotonin (5-HT) causes 5HT1A receptors to become desensitized to Psychopharmacology book for a full visual explanation.
PLACEHOLDER
Presynaptic neuron Immediate SSRI effect (which does not

correlate to therapeutic response)
Serotonin- Serotonin
containing reuptake
vesicle transporter
(SERT)
Serotonin
(5-HT)
Synapse Increased
5-HT levels
in synapse
SSRI
Increased
Serotonin serotonin
receptor binding (enhanced
Postsynaptic neuron neurotransmission)
The main side effect leading to patients quitting their SSRI is sexual dysfunction. Unlike TCAs, SSRIs do not cause hypotension or major
anticholinergic effects. Other than citalopram (Celexa), SSRIs do not cause significant cardiac conduction delays. SSRIs are initially associated
with modest weight loss, which may be followed by modest weight gain with long-term use. SSRIs can cause hyponatremia (low serum
sodium) secondary to inappropriate antidiuretic hormone secretion (SIADH) from the pituitary gland.
Rx SSRI Antidepressant Interactions Half–life Comments

#1 Sertraline (ZOLOFT) Minimal 26 hr More likely to cause nausea and diarrhea. OK for first-line
#2 Escitalopram (LEXAPRO) The fewest interactions of 30 hr Recommended as first-line SSRI. Fewer side effects and slightly more
the SSRIs effective than the other SSRIs.
#3 Citalopram (CELEXA) Minimal (substrate) 35 hr QT prolongation if 40 mg dose is exceeded. Choose escitalopram
instead.
#4 Fluoxetine (PROZAC) Strong CYP inhibitor 7 days More activating. Possible insomnia and appetite suppression. 5-HT
discontinuation symptoms less likely thanks to long half-life.
#5 Paroxetine (PAXIL) Strong CYP inhibitor 20 hr “More calming”. The most sexual side effects, weight gain, sedation, and
anticholinergic constipation.
#6 Fluvoxamine (LUVOX) Very strong CYP inhibitor 16 hr For OCD only; Lots of kinetic interactions. Short half-life, dosed BID
(other SSRIs are QD); Other SSRIs at high doses are similarly effective
for OCD.
Uses of SSRIs SSRI side effects

❖ Depression ❖ Sexual dysfunction (all, especially paroxetine)
❖ Anxiety ❖ Modest weight gain with long term use (especially paroxetine)
❖ Panic disorder (start low dose) ❖ Insomnia (especially fluoxetine)
❖ OCD (titrate to high dose) ❖ Nausea (short-lived)
❖ Menopausal hot flashes ❖ Diarrhea (sertraline) or constipation (paroxetine)
❖ Somatoform disorders ❖ Restlessness / dizziness (short-lived)
❖ Premature ejaculation ❖ Bruxism (teeth grinding) which can improve with addition of
❖ Premenstrual dysphoric disorder (PMS) buspirone (Buspar)
SSRI risks
FYI—Medications with the -oxetine suffix:
❖ GI bleed (inhibition of serotonin uptake by platelets) ❖ Fluoxetine (Prozac) – SSRI
❖ Hyponatremia (low serum sodium) ❖ Paroxetine (Paxil) – SSRI
❖ Duloxetine (Cymbalta) – SNRI
❖ Serotonin syndrome ❖ Vortioxetine (Trintellix) – Serotonin modulator & stimulator (SMS)
❖ Suicidality (under age 24) ❖ Atomoxetine (Strattera) – Norepinephrine reuptake inhibitor for ADHD
❖ Mania, destabilization of bipolar disorder

]
#14 Sertraline (ZOLOFT) ❖ Antidepressant 25
1991 SER tra leen / ZOE loft ❖ Selective serotonin 50
$3–$49 reuptake inhibitor (SSRI) 100
“So Soft (on the) Shirt Line” mg
FDA-approved for:
❖ Major depressive disorder Sertraline is the preferred antidepressant
❖ Obsessive-compulsive disorder for pregnancy and breastfeeding.
❖ Panic disorder Medication exposure to the fetus/baby is
❖ Post-traumatic stress disorder minimal.
❖ Premenstrual dysphoric disorder
❖ Social anxiety disorder Ideally, all psychotropic drugs should be
avoided from weeks 3 - 10
Used off-label for: post-conception, the period of
❖ Generalized anxiety disorder organogenesis. However, untreated
❖ Bulimia nervosa depression may be worse for mother and
❖ Premature ejaculation fetus than risk of exposure to most
antidepressants..
“Sertraline blocks the serotonin transporter (SERT)” as do all SSRIs. On drug screens, Zoloft can cause a false positive result for
Sertraline (Zoloft) is the #1 prescribed antidepressant and the #14 benzodiazepines.
overall prescribed medication in the United States. It is a reasonable
first-line treatment for any of its FDA-approved conditions. Sertraline Risk of mortality with single-drug overdose on sertraline is about 1
has no real advantage over escitalopram (Lexapro), which has a in 10,000 (Nelson & Spyker, 2017), which is similar to mortality risk
slight advantage over sertraline in terms of side effects. of escitalopram.
Among SSRIs, sertraline is the most likely to cause diarrhea—”Zoloft Zoloft combines well with bupropion (Wellbutrin) for depression
makes your stools So Soft”. “So soft” also refers to sertraline’s with prominent fatigue (“Well-off”). Trazodone (Desyrel) is a
potential to cause erectile dysfunction, which is a side effect of all common add-on for insomnia. For anxiety, sertraline combines well
SSRIs. In terms of antidepressant-associated sexual dysfunction, with buspirone (Buspar) or any benzodiazepine. For bipolar
sertraline is slightly better than paroxetine (Paxil) and slightly worse depression or refractory unipolar depression, sertraline can be
than escitalopram. combined with any mood stabilizer or antipsychotic. Buspirone can
counter SSRI-induced sexual dysfunction and bruxism.
For any SSRI, treatment of obsessive-compulsive disorder (OCD)
may require significantly higher doses than used for depression. Dosing: 50 mg is the starting dose for most indications; FDA max
Although the FDA max for Zoloft is 200 mg, it may be necessary to is 200 mg; For treatment of OCD the dose may need to go as high
go as high as 400 mg for treatment of OCD (titrated gradually). as 400 mg (Stahl, 2016). Taper gradually to avoid unpleasant
serotonin discontinuation symptoms.
Information applicable to all SSRIs:
SSRIs block the serotonin reuptake pump. Onset of therapeutic effect use, but some patients complain of feeling emotionally flat or
is delayed 2–4 weeks. They start working when serotonin 5HT1A “blah”, experiencing what has been described as SSRI-Induced
receptors become desensitized. Some patients experience immediate Apathy Syndrome. SSRIs may cause a modest weight loss
increased energy or unpleasant restlessness, which is more common initially, and a modest weight gain with long-term use.
with bipolar disorder. Side effects occur sooner than therapeutic effects With bipolar individuals, SSRIs may cause “switching” to mania or
and often improve over time—nausea, sweating, headache, and destabilize mood over time.
bruxism (teeth grinding). Sexual dysfunction is often problematic, and
less likely than other side effects to improve with time. SSRIs may When abruptly discontinued, SSRIs may cause serotonin
increase suicidal thoughts in individuals under age 24. withdrawal symptoms including lightheadedness, "brain zaps",
paresthesias, nausea, fatigue and irritability.
Following resolution of a single depressive episode, the antidepressant
should generally be continued for a year to consolidate recovery. For SSRIs may decrease serum sodium levels and impair platelet
recurrent episodes, treatment may need to be continued indefinitely. functioning, but risk of significant hyponatremia or bleeding is
SSRIs are safe and effective for long-term placeholder
minimal.
The Zoloft Sad Blob debuted

as an advertising mascot in page page
2001.
❖ Serotonergic (strong)
❖ Antiplatelet effect
❖ Hyponatremia
❖ Although sertraline is a substrate of 2B6
and 2C19, drug interactions involving
sertraline are unlikely to be of much
clinical significance. ZOLOFT
❖ Zoloft is a 2D6 inhibitor when dosed 150
mg or higher, with the potential to modestly
increase serum levels of some
antipsychotics.
2B6 substrate (minor) 2C19 substrate (minor)

[ ]
#26 Escitalopram (LEXAPRO) ❖ Antidepressant 5
2002 10
ess sit AL o pram / LEX a pro ❖ Selective serotonin
$3–$98 reuptake inhibitor (SSRI) 20
“Lexus Pram” mg
FDA-approved for:
❖ Major depressive disorder
❖ Generalized anxiety disorder
Used off-label for EXAPRO

❖ Obsessive-compulsive disorder
❖ Post-traumatic stress disorder
❖ Premature ejaculation
❖ Premenstrual dysphoric disorder “Pram” is the
❖ Social anxiety disorder British word for
baby carriage.
❖ Autism spectrum disorder
❖ Bulimia nervosa
Escitalopram (Lexapro) is the “pure” form of Celexa Although escitalopram may be the overall winner among
(citalopram). Escitalopram is the S-enantiomer of the SSRIs, with all psychotropic drugs there is marked
molecule, as explained in the citalopram monograph on inter-individual variability in tolerability and therapeutic
the following page. Compared to Celexa, Lexapro is response. If an individual is doing wonderfully on
safer, often better tolerated, and possibly more effective. another antidepressant, there is usually no reason to
There is no reason to choose citalopram over change to escitalopram.
escitalopram—“S-citalopram is Superior to racemic
citalopram”. Escitalopram is regarded as safe for pregnancy and
breastfeeding, but sertraline (Zoloft) is safer.
S for “Sinister” = L for Left-handed enantiomer
Serum levels of escitalopram peak about 5 hours after
Escitalopram is the best choice for a first-line ingestion. Half-life is around 30 hours, so steady-state
antidepressant. It is the most selective inhibitor of the concentration should be achieved within 7 days. Upon
serotonin pump among all SSRIs. Several clinical trials discontinuation, escitalopram should be cleared from
and meta-analyses indicate escitalopram may be the body within 7 days.
slightly more effective than other SSRIs. Escitalopram
has an allosteric effect at the serotonin transporter that Dosing: Start escitalopram 10 mg QD (AM or PM), after
distinguishes it from other SSRIs. 10 mg of escitalopram meals for the first few days, then with or without food.
is predictably more effective than 20 mg of citalopram May increase to 20 mg in one week, but generally you
(which contains 10 mg escitalopram and 10 mg would wait about 4 weeks to see if it is necessary to
R-citalopram). advance the dose. Although the FDA max for Lexapro is
20 mg, it is not unusual to see it prescribed up to 30 mg
Lexapro has the fewest side effects of all the SSRIs. At for major depression. It can be safety dosed up to 60
the starting dose of 10 mg, side effects are comparable mg daily for OCD (Stahl, 2016). When converting from
to placebo. It is unlikely to cause weight gain or citalopram (Celexa), use half the milligram dose of
sedation. It has minimal drug-drug interactions. Lexapro escitalopram. 20 mg of Lexapro is predictable more
is safe. Risk of mortality with single-drug overdose on effective than 40 mg of Celexa. Use a lower dose for
escitalopram is about 1 in 9,000 (Nelson & Spyker, elderly individuals because serum levels will be about
2017). 50% higher. If the patient is taking omeprazole
(Prilosec) or esomeprazole (Nexium), consider starting
For depression, escitalopram is at least as effective as escitalopram at 5 mg. Renal impairment: no adjustment
SNRI antidepressants. Although venlafaxine (Effexor) needed. Hepatic impairment: consider lower dose.
and duloxetine (Cymbalta) have the additional Taper to discontinue to avoid unpleasant serotonin
mechanism of blocking the norepinephrine transporter, withdrawal symptoms.
do not expect either of them to outperform Lexapro.
page
❖ Serotonergic (strong)
❖ QT prolongation (minimal)
❖ Hyponatremia
❖ Fewer interactions than most SSRIs
❖ As a 2C19 substrate, escitalopram levels are increased by proton
pump inhibitors (PPIs). Avoid omeprazole (Prilosec) and LEXAPRO
and esomeprazole (Nexium), which increase escitalopram levels
by 80–90%. Instead, choose pantoprazole (Protonix) or
lansoprazole (Prevacid), which only increase escitalopram by
about 20%. Although more expensive, rabeprazole (Aciphex) does
not affect escitalopram levels. 2C19 substrate

]
#21 Citalopram (CELEXA) ❖ Antidepressant 10
20
1998 si TAL o pram / SEL ex a ❖ Selective serotonin
reuptake inhibitor (SSRI) 40
$2–$35
“Sell Lexus Pram” mg
FDA-approved for:
Used off-label for

ELEXA QT prolongation
❖ Social anxiety disorder
❖ Autism spectrum disorder
❖ Bulimia nervosa
QT prolongation
Celexa is a combo of: S-citalopram = the active Left-handed molecule (available as Lexapro), page
page
41
95
and its mirror image molecule: R-citalopram: R-citalopram = “Rubbish” Right-handed molecule, in a 50/50 ratio
Citalopram (Celexa) is the old 50% pure version of escitalopram Celexa 20 mg is roughly equivalent to Lexapro 10 mg, as would
(Lexapro). 50% of Celexa is the right-handed enantiomer be expected, given that half of Celexa is junk. Even at double
R-citalopram. S-citalopram is the most selective (for serotonin the milligram dose, Celexa is predictably less effective than
reuptake inhibition) of all SSRIs. R-citalopram is ineffective and Lexapro. L-citalopram has an allosteric effect at the serotonin
causes QT interval prolongation. transporter that R-citalopram interferes with.
The plasma concentration of S-citalopram (escitalopram) is For initiation of antidepressant treatment, there is no reason to
usually one third of the total citalopram concentration, with the choose Celexa over Lexapro. So, why is anyone on citalopram?
implication that the other two thirds of the total citalopram Many patients are on Celexa because, when their medication
concentration is inactive as an antidepressant (Burke & was started, Lexapro was more expensive. Celexa has been
Kratochvil, 2002). available generically since 2004. Lexapro went generic in 2012.
When a drug goes off patent, it generally takes several years for
In 2012 the FDA released a warning for QT prolongation with enough manufacturers to enter the market for the drug to
Celexa and reduced the maximum approved dose from 60 mg to become dirt cheap.
40 mg. Lexapro does not have this warning. The warning may
have been unwarranted, because rates of sudden unexpected Of the other SSRIs, paroxetine (Paxil) and sertraline (Zoloft)
death with high-dose citalopram is no higher than with other have always been pure enantiomers. Fluvoxamine (Luvox) lacks
high-dose SSRIs (Ray et al, 2017). When VA patients were taken a chiral center, so a mirror image molecule does not exist.
off citalopram because of the FDA warning, rates of depression Fluoxetine (Prozac) is a racemic mixture, but R-fluoxetine and
increased and incidents of arrhythmias were not affected (Rector L-fluoxetine inhibit serotonin reuptake equally.
et al, 2016).
Bottom line: If starting an SSRI, choose escitalopram rather
Although rarely clinically significant, QT prolongation by than citalopram. If a patient already established on citalopram is
R-citalopram poses some risk in overdose situations. Although doing wonderfully, “don't try to fix what ain’t broken”.
the risk of single-drug overdose death with Celexa is only about 1
in 1,850, mortality risk is over 4x higher than with Lexapro. QT Dosing: Celexa is started at 20 mg QD, dosed in AM or PM. In
prolongation by Celexa could potentially be risky when it is about 4 weeks may increase to FDA maximum of 40 mg. If
prescribed along with other QT-prolonging medications. higher strength is needed, change to Lexapro 20 mg, which is
predictable more effective than Celexa 40 mg.

❖ Serotonergic (strong) 14
❖ QT prolongation (moderate)
❖ Hyponatremia
❖ 2C19 substrate CELEXA
❖ 2C19 poor metabolizers should not
exceed 20 mg of citalopram
❖ See escitalopram monograph for preferred
proton pump inhibitors (2C19 inHibitors)
2C19 substrate

]
#29 Fluoxetine (PROZAC) ❖ Antidepressant 10
20
1987 flu OX e teen / PRO zak ❖ Selective serotonin
40
$2–$36 reuptake inhibitor (SSRI)
“Prolonged sack of the Flustered ox” mg
as
pag

❖ Major depressive disorder ❖ Other anxiety disorders
❖ Obsessive-compulsive disorder ❖ Premature ejaculation
❖ Bulimia nervosa (to Prolong intercouse)
❖ Panic disorder ❖ Binge eating disorder
(Sarafem brand)
“Prolonged” refers to
Fluoxetine (Prozac) was the first available SSRI, released to the US Prozac’s prolonged
presence in the body, with
market in 1987. Among antidepressants, Prozac has the best
half-life of 1 week.
evidence for treatment of depression among children and
adolescents. It is the only FDA-approved medication for treatment of
depression in children (age 8 and older).
For adults, Lexapro and Zoloft are generally preferred because

58 For the sake of trivia, there exists a 90 mg fluoxetine ER capsule
Prozac interacts with numerous medications. Specifically, Prozac is
intended for once weekly dosing called PROZAC WEEKLY. It runs
an inHibitor of several CYP enzymes. If Prozac were a newly
$50 per capsule. That’s $200 monthly, compared to $4–$10 for a
introduced drug, it would be unlikely to receive FDA approval due to
month of generic QD fluoxetine.
the magnitude of these interactions.
When discontinuing fluoxetine 40 mg or less, it may be ok just to
Among SSRIs, Prozac is considered the most activating/energizing
stop without tapering, thanks to is long half-life. However, some
(as opposed to calming). As a result it is more likely to cause anxiety
patients may need a hyperbolic taper as described on page 58. To
and insomnia than other SSRIs. It is safe for those with sleep apnea
come off of higher doses, you will want to taper over several
because it is a respiratory stimulant. It is not expected to cause
months. Switching from fluoxetine to another antidepressant can
weight gain and may result in modest weight loss. As with other
be tricky due to fluoxetine’s long half-life. When switching to
SSRIs, the most troublesome side effect is sexual dysfunction.
another modern serotonergic antidepressant, consider a washout
period before starting the new antidepressant. The risk of
Prozac has a very long elimination half-life of about 7 days. In other
serotonin syndrome is minimal with some overlap of two SSRIs
words, Prozac has a Prolonged presence in your body. A mnemonic
(or an SSRI and an SNRI), so you do not have to wait for
from Dr. Jonathan Heldt’s book Memorable Psychopharmacology
fluoxetine to be entirely cleared by the body. However, when
compares the half-life of fluoxetine to the 7 days its takes to recover
switching from fluoxetine to an MAOI, there can be no overlap,
from the flu (influenza).
because serotonin syndrome is a major risk. You need to wait at
least five weeks after stopping fluoxetine to start the MAOI. For
With chronic use, fluoxetine is detectable in the body up to five
the other SSRIs, you only have to wait 2 weeks to start the MAOI.
weeks after discontinuation (elimination half-life x 5). Since Prozac
“tapers itself” off over weeks when stopped abruptly, there should be
Dosing:
no serotonin withdrawal symptoms. Thanks to long half-life, missed
doses are of less consequence (compared to antidepressants with Fluoxetine, available in 10 mg, 20 mg, and 40 mg capsules, is
shorter half-lives). If the patient forgets to take a dose on Monday, it typically started (for adults) at 20 mg QD. It can be titrated in 20
is OK to take a double dose on Tuesday. This would not be advisable mg increments to the FDA max dose of 80 mg QD. As a rule of
with most other psychotropics. thumb, you would want to wait about 4 weeks between dose
increases. If there is a prior effective dose (for a particular patient)
Fluoxetine is safe. Risk of death with single-drug overdose is no you are targeting, you can titrate faster. See above for
more than 1 in 10,000. discontinuation strategies.
SYMBYAX is a fixed dose combination of fluoxetine with the For obsessive-compulsive disorder (OCD), you can go as high as
antipsychotic olanzapine (Zyprexa), approved for acute depressive 120 mg daily (Stahl, 2016). OCD often requires heroically high
episodes of bipolar I disorder and for treatment-resistant major doses of SSRIs, and fluoxetine is a safe option.
depression. Released in 2003, Symbyax (mnemonic Symbiotic Ox)
was marketed heavily to primary care physicians, who likely For premenstrual dysphoric disorder (PMDD), you can take 20 mg
underestimated olanzapine's potential for causing significant weight QD starting 14 days prior to the anticipated onset of menses
gain and diabetes. The fixed doses of olanzapine/fluoxetine in through the first full day of menstruation and repeating with each
Symbyax are 3/25mg, 6/25 mg, 6/50 mg, and 12/50 mg taken in the cycle. The brand SARAFEM (10 mg, 20 mg) is FDA-approved for
evening. this indication, but you will want to prescribe generic fluoxetine.
For PMDD there is no proven benefit in exceeding 20 mg/day.
❖ Serotonergic (strong) page
❖ Antiplatelet effect 14
The “fluffers” - infamous ❖ Hyponatremia SSRI
page
inHibitors of CYP enzymes: 15
❖ Fluvoxamine (Luvox) ❖ Fluoxetine is an inHibitor of 2D6 and 2C19.
This results in numerous interactions that PROZAC
❖ Fluoxetine (Prozac) PROZAC
markedly increase blood levels of various Fluoxetine
❖ Fluconazole (Diflucan)
victim drugs (substrates).
Fluoxetine is a less potent ❖ Although fluoxetine itself is a 2D6 and 2C9 2D6 inHibitor 2C19 inHibitor
enzyme inhibitor than the substrate,clinically significant victimization is (strong) (moderate)
other two. not expected.

#64 Paroxetine (PAXIL) ❖ Antidepressant ER
12.5
10
20
1992 ❖ Selective serotonin
par OX e tine / PAX il 25 30
IR $3–$37 reuptake inhibitor
ER $55–$140 “Pear rocks a teen (Paxil Rose)” (SSRI) 37.5
mg
40
mg
FDA-approved for: Paroxetine (Paxil) has the reputation as a calming (as opposed to
❖ Major depressive disorder energizing) antidepressant. However, there are several reasons to
❖ Obsessive-compulsive disorder choose a different SSRI. Although paroxetine is FDA-approved for
❖ Generalized anxiety disorder more anxious conditions than other SSRIs, it has performed no
❖ Panic disorder better for anxiety in head-to-head trials (Sanchez et al, 2014).
❖ Social anxiety
❖ Post-traumatic stress disorder Disadvantages of paroxetine compared to other SSRIs:
❖ Menopausal vasomotor symptoms ► More fatigue
(hot flashes) at low 7.5 mg strength ► More weight gain
branded as BRISDELLE ► More sexual dysfunction
► More likely to cause withdrawal symptoms with missed doses
Used off-label for: ► More CYP interactions (excluding fluvoxamine)
❖ Premenstrual dysphoric disorder ► More anticholinergic effects
❖ Premature ejaculation ► Risk of dementia (anticholinergic), unlike other SSRIs
► Risk of birth defects
► Less effective than escitalopram, even for anxiety disorders
Axl Rose has short stature. Among antidepressants, Paxil has a

relatively short elimination half-life of 21 hours. A missed dose may
Axl Rose result in unpleasant serotonin withdrawal symptoms.
(Guns N' Roses)
Paroxetine is the only SSRI with significant anticholinergic effects, making it a bad SSRI
choice for elderly individuals. As a result of this anticholinergic activity, Paxil is the most
constipating SSRI—“Paxil packs it in”. Paroxetine is the most likely SSRI to cause
tachycardia, which is an anticholinergic effect. Prolonged exposure to anticholinergic
medications is a risk factor for cognitive decline. Paxil is the only SSRI associated with
increased risk (2-fold) of developing dementia (Heath et al, 2018).
Among SSRIs, Paxil
Paroxetine has more potential to cause fatigue and weight gain than other modern
has a relatively short
antidepressants, but less so than some TCAs.
half-life of 21 hours.
All SSRIs commonly decrease sexual desire, disrupt the sexual pleasure response, and
short increase latency to orgasm. Among SSRIs, Paxil is the most likely to cause sexual
dysfunction. Since Paxil is the “best” at interfering with orgasms, it is the SSRI of choice for
off-label treatment of premature ejaculation. Its short half-life makes it handy as a PRN for
this purpose.
There may be a possibility of birth defects if Paxil is taken in early pregnancy. Under
pre-2015 FDA pregnancy risk categories, paroxetine was pregnancy Category D, while
other SSRIs were Category C.
As a strong 2D6 inhibitor, paroxetine is more likely to cause problematic drug-drug
interactions than the other commonly used SSRIs. Fluvoxamine (Luvox), a stronger inhibitor
of CYP enzymes, is worse than Paxil in terms of interactions.
ge
2 Signs of serotonin page
The enteric coated controlled-release formulation of paroxetine, Paxil CR, is less likely to
discontinuation include: 58 cause nausea. Nausea is a short-lived side effect, and after the first week the CR
formulation offers little advantage over immediate-release paroxetine.
► Lightheadedness
Dosing: Start 20 mg AM. Depending on the indication, FDA max is 50–60 mg. For OCD
► Paresthesias
start 20 mg AM, increase by 10 mg weekly to target of at least 40 mg. FDA max for OCD is
► Nausea
60 mg, but can go as high as 100 mg (Stahl, 2016). The target dose for panic disorder is 40
► Fatigue
mg. Consider twice daily dosing ≥ 40 mg. For menopausal hot flashes, rather than using
► Irritability
expensive 7.5 mg paroxetine (Brisdelle), prescribe 10 mg generic paroxetine HS. Taper
gradually to discontinue to avoid serotonin withdrawal symptoms.
page
13
❖ Serotonergic (strong) page
❖ Antiplatelet effect 15 PAXIL
❖ Hyponatremia
PAX
IL
❖ 2C9 inHibitor (moderate)
❖ 2D6 inHibitor (strong)
❖ 2D6 substrate 2C9 inHibitor
2D6 inHibitor
(strong) (weak)

Fluvoxamine (LUVOX) ❖ Selective serotonin 25
1996 reuptake inhibitor (SSRI) 50
flu VOX a meen / LU vox
$20–$120 ❖ OCD medication 100
“Glove-ox” ❖ Potent CYP inHibitor mg

❖ Obsessive-compulsive ❖ Social anxiety disorder (rarely)
disorder (OCD) ❖ Strategic inHibition of CYP1A2 with
clozapine as described on page 11
*
Fluvoxamine (Luvox) is an SSRI

approved exclusively for OCD, a 50 mg HS is the starting fluvoxamine
disorder characterized by obsessions dose for the first week, then 50 mg BID.
(recurrent intrusive thoughts) that the Envision the mascot flicking a light switch
individual may attempt to neutralize 50 times. Additional dose increases will
with a compulsive repetitive behavior likely be necessary for fluvoxamine to be
or ritual, e.g., flicking a light switch 50 effective for OCD. With any SSRI,
times. effective treatment of OCD demands a
high dose, often exceeding the FDA max.
Three other SSRIs are FDA-approved
for OCD—fluoxetine (Prozac), Fluvoxamine should be dosed BID for
paroxetine (Paxil), and sertraline maintenance because it has the shortest
(Zoloft). Off-label, escitalopram half-life of all available SSRIs (15 hours).
(Lexapro) at high dose may be a Other SSRIs are generally dosed once
better choice than fluvoxamine for daily.
OCD because it highly selective for
blocking serotonin transporters and Among SSRIs, fluvoxamine is the least
has fewer side effects. likely to cause sexual dysfunction (La
Torre et al, 2013), although > 50% of
* Although not used for depression,
fluvoxamine is properly referred to as
patients are still affected. Owing to short
half-life, fluvoxamine is a reasonable PRN
an antidepressant. treatment for premature ejaculation.
Luvox is a potent inHibitor of multiple Dosing: For OCD start 50 mg HS, then Serotonergic medications need to be
CYP enzymes, causing increased increase to 50 mg BID in 4–7 days. May prescribed at high dose to effectively treat
serum levels of many co-administered increase by 50 mg/day every 4–7 days. obsessive-compulsive disorder.
medications. CYP1A2 inhibition by FDA maximum is 300 mg/day but may go
fluvoxamine can be used for strategic as high as 450 mg (Stahl, 2016) in *Escitalopram is used off-label for OCD.
advantage in combination with divided doses. Dosing is similar for social
clozapine (Clozaril) as explained on anxiety disorder. Taper gradually to Serotonergic Class FDA Max for OCD
page 11. discontinue. med max (Stahl, 2016)
Clomipramine TCA 250 mg 250 mg
page
(Anafranil)
112 For maintenance,
Due to short half-life, page
Luvox is dosed Fluvoxamine SSRI 300 mg 450 mg
58
serotonin BID because it (Luvox)
discontinuation has the shortest
symptoms are half-life among Escitalopram SSRI 20 mg 60 mg
common if Luvox is SSRIs (15 hr). (Lexapro)*
stopped abruptly:
Fluoxetine SSRI 80 mg 120 mg
► Lightheadedness (Prozac)
short
► Paresthesias
► Nausea Paroxetine SSRI 60 mg 100 mg
► Fatigue (Paxil)
► Irritability
Sertraline SSRI 200 mg 400 mg
(Zoloft)
page page page
❖ Serotonergic (strong) 10 14 16
❖ Hyponatremia
Kinetic interactions: LUVOX

❖ Luvox is a “fluffer”, i.e., inHibitor of several CYP
enzymes. This results in numerous drug-drug
interactions causing the serum level of the victim
drug (substrate) to increase markedly
LUVOX
❖ Ramelteon (Rozerem) is contraindicated
because ramelteon levels increase 100-fold! (1A2) LUVOX
❖ Tizanidine (Zanaflex) is contraindicated
because tizanidine levels increase 10-fold (1A2)
❖ Pimozide (Orap) is contraindicated (3A4) 1A2 inHibitor 2C19 inHibitor 3A4 inHibitor
❖ Although fluvoxamine Itself is a 2D6 and 1A2 (strong) (strong) (moderate)
substrate, clinically significant victimization
is not expected

]
Serotonin-norepinephrine reuptake inhibitors (SNRIs)
SNRIs increase the extracellular availability of neurotransmitters serotonin (5-HT) and norepinephrine (NE).
Think of serotonin as calming (“serene”) and norepinephrine (NE), also known as noradrenalin, as eNErgizing.
SNRI Antidepressant U.S. Market Uses Comments

Duloxetine (CYMBALTA) 2004 Depression, Fibromyalgia, Neuropathic Duloxetine is involved in more CYP
pain, Anxiety interactions, than the other SNRIs.
Venlafaxine (EFFEXOR) 1994 Depression, Anxiety, Chronic pain More dangerous in overdose than other
SNRIs
Desvenlafaxine (PRISTIQ) 2007 Depression Less effective and more side effects than
Effexor XR.
Milnacipran (SAVELLA) 2009 Fibromyalgia Titration pack 12.5 mg (#5), 25 mg (#8), 50
mg (#42)
Levomilnacipran (FETZIMA) 2013 Depression L-enantiomer of milnacipran (Savella)
Some tricyclic antidepressants (TCAs) are SNRIs by mechanism, although TCAs also block off-target receptors (acetylcholine, histamine, alpha-1).
TCA Antidepressant U.S. Market Uses Comments

Amitriptyline (ELAVIL) 1961 Depression, Neuropathic pain, Migraine 5-HT > NE
prophylaxis, Fibromyalgia, Postherpetic More sedating than newer SNRIs;
neuralgia, Insomnia Also 5-HT2 receptor antagonist
Doxepin (SINEQUAN, SILENOR) 1969 Depression, Insomnia Sedating at low dose due antihistamine
properties; NE > 5-HT at higher doses; Also
5-HT2 receptor antagonist
Clomipramine (ANAFRANIL) 1990 Obsessive-compulsive disorder (OCD) 5-HT > > NE
Imipramine (TOFRANIL) 1957 Depression 5-HT > NE
Amoxapine (ASENDIN) 1992 Depression NE > 5-HT, Antipsychotic properties due to D2
antagonism
SNRIs that are not classified as antidepressants:
Other SNRIs U.S. Market Uses Comments

Tramadol (ULTRAM) 1995 Pain Weak opioid also; Schedule IV controlled substance
Sibutramine (MERIDIA) 1997–2010 Obesity Removed from market in 2010 due to risk heart attack
and stroke
“Atypical Antidepressants”
Newer antidepressants not classified as TCAs, MAOIs, SSRIs, or SNRIs
Atypical antidepressant Class Abbrev Cost/mo

Nefazodone (SERZONE) Serotonin Antagonist & SARI $68 Developed as a non-sedating variant of trazodone. Rarely
Reuptake Inhibitor prescribed. Rare occurrence of severe liver damage.
Trazodone (DESYREL) SARI $4 Widely prescribed at low dose, solely as a sleep
medication
Mirtazapine (REMERON) Noradrenergic & Specific NaSSA $11 Great for sleep and appetite stimulation, more so at lower
Serotonergic dose. At higher dose, noradrenergic (NE) activity is more
Antidepressant prominent.
Bupropion (WELLBUTRIN) Norepinephrine & NDRI $25 Like a mild stimulant—helpful for ADHD, appetite
Dopamine Reuptake suppression and smoking cessation. Improves sexual
Inhibitor functioning. Seizures at high dose.
Vilazodone (VIIBRYD) Serotonin Modulator & SMS $200 “Hybrid” of SSRI & 5-HT1A partial agonist. Mechanism of
Stimulator action is like a combo of an SSRI and the anxiolytic
buspirone (Buspar).
Vortioxetine (TRINTELLIX) SMS $300 Serotonin reuptake inhibitor, 5-HT1A agonist, 5-HT1B
partial agonist, 5-HT3 antagonist & 5-HT7 antagonist.

Duloxetine (CYMBALTA) ❖ Antidepressant 20 ]
#48 ❖ Serotonin-norepinephrine 30
2004 du LOX e tine / cym BAL ta reuptake inhibitor (SNRI) 40
$6–$166 “Dueling Cymbals” ❖ 5-HT > NE 60
mg
FDA-approved for:
❖ Diabetic neuropathy
❖ Fibromyalgia
❖ Chronic musculoskeletal pain Cymbal duel
Used off-label for:

❖ Stress urinary incontinence
❖ ADHD
Rare risk
of liver
damage
The SNRI duloxetine (Cymbalta) is reasonable first-line Avoid prescribing duloxetine to alcoholics or those
choice for depressed patients with comorbid pain with known liver problems.
syndromes. Among antidepressants, it stands out as
being particularly effective for generalized anxiety Risk of death from a single-drug overdose with
disorder (GAD). duloxetine is about 1 in 3,500, making it safer than
venlafaxine (1 in 800).
Side effects may include nausea (22%), dry mouth
(16%), fatigue (11%), dizziness (11%), somnolence, Peak plasma levels are achieved at 3 hours. Half-life
constipation, diarrhea, insomnia, agitation, sweating, is 12 hours, so steady-state concentrations are
headaches, and sexual dysfunction. Duloxetine is not achieved within 3 days of oral dosing (5 x 12 hours).
expected to cause appreciable weight gain. Upon discontinuation, duloxetine is cleared from the
Hypertension (1%) due to duloxetine does not appear body within 3 days (also 5 x 12 hours) and there are
to be dose-dependent. The discontinuation rate of no active metabolites.
duloxetine due to side effects was 15% (versus 5% for
placebo). For depression, the FDA maximum of 120 mg was
found no more effective than 60 mg. For pain, the 120
Compared to the SNRI venlafaxine (Effexor), mg dose (divided 60 mg BID) can be more effective.
duloxetine is more likely to cause nausea but less likely
to elevate blood pressure. Duloxetine is less likely than Dosing: Duloxetine can be dosed BID or QD, either
venlafaxine to cause serotonin withdrawal symptoms AM or HS. Consider starting 30 mg QD x 1 wk, then
upon discontinuation. increase to target dose of 60 mg QD or 30 mg BID.
For depression, the FDA maximum of 120 mg is rarely
Duloxetine is more likely to be involved in clinically more effective than 60 mg. Doses over 60 mg may be
significant CYP interactions than venlafaxine. more effective for pain. 120 mg dose is usually divided
to 60 mg BID. Taper gradually to discontinue to avoid
Serious liver damage is possible with duloxetine, serotonin withdrawal symptoms.
although rare. It is not considered necessary to closely
monitor liver enzymes (beyond routine screening labs
for all patients).
page page
page
❖ Serotonergic 15
❖ Hyponatremia
“Cym-
❖ Hypertension
BALL-ta”
CYM
Kinetic interactions: BAL
TA
❖ 2D6 inHibitor (moderate)
❖ 1A2 substrate
– decreased 30% 2D6 inHibitor
by smoking (moderate)
– increased 3-fold by
fluvoxamine (Luvox) 1A2 substrate 2D6 substrate
❖ 2D6 substrate

Venlafaxine (EFFEXOR) ❖ Antidepressant
XR
37.5
]
#51
ven la FAX ine / e FEX er ❖ Serotonin-norepinephrine 75
1995
$6–$105
“Vanilla faxing (eFax’er)” ❖ 5-HT > NE mg
FDA-approved for:
I’m depressed.
Must fax for help.
❖ Social anxiety disorder
❖ Panic disorder
80’s rapper
Vanilla Ice
Used off-label for:
❖ ADHD
❖ Migraine prophylaxis
❖ Fibromyalgia
❖ Cataplexy
❖ Vasomotor symptoms of menopause
possible BP
elevation
The SNRI venlafaxine (Effexor) is a reasonable second-line In addition to raising blood pressure, venlafaxine may induce
antidepressant, potentially first-line for depressed individuals seizures in overdose, making it the most dangerous modern
suffering from chronic pain. Effexor XR and duloxetine antidepressant (non-TCA, non-MAOI). Risk of single-drug
(Cymbalta) are equally popular SNRIs, #51 and #48 most overdose death with venlafaxine is about 1 in 839.
prescribed medications in the US, respectively.
For depression, venlafaxine is no more effective than the SSRI
When Effexor was introduced in 1995 prescribers nicknamed it escitalopram (Lexapro), which has fewer side effects. For
“Side-Effexor” due to nausea and fatigue. Effexor XR generalized anxiety disorder, venlafaxine is more effective than
(extended-release) was introduced in 1998 and became widely buspirone (Buspar).
prescribed because it is much better tolerated. Choose the XR
formulation, which is also less expensive than the rarely Venlafaxine can cause false positives for PCP on drug tests.
prescribed immediate-release venlafaxine. The only scenario
when immediate-release Effexor is preferred is with bariatric FDA max is 225 mg, but for severe depression 300 mg may be
surgery patients. For either formulation of Effexor, it is more effective. Take caution because blood pressure elevation is
recommended to take it with food to minimize nausea. dose dependent. Taper off Effexor slowly to avoid symptoms of
serotonin withdrawal syndrome.
Peak plasma concentrations are achieved within 2 to 3 hours for
the IR formulation and within 5.5 hours for the XR formulation. XR Dosing: Specify the extended-release formulation Effexor
XR, (venlafaxine ER) except for in bariatric surgery patients.
Effexor acts as an SSRI at low doses (37.5 mg, 75 mg) and an Start Effexor XR 37.5 or 75 mg QD with food (to ameliorate
SNRI at higher doses (150 mg plus). 75 mg/day is the minimum nausea), with target of 150–225 mg QD. FDA max is 225 mg,
effective dose for treatment of depression but 300 mg may be more effective for depression. For treatment
of pain the dose can go as high as high as 450 mg/day if blood
Venlafaxine has a short half-life of 5 hours, and the half-life of pressure is monitored closely. May increase in 75 mg increments
the active metabolite O-desmethylvenlafaxine (ODV) is 11 hours. every 4–7 days.
ODV is available as the antidepressant desvenlafaxine (Pristiq),
which appears to be less effective than Effexor for depression. IR dosing: For bariatric surgery patients, prescribe venlafaxine
IR which is available in 25, 37.5, 50, 75, and 100 mg tablets,
Incidence of blood pressure elevation with the XR formulation is given in divided doses BID or TID. The FDA maximum for IR
1%. With the IR formulation, incidence of hypertension is about venlafaxine is 375 mg/day in divided doses (125 mg TID).
5%, and as high as 13% at doses exceeding 300 mg.
Signs of serotonin page Effexor XR

page
ge discontinuation include: 58 18
2
37.5 75 150
mg mg mg Dynamic interactions: EFFEXOR
❖ Lightheadedness ❖ Serotonergic
❖ Paresthesias ❖ Antiplatelet effect
❖ Nausea ❖ Hyponatremia
❖ Fatigue ❖ Hypertension
❖ Irritability
“SSRI” “SSRI” SNRI Kinetic interactions:

❖ 2D6 converts venlafaxine to an active metabolite
(desvenlafaxine). 2D6 metabolizer phenotype does not
Effexor acts as an SSRI at affect efficacy, although Individuals with 2D6 poor
low doses (37.5 mg, 75 mg) metabolizer genotype may experience more side effects.
and an SNRI at higher ❖ Also a substrate of 2C19 and 3A4 substrate
doses (150 mg plus). ❖ Kinetic interactions occur but are unlikely to be clinically
relevant—“in a box”.

[ Desvenlafaxine (PRISTIQ) ❖ Antidepressant 25
]
#272 ❖ Serotonin-norepinephrine
2007 des ven la FAX ine / Pris TIQ 50
$33–$274 “Desk faxing Pressed steak” ❖ 5-HT > NE mg
FDA-approved for:
I’m (de)pressed Used off-label for:

You have to
❖ Same as venlafaxine (Effexor)
press a steak
before you can
Desvenlafaxine (Pristiq), also known as O-desmethy-
fax it.
venlafaxine (ODV), is an active metabolite of venlafaxine
(Effexor). Pristiq was introduced to the US market in 2007,
thirteen years after the release of Effexor. The European Union
did not approve Pristiq because it is probably less effective than
Effexor and has no clear advantage over Effexor.
Pristiq is one of the few antidepressants visualized in a bubble,

to signify that kinetic interactions are highly unlikely. Pristiq is
subject to fewer kinetic interactions than Effexor, but Effexor
has relatively low potential for clinically significant interactions
Unnecessarily anyhow (visualized in a box).
expensive desk—now
available generically but still
All desvenlafaxine (Pristiq) tablets are extended-release (ER),
more expensive than Effexor
page 48 XR
so you don’t have to write “ER” on a desvenlafaxine script. To
get ER venlafaxine (page 48) you have to specify “Effexor XR”
or “venlafaxine ER”,
Dosing: 50 mg QD is the only recommended dose. The 100

Pill formulations with Antipsychotics mg dose adds no benefit, and is more likely to cause nausea.
“ghost pill” shells Invega (paliperidone ER)
passing in feces: Antidepressants
Wellbutrin XL (bupropion XL)
Effexor XR (venlafaxine ER) page
Pristiq (desvenlafaxine ER) 18
❖ Serotonergic
Stimulants
Concerta (methylphenidate ER)
❖ Hyponatremia PRISTIQ
Ritalin SR (methylphenidate SR)
❖ Hypertension
Focalin XR (dexmethylphenidate ER)
Mood Stabilizer
Tegretol XR (carbamazepine ER)
❖ Minimal potential for clinically
Opioid
Sources include: relevant pharmacokinetic
Oxycontin (oxycodone ER)
Tungaraza et al, 2003 interactions - “in a bubble”
Exalgo (hydromorphone ER)
Desvenlafaxine (KHEDEZLA) ❖ Antidepressant

50
2014 des ven la FAX ine / kah DEZ la ❖ Serotonin-norepinephrine
$120–$340 reuptake inhibitor (SNRI) 100
“Desk faxing on Kid’s desk” ❖ 5-HT > NE
mg
FDA-approved for: Desvenlafaxine is also available as the brand name

❖ Major depressive Khedezla (released 2014) which is equivalent to Pristiq
disorder (adults) (2007). Both Pristiq and Khedezla are extended-release
(ER) formulations of desvenlafaxine, both indicated for
major depressive disorder, both dosed once daily. Pristiq
is a succinate salt with a half-life of 10.4 hours, while
Khedezla is a base with a half-life of 10.6 hours.
The approval of Khedezla was based on the original

page
Pristiq efficacy studies. 18
Studies have found desvenlafaxine to be ineffective for

children with depression (Weihs et al, 2017). “Kid’s desk KHEDEZLA
ain’t for kids.”
Desvenlafaxine has been available generically since

2017.
Dosing: Same as Pristiq

]
2009
Milnacipran (SAVELLA) ❖ Serotonin-norepinephrine
reuptake inhibitor (SNRI)
12.5
25
$384–$476 mil NA si pran / sa VEL la ❖ Fibromyalgia medication 50
“Milhouse ran to Save Ella” ❖ 5-HT = NE 100
mg
* Not approved for depression
FDA-approved for:
HELP ! ❖ Fibromyalgia
my
fibromyalgia
* Milnacipran (Savella) is the SNRI approved for

fibromyalgia only, not for depression. It is properly
referred to as an antidepressant and is approved for
depression in some other countries. It has not shown
robust antidepressant efficacy.
Fibromyalgia
At the usual maintenance dose milnacipran is a
tender points “balanced” SNRI that enhances serotonin and
norepinephrine activity by similar magnitude. At lower
doses, e.g., 25 mg BID, noradrenergic effects are more
pronounced than serotonergic effects.
Milnacipran is fairly well tolerated, with fewer

Jazz singer Ella gastrointestinal issues than SSRIs. Side effects that are
Fitzgerald more prominent with milnacipran (compared to SSRIs)
include dizziness, sweating, and urinary hesitancy.
Levomilnacipran (Fetzima), the pure L-enantiomer of

milnacipran, is FDA-approved for depression.
Of 236 single-drug exposures to milnacipran reported to

Poison Control, there were 5 major serious outcomes but
no deaths (Nelson & Spyker, 2017).
Dosing: Titrate to 50 mg BID using the starter pack

shown below. Maximum dose is 200 mg (100 mg BID).
Taper to discontinue to avoid unpleasant serotonin
withdrawal symptoms.
SAVELLA (fibromyalgia) FETZIMA (depression) Savella is initiated by a

titration that would be quite
NE > 5-HT 5-HT > NE NE > 5-HT
inconvenient without the “4
week convenience pack”.
► 12.5 mg QD x 1 day,
► 12.5 mg BID x 2 days,
► 25 mg BID x 4 days,
L-milnacipran R-milnacipran L-milnacipran ► then 50 mg BID
Medications for fibromyalgia

page
❖ Serotonergic
FDA-approved: 18
❖ Duloxetine (Cymbalta) – SNRI ❖ Hyponatremia
❖ Milnacipran (Savella) – SNRI ❖ Hypertension
❖ Pregabalin (Lyrica) – AED SAVELLA
Off-label: ❖ Milnacipran undergoes minimal
❖ Venlafaxine (Effexor) – SNRI CYP-related metabolism,
❖ Gabapentin (Neurontin) – AED with 55% of the dose excreted
❖ Amitriptyline (Elavil) – TCA unchanged in urine. Kinetic
❖ Tramadol (Ultram) – weak opioid interactions occur but are
& SNRI unlikely to be clinically
relevant—“in a box”.

20
2013
Levomilnacipran (FETZIMA) ❖ Antidepressant
❖ Serotonin-norepinephrine 40
$394–$484 LEE voe mil NA si pran / fet ZEE ma reuptake inhibitor (SNRI) 80
120
“Leave Milhouse with a Zima Fetish” ❖ NE >> 5-HT
mg
FDA-approved for:
Used off-label for:

❖ Fibromyalgia Now that’s
❖ Diabetic peripheral neuropathy stimulating!
❖ Chronic musculoskeletal pain
❖ Vasomotor symptoms of menopause
Levomilnacipran (Fetzima), released in 2013, is the pure

L-enantiomer of milnacipran (Savella). Fetzima will be
expensive until the patent expires in 2031.
Compared to other SNRIs, levomilnacipran enhances

norepinephrine >> serotonin, making it more stimulating. By
contrast, milnacipran is a “balanced” SNRI that enhances
serotonin and norepinephrine activity by similar magnitude at the
usual maintenance dose.
Zima was a clear malt
beverage available
Levomilnacipran causes no weight gain. The most relevant side 1993–2008.
effect is nausea, especially as treatment is initiated. This why the
dose should be titrated. Dose dependent urinary retention (5%)
and tachycardia and may occur. It increases heart rate by an
average of 7 beats/minute, which is a noradrenergic effect.
Levomilnacipran was found effective in patients over age 60, a

population that is generally resistant to antidepressants.
It reaches peak serum concentration about 7 hours after

ingestion. Half-life is about 12 hours. Kinetic interactions are
unlikely to be clinically significant.
Of 56 single-drug exposures to milnacipran reported to Poison

Control, there were no deaths or major serious outcomes,
although this is a small sample size (Nelson & Spyker, 2017).
Dosing: Start 20 mg QD x 2 days, then increase to 40 mg QD.

This can be accomplished with the 28-day starter pack that
contains #2 of 20 mg caps and #26 of 40 mg caps. FDA page
maximum is 120 mg QD if renal function is normal. Do not use if 18
❖ Serotonergic FETZIMA
severe renal impairment. Do not exceed 80 mg/day in the
presence of a strong 3A4 inHibitor (e.g., ketoconazole, ❖ Hyponatremia
clarithromycin, ritonavir). Taper gradually to discontinue. ❖ Hypertension
SAVELLA (fibromyalgia) FETZIMA (depression) ❖ 85% is excreted in urine, 58% unchanged. Otherwise, it is
primarily metabolized through 3A4/
NE > 5-HT 5-HT > NE NE > 5-HT
❖ The package insert says not to exceed 80 mg/day in the
presence of a strong 3A4 inHibitor (e.g., ketoconazole,
clarithromycin, ritonavir). Otherwise, the max is 120 mg.
The label for milnacipran (Savella) does not describe this
interaction. As with Savella, we’re putting Fetzima “in a
box” to signify that kinetic interactions occur but are
L-milnacipran R-milnacipran L-milnacipran unlikely to be clinically significant.

]
#24 Trazodone (DESYREL) ❖ Antidepressant/sleep medication
❖ Serotonin antagonist and
50
100
1981 TRA zo dohn / DES zi rel reuptake inhibitor (SARI) 150
$3–$18 300
“Trays o’ bone / Dizzy reel” – 5-HT2 antagonist
– 5-HT1A agonist mg
*
FDA-approved for:
❖ Major Depressive “Trays of
Disorder (MDD) bone” make
—rarely used for you sleepy
this indication
Used off-label for:

❖ Insomnia (first-line) Risk of Mouth
❖ PTSD nightmares prolonged “dry as
“boner” a bone”
Trazodone (Desyrel) was the first non-tricyclic / non-MAOI Priapism (painful prolonged erection) is a rare risk of Trazodone,
antidepressant approved in the US, predating the SSRIs. Many and a medical emergency. Priapism is not considered a
psychiatrists consider trazodone their first-line sleep significant risk with any other psychotropic medication. Although
medication. It is the author’s #1 most prescribed drug. It can be the risk is low (1 in 6,000), think twice before prescribing
combined with any other medication. Low-dose Trazodone trazodone to a man being discharged to jail, where prompt
50–75 mg can even be combined with an MAOI (Jacobsen, medical treatment for priapism might not be provided.
1990). The author regards significantly prolonged QTc interval Trazodone-induced priapism is likely attributable to antagonism of
(over 490 msec or so) as the only contraindication. alpha-1 adrenoceptors, which interferes with the sympathetic
control of penile detumescence.
Although it is approved as an antidepressant, trazodone is
usually prescribed at low dose for insomnia, with no Animal studies suggested trazodone could reduce the risk of
antidepressant benefit expected. It is seldom used as a dementia, but this does not appear to apply to humans (Brauer et
stand-alone treatment for depression due to sedation and al, 2019). At worst, trazodone does not contribute to dementia
orthostatic hypotension if dosed at antidepressant strength. risk. Anticholinergic sleep medications like diphenhydramine
Trazodone is often prescribed as an adjunct to SSRIs. It may (Benadryl) and doxylamine (Unisom) do increase risk of
be helpful for reducing PTSD nightmares (Warner MD et al, dementia.
2001).
The original trade name of trazodone was DESYREL, but no one
Trazodone induces and maintains sleep without causing calls it that because the generic name has such a nice ring to it.
tolerance. Its half-life of 3–6 hours is ideal for sleep without An extended-release version of trazodone branded as OLEPTRO
causing daytime drowsiness. The most common side effect is (150, 300 mg) was available, but virtually no one prescribed it.
xerostomia—a mouth that’s “dry as a bone”. Most medications
causing dry mouth do so as an anticholinergic effect. This is not It is commonly misspelled as trazadone.
the case with trazodone, which lacks anticholinergic effects.
Dosing: Titrate slowly. The dose for insomnia is 25–200 mg,
It is a preferred sleep medication for those with obstructive usually started at 50 mg, for routine or PRN use. For healthy
sleep apnea (OSA) because it does not depress respiration. It adults, the author often prescribes 150 mg tablets with
does not cause weight gain or sexual side effects. instructions to take ⅓ to 1 tab PRN which allows doses of 50, 75,
100, or 150 mg. QT prolongation may occur if the FDA max of
Many sedatives work by blocking H1 histamine receptors. 400 mg is exceeded. Antidepressant dosing is 300–600 mg,
Trazodone is sedating due to a combination of moderate H1 divided BID (as the label instructs) or taken all at HS which is
antihistamine effect plus antagonism of 5-HT2A and alpha-1 better tolerated. 150 mg may be useful for depression for some
adrenergic receptors. patients.
The tabs are

designed to be All generic trazodone tabs are scored. The 150 mg and 300 mg generics are usually multi-scored:
split, like a
wishbone.
50 mg
generic Some 300 mg
150 mg generic
100 mg generics
generic

❖ Sedation/CNS depression 18
❖ We’re depicting trazodone in a box because clinically significant kinetic interactions are unlikely, or at least not clearly TRAZODONE
defined. Trazodone is metabolized to m-chlorophenylpiperazine (mCPP) by 3A4. mCPP is then disposed of by 2D6.
mCPP is a 5-HT agonist that can be associated with dysphoria, anxiety, and (rarely) hallucinations. mCPP only
causes these effect when levels escalate quickly. Adding trazodone to a 2D6 inhibitor will rarely be an issue,
especially if trazodone is started at a low dose for sleep. Adding a 2D6 inhibitor (e.g., fluoxetine, duloxetine,
bupropion) to trazodone could cause transient anxiety/dysphoria by increasing mCPP abruptly. Note mCPP
is also a metabolite of nefazodone, the other SARI antidepressant.
❖ Trazodone is an inducer of P-glycoprotein (P-gp), which pumps P-gp substrates out of the brain—“pumpers Kinetic interactions are
gonna pump” rarely an issue

[ Nefazodone (SERZONE) ❖ Antidepressant/sleep medication
50
❖ Serotonin antagonist and
100 ]
1994 nef FAH zoe dohn / SARE zone 150
reuptake inhibitor (SARI)
$79–$173 200
“Nefarious Sear zone” – 5-HT2 antagonist
– 5-HT1A agonist 250
mg
FDA-approved for: “The nefarious Trazodone”

❖ Major Depressive Disorder (MDD) Nefazodone (Serzone) is the second serotonin antagonist and reuptake
inhibitor (SARI), developed as a less sedating derivative of trazodone.
Nefazodone was released in 1994, and voluntarily withdrawn from market
in 2004 by the original manufacturer due to decreasing sales related to
rare occurrences of severe liver damage. The risk of severe liver damage
is only 1 in every 250,000 to 300,000 patient-years.
Rare risk of
Nefazodone is currently available, but rarely prescribed. It has a relatively
“searing” the liver
mild side effect profile. Nefazodone has no anticholinergic activity, and
only mildly antihistaminic. It does not cause priapism, which is a possible
adverse event with trazodone. Nefazodone does not impair sexual
functioning and may actually enhance it.
There are case reports of nefazodone causing visual trailing, which is a

disturbance of motion perception where moving objects appear as a
series of stroboscopic images. The illusion of trailing is common with LSD
(via serotonergic mechanism), but is not associated with prescription
psychotropic medications other than nefazodone.
Dosing: The target dose for

page
depression is 200–300 mg divided Dynamic interactions:
16
BID, with max of 600 mg/day (300 mg ❖ Serotonergic
BID); Start 100 mg BID; May increase
by increments of 100–200 mg/day Kinetic interactions: SERZONE
every week; Taper gradually to stop. ❖ Nefazodone is a potent 3A4 inhibitor, raising levels of some 3A4
3A4 substrates 5-fold. Trazodone does not do this. inhibitor
❖ Nefazodone is a competitive inhibitor of 3A4, i.e., nefazodone
is itself a 3A4 substrate.
❖ Nefazodone is metabolized to m-chlorophenylpiperazine
(mCPP). Refer to the trazodone monograph for the possible
significance of mCPP.
5-HT2 serotonin
receptor antagonists
Antidepressants:
Antidepressants: ❖ Trazodone – SARI
❖ Mirtazapine – NaSSA 5-HT1A serotonin
❖ Nefazodone – SARI
❖ Amitriptyline – TCA
❖ Doxepin – TCA receptor agonists
Libido enhancer:
❖ Amoxapine – TCA
❖ Flibanserin
❖ Trimipramine – TCA
2nd gen antipsychotics (SGAs):

❖ Olanzapine
❖ Paliperidone
SGAs: 5-HT1A
❖ Pimavanserin
❖ Aripiprazole
❖ Risperidone
❖ Asenapine
partial
❖ Brexpiprazole agonists
FGAs:
❖ Cariprazine
❖ Chlorpromazine
❖ Clozapine
❖ Loxapine
❖ Lurasidone
❖ Thioridazine Anxiolytic:
❖ Quetiapine
❖ Trifluoperazine ❖ Buspirone
❖ Ziprasidone
Antidepressants:
❖ Vilazodone
❖ Vortioxetine
FGA – first generation
antipsychotic
SGA – second generation
antipsychotic

❖ Noradrenergic and Specific
#128 Mirtazapine (REMERON) Serotonergic Antidepressant
7.5
15
1996 mir TAZ ah peen / rim er ON (NaSSA)
– Alpha-2 antagonist
30
$9–$52 45
“Mr Taz zapping (R.E.M.-a’roni)” – 5-HT2 antagonist
mg
– 5-HT3 antagonist
FDA-approved for:
Used off-label for:

❖ SSRI-induced sexual dysfunction
❖ Appetite stimulation
❖ Akathisia R.E.M.-a’roni
Taz is too Eating and sleeping

depressed to well on Remeron
sleep or eat
Mirtazapine (Remeron) is a noradrenergic and specific “California Rocket Fuel” is a combination of mirtazapine with
serotonergic (5-HT) antidepressant (NaSSA) with a relatively the SNRI venlafaxine (Effexor). This combo was previously
high response rate and low dropout rate (Cipriani et al, felt to be exceptionally effective for depression due to
2018). It is an antagonist at norepinephrine (alpha-2), 5-HT2, complementary mechanisms of action. Unfortunately,
and 5-HT3 receptors. Mirtazapine is a suitable first-line mirtazapine augmentation was recently found to be no better
antidepressant option for an underweight patient who can’t than placebo for individuals who had failed antidepressant
sleep. Mirtazapine has antiemetic properties thanks to 5-HT3 monotherapy (Navarro et al, 2019).
antagonism, which is the principal mechanism of action of
ondansetron (Zofran). Mirtazapine is a third-line treatment for akathisia (behind
propranolol and clonazepam) at 15 mg. At higher doses
Remeron is a potent antihistamine, leading to sedation and mirtazapine may exacerbate akathisia. Other side effects of
appetite stimulation. About half of patients gain significant mirtazapine include dry mouth and constipation. There is a
weight. However, at higher doses, its noradrenergic risk of neutropenia, although rare.
characteristics outshine its antihistamine effects. Hence, at
high doses mirtazepine can be less sedating and cause less Remeron does not inhibit sexual functioning, and can
appetite stimulation. This is a unusual property among actually be used as an adjunct to reverse SSRI-induced
psychotropics, also noted with the TCA doxepin (Sinequan). sexual dysfunction.
Mirtazapine may work a bit faster than other antidepressants. Dosing: Start 15 mg HS; FDA maximum is 45 mg, but 60
The patient will “remember” the prescriber fondly for making mg is safe and may be more effective for depression. Note
them feel better quickly with Remeron, then not so fondly for that mirtazapine causes less somnolence and less weight
making them fat. Consider using Remeron for an acute gain at higher doses. For treatment of akathisia, do not
depressive episode, then changing to another antidepressant exceed 15 mg.
(or increasing the dose of mirtazapine) if the patient starts
gaining weight.
Refer to the next page to see
page
mirtazapine’s mechanism of action
e 55
in context of other medications.
Dynamic interactions: Kinetic interactions:

❖ Sedation/CNS depression (strong) ❖ Mirtazapine is metabolized by
❖ QT prolongation (mild) several CYP enzymes (1A2,2D6, 3A4).
❖ Serotonergic effects (weak) CLON- Kinetic interactions occur but are unlikely
❖ Alpha-2 adrenoceptor antagonist IDINE to be clinically significant.
– Do not add mirtazapine to alpha-2 agonists
such clonidine (Catapres) or guanfacine (Tenex) page
because mirtazapine will block the effect of the REMERON 18
alpha-2 agonist, potentially leading to
hypertensive rebound. Do not add an alpha-2
agonist to Remeron, because the alpha-2
agonist may be ineffective. GUANFACINE REMERON
REMERON
Multi-CYP

[ ]
Alpha-2 norepinephrine
5-HT serotonin receptor antagonists receptor agonists
2
Alpha-2
norepinephrine ❖ Clonidine (CATAPRES)
1st gen antipsychotics (FGAs): receptor antagonists ❖ Guanfacine (TENEX)
❖ Chlorpromazine ❖ Dexmedetomidine (PRECEDEX)
❖ Loxapine ❖ Lofexidine (LUCEMYRA)
❖ Thioridazine ❖ Tizanidine (ZANAFLEX)
❖ Trifluoperazine
2nd gen antipsychotics (SGAs):
❖ Aripiprazole
❖ Asenapine
❖ Brexpiprazole
❖ Cariprazine SGAs:
❖ Lurasidone ❖ Clozapine
❖ Olanzapine ❖ Paliperidone
❖ Pimavanserin ❖ Risperidone
❖ Quetiapine
❖ Ziprasidone
Antidepressants: Mirtazapine
❖ Trazodone – SARI (REMERON)
❖ Nefazodone – SARI
❖ Amitriptyline – TCA
❖ Vortioxetine
❖ Doxepin – TCA
(TRINTELLIX)
❖ Amoxapine – TCA
❖ Zofran
❖ Trimipramine – TCA
(ONDANSETRON)
Antagonistic dynamic page
Libido enhancer:
interaction —“fightin’ dynos” 5
❖ Flibanserin
5-HT antagonists
3
Alpha-2 Alpha-2
antagonist agonist
California Rocket Fuel ❖ Antidepressant

SNRI + NaSSA Venlafaxine (EFFEXOR) + Mirtazapine (REMERON) combination
e page Strategic dynamic interaction

“California Rocket Fuel”, popularized by page
48
psychiatrist Stephen Stahl, is a 48
page
combination of venlafaxine (SNRI) and 54 EFFEXOR
mirtazapine (noradrenergic and specific Depression
serotonergic antidepressant, NaSSA). REMERON Venlafaxine
This combination boosts serotonin and Mirtazapine SNRI
norepinephrine neurotransmission in
NaSSA
multiple ways. The STAR-D study found
this combination to be at least as
effective as the MAOI tranylcypromine
(Parnate). In a series of 32 patients with
refractory depression, 44% responded
at four weeks and 50% at eight weeks
(Hannan et al, 2007). The combination
was generally well tolerated, although Dosing: In a case series, most patients
This “heroic” treatment should be
12% of patients reported moderate to who responded were titrated to
prescribed with caution due to risk of
severe weight gain and, 12% reported relatively high doses of both
serotonin syndrome. California Rocket
at least moderate sedation. medications —venlafaxine ER at least
Fuel should be reserved for treatment
of refractory unipolar depression. The 225 mg/day and mirtazapine 30–45 mg
Unfortunately, larger studies were HS.
disappointing. For 112 patients who combo should not be given to patients
failed to respond to venlafaxine, with a personal or family history of
bipolar disorder due to risk of Bottom line: There appears to be
remission rate was 39% when nothing magical about this combination.
mirtazapine was added, compared to precipitating mania.
This combination is an example of two
72% when venlafaxine was changed to antidepressants with mechanisms that
the TCA imipramine (Navarro et al, A similar combination of the SNRI
duloxetine (Cymbalta) with mirtazapine are synergistic on paper but
oven options for 2019).
has been referred to as “Limerick disappointing in practice. See page 23
ression.
Rocket Fuel”. for proven options for
treatment-resistant depression.

❖ Multimodal antidepressant
#260 Vortioxetine (TRINTELLIX) ❖ Serotonin modulator 5
2013 vor tye OX e teen / trin TELL ix and stimulator (SMS) 10
$357–$462 - 5-HT reuptake inhibitor 20
“Trent’s Vortex” - 5-HT1A partial agonist mg
- 5-HT3 antagonist

❖ Major depressive disorder ❖ OCD
“Serotonergic vortex”—Vortioxetine (Trintellix) is a “serotonin modulator

and stimulator” (SMS) approved in 2013 for treatment of depression. The Trying to learn all of these
serotonergic mechanisms
original trade name was BRINTELLIX, suggestive of “Bring Intelligence”. is making me nauseous!
In 2016 the trade name was changed to Trintellix to avoid confusion with
antiplatelet drug BRILINTA (ticagrelor).
Trent ays
Although expensive, Trinetellix is a reasonable first-line option for “serotonergic f3d
Reznor vortex” of alf-life o
depression if cognitive deficits are prominent. Cognitive dysfunction (Nine Inch nausea Lo ng h
characteristic of profound depression can be referred to as Nails)
pseudodementia. Trintellix’s marketing slogan is “fight the fog of
depression”, which refers to its ability to improve pseudodementia. This is
useful because, on average, depression impairs cognition similarly to 24
hours of sleep deprivation (Mahableshwarkar et al, 2016). Vortioxetine
improves cognition, although the effect is modest, roughly equivalent to
50 mg of caffeine (Jaeger et al, 2018).
Side effects: Vortioxetine is relatively well-tolerated. At the suggested Guitar pick-

maintenance dose of 20 mg, incidence of sexual dysfunction is 44%. At shaped tablets
“Fight the fog (machine)
10 mg vortioxetine has fewer sexual side effects than SSRIs. Vortioxetine of depression” (cognitive benefits)
is more likely to cause constipation than diarrhea. Headache and
dizziness have been reported. It does not cause weight gain or prolong
QT interval. Vortioxetine appears to be among the safest psychotropic
medications in overdose, with no known deaths, although sample size is
small. Due to long half-life of 3 days, it does not cause discontinuation
symptoms with missed doses.
page
❖ Serotonergic effects (strong)
About 30% of patients experience nausea, as could be expected from a 15
❖ Antiplatelet effects
“vortex” of serotonergic mechanisms. Nausea due to antidepressants ❖ Hyponatremia
(including vortioxetine) typically resolves after a couple of weeks. Nausea
with vortioxetine is tempered by 5-HT3 antagonism. Other drugs that Kinetic interactions: Primarily
block 5-HT3 include the antiemetic ondansetron (Zofran) and the NaSSA ❖ 2D6 substrate metabolize
antidepressant mirtazapine (Remeron). Ginger also relieves nausea via ❖ 2D6 poor metabolizersd should not
the same mechanism. exceed 10 mg.
by 2D6
❖ Vortioxetine levels are doubled by
bupropion (Wellbutrin), which is a
Dosing: The starting dose is 10 mg. The suggested maintenance dose
strong 2D6 inHibitor. 2D6 substrate
for MDD is 20 mg, but staying at 10 mg may be adequate, with fewer side
effects.
5-HT1A
partial agonists
5-HT1A agonists
Serotonin (5-HT) reuptake inhibitors
Anxiolytic: SGAs:
❖ Buspirone ❖ Aripiprazole
❖ Vilazodone ❖ Asenapine Antidepressants:
❖ SSRIs
❖ Brexpiprazole ❖ Trazodone - SARI
❖ SNRIs ❖ Cariprazine ❖ Nefazodone - SARI
❖ Clozapine
❖ Some TCAs ❖ Lurasidone
Vortioxetine
(TRINTELLIX) ❖ Quetiapine Libido enhancer:
❖ Ziprasidone ❖ Flibanserin
❖ Mirtazapine
❖ Ondansetron
5-HT3 antagonists
SGA – second generation antipsychotic

[ ❖ Antidepressant ]
#278 Vilazodone (VIIBRYD) ❖ Serotonin Modulator
10
20
2011 vil AZ o dohn / VY brid and Stimulator (SMS) 40
$276–$343 - 5-HT reuptake inhibitor (SRI)
“(what that) Vile lazer done (to that) Virile hybrid” mg
- 5-HT1A partial agonist
FDA-approved for:
I’m depressed!
I’m just fine !
Vilazodone (Viibryd) is an atypical antidepressant released in 2011. It Until it goes generic, Viibryd is $300/month, and is unproven to
was described as the first serotonin partial agonist/reuptake inhibitor be superior to an SSRI for treatment of depression.
(SPARI). Alternately, it can be grouped with vortioxetine (Trintellix,
2013) as a serotonin modulator and stimulator (SMS). Vilazodone is Vilazodone needs to be taken with food for adequate
less complicated than vortioxetine in terms of mechanism of action. absorption. Only 50% of the dose is absorbed on an empty
stomach.
“Virile” Viibryd was marketed as having fewer sexual side effects than
SSRIs, though it does cause slightly more sexual dysfunction than At 40 mg/day, the most common adverse effects are diarrhea
placebo. (28% vs 9% placebo), nausea (23% vs 5% placebo), and
insomnia (6% vs 2% placebo).
Viibryd’s mechanism is a “Hybrid” an SSRI and a 5-HT1A partial
agonist. In other words, vilazodone combines the pharmacologic Dosing: Target dose is 20–40 mg QD with food. Must titrate
actions of an SSRI and the anxiolytic buspirone (Buspar). SSRIs are with 10 mg QD for the first week, as shown below. The 30-day
famously detrimental to sexual functioning. Buspirone improves starter pack contains 10 mg tab x 7 and 20 mg tab x 23. To
sexually functioning. To concoct a “Poor Man’s Viibryd”, prescribe discontinue, taper off over about a week.
buspirone with the purest SSRI, escitalopram (Lexapro).
To avoid side 10 mg QD for days 1–7 The 3 psychotropic medications that must be taken with food
effects, vilazodone for adequate absorption—the DONE-nuts.
needs to be titrated.
20 mg QD day 8 onward ❖ Vilazodone (VIIBRYD) - antidepressant
❖ Ziprasidone (GEODON) - antipsychotic
❖ Lurasidone (LATUDA) - antipsychotic
40 mg QD as early as day 15
onward (versus staying at 20 mg)
Without food, absorption is only 50%.
“Poor Man’s Viibryd” Escitalopram (Lexapro) Buspirone (Buspar) Vilazodone (Viibryd)

SSRI 5-HT1A partial agonist SRI + 5-HT1A partial agonist
An approximation of $10 $10 $300
vilazodone’s mechanism of sexual dysfunction sexual enhancement minimal sexual dysfunction
action can be achieved by
co-prescribing escitalopram and “Bus spear”
buspirone.
page
Vilazodone causes slightly more sexual dysfunction than placebo. 16
Here are some medications that can actually improve sexual functioning: ❖ Serotonergic effects (strong)
❖ Antiplatelet effects
❖ Trazodone (Desyrel) ❖ Hyponatremia
❖ Nefazodone (Serzone)
❖ Mirtazapine (Remeron) Kinetic interactions:
❖ Bupropion (Wellbutrin) ❖ 3A4 substrate (major)
❖ Buspirone (BuSpar) - anxiolytic 3A4 substrate

Serotonin Discontinuation Syndrome ]
“withdrawal” if an antidepressant is stopped abruptly
Serotonergic antidepressants are nonaddictive, but “withdrawal” (Paxil), venlafaxine (Effexor), and fluvoxamine (Luvox).
symptoms may occur upon discontinuation, especially if the Discontinuation syndrome is problematic even with
course of treatment has been > 2 months. Serotonin extended-release Effexor XR. These unpleasant side effects
discontinuation syndrome includes flu-like symptoms, irritability, can be avoided if the antidepressant is tapered to discontinue.
and unusual sensations described as “brain zaps”. Serotonin Some patients may require a long-tail taper over several
withdrawal is unpleasant but not physically dangerous. It is more months to avoid serotonin withdrawal symptoms.
likely with serotonergics of short half-life, such as paroxetine
PLACEHOLDER
Venlafaxine (Effexor) Paroxetine (Paxil)

Lightheadedness Paresthesias Lightheadedness
(pins-and-needles
tingling)
Paresthesias
Nausea
Nausea
page
48 page
44
Fatigue Irritability Fatigue Irritability
Fluvoxamine (Luvox) Linear tapering

Psychiatrists have traditionally tapered off
antidepressants linearly, for instance decreasing from 40
Lightheadedness
mg to 30 mg x 1 week, then 20 mg x 1 week, then 10 mg
x 1 week. Linear tapers are not ideal, often providing
minimal benefit over abrupt discontinuation for avoiding
Paresthesias serotonin withdrawal symptoms.
Hyperbolic tapering
Horowitz & Taylor in The Lancet Psychiatry
(June 2019) explain a more effective
approach, referred to as the hyperbolic
taper (as traditionally used to get off of
benzodiazepines). Hyperbolic tapering
involves a quick decrease to the usual
starting dose,PLACEHOLD
then a long-tail taper over a period of
months, getting down to tiny doses well below the
therapeutic range.
To get low-enough doses you need to use a
compounding pharmacy, liquid formulations, or chop
Nausea tablets into tiny fragments. Capsules are not ideal, but a
patient who understands the concept could open them,
discard an inexact fraction of the medication and
reassemble.
page
45 Among SSRIs, liquid formulations are available for
citalopram, escitalopram, fluoxetine, and sertraline (but
Fatigue Irritability not for fluvoxamine or paroxetine).
For the nitty gritty on parabolic tapering, Refer to my
favorite newsletter, The Carlat Psychiatry Report (Drs
Sazima & Aiken, Jun/Jul 2019).
Catecholamines
Neurotransmitter Abbrev Normal activity Low activity High activity Comments
Norepinephrine NE Energy, Fatigue Insomnia NE is also known as

Motivation, Inattention Anxiety noradrenaline. Stimulants
Ability to focus and Sexual dysfunction Loss of appetite increase noradrenergic
respond to stress Hypertension (NE) activity.
Seizure
Dopamine DA Ability to Anhedonia, Inattention, Sexual Mania, Euphoria, Agitation, Think pleasure, passion,
experience dysfunction, Parkinsonism, Anger, Aggression, Chemical paranoia. Drugs of abuse,
pleasure and Akathisia, Dystonia, Neuroleptic “high”, Paranoia, colloquially known as
strong emotions malignant syndrome (NMS), Auditory hallucinations, “dope”, cause euphoria by
Restless legs syndrome Hypersexuality, Insomnia, spiking DA in the nucleus
Compulsive behaviors accumbens.
Norepinephrine reuptake inhibitors (NRIs)
NRIs increase the availability of norepinephrine (NE) in the extracellular space. NE is energizing and may contribute to hypertension.
NRI Main use Comments
Atomoxetine (STRATTERA) ADHD Non-controlled substance; Less effective for ADHD than Schedule II stimulants; Rare
hepatotoxicity
Some tricyclic antidepressants (TCAs) are NRIs by mechanism. While other TCAs are anxiety-reducing, these are drive-enhancing.
Since TCAs are non-selective, their stimulating effects are tempered by antihistaminic effects. These noradrenergic TCAs could be
co-prescribed with a monoamine oxidase inhibitor (MAOI) without causing serotonin syndrome, but expect the pharmacist to flip out.
Taking serotonergic TCAs (amitriptyline, imipramine, clomipramine) with an MAOI could be catastrophic.
Tricyclic (TCA) Main use Comments
Nortriptyline (PAMELOR) Depression The major active metabolite of amitriptyline. While amitriptyline is sedating, nortriptyline (like all
Migraine prevention medications on this page) is stimulating. It is safer and better tolerated than most TCAs.
Desipramine Depression Exceptionally fatal in overdose.

(NORPRAMIN)
Maprotiline (LUDIOMIL) Depression Rarely prescribed. Tetracyclic structure. Most likely to induce seizures among available
antidepressants.
Dopamine (or dopamine/norepinephrine) reuptake inhibitors

Norepinephrine-dopamine reuptake inhibitors (NDRIs) block reuptake of NE > DA
NDRI Main use Comments
Bupropion (WELLBUTRIN) Depression Non-controlled; In addition to inhibiting reuptake of NE and DA, bupropion is a NE and DA
Smoking cessation releaser (NE > DA); Used off-label for ADHD and for SSRI associated sexual dysfunction.
Solriamfetol (SUNOSI) Daytime sleepiness Schedule IV controlled
Dopamine-norepinephrine reuptake inhibitors (DNRIs) block reuptake of DA > NE
DNRI Main use Comments
Methylphenidate (RITALIN) ADHD Schedule II controlled
Amphetamine (ADDERALL) ADHD Schedule II controlled; Also DA and NE release (DA > NE)
Lisdexamfetamine ADHD Schedule II controlled; Also DA and NE release (DA > NE); Long-acting amphetamine less
(VYVANSE) Binge-eating likely to be abused because of delayed onset of action. It is a prodrug converted to
disorder dextroamphetamine in red blood cells.
Dasotraline (trade name to Binge-eating FDA-accepted 2019 for binge-eating disorder; It failed approval for ADHD
be announced) disorder
Dopamine reuptake inhibitors (DRIs) block reuptake of DA but not NE
DRI Main use Comments
Modafinil (PROVIGIL) Daytime sleepiness Schedule IV controlled; Binds dopamine transporter weakly
Armodafinil (NUVIGIL) Daytime sleepiness Schedule IV controlled; R-enantiomer of modafinil

10 mg
#245 Atomoxetine (STRATTERA) ❖ ADHD medication 18 ]
❖ Norepinephrine 25
2002 at om OX e tine / stra TARE uh 40
reuptake inhibitor (NRI)
$90–$352 60
“Atomic Stratosphere” ❖ Non-controlled 80
100
Not an antidepressant
FDA-approved for:
❖ Attention-deficit/
hyperactivity disorder
(ADHD) ≥ 6 years old
Used off-label for:

The consequence of
❖ Cataplexy Homer’s inattention
❖ Dyslexia at the nuclear plant
Strattera straightens out your attention. Atomoxetine (Strattera) Advantages of Strattera over Schedule II stimulants for treatment
is a norepinephrine reuptake inhibitor (NRI) with the sole of ADHD:
FDA-approved indication of ADHD. Although atomoxetine is not
► not a controlled substance
properly referred to as an antidepressant, it resides in the
► no abuse potential
antidepressant chapter because its mechanism is similar to
► does not worsen tics
some antidepressants used off-label for ADHD including
► less likely to cause insomnia
bupropion (Wellbutrin) and TCAs such as desipramine,
nortriptyline, and protriptyline.
Disadvantages:
Although it has stimulating properties, atomoxetine is referred ► Less effective than stimulants—40% of patients are left
to as a “non-stimulant” to contrast it with the Schedule II ADHD with residual ADHD symptoms.
stimulants (amphetamine, methylphenidate). Atomoxetine is not ► Initial therapeutic effects are not seen until 2–4 weeks
a controlled substance. (whereas Schedule II stimulants work immediately).
► Rare risk of serious hepatic injury
By inhibiting the norepinephrine transporter (NET), atomoxetine
indirectly increases dopamine (DA) transmission in the
prefrontal cortex (which is underactive with ADHD) without Side effects of atomoxetine include headache, abdominal pain,
increasing DA in the nucleus accumbens (reward center). and nausea. It may increase BP and heart rate.
Therefore atomoxetine has no abuse potential because it does
not increase DA in the nucleus accumbens. If atomoxetine is stopped abruptly, withdrawal or other issues are
not expected.
When used to augment an SSRI, atomoxetine has the potential
to improve anxiety and depression. Atomoxetine appears to A similar “non-stimulant” option for off-label treatment of ADHD is
improve reading skills in children with dyslexia (Shaywitz et al, the stimulating antidepressant bupropion (Wellbutrin), which has
2017). fewer risks and side effects than Strattera.
Atomoxetine poses a risk of suicidality in children/adolescents Adult dosing: For ADHD the target dose is 80 mg/day, either q
with ADHD, especially during the first months of treatment. AM or divided BID; Start 40 mg AM for at least 3 days, then may
Average risk of suicidal thoughts was 0.4% with atomoxetine vs increase to maximum dose of 100 mg/day after 2–4 weeks; Use
0% with placebo, but no suicides were reported. All a lower dose with individuals who are known CYP2D6 poor
antidepressants have a similar warning about suicide, which is metabolizers. When stopping, a gradual taper is considered
another reason atomoxetine resides in this chapter. Other unnecessary.
treatments for ADHD (Adderall, Ritalin, Tenex, Intuniv, etc) do
not have this boxed warning.
Rarely, atomoxetine ❖ Hypertensive effects
may cause serious page
hepatotoxicity. 15
❖ 2D6 substrate
❖ For individuals with 2D6
poor metabolizers genotype atomoxetine
(PM), blood levels may be
increased two-fold
2D6 substrate

[ #28 Bupropion (WELLBUTRIN) ❖ Antidepressant SR:
XL:
]
❖ Norepinephrine- 100
1985 bu PRO pi on / wel BYU trin 150
dopamine reuptake 150
XL $12–$109 (#30) 300
SR $9–$76 (#60) “Boop ropin’ Well booty” inhibitor (NDRI) 200
mg
mg
❖ Non-controlled
Betty Boop is slender,

FDA-approved for: Used off-label for: and bupropion may
cause weight loss.
❖ Major depressive disorder ❖ ADHD
❖ Seasonal affective disorder ❖ Appetite suppression/
❖ Smoking cessation weight loss
(Zyban brand) ❖ SSRI-associated sexual
dysfunction
“Wellbutrin helps your mood get well”. Bupropion (Wellbutrin), the

#28 most prescribed overall medication, is a stimulating
antidepressant that enhances norepinephrine and dopamine
activity. Unlike most other modern antidepressants, it does not
enhance serotonin activity. It is used for smoking cessation
because it is stimulating like nicotine. These stimulating properties
also make it useful for ADHD. Bupropion has demonstrated
cognitive benefits. Clinicians tend to avoid prescribing it to Bupropion’s chemical structure is similar to synthetic “bath salt”
individuals with anxiety disorders, but despite its stimulating drugs. Wellbutrin is not a controlled substance and is not generally
properties, bupropion does not appear to exacerbate anxiety considered a drug of abuse. It increases dopamine levels in the
(Wiseman, 2012). prefrontal cortex (underactive in ADHD) but not in the nucleus
accumbens (reward center), at least not at standard doses.
The serotonergic antidepressants cause sexual dysfunction. However, bupropion is avoided by many prescribers in correctional
Bupropion is not serotonergic and actually improves sexual facilities because inmates have collected tabs to crush and snort as
functioning. It is used as an add-on to SSRIs to ameliorate sexual “poor man’s cocaine”.
problems (off-label).
Bupropion, an NDRI, is a much weaker inhibitor of DA and NE
Bupropion is contraindicated in patients with a current or prior reuptake than the Schedule II controlled stimulants approved for
diagnosis of bulimia or anorexia because of a higher reported ADHD like methylphenidate (Ritalin) and amphetamine (Adderall).
incidence of seizures in such patients taking Wellbutrin. Ritalin and Adderall are referred to as DNRIs because their
dopaminergic effect is stronger than their noradrenergic effect.
Wellbutrin suppresses appetite and may cause modest weight Solriamfetol (Sunosi), approved for excessive daytime sleepiness
loss. As with other stimulant-type medications, bupropion (due to narcolepsy or sleep apnea) is a Schedule IV NDRI.
decreases appetite via adrenergic and dopaminergic receptors in
REMOVE for Bupropion has anti-inflammatory properties as a tumor necrosis
the hypothalamus. The incidence of weight loss greater than 5
aDe factor (TNF) inhibitor. For treatment-resistant depression, adding
pounds is about 28%. CONTRAVE is a fixed-dose combination of
book:ment of bupropion to an SSRI is effective for patients who are overweight
bupropion with the opioid antagonist naltrexone, approved for long
obesity page or have high C-reactive protein (CRP), a marker of inflammation
term treatment of obesity.
259). (Jha MK, 2017). Otherwise, adding bupropion to an SSRI appears
to be of no benefit for treatment-resistant depressant.
If taken by individuals with bipolar disorder, bupropion appears
less likely to induce mania compared to serotonergic Risk of overdose mortality with bupropion is higher than with most
antidepressants. other modern antidepressants. Of 51,118 single-drug exposures to
bupropion reported to Poison Control, there were 3,239 major
serious outcomes and 47 deaths (Nelson & Spyker, 2017).
Dosing:
Formulation Dosing Starting dose Usual target dose Max To minimize seizure risk:
Wellbutrin XL QD 150 mg AM 300 mg AM 450 mg AM XL (ER) is the preferred formulation because seizure risk is
(bupropion ER) minimal.
Wellbutrin SR BID 100 mg BID 150 mg BID 400 mg/day = Separate doses by at least 8 hours.
200 mg BID
Wellbutrin IR TID 75 mg TID 100 mg TID 450 mg/day = Not recommended due to seizure risk, except for gastric
150 mg TID bypass patients. Separate doses by at least 6 hours.
The maximum dose of Wellbutrin XL is 450 mg, taken once

daily in the morning. This is typically accomplished with a
Bupropion may cause 300 mg plus 150 mg tablet, or by three 150’s. An expensive
seizures at high doses or 450 mg tablet branded as FORFIVO exists. It is only
with the immediate- mentioned for the cute name (4-5-0), and to aid in
release formulation. remembering the maximum dose of Wellbutrin XL.
Convulsant effect of
standard doses of
extended-release
bupropion is minimal page page
12 15
(Alper et al, 2007).
2B6 substrate 2D6 inHibitor

continued...

continued...
]
Bupropion (Wellbutrin)
page page
❖ CNS stimulation
❖ Hypertensive effects
❖ 2D6 inHibitor (strong) 2B6 substrate 2D6 inHibitor (strong)
❖ 2B6 substrate
❖ Active metabolite hydroxy-bupropion
is a 2D6 substrate (see below)
bupropion hydroxy-bupropion 2D6 poor metabolizers (10%

active drug active metabolite with of population) may have
more side effects more side effects from
bupropion, including
increased risk of seizure.
page
15
2B6 poor me!

2D6
inactive
metabolite
2B6 substrate 2D6 substrate
Solriamfetol (SUNOSI) ❖ Norepinephrine-dopamine 75

2019
SOL ri AM fe tol / su NO see reuptake inhibitor (NDRI) 150
$657–$714
❖ Schedule IV
“Sun nosey with Solar feet” mg
Solriamfetol (Sunosi) is a new wakefulness An advantage over bupropion is that

Not an antidepressant
promoting medication that lasts for 9 hours. solriamfetol is free from significant kinetic
It is stimulating but not considered a drug/drug interactions.
“stimulant”. It is a norepinephrine and weak
FDA-approved for: dopamine reuptake inhibitor. Sunosi could The two other wakefulness promoters
❖ Excessive daytime sleepiness due to: be conceptualized as an atypical approved for narcolepsy/sleep apnea are
- Narcolepsy antidepressant with a mechanism similar modafinil (Provigil) and armodafinil (Nuvigil),
- Obstructive sleep apnea (OSA) bupropion (Wellbutrin). However, which are also Schedule IV. For context,
solriamfetol is not approved for depression, methylphenidate (Ritalin) and amphetamine
s is and clinical trials did not include psychiatric (Adderall) are more strictly regulated as
ook patients. About 1 in 25 subjects treated for Schedule II controlled substances, and are
wo narcolepsy/sleep apnea had psychiatric referred to as stimulants.
side effects such as irritability and anxiety.
ts. Dosing: Start 75 mg q AM. Dose may be
Solriamfetol is a Schedule IV controlled increased to 150 mg after 3 days based on
substance. By comparison, bupropion is efficacy and tolerability. Maximum dose is
non-controlled but does have potential for 150 mg/day.
abuse at high doses.
Subjects who abused drugs reported “drug

page
liking” similar to the appetite-suppressing 18
stimulant phentermine (Adipex) when
❖ Dopaminergic
solriamfetol was taken at supratherapeutic
❖ Hypertensive
dose. Phentermine is also Schedule IV.
Other effects include nausea and appetite ❖ None significant
suppression. It may increase blood - “in a bubble”
pressure and heart rate.
SUNOSI

Chapter 5 – Monoamine Oxidase Inhibitors
[ Chapter 9 – Monoamine Oxidase Inhibitors ]
Monoamine Oxidase Inhibitors (MAOIs) ❖ Antidepressants

❖ Parkinson’s
“Chairman Mao” disease medications
Monoamine Oxidase (MAO) is the enzyme that breaks down the monoamine neurotransmitters:
Serotonin (5-HT) Norepinephrine (NE) Dopamine (DA)
MAOI Use Year Cost/mo 5-HT NE DA MAO Dietary Wt Sed- Anti- Rever-
select- tyramine gain ation cholin sible?
ivity * risk ergic
Tranylcypromine (PARNATE) MDD 1961 $240 +++ +++ +++ A&B ++++ - low no no
Isocarboxazid (MARPLAN) MDD 1959 $780 +++ +++ +++ A&B ++++ - low no no
Phenelzine (NARDIL) MDD 1961 $43 +++ +++ +++ A&B ++++ ++ low no no
Selegiline transdermal
MDD 2006 $1650 ++ ++ +++ (A) & B ++ loss low no no
(EMSAM)
Selegiline PO (ELDEPRYL) Parkinson’s 1989 $26 ++ ++ +++ B + loss low no no
Rasagiline (AZILECT) Parkinson’s 2006 $270 ++ ++ +++ B + loss low no no
Safinamide (XADAGO) Parkinson’s 2017 $780 + + +++ B +/- - low no yes
MDD – Major Depressive Disorder; 5-HT – serotonergic; NE – noradrenergic; DA – dopaminergic
*Selectivity is dose dependent. Above recommended doses, selective MAO-B inhibitors can also inhibit MAO-A.
Monoamine Oxidase Inhibitors (MAOIs) are among the oldest treatment of depression. Selective MAOIs available in the US
antidepressants, available since 1959. The first MAOI block MAO-B for treatment of Parkinson’s disease, and only one
(isocarboxazid) entered the market two years after the oldest of these is reversible—safinamide (Xadago).
TCA (imipramine, 1957). MAOIs are highly effective for
treatment of depression, including cases resistant to modern Due to risk of serotonin syndrome, all serotonergic medications
antidepressants. MAOIs are particularly effective for “atypical are contraindicated with MAOIs. A washout period is necessary
depression”, characterized by increased appetite, excessive when switching to an MAOI, dependent on the half-life of the
sleep, fatigue, sensitivity to rejection, and moods that are highly serotonergic agent (SSRI, SNRI, etc). As a rule of thumb, a drug
reactive to circumstances. clears the body after 5 half-lives. Wait at least 5 weeks after
stopping fluoxetine (Prozac), which has a long half-life of 1
“TIPS” – the MAOIs approved for depression: week. For the other SSRIs, wait two weeks after stopping the
► Tranylcypromine (PARNATE) SSRI to start the MAOI.
► Isocarboxazid (MARPLAN)
► Phenelzine (NARDIL) A few antidepressants are safe to pair with MAOIs, including
► Selegiline transdermal (EMSAM) bupropion, trazodone, and those TCAs with minimal
serotonergic activity such as nortriptyline, desipramine,
The three oral MAOIs approved for treatment of depression in maprotiline and trimipramine (Thomas and Shin, 2015)—
the U.S. are irreversible inhibitors of both MAO-A and MAO-B. “Non-Disparaged MOAI Tagalongs”.
Strict dietary restrictions are necessary to avoid the “cheese
effect” of hypertensive crisis described in the isocarboxazid It is recommended that MAOIs be discontinued at least 10 days
monograph, which is also applicable to phenelzine and prior to elective surgery to avoid potentially fatal interactions with
tranylcypromine. Half-life for these MAOIs is irrelevant because anesthetic agents.
inhibition of MAO is irreversible, with effect continuing for up to
two weeks after the medication is discontinued.
In a simplified sense, MAO-A is more responsible for breaking page

Very serious dynamic 5
down 5-HT and NE, while MAO-B is more specific for DA. For interactions with
treatment of Parkinson's disease, MAO-B needs to be blocked. serotonergic
For treatment of depression, MAO-A needs to be blocked (to medications and
tyramine-rich foods
enhance 5-HT and NE), and blocking MAO-B may also be
helpful (to enhance DA). In some countries, safer reversible
inhibitors of monoamine oxidase A (RIMAs) are available for
PLACEHOLDER
Isocarboxazid (MARPLAN) ❖ Monoamine Oxidase Inhibitor ]
1959 – Irreversible MAOI 10
$262–$286 eye so kar BOX a zid / MAR plan mg
– MAO-A & MAO-B
“Ice box Mars plan” – 5-HT > NE > DA
FDA-approved for: “TIP”

❖ Depression
The following information applies to all of the

non-selective MAO inhibitors used for
To Mars is the plan,
treatment of depression —”TIP” to escape depression
► Tranylcypromine (PARNATE)
► Isocarboxazid (MARPLAN)
► Phenelzine (NARDIL)
Patients taking MAOIs (with the exception of the low

strength EMSAM patch) must avoid tyramine-rich Must not eat:
foods. The list of forbidden foods is long. Failure to
adhere to a low tyramine diet may lead to what was
originally called the “cheese effect”, a potentially fatal aged cheese
hypertensive crisis.
Tyramine = “Tire Rim”

cured meats
fava beans
Tyramine is broken down by monoamine oxidase soy sauce,

(MAO), which by definition MAOIs block. Without sauerkraut
functioning MAO enzymes, tyramine accumulates and
raises blood pressure. wine
The “tire rim” mnemonic can keep you from confusing Unpasteurized beer
tyramine with the amino acid tyrosine. (Bottled beer is usually
OK, draught beer often
Note that if a patient is taking an oral MAOI for not OK).
depression, phenelzine (Nardil) is the most likely
prescription. Isocarboxazid (Marplan) scripts are
exceedingly rare—it is the least prescribed of all
antidepressants.
Dosing: Target dose is 20–60 mg/day divided BID–QID:

Start 10 mg BID; May increase by 10 mg/day every 2–4
days; Max is 60 mg/day (20 mg TID or 30 mg BID);
Taper gradually to stop.
Tyramine accumulates,
causing hypertensive
crisis.
page
Dynamic interactions
18
❖ Serotonergic (strong) - contraindicated
with other serotonergics
❖ Blocks tyramine breakdown MAOI
(food interaction)
❖ Anticholinergic (mild)
Kinetic interactions
❖ None significant– “in a bubble”

[ ]
1961
Phenelzine (NARDIL) ❖ Monoamine Oxidase Inhibitor
15
– Irreversible MAOI
$25–$86 FEN el zeen / NAR dil mg
– MAO-A & MAO-B
“Gnarly Funnel” – 5-HT > NE > DA
FDA-approved for: Phenelzine is the least expensive ($43 monthly) and most commonly prescribed of
❖ Depression the oral MAOIs for depression, although prescriptions for any MAOI are rare due to
risk of serotonin syndrome and hypertensive crisis. Dietary tyramine must be
restricted, as shown in the isocarboxazid (Marplan) monograph on the preceding
page.
How could I be Phenelzine inhibits MAO-A and MAO-B almost equally, with slight preference for
depressed while MAO-A. It is metabolized to phenylethylamine (PEA), which produces effects similar
wearing this (g)narly to a short acting amphetamine.
phunnel?
“Does this phunnel make me look phat?”– Unlike the other MAOIs, phenelzine may
cause weight gain.
Risk of mortality in single-drug overdose with MAOIs is similar to that of tricyclics. Of

392 single-drug exposures to phenelzine reported to Poison Control, there were 2
deaths (Nelson & Spyker, 2017).
Dosing: Start 15 mg TID and rapidly increase to 30 mg TID (which is the maximum
dose of 90 mg/day) then decrease slowly over several weeks to the lowest effective
dose. Use lower dose with elderly patients. Taper slowly to stop.
Dynamic interactions page

phenylethylamine MAOI 18
(metabolite of ❖ Serotonergic (strong) – contraindicated
phenelzine) with other serotonergics
❖ Blocks tyramine breakdown
(food interaction)
methamphetamine ❖ Hypertensive effects
❖ None significant
– “in a bubble”
❖ Monoamine Oxidase Inhibitor

1961
Tranylcypromine (PARNATE) – Irreversible MAOI
tran yl CY pro meen / PAR nate – MAO-A & MAO-B 10
$187–$588 mg
– DA & NE releaser
racemic mix
“(Mao’s) Trans prom Partner” – 5-HT > NE > DA
FDA-approved for:
❖ Depression
Tranylcypromine was released in 1961, the same year as

phenelzine. Tranylcypromine has a short elimination half-life of 2.5
hours. The half-life is irrelevant, because inhibition of MAO is
irreversible and the effect continues for up to 2 weeks after the
medication is discontinued.
Dietary tyramine restriction is necessary to avoid hypertensive crisis,
as depicted in the isocarboxazid (Marplan) monograph.
Risk of serious outcome from a single-drug overdose of
tranylcypromine is about 40%, which is one of the highest morbidity
It don’t Short half-life but rate among antidepressants. There was 1 death out of 330
matter that this is irrelevant single-drug overdoses (Nelson & Spyker, 2017).
you’re short. because inhibition
of MAO is Dosing: Start: 10 mg TID; After 2 weeks may increase by 10 mg/day
irreversible q 1–3 weeks; Max is 60 mg/day (20 mg TID); Taper gradually to stop.
Dynamic interactions
page
❖ Serotonergic (strong) MAOI 18
– contraindicated
(food interaction) Kinetic interactions
❖ Anticholinergic (mild) ❖ None significant
❖ Hypertensive effects – “in a bubble”

]
Selegiline transdermal (EMSAM) ❖ Monoamine Oxidase
Inhibitor
6
9
2006 se LE ji leen / EM sam
$1,631–$1,925 – MAO-B > MAO-A 12
“YosEmite Sam Seals gills” – DA > NE > 5-HT mg
FDA-approved for:
❖ Depression
Oral selegiline, at doses used for treatment of

Parkinson’s disease, is a selective inhibitor of MAO-B,
which breaks down dopamine (DA). Oral selegiline at
recommended doses does not inhibit MAO-A, making it
ineffective for depression. It is necessary to block
MAO-A to keep norepinephrine and serotonin from
being broken down (oxidized).
The transdermal formulation of selegiline (EMSAM)

allows the drug to achieve higher levels in the brain
(where MAO-A breaks down serotonin) than in the gut
(where MAO-A breaks down dietary tyramine). Chairman Mao
patch being used
Transdermal selegiline is the only MAOI available in the to seal his gills
US for the treatment of depression that does not require
dietary tyramine restriction at the clinically effective daily
dose of 6 mg However, at higher doses, dietary
restriction of tyramine is recommended.
Metabolism of selegiline produces a tiny amount of Dosing: Start with 6 mg patch QD; may
methamphetamine, which blocks dopamine reuptake increase strength by 3 mg QD in 2-week
and may contribute to the antidepressant benefit. The intervals; Max is 12 mg patch/24 hours.
methamphetamine metabolite may produce a false Dietary tyramine restriction is
positive on drug screens. Selegiline is not a controlled recommended above 6 mg. Taper to
substance. discontinue.
Selegiline is associated with a slight weight loss, which

would be expected for something that is metabolized to
methamphetamine.
$41–
Selegiline (ELDEPRYL) selegiline methamphetamine
$150 se LE ji leen / ELD e pril
H
“Elderly Seal’s gills”
page
gills Dynamic interactions 12
❖ Serotonergic (strong) – contraindicated
(food interaction)
Oral selegiline, approved for Parkinson’s
❖ 2B6 substrate
disease, does not inhibit MAO-A to the
extent needed for antidepressant effect. 2B6 substrate (sock)

Chapter 10 – Other Medications for Depression
[ Chapter 6 – Other Medications for Depression ]
2010
$172–$225 Deplin
L-Methylfolate (DEPLIN) 7.5
❖ “Medical food” for depression
$30–$45 MethylPro meth il FO late / DEP lin 15
❖ Biologically active form of folate mg
$18–$25 other generics
$2–$12 folic acid
“Deep in My foliage”
FDA-approved for: Used off-label for: This “L” is for you,

❖ Augmentation of an antidepressant ❖ MTHFR deficiency poor M*TH**F***R!
Folate (Vitamin B9), also known as folic acid, is necessary for synthesis of Garbanzo beans
neurotransmitters including dopamine, norepinephrine, and serotonin. (chickpeas)
L-methylfolate is the active form of folate that crosses the blood-brain
barrier with no need for enzymatic conversion.
About 1 in 3 individuals have difficulty converting folate to methylfolate due
to a deficiency of the MTHFR enzyme (methylene tetrahydrofolate
reductase). Among individuals with depression, about 60% have MTHFR
mutations (Mischoulon et al, 2012). The 10% of individuals with 2 copies of
the C677T MTHFR allele—“poor M*TH**F***Rs"—should be taking
L-methylfolate.
Deplin is the brand of L-methylfolate marketed to physicians as a

prescription-only “medical food” for depression. Other brands of
L-methylfolate are now available without a prescription, though they are not
FDA-regulated. There is no reason to believe Deplin is of higher quality than
MethylPro, a reputable OTC version of L-methylfolate. Insurance rarely
covers either brand, so the expense is borne out-of-pocket. Deplin costs 5x Now let’s talk about actual folate deficiency. About 20% of
more than MethylPro and 50x more than generic folic acid. depressed patients have low folate levels. Individuals with
low folate do not respond as well to antidepressants.
L-methylfolate is intended to be an augmenting agent (add-on) to an Patients with normal serum folic acid levels may still
antidepressant) in individuals who are not necessarily folate deficient. Refer respond to treatment with folate because levels in the CNS
to the “steps” advertisement below. As an augmenting agent, the number may be low.
needed to treat with L-methylfolate was 6 (Papakostas et al, 2012).
Folate deficiency leads to an elevation of homocysteine, a
Now that affordable brands are available, L-methylfolate is recommended nonessential amino acid. Homocysteine is an NMDA
over folic acid because it is more likely to be effective. There are no receptor agonist and oxidant, i.e., something damaging to
head-to-head trials of L-methylfolate vs folic acid, but results of human cells An elevated homocysteine level is associated
L-methylfolate trials were more impressive. with cardiovascular disease.
Obese patients are more likely to respond to L-methylfolate, possibly No homo!
because obesity causes inflammation, which impedes serotonin production
(Shelton et al, 2015; The Carlat Psychiatry Report, Aug 2019). Generic folic
acid may be adequate for non-obese individuals with normal MTHFR
genes.
Folic acid deficiency during pregnancy leads to neural tube
Supplementation of an antidepressant (fluoxetine specifically) with generic defects.
folic acid 0.5 mg/day demonstrated modest benefit at 10 weeks of
treatment (Coppen & Bailey, 2000). The effect size was small, and some Dosing: For Deplin (expensive, prescription) or MethylPro
studies have not shown benefit from folate augmentation of (affordable, OTC) start 7.5 mg QD and increase to 15 mg,
antidepressants. Regardless, adding folate (vitamin B9) is a benign which is the target and maximum dose. MethylPro is
intervention—folate is “Vitamin Be-nign”. available in 2.5, 5, 7.5, 10, 15 mg capsules. For generic
folic acid (cheap) to augment an antidepressant you would
Some studies combined folate (vitamin B9) with vitamins B6 and B12, give 0.5–5 mg QD. To treat folic acid deficiency, use 1 mg
Count by 3’s—B6, B9, B12 = pyridoxine, folate, and cobalamin, daily of generic folic acid plus a multivitamin. For a patient
respectively. Folic acid (B9) supplements can mask megaloblastic anemia who responds to L-methylfolate for depression, consider
that would otherwise lead to a diagnosis of vitamin B12 (cobalamin) changing to folic acid 3 mg (cheaper) at 6 months and see
deficiency. If untreated, B12 deficiency leads to peripheral neuropathy. if recovery is maintained (Chris Aiken, MD, The Carlat
Psychiatry Report, Aug 2019).
EnLyte is another prescription-only medical food containing 7 mg of
L-methylfolate 7 mg and other “brain-ready, pre-metabolized coenzymes
and cofactors”. It costs about $170 monthly. FOLINIC acid is a similar supplement, which may be
better (than L-methylfolate) for individuals who do not have
Folate is present in fresh green vegetables and other sources listed below. MTHFR mutations. Folinic acid has advantages over the
Garbanzo beans (chickpeas) contains an abundance of folate. Cooking other forms of folate for those with folate receptor-alpha
reduces folate content by as much as 90%. autoantibodies.
From a Deplin advertisement: Top sources of folate in food: page

#1 Garbanzo beans (chickpeas) Dynamic interactions: 18
#2 Liver ❖ None significant
#3 Pinto beans
#4 Lentils Kinetic interactions:
#5 Spinach ❖ Valproic acid and other
#6 Asparagus anticonvulsants can deplete
#7 Avocado folate levels. This is unlikely
#8 Beets to be relevant for medication
#9 Black eyed peas management involving Deplin.
#10 Broccoli

]
1970
Ketamine (KETALAR) ❖ NMDA receptor antagonist
$5–$20
KET a meen / KET a lar ❖ Dissociative anaesthetic
“Cat (is) taller (than) Cat tamer” ❖ DEA Schedule III
FDA-approved for:
❖ General anesthesia The presumed antidepressant mechanism of
ketamine is NMDA receptor antagonism,
Used off-label for: which reduces the activity of glutamate, the
❖ Treatment-resistant depression brain’s most important excitatory
❖ Agitation in emergency department neurotransmitter. The mechanism appears to
or ambulance somehow involve the endogenous opioid
❖ Refractory chronic pain system (endorphins). Ketamine is not an
opioid, but when naltrexone (opioid
Ketamine (Ketalar) is a dissociative antagonist) was administered prior to a
anaesthetic that has shown rapid efficacy in ketamine infusion, ketamine was ineffective
relieving refractory depression following for depression (Williams NR et al, 2018).
intravenous infusion. It is not FDA-approved Naltrexone does not block the dissociative
for this indication but is increasingly utilized effect of ketamine. Benzodiazepines and
as an alternative to electroconvulsive therapy Z-drugs (zolpidem, etc) can attenuate the
(ECT). antidepressant effect of ketamine, so they
should be washed out prior to treatment.
Ketamine’s rapid antidepressant effect has
been demonstrated by over 20 controlled Originally synthesized from phencyclidine
trials. The effects of ketamine on depression (PCP, “angel dust”), ketamine is a Schedule
are apparent as early as 40 minutes after III controlled substance with potential for
infusion and are maintained for at least 2–3 abuse and psychological dependence.
days. Within two hours of ketamine Ketamine has a half-life of 10–15 minutes,
treatment, patients are generally lucid and which is shorter than other dissociatives
not sedated. By four hours, there appears to such as PCP and dextromethorphan. The
be continued improvement in positive total dissociative experience should last no
thinking and hopefulness. By one week after longer than 1–2 hours.
a single infusion, depressive symptoms are
likely to recur to some extent. Recreational users of “special K” can snort, Ketamine is an alternative to:
inject, or take it orally. The desired ► Electroconvulsive therapy (ECT)
Side effects of ketamine include dissociation, recreational effects include euphoria, ► Transcranial magnetic stimulation
visual hallucinations, sialorrhea derealization, visual hallucinations, and (TMS)
(hypersalivation), nausea, vertigo, increasing awareness of sound and color. A ► Deep brain stimulation (DBS)
tachycardia, and elevated blood pressure. bad experience from too much ketamine is
Serious risks include increased intracranial referred to as falling into a “K-hole”, where
and intraocular pressure. Unlike other the user feels trapped in a frozen state, as if
general anesthetics, ketamine does not stuck in a hole peering out, detached from
suppress respiratory drive, which makes it their physical presence. While stuck in a
great for anesthesia in third world countries. “K-hole”, the user can, for instance, think
However, there is a possibility of about moving their arm and then see an arm
laryngospasm [ luh RING go spaz um ], moving in front of them, but the association
sudden involuntary contraction of vocal cords between the thought and the movement
that can be fatal via suffocation. Catastrophic does not register.
outcomes are rare when ketamine is used at
subanesthetic antidepressant doses, but the Risks with long-term maintenance treatment
patient needs to be monitored with of depression with ketamine are unknown.
emergency services available. Studies in mice suggest the potential for
irreversible cognitive decline with chronic use
Ketamine has a black box warning of a 12% (Ding et al, 2016).
risk of emergence reactions (as in emerging
from general anesthesia) varying in severity Dosing: For treatment-resistant depression,
from pleasant dream-like states to the optimal ketamine protocol has not been
hallucinations, or delirium. This may manifest clearly established. The most common
as confusion, excitement, or irrational frequency is twice weekly infusions for up to
behavior. The duration of an emergence 4 weeks using a relatively low dose of 0.5
reaction is usually a few hours, with mg/kg administered over 40 minutes.
recurrences up to 24 hours post-op in some Compare this to the anesthetic dose of 1–4.5 Physical harm is subjectively applied, as we
cases, but with no residual psychological mg/kg—also the IV/IM dose used for are not comparing apples to apples. Since
effects. usually agitation in the ambulance or emergency tobacco is responsible for 20% of deaths in
department. the US, one could reasonably argue its
relative harm is understated.
page
Dynamic interactions: Kinetic interaction: 12
❖ Naltrexone can block the
antidepressant effect of ketamine.
❖ Benzodiazepines and Z-drugs
make ketamine less effective for ketamine
depression.
❖ Hypertension
PCP Ketamine ❖ Sedation 2B6 substrate
“angel dust” “special K”

[ ]
2019
Esketamine (SPRAVATO) ❖ NMDA receptor antagonist 56
$5,000/first mo es KET a meen / sprah VAH toe ❖ Dissociative drug 84
mg
“Scat tamer – Spray gato” ❖ DEA Schedule III
FDA-approved for: Esketamine nasal spray (Spravato) is the 8 to 17% of patients have elevated blood
❖ Treatment-resistant depression first novel antidepressant approved (2019) pressure > 40 mmHg or diastolic BP
in over three decades. Esketamine is elevation > 20 mmHg. 3% of patients will
indicated for treatment-resistant depression have systolic blood pressure elevation to
(TRD) in conjunction with an oral about 180 mmHg . Blood pressure
antidepressant. It was developed for elevation peaks 40 minutes after
commercial purposes because the patent administration and lasts about 4 hours. Due
for ketamine was long expired. to this risk, esketamine is contraindicated
with arteriovenous malformation or
As the name would suggest, esketamine is aneurysmal vascular disease (including
the S-enantiomer of ketamine, which has aortic, intracranial, and peripheral arterial
been increasingly used off-label for TRD. vessels). Stimulants such as Adderall or
Like racemic ketamine, esketamine is a Ritalin could increase the risk of BP
Schedule III controlled substance. elevation.
It is unknown whether the antidepressant With an 18% drug-placebo separation in
action of the S-enantiomer is superior, relapse rates, esketamine’s long-term
inferior, or equal to racemic ketamine. The benefits appear comparable to those seen
opposite enantiomer, R-ketamine with augmentation of an antidepressant
(arketamine) is also under investigation. with an atypical antipsychotic (Borges et al,
S-ketamine is more responsible for the 2014; The Carlat Psychiatry Report, Jun/Jul
anesthetic effect, while R-ketamine is more 2019). Long term use past one year has not
responsible for hallucinations because it is been tested for the potential of cognitive
3–4 times more potent at blocking NMDA impairment.
receptors than R-ketamine. S-ketamine
appears to be less effective than Esketamine prescribers must register
R-ketamine at reducing depressive through a Risk Evaluation and Mitigation
symptoms (Stahl, 2015) but may be less Strategy (REMS) program, and the DEA will
likely to cause psychoactive side effects. do an in-person inspection of the provider’s
office.
The induction phase for Spravato is twice
weekly over 4 weeks, then weekly x 4, then For cost savings, generic ketamine can be
every 1–2 weeks for maintenance put into an atomizer for intranasal delivery
treatment. It costs about $625 per dose. as off-label option for 1% of the cost of
Ketamine (racemic) esketamine.
Spravato is less convenient than would be
expected for a nasal spray. It must be given The two available strengths of esketamine
in the presence of a health care provider are 56 mg and 84 mg. The 56 mg dose is
Es and should never be dispensed to the supplied in two 28 mg vials, and the 84 mg
patient for home use. The patient must be dose in three 28 mg vials. Each vial is
observed for 2 hours and cannot drive for delivered by 2 sprays, one in each nostril.
the rest of the day. Due to the risk of Therefore 56 mg is delivered by 4 total
vomiting, the patient must fast for 2 hours sprays, and 84 mg by 6 total sprays. Wait 5
esketamine arketamine minutes between each 28 mg vial. Check
(no fluid for 30 minutes) prior to treatment.
(S) enantiomer (R) enantiomer BP before each dose and 40 minutes
Most of the therapeutic effect of esketamine afterwards. Weigh risk/benefit if
is apparent by 24 hours after the first dose. pre-treatment BP is > 140/90.
Up to 75% of patients experience
Es Dosing: The first dose should be 56 mg.
dissociation with Spravato. None of the
clinical trials were controlled for the Subsequent doses can be either 56 mg or
dramatic “high” esketamine produces. It 84 mg, depending on response and
more of an more of a was well-tolerated, with only 5% of subjects tolerability. Treatment is 2x/wk for first 4
anaesthetic hallucinogen dropping out within one year due to side weeks (8 treatments), then once weekly for
effects. the next 4 weeks (4 treatments), then every
1–2 weeks thereafter.
NMDA receptor
NMDA receptors are involved in ❖ Naltrexone can block the
binding site for: antidepressant effect of ketamine.
❖ memantine synaptic plasticity and memory.
glutamate in ❖ Benzodiazepines and Z-drugs
❖ amantadine glycine in Lightly blocking the receptor is
glutamate make ketamine less effective.
❖ ketamine glycine neuroprotective. However, if the
binding site ❖ Hypertension
❖ PCP binding site receptor is blocked completely,
neurons cannot function. The street ❖ Sedation
drug PCP, aka “angel dust”, strongly
blocks NMDA receptors, causing Kinetic interaction: page
extracellular psychosis. Ketamine is weaker than 12
PCP, but strong enough to cause
anaesthesia and dissociation.
intracellular Memantine (Namenda) is an esketamine
Alzheimer’s medication that blocks
the NMDA receptor just enough to
Ca2+ channel improve memory. 2B6 substrate

]
2019
Brexanolone (ZULRESSO) ❖ Neurosteroid for
$34,000
brex AN oh lone / zul RESS o postpartum depression
“Zulu resigns (to) Brex (feed) alone”
Allopregnanolone
FDA-approved for:
❖ Postpartum depression
In 2019, the first two novel antidepressants in over three

decades were approved—esketamine (Spravato) and
brexanolone (Zulresso). Brexanolone is the first
medication FDA-approved for postpartum depression.
Brexanolone is a synthetic version of allopregnanolone
(“all pregnant and alone”), an endogenous neurosteroid
made from progesterone that is increased during
pregnancy.
It is theorized that withdrawal from allopregnanolone

after childbirth can lead to postpartum depression and
anxiety. Conventional antidepressants are known to
raise levels of endogenous allopregnanolone.
Brexanolone acts at the GABA-A receptor complex, as

do several classes of drugs that calm down the central
nervous system, including benzodiazepines and
barbiturates (see below). Unsurprisingly for something
that works through the GABA-A receptor, brexanolone
has anxiolytic, sedative, and anticonvulsant properties.
Brexanolone is insultingly expensive and must be given

as an IV infusion over 60 hours! The cost of the drug is
$34,000 not including the cost of hospitalization.
The advantage of brexanolone is speed of symptom

improvement. Roughly 75% of patients reported at least
a 50% reduction in depressive symptoms. Remission of Dosing: Given intravenously over 60 hours; Start 30
depression may occur within a couple of days. 94% of mcg/kg/hr for 4 hours, then 60 mcg/kg/hr for 20 hours
patients who responded maintained their response at then 90 mcg/kg/hr for 28 hours, then 60 mcg/kg/hr for 4
one month. Not bad! hours, then 30 mcg/kg/hr for 4 hours = 60 hours total
It appears to be safe with breastfeeding—“Brex (feed)

alone”. The infant receives only 1–2% of maternal
weight-adjusted dose. Excessive sedation is possible,
so another adult should be present during treatment page
18
when mom has the baby. So you’re technically not
supposed to brexfeed alone on brexanolone. Dynamic interactions:
❖ Sedation / CNS depression
Oral brexanolone is in development.
Allopregnanolone balance may play a role in other ❖ No relevant kinetic
interactions - “in a bubble”
psychiatric disorders. Low levels are associated with
depression and PTSD. High levels are also associated ZULRESSO
with depression, as well as anxiety and irritability
(Bäckström et al, 2014).
GABA(A) receptor
Site for alcohol and GABA receptor ligands

GABA binding site Cl-
anaesthetics, e.g., propofol
Binding site for benzos and GABA(A) agonists GABA(B) agonists
Z-drugs (Ambien, etc) ❖ Alcohol ❖ Baclofen (antispasmodic)
Site for barbiturates
❖ Ativan, alprazolam, etc (benzos) ❖ GHB (Xyrem)
and meprobamate
Site for neurosteroids ❖ Amytal, etc (barbiturates)
like allopregnanolone extracellular ❖ Ambien, etc (Z-drugs)
GABA(A) ❖ Anesthetics
ligand- Note that gabapentin
gated ❖ Allopregnanolone (brexanolone)
(Neurontin) and pregabalin
ion
channel (Lyrica) have chemical
intracellular GABA(A) antagonist structures similar to GABA
❖ Flumazenil (Romazicon) at the but they do not bind GABA
benzodiazepine site receptors.
Chloride ions flow into the
Cl- neuron, calming it down

300
[ St John’s Wort (SJW)
350
450
]
SJW ❖ Herbal 500
$7–$35 Hypericum perforatum antidepressant 700
900
hypericin hyperforin St John’s “wart” 1000
mg
FDA-approved for: Possibly effective for:

❖ N/A ❖ Menopausal symptoms
❖ Social anxiety
Effective for: ❖ Somatoform disorders
❖ Mild depression
St John’s wort (SJW) is an OTC herbal antidepressant. SJW

has demonstrated superiority to placebo for treatment of
mild depression. It is considered ineffective for moderate to
severe depression. Most psychiatrists do not recommend it,
although psychiatrists are rarely consulted for mild
depression.
The only advantage of SJW is obtainability without a

doctor’s order. The main drawback is potential for drug-drug
interactions.
As with any herbal supplement, St John’s wort contains

many chemicals. It is not entirely clear which are
responsible for the antidepressant effect, but hypericin
(about 0.3% of the extract) is likely involved. The primary
phytochemical constituent of St John's wort is hyperforin
(about 3%). The composition of various chemicals may vary
greatly between brands.
The likely mechanism of SJW is serotonin reuptake

inhibition, like many prescription antidepressants. It also
inhibits reuptake of norepinephrine and dopamine. It also
has potent affinity for the adenosine, serotonin 5HT1,
benzodiazepine and γ-aminobutyric acid (GABA) receptors.
Plus, it may weakly inhibit monoamine oxidase. Lots of
chemicals, lots of pharmacologic effects.
There is no FDA-approved indication for SJW. In 2000, the

FDA issued a warning that SJW can reduce the serum
levels of many drugs through inDuction of CYP450
enzymes.
Side effects of SJW are generally mild and may include

insomnia, vivid dreams, irritability and GI discomfort. At high Hypericin - “Hyper rice”
doses it may cause phototoxic skin reactions. It is not
recommended to combine SJW with antidepressants due to Hypericin may be the main chemical in St John’s
risk of serotonin syndrome. wort responsible for the antidepressant effect.
Hypericin is metabolized through the liver with half-life of

about 25 hours. (There’s)
HYPER RICE IN
St. John’s wort is so named because it blooms near June (my sushi)
24th, the birthday of John the Baptist. “Wort” is an old
English word for plant.
Dosing: 250 mg BID to 600 mg TID (Typically 300 mg TID).

Products are generally standardized to contain 0.1–0.3%
hypericin and/or 3–6% hyperforin
Dynamic interactions: page page page

10 13 16
❖ Serotonergic
❖ Photosensitivity
❖ 1A2 inducer (major)
❖ 2C9 inducer (minor)
❖ 3A4 inducer (major)
❖ P-glycoprotein inducer
(increased removal of P-gp
substrates from the brain) 1A2 inDucer 2C9 inDucer (weak) 3A4 inDucer

Discount code for the big book

of 270 medication mascots,
Cafer’s Psychopharmacology:
EMBIGGEN

- Chapter 7 – Other Serotonergics
267
2015
Flibanserin (ADDYI) ❖ Norepinephrine-dopamine
disinhibitor (NDDI) 100
$99–$427
fli BAN se rin / ADD ee ❖ 5-HT1A agonist mg
“Flibbin’ Addicted (to love)” ❖ 5-HT2A antagonist
FDA-approved for: Flibanserin (Addyi), released in 2015, is FDA-approved for Hypoactive Sexual Desire Disorder in
❖ Hypoactive Sexual Desire premenopausal women (it has not been tested in men or postmenopausal women). It was originally
Disorder in premenopausal developed as an antidepressant.
women Addyi has been colloquially referred to as the “female Viagra”, but it has nothing in common with
Viagra (sildenafil). Its mechanism involves dopamine, norepinephrine, and serotonin (5-HT).
Viagra (sildenafil) Addyi (flibanserin)

Mechanism PDE inhibitor
5-HT agonist and 5-HT antagonist, which leads to
1A 2A
increase of DA and NE activity
For use by Men Women
Purpose Erection Increased interest in sex
Response rate 80% 10% showed benefit over placebo
Effect size Substantial improvement Slight improvement
# scripts/year > 2,000,000 About 5,000
Cost $6 per tablet $14 per tablet ($415/mo)
Instructions PRN Every day at HS
flibber
Contraindicated Nitroglycerine Alcohol within 2 hours (hypotension); 3A4 inhibitors;
with (hypotension) Fluconazole (fluffer inHibitor of several relevant CYPs)
Other uses Pulmonary arterial HTN None
Physicians had to be certified to prescribe Addyi, but this restriction was

lifted in 2019. Originally women taken Addyi were expected to abstain
Flibanserin does not appear to contribute
from alcohol because the combination can cause severe
hypotension/syncope. In 2019 the contraindication with alcohol was to serotonin syndrome.
softened. Addyi is contraindicated with liver impairment and with (strong
to moderate) 3A4 inHibitors. These contraindications all relate to
increased risk of hypotension/syncope and are all presented as black box Comparison with other medications that can improve sexual
warnings. functioning via serotonin receptors:
Women taking flibanserin reported an increase in “satisfying sexual Indication 5-HT1A 5-HT2A
events” from 2.8 to 4.5 events per month. Women taking placebo
improved from 2.7 to 3.7 events per month. Flibanserin Hypoactive sexual Agonist (Antagonist)
(ADDYI) desire disorder
Flibanserin has turned out to be a flop of a medication, with only about
5,000 annual prescriptions. Its lack of popularity is unsurprising given its Trazodone Depression (Agonist) Antagonist
disappointing efficacy, costs, and (previously) mandated alcohol (DESYREL) (off-label for
insomnia)
abstinence pledge. In 2019 the label warning for alcohol use was
softened to state “women should discontinue drinking alcohol at least two Nefazodone Depression (Agonist) Antagonist
hours before taking Addyi at bedtime or skip the Addyi dose that evening. (SERZONE)
Women should not consume alcohol at least until the morning after taking
Buspirone Anxiety Partial -
Addyi at bedtime”. (BUSPAR) agonist
For context, blocking 5-HT2A is the opposite of what hallucinogens do. Pimavanserin Hallucinations - Inverse
LSD is a 5-HT2A agonist. Second generation antipsychotics also block (NUPLAZID) and delusions agonist
5-HT2A—2A for 2nd gen Antipsychotic. associated with
Parkinson’s
Dosing: The starting and maintenance dose is 100 mg QD HS.
page
❖ Sedation/CNS depression page page
❖ Hypotensive 16 13
- contraindicated with alcohol
❖ 3A4 substrate
- contraindicated with moderate to strong 3A4 inHibitors, which
may increase flibanserin levels, leading to hypotension.
❖ 2C9 substrate
❖ 2C19 substrate
❖ Contraindicated with fluconazole (Diflucan) which is a “fluffer”
3A4 substrate 2C9 substrate
inHibitor of the 3 CYPs that metabolize flibanserin, causing
7-fold increase in flibanserin levels, leading to hypotension
2C19 substrate

5 mg ]
#90 Buspirone (BUSPAR) ❖ Anxiolytic
❖ 5-HT1A serotonin receptor
7.5
1986 BU spi rone / BU spar partial agonist
10
$7–$62 15
“Bus spear” ❖ Non-addictive
30
Some of the generic multi-scored tablets look like

yellow school buses. However, most generics
FDA-approved for: buspirone tabs are white, and “school bus” is slang for
a multi-scored yellow 2 mg alprazolam (Xanax) tablet.
❖ Anxiety
Used off-label for:

❖ Augmentation of SSRI for depression 5 - H T 1 A
❖ Antidepressant-associated sexual
dysfunction ANXIETY
❖ SSRI-induced bruxism (tooth grinding)

❖ Movement disorders (high dose)
- Tardive dyskinesia
- Chorea
- Levodopa induced dyskinesias
❖ Hostility in patients with cardiac
impairment TRD include lithium, aripiprazole (Abilify), quetiapine (Seroquel),
risperidone (Risperdal), and liothyronine (Cytomel—T3 thyroid
hormone). However, buspirone is safer and better tolerated than these
Buspirone (BuSpar) is a serotonin 5-HT1A receptor partial agonist more proven adjuncts.
(SRA) FDA-approved for generalized anxiety disorder (GAD). It is Unlike most serotonergics, buspirone may enhance sexual functioning.
unrelated to other anxiolytics. Buspirone is non-addictive and Buspirone shares some properties with flibanserin (Addyi), a 5-HT1A
73 in generally non-sedating. Unlike other medications in this chapter,
ok receptor agonist approved for hypoactive sexual desire disorder (page
buspirone works in a slow and steady fashion, like an 73).
antidepressant. Contrast this with benzodiazepines, which work
immediately but are addictive. Unlike benzodiazepines, buspirone is Buspirone can serve as an antidote for SSRI-induced bruxism (tooth
generally not useful as a PRN anxiolytic because optimum efficacy grinding). Buspirone is used off-label at high dose for treatment of
usually requires 2 to 4 weeks of regular administration. Some movement disorders including chorea, tardive dyskinesia and
patients regard buspirone as an effective PRN, likely due to placebo levodopa induced dyskinesias. It may improve cognitive functioning in
effect. schizophrenia and Alzheimer’s disease. When used for anxiety with
alcohol use disorder, it decreases drinking days (Kranzler et al, 1994).
“Buspar is benign.” Buspirone is one of the safest psychotropic
medications, with no need for laboratory monitoring. There are no “This school bus ain’t for kids”—Although there are no safety issues,
absolute contraindications (other than allergy to buspirone). No buspirone does not appear to be effective for treatment of GAD in
deaths have been reported with single-drug overdose. It is generally individuals under age 18.
well tolerated, but potential side effects include nausea, headache
and jitters. It does not cause weight gain. Withdrawal is not an issue Buspirone has a short half-life of 2–3 hours, so it requires BID or TID
if buspirone is stopped without tapering. dosing (usually TID). Although inconvenient, some patients prefer
multiple daily dosing for better perceived control of symptoms.
“Buspirone doesn’t have to be used alone!” (Madalyn Hoke, PA-S). However, it is not expected to be immediately effective. Benefit is
Buspirone can be combined with practically any other psychotropic achieved gradually over 2–4 weeks, but placebo effect can be a
medication, with a couple of exceptions. powerful thing.
Buspirone is avoided with MAOIs, although there is evidence that Dosing: Buspirone is typically started 7.5–10 mg BID or TID and
buspirone does not cause serotonin syndrome (The scoop on titrated quickly to a target dose of 15 mg TID or 20 mg BID, with FDA
serotonin syndrome; Foong et al; Canadian Pharmacists Journal, maximum dose of 60 mg/day. Starting at 15 mg BID is ok. It is
2018) recommended to take buspirone consistently with food or consistently
without food, because it is better absorbed when taken with meals. For
off-label treatment of movement disorders, it may be necessary to
Buspirone does not appear to cause serotonin syndrome. titrate buspirone as high as 180 mg/day. A higher dose of buspirone
will be needed if it is combined with a strong 3A4 inDucer such as
It is redundant to combine buspirone with vilazodone (Viibryd) carbamazepine (Tegretol). Unless the dose is very high, buspirone
because vilazodone has intrinsic 5-HT1A receptor partial agonist may be discontinued without tapering.
activity. Pharmacologically, “Viibryd is like a hybrid” of an SSRI and
7 in buspirone (page 57).
ok BuSpar was
Buspirone is commonly prescribed along with an antidepressant,
although caution is advised due to a small possibility of serotonin found to be
syndrome. An SSRI plus buspirone is good for anxiety, but there is ineffective for
better evidence for other augmenting agents for treatment-resistant panic disorder.
depression (TRD). More effective adjuncts for PLACEHOLDER
Comparison with other medications that can improve sexual functioning via serotonin receptors:
Serotonergic medication Indication 5-HT1A 5-HT2A
page
Flibanserin (ADDYI) Hypoactive sexual desire Agonist (Antagonist) 16
Trazodone (DESYREL) Depression/insomnia (Agonist) Antagonist ❖ Serotonergic
Nefazodone (SERZONE) Depression (Agonist) Antagonist ❖ Sedative (weak)
Buspirone (BUSPAR) Anxiety Partial agonist -
❖ 3A4 substrate
Pimavanserin Hallucinations and delusions - Inverse agonist
3A4 substrate
(NUPLAZID) associated with Parkinson’s disease

1942
Meperidine (DEMEROL) ❖ Opioid 50
me PER i deen / DEM er ol ❖ Serotonergic 100
$17 - $41
“Meeper Demoralized” ❖ Schedule II mg
FDA-approved for: Meperidine (Demerol), also called pethidine, was the first synthetic opioid. Since it is
❖ Moderate-to-severe pain synthetic, you would not refer to it as an opiate. Eduardo Fraifeld, MD opined that
Demerol is “toxic and sedating” and “should not be used at all”. Withdrawal symptoms
are worse than with morphine. Meperidine should not be used for chronic pain. Its
You are toxic and use for acute pain should be reserved for those allergic to first-line opioids. Oral
sedating. You should administration is not advised due to extremely poor bioavailability. The usual route of
not be used at all. administration is intramuscular (IM). It is not available for intravenous (IV)
administration. Duration of action is very short, about 3 hours.
Meperidine is distinguished from other opioids by its serotonergic properties, caused

by 5-HT reuptake inhibition. Meperidine was involved in a high-profile death from
serotonin syndrome in 1984, which killed an 18-year-old college student named Libby
Zion. The reaction occurred when meperidine was added to the MAOI phenelzine
(Nardil).
Opioids, meperidine excluded, are potent pupillary constrictors. Due to meperidine’s

serotonergic and anticholinergic effects, it can cause dilation of pupils in some
individuals. Withdrawal from meperidine manifests with dilated pupils like the other
opioids. It is more likely than other opioids to cause seizures with overdose.
Although primarily a mu opioid receptor agonist, meperidine has more affinity for the
kappa receptor than morphine, making meperidine more likely to cause dysphoria,
Meperidine can certainly hallucinations, and dissociation.
contribute to
serotonin syndrome. The metabolite of meperidine (normeperidine) is neurotoxic and may accumulate in
cases of renal or hepatic impairment.
meperidine is also
known as pethidine Dynamic interactions: Kinetic interactions: page
❖ Opioid agonist 16
❖ Delayed gastric
You’re PETHetic! - Constipation emptying
- Sedation / CNS depression ❖ 3A4 substrate
- Respiratory depression ❖ Black box warning:
- Hypotension concomitant use with 3A4
❖ Lowers seizure threshold inhibitors or discontinuation
❖ Prolongs QT interval of 3A4 inducers may cause
❖ Serotonergic (moderate) fatal fentanyl concentration
3A4 substrate (major)
❖ Anticholinergic
❖ Neurotoxicity
Causes of mydriasis and miosis
Mydriasis - dilated pupils Sympathetic ❖ Anticholinergics – atropine eye drops are highly
(fight or flight) anticholinergic and given for the purpose of dilating
pupils for ophthalmologic exam
With anticholinergic
“mad as
toxicity, also expect to ❖ Antidepressants
a hatter”
see facial flushing. ❖ Serotonin syndrome
5-H
Mydriasis - “Oh my... ❖ Stimulants T
❖ LSD, PCP, Hallucinogens
anti
cholin- what big eyes you have”
❖ Opioid withdrawal
ergic
Pronounced
[ mi DRAHY uh sis ] or ❖ Meperidine (Demerol) - an opioid with anticholinergic
[ mahy DRAHY uh sis ] and serotonergic properties
Miosis - constricted pupils Parasympathetic ❖ Opioids (other than meperidine) are the most potent
(rest and digest) pupillary constrictors
❖ Antipsychotics
Miosis - “mini-pupils”
pioid ❖ Trazodone (Desyrel) and mirtazapine (Remeron) –
antidepressants with sedative properties
❖ Cholinergics, e.g., donepezil (Aricept)

Methadone (DOLOPHINE) ❖ Long-acting opioid 10
5 253
1947 10
METH a dohn / DOLE o fene mg /
$12 - $41 ❖ Schedule II 40
“Dolphin’s Method (to be) done” (using heroin) ml mg
FDA-approved for:
❖ Opioid dependence
❖ Chronic pain
Methadone (Dolophine), commonly used as maintenance treatment

for heroin addiction, is a synthetic opioid with an exceptionally long
half-life of 24 to 55 hours. Like other opioids, methadone is a
Schedule II controlled substance. It has a 60 – 90% success rate for
treating opioid use disorder (OUD), substantially more effective than QT prolongation
abstinence-based treatment. This approach to addiction is considered
“harm reduction” – the patient remains addicted to an opioid but
avoids the social, health (overdose, dirty needles) and legal morbidity
of using heroin. For short-acting opioids (heroin, morphine,
oxycodone, etc) withdrawal symptoms may start within 6 – 8 hours
from the last dose. The advantage of methadone is that withdrawal Methadone, when used for opioid addiction (21-day detox or
does not start until 24 hours. long-term maintenance) must only be dispensed by certified
opioid treatment programs, under strict regulation.
Side effects are those typical of opioids. However, thanks to Originally, clinics had to dispense methadone in liquid form.
methadone’s long half-life, tolerance to side effects develops quickly.
So, with methadone there will be less persisting constipation, Methadone has weak serotonergic properties, making it a
dizziness, sedation, nausea, and miosis compared other opioids possible (but unlikely) contributor to serotonin syndrome
Since methadone accumulates, the dose may need to be reduced when combined with antidepressants.
after about 5 days to avoid toxicity.
The main risk of methadone is death by overdose due to respiratory

Methadone can contribute to serotonin syndrome.
depression. Methadone prolongs QT interval and increases risk for
torsades de pointes at high dose.
page
Dynamic interactions: Kinetic interactions: 3% of the population are 2B6 ultrarapid 14
❖ Opioid agonist ❖ Delays gastric emptying metabolizers (UMs). Methadone will be
- Constipation ❖ 2B6 substrate (major) poorly effective for these individuals, page
❖ 2C19 substrate and methadone may even be negative 16
- Sedation / CNS depression
- Respiratory depression ❖ 3A4 substrate on standard drug screens.
- Hypotension Black Box Warning: concomitant page
❖ Lowers seizure threshold use with inhibitors of 3A4, 2B6, 12
❖ Prolongs QT interval (moderate) 2C19, 2C9, or 2D6 or
❖ Serotonergic (weak) discontinuation of concomitant METHADONE
inducers of these enzymes may
cause potentially fatal
respiratory depression. 2B6 substrate (major) 3A4 substrate
2C19 substrate
Fentanyl (DURAGESIC)
1984 FEN ta nil / dur a GEES ik ❖ Potent opioid
$41 - $151 ❖ Schedule II
“Fountain eel’s Durable analgesic”
FDA-approved for: Fentanyl is a very high-potency opioid, dosed by mcg rather than mg. It is 100 times stronger
❖ Severe chronic pain than morphine. Recreational drugs (heroin, cocaine, etc.) may be laced with illegally-made
fentanyl from China. Fentanyl is the most common cause of opioid overdose fatality. Fentanyl
transdermal (Duragesic) is for opioid-tolerant patients only.
Opioids
constrict
pupils Fentanyl is weakly serotonergic. There are case studies of it causing
serotonin syndrome when combined with an antidepressant.
Used patches
are to be flushed
down the toilet page
Dynamic interactions: Kinetic interactions: 16
❖ Opioid agonist ❖ Delayed gastric
- Constipation emptying
- Sedation / CNS depression ❖ 3A4 substrate
- Respiratory depression ❖ Black box warning:
- Hypotension concomitant use with 3A4
❖ Lowers seizure threshold inhibitors or discontinuation
❖ Serotonergic (weak) of 3A4 inducers may cause
fatal fentanyl concentration 3A4 substrate

#39 Tramadol (ULTRAM) Pain medication
Pain medication
1995 ❖ Weak opioid
❖ Weak opioid 50
TRAM a dol / UL tram
IR: $7 - $41 ❖ SNRI ❖ SNRI mg
ER: $32 - $123
Racemic mix
“Ultra ram Trauma doll” ❖ DEA Schedule
❖ IV Schedule II
DEA
FDA-approved for:
Ouch!
❖ Acute pain (mod to severe)
❖ Chronic pain (mod to severe) – ER formulation
Used off-label for:

❖ Fibromyalgia
Opioids
constrict
Tramadol is a partial (weak) agonist at the μ (mu) opioid pupils
receptor with onset of pain relief in about 1 hour, with duration
of about 6 hours. Tramadol is also a
serotonin–norepinephrine reuptake inhibitor (SNRI) like
venlafaxine (Effexor) and duloxetine (Cymbalta). Tramadol is
not considered an antidepressant but may have some
antidepressant and anxiolytic properties. Tramadol is not
typically prescribed by psychiatrists. Tramadol can contribute
to serotonin syndrome if combined with serotonergic
antidepressants. Tramadol can contribute to serotonin syndrome.
Tramadol was released in the US in 1995 and became a
Schedule IV controlled substance in 2015 due to potential for
abuse as an opioid. Compared to other opioids, respiratory Tramadol is available in a fixed dose combination with acetaminophen
depression and constipation are less of a problem with (Tylenol) called Ultracet.
tramadol. With overdose, tramadol is more likely (than
traditional opioids) to cause seizures than traditional opioids. Dosing: The standard dose is 50 - 100 mg q4-6 hr PRN; Although it tends
to be started at 50 mg, the label recommends to go slower “unless
Side effects are similar to other opioids. In order of frequency, immediate onset is required” by starting 25 q AM; May increase by 25
adverse effects occurring within 90 days included constipation mg/day in 3-day intervals to 25 mg q 6 hr PRN, then may increase by 50
(46%), nausea (40%), dizziness (33%), headache (32%), mg in 3-day intervals to 50 mg q 6 hr PRN; Maximum is 400 mg /day
somnolence (25%), vomiting (17%), pruritus (11%) and (300 mg/day for > 75 years); use lowest effective dose and shortest
psychiatric effects (14%). Tramadol has 8 black box warnings, effective treatment duration; To stop (if prolonged use), taper slowly, by no
comparable to other opioid medications. more than 10-25% in 2-4 week intervals.
. Dynamic interactions: Kinetic interactions:

page
❖ Opioid agonist ❖ Delays gastric emptying
15
- Constipation ❖ 3A4 substrate
- Sedation / CNS depression ❖ Tramadol is transformed by 2D6 to an active
- Respiratory depression metabolite (desmethyltramadol) which is responsible page
- Hypotension for most of the opioid effect. 16
❖ Lowers seizure threshold ❖ Tramadol may be less effective for individuals
❖ QT prolongation with 2D6 poor metabolizer (PM) genotype (10% of
❖ Serotonergic population) or for individuals taking 2D6 inHibitors
such as fluoxetine, paroxetine or bupropion.
❖ Black box warning: Respiratory depression and
ULTRAM
death have occurred in children with 2D6 ultra-rapid
metabolizer (UM) genotype (5% of population).
3A4 substrate
❖ Black box warning: “Concomitant use or
discontinuation of concomitant 3A4 inDucers, 3A4 2D6 prodrug
inHibitors, or 2D6 inHibitors are complex; Such
interactions require careful consideration of the
effects on tramadol and its active metabolite”.
Tapentadol (NUCYNTA) Tapentadol does not appear to contribute to serotonin syndrome.

ta PENT a dol / Nu SEN ta
“Tap into doll’s New scent” “The ‘Nu’ Tramadol” - tapentadol (Nucynta) was approved in 2009 for acute pain
(moderate to severe) such as post-surgical pain. Tapentadol works as a mu
opioid agonist and norepinephrine reuptake inhibitor (NRI). Tapentadol does not
significantly inhibit serotonin reuptake like Tramadol does.
Opioids
constrict
pupils Tapentadol is a Schedule II controlled substance like traditional opioids such as
morphine, oxycodone, hydrocodone, etc. Its actual opioid strength is weaker than
oxycodone, and about equal to hydrocodone. Its (total) analgesic efficacy is about
equivalent to oxycodone, with fewer gastrointestinal side effects. Nausea
occurred about 50% of the time with tapentadol, compared to 70% with
oxycodone.
The label warns not to combine tapentadol with serotonergic antidepressants, but
in clinical trials patients took it concurrently with SSRIs without adverse effects.

Triptans for acute migraine headaches
Triptans are a family of tryptamine-based drugs used as abortive

medication for migraines and cluster headaches. Triptans should Triptans do not appear to cause serotonin syndrome.
be administered as quickly as possible upon headache onset.
Early treatment decreases the likelihood of recurrence within 24
hours. The subcutaneous route is more effective but brings more About 25% of triptan users are also prescribed an SSRI or SNRI.
side effects. Weakness or somnolence following triptan therapy In 2006 the FDA issued a warning that triptans could contribute to
may be part of the migraine attack, unmasked by the successful serotonin syndrome when combined with SSRIs or SNRIs. The
treatment of pain. warning did not change prescribing practices, and the risk appears
miniscule to nonexistent. Orlova et al (2018) estimated the risk at
Longer-acting triptans such as naratriptan (Amerge) and about one case of serotonin syndrome per 10,000 person-years of
frovatriptan (Frova) have a slower onset of action and lower initial exposure to a triptan plus an SSRI/SNRI.
response rate than other triptans, but they are better tolerated.
Serotonin syndrome is hypothesized to involve 5-HT1A and
Triptans constrict blood vessels. They carry a small risk of heart 5-HT2A receptors, while triptans are agonists at 5-HT1B and
attack, stroke, or seizure. All triptans are contraindicated with 5-HT1D receptors.
coronary artery disease, peripheral vascular disease, uncontrolled
hypertension, history of stroke, or Wolff-Parkinson-White
syndrome (extra electrical pathway in the heart with tachycardic
episodes).
#115 Sumatriptan (IMITREX) ❖ Triptan for acute migraine 25

1992 SOO ma TRIP tan / EM i trex ❖ 5-HT1B receptor agonist 50
$6–$112 100
“Sumo tripped (in my tracks)” ❖ 5-HT1D receptor agonist mg
FDA-approved for: Sumatriptan (Imitrex) is a triptan available via several methods of delivery. Subcutaneous
❖ Migraine headache (acute) administration is the most effective but brings more side effects than the PO route. Onset of
❖ Cluster headache (acute) migraine relief is within 30–60 minutes with oral formulation, 10 minutes with subcutaneous, and
- subcutaneous route 10–15 minutes with nasal powder.
Elimination half-life of sumatriptan is about 2 hours. Side effects may include paresthesia, chest
tightness, warm/cold sensation, vertigo, and fatigue. TREXIMET is a fixed-dose oral combination
of sumatriptan with the NSAID naproxen.
Dosing: Oral sumatriptan is dosed page

18
50–100 mg, may be repeated after 2 Dynamic interactions:
hours of PO or after 1 hour of SC dose. ❖ Serotonergic, but highly
PO maximum of 200 mg/day. unlikely to contribute to IMITREX
Subcutaneous dosing is 1–6 mg SC x serotonin syndrome
my 1, may repeat after 1 hour for max of 12 ❖ Hypertensive effects
tracks mg/day. With mild to moderate hepatic
impairment, the PO max is 50 mg/dose. Kinetic interactions:
With severe hepatic impairment both ❖ None significant
PO and SC sumatriptan is
contraindicated.
#232 Rizatriptan (MAXALT) ❖ Triptan for acute migraine 5

1998 RYE za TRIP tan / MAX alt ❖ 5-HT1B receptor agonist 10
$15–$186 mg
“RZA tripped (on) Max altitude” ❖ 5-HT1D receptor agonist
FDA-approved for:
❖ Migraine headache (acute)
Unlike sumatriptan, rizatriptan (Maxalt) is not

approved for cluster headaches and is not page
available by subcutaneous route. Dynamic interactions:
18
❖ Serotonergic, but highly
Rizatriptan is metabolized by monoamine unlikely to contribute to
oxidase-A, which is inhibited by propranolol. serotonin syndrome
Concomitant use with propranolol increases ❖ Hypertensive effects MAXALT
blood levels of rizatriptan by 70%.
No dosage adjustment is needed with ❖ Minimal, but propranolol
hepatic impairment, which is an advantage increases plasma
RZA of the Wu-Tang Clan, of rizatriptan over sumatriptan. concentrations of rizatriptan
pronounced "rizza“, while the
by 70% by inhibiting
medication is spelled “Riza” and Dosing: 5 or 10 mg PO, may be repeated in
monoamine oxidase-A
pronounced [ RYE-za ] 2 hours.

Centrally acting spasmolytics – “muscle relaxers”
Central muscle relaxants relieve muscle spasms through action in the central nervous system (CNS)—in the brainstem and spinal cord.
They have no direct action on the contractile mechanism of muscles or the neuromuscular end plate.
Non-addictive spasmolytics
These centrally acting muscle relaxants are not controlled substances.
Muscle relaxant cost/mo Class Details
Cyclobenzaprine $14 Tricyclic #1 prescribed muscle relaxant. Structure is very similar to the TCA
amitriptyline (Elavil). Cyclobenzaprine is a 5-HT2 antagonist that works
(FLEXERIL)
in the brainstem to reduce muscle tone by decreasing the activity of
descending serotonergic neurons. Amitriptyline also does this.
Baclofen (LIORESAL) $13 GABA(B) agonist Baclofen is a derivative of the neurotransmitter GABA and works as a
GABA(B) receptor agonist.
Methocarbamol (ROBAXIN) $18 Carbamate Methocarbamol lacks the abuse potential of the Schedule IV
carbamate carisoprodol (Soma). It is also much safer.
Tizanidine (ZANAFLEX) $17 Central alpha Same mechanism as clonidine (Catapres) and guanfacine (Tenex)
agonist with less antihypertensive effect.
Metaxalone (SKELAXIN) $45 Oxazolidinone Can contribute to serotonin syndrome; Most oxazolidinones are
antibiotics, e.g., linezolid, which can also cause serotonin syndrome.
Orphenadrine (NORFLEX) $42 Antihistamine/ Structure very similar to diphenhydramine (Benadryl). Muscarinic
anticholinergic antagonist and NMDA antagonist. Rarely prescribed.
Schedule IV spasmolytics
These centrally acting muscle relaxants are DEA Schedule IV controlled substances with potential for abuse and addiction.
Muscle relaxant cost/mo Class Details
Meprobamate (MILTOWN) $110 Carbamate Was the most-prescribed anxiolytic in the pre-benzodiazepine era
Carisoprodol (SOMA) $12 Carbamate The prodrug of meprobamate (Miltown). Soma is the #3 most
prescribed muscle relaxant (behind Flexeril and Robaxin), despite
being addictive and dangerous.
Diazepam (VALIUM) $9 Benzodiazepine FDA-approved for anxiety, seizures, and muscle spasms.
Metaxalone (SKELAXIN) ❖ Antispasmodic 400

1962 me TAX a lone / ska LAX in
$40–$144 ❖ CNS depressant 800
“Skeletor Relaxin’ (with a) Meat ax, alone” ❖ Serotonergic mg
FDA-approved for: Metaxalone can contribute to serotonin syndrome.

❖ Acute musculoskeletal pain
The spasmolytic mechanism of metaxalone (Skelaxin) is unknown,

other than being a general CNS depressant. It may be weak
monoamine oxidase inhibitor (MAOI). If taken in large doses
metaxalone may be sufficiently potent to cause serotonin syndrome.
Metaxalone is not commonly prescribed.
Dosing: For acute musculoskeletal pain, give 800 mg TID–QID on

Muscle (relaxant) an empty stomach.
muscle
(relaxant)
18
❖ Serotonergic (weak)
SKELAXIN
❖ Metabolized by seven different
P450 enzymes (multi-CYP); Kinetic
Our spooky mascots are generally reserved for interactions occur but are unlikely to
antipsychotics, with Skelaxin as an exception.
be clinically significant with so many
Metabolic pathways—“in a box”.
Multi-CYP

#46 Cyclobenzaprine (FLEXERIL) ❖ Antispasmodic 5
cy kloe BEN za preen / FLEX er il ❖ Tricyclic structure 7.5
1977
❖ 5-HT2 antagonist 10
$2–$24
“(tri) Cycle bends, Flexes ‘n’ rolls” ❖ Non-controlled mg
FDA-approved for:
❖ Muscle spasms Muscles
(muscle
Gumby is relaxant)
Used off-label for: flexible
❖ Fibromyalgia
❖ Insomnia
Released in 1977, cyclobenzaprine (Flexeril) remains the

#1 most prescribed muscle relaxant. It is not a controlled
substance. Half-life is 18 hours, and it is generally dosed
TID. Flexeril is modestly effective for acute lower back pain Tricycle
with muscle spasm, although efficacy begins to decrease (TCA structure)
after about 4 days. It is not intended for long-term use
because it is not effective for muscle spasms beyond 2–3
weeks. It is not useful for spasticity due to neurologic
conditions such as cerebral palsy. Kinetic interactions with cyclobenzaprine differ from
interactions with TCAs. Cyclobenzaprine is a 1A2 substrate
Flexeril is not used for the treatment of depression, but it (tree) while all TCA antidepressants are 2D6 substrates
has the structure of a tricyclic antidepressant (TCA) by (beach balls).
structure. It differs from amitriptyline (Elavil) by just one
double bond. Flexeril causes similar side effects as TCAs, Incidence of drowsiness with cyclobenzaprine is 38%. As
but is much less dangerous in overdose. Of 209 with some TCAs, cyclobenzaprine can be used as a sleep
cyclobenzaprine overdose cases, there were no deaths medication due to its effects on 5-HT2A, alpha-1
and the QT interval was not prolonged (Bebarta et al,
adrenergic, and H1 histamine receptors. Flexeril causes
2011).
anticholinergic side effects, but less so than carisoprodol
(Soma) or tizanidine (Zanaflex). None of these
Flexeril reduces spasticity through central action, possibly
spasmolytics should be taken by elderly individuals.
at the brainstem level. It is a 5-HT2 antagonist that reduces
muscle tone by decreasing activity of descending
When taken orally, first-pass metabolism in the liver
serotonergic neurons. Amitriptyline (Elavil) and
converts much of the dose to norcyclobenzaprine, which is
cyproheptadine (Periactin) have been shown to do this also
more responsible for the persistent grogginess of the drug.
(Honda et al, 2003).
Tonix Pharmaceuticals was testing sublingual
cyclobenzaprine for military-related PTSD at 2.8 mg and
Dynamic interactions are similar to those of TCAs.
5.6 mg strengths, but the trial was halted in Phase III
(2018) due to inadequate separation from placebo.
Cyclobenzaprine can theoretically contribute to serotonin
syndrome when combined with other serotonergics and is
Although it only works short-term as a muscle relaxant,
contraindicated with monoamine oxidase inhibitors
some patients take cyclobenzaprine long-term for
(MAOIs). However, the risk is very low.
insomnia.
Dosing: For muscle spasms the recommended dose is

Cyclobenzaprine is highly unlikely to 5–10 mg TID for up to 3 weeks. When used off-label for
contribute to serotonin syndrome. fibromyalgia, start 10 mg HS, with a maximum of 40 mg
total daily dose divided BID–TID.
ge
page page
30 10
cyclobenzaprine amitriptyline ❖ 1A2 substrate
(Flexeril) (Elavil)
1A2 substrate

Cough suppressant
Dextromethorphan (DXM) ❖
❖ Dissociative
1953 dex troe meth OR fan 30 mg/
❖ NMDA antagonist
$7–$11 5 mL
Sigma-1 agonist
“Dexter the Thor fan” ❖
❖ SRI
FDA-approved for: Dextromethorphan (DXM) is an emotions, possibly explaining the

❖ Cough suppression over-the-counter cough suppressant. It benefit of DXM for treatment of
is kept behind the counter due to its pseudobulbar affect (in combination
dissociative properties, which lend to with quinidine, which serves to extend
Used off-label for: recreational use among young people. half-life of DXM). An endogenous
❖ Neuropathic pain DXM is a component of Robitussin, ligand for the sigma-1 receptor is yet to
❖ Opioid withdrawal NyQuil, Dimetapp, and Mucinex DM. be identified, but we know some
❖ Postoperative pain androgenic steroids activate the
❖ Premature ejaculation At high doses, DXM may produce receptor.
❖ Agitation of dementia euphoria and dissociative effects
similar to ketamine. With prolonged Experimentally, DXM is being used to
use, psychological dependence is treat depression and negative
possible. It does not cause physical symptoms of schizophrenia.
dependence, but can produce
DX
symptoms of antidepressant Dextromethorphan cough syrup is not

M
discontinuation syndrome owing to to be confused with the cough syrup

DXM’s effects as a serotonin reuptake used to make “purple drank” (aka
inhibitor (SRI). sizzurp), would is prescription-strength
codeine and promethazine syrup.
In addition to being a SRI, DXM is an Unlike DXM, codeine can cause
NMDA receptor antagonist and physical dependence.
sigma-1 receptor agonist. Sigma-1
cough receptors in the limbic system of the
brain may be involved in control of
PLACEHOLDER
page
Dynamic interactions: Kinetic interactions: 15
❖ Serotonergic ❖ 2D6 substrate (major)
Dextromethorphan is a 2D6 substrate. When

combined with a strong 2D6 inhibitor, its half-life
DXM can contribute to is extended. This interaction is used for
serotonin syndrome. therapeutic effect by NUEDEXTA—a combination
of DXM and quinidine (a strong 2D6 inhibitor).
2D6 substrate
Serotonergic hallucinogens
Hallucinogens, also referred to as psychedelics, cause perceptual changes in a state of full wakefulness and alertness (as opposed to
a state of delirium or sedation). It may be more accurate to refer to these drugs as “illusionogens” because their prominent effect is
distortion or enhancement of existing stimuli (Abigail Herron, DO). The following hallucinogens can cause serotonin syndrome.
Hallucinogen Mechanism Comments
Lysergic acid 5-HT2A serotonin Synthesized in 1938, not naturally occurring. Consumed by piece of blotter paper on the
diethylamide (LSD) receptor agonist tongue; More info on subsequent page.
Dimethyltryptamine 5-HT2A serotonin Nicknamed “Dimitri” and “Businessman’s Trip” due to short duration of about 1 hour; May be
(DMT) receptor agonist smoked; Tiny amounts are present endogenously, produced by the pineal gland.
Mescaline (peyote) 5-HT2A serotonin Ingested as buttons from the crown of the peyote cactus; Lasts 4–8 hours; DEA Schedule I
receptor agonist (illegal) with an exception for Native American religious ceremonies.
Psilocybin 5-HT2A serotonin “Magic mushrooms” or “shrooms”; Ingested for a trip lasting 4–6 hours; DEA Schedule I
(mushrooms) receptor agonist (illegal); May cause psychosis/detachment from reality; Reported mystical-like experiences
MDMA Highly Described as a “psychedelic amphetamine” and “empathogen”. Only 55% of users
(Ecstasy, X, Molly) serotonergic, hallucinate; Extended duration; Altered perception of time (90%), euphoria (97%), increased
with stimulant awareness of emotions (50%), decreased impulsivity (25%), increased empathic connection
and oxytocin- to others due to oxytocin release from the pituitary. Can cause bruxism—it’s the reason
mediated effects pacifiers are seen at raves; Risk of irreversible brain damage from massive release of
serotonin. Risk of hyponatremia and toxidrome including rhabdomyolysis; The only
X hallucinogen with a defined withdrawal syndrome. "Molly" is powdered MDMA in a capsule;
"Ecstasy" is a pressed pill. Both are commonly laced with other drugs.
Bufotenine Serotonergic Bufotenine has been consumed by licking toads of the genus Bufo or drinking their venom.

1943
Lysergic acid diethylamide (LSD) ❖ Hallucinogen
❖ DEA Schedule I (illegal)
“Lucy’s Serotonergic Drug” ❖ 5-HT2A agonist
Lysergic acid diethylamide (LSD) is a semisynthetic product of lysergic

LSD can cause serotonin syndrome. acid, a natural substance from an ergot fungus. Referred to as “acid”,
LSD is a recreational hallucinogenic typically consumed in small doses
on the tongue as blotter paper that was soaked in an LSD-containing
solution and dried.
The hallucinogenic effect of LSD was discovered in 1943. It was a

popular legal recreational drug in the early 1960s, but has been illegal
since 1968.
LSD is gaining traction as a therapeutic drug. It has been found to treat

and prevent cluster headaches and may work for treatment-resistant
5- depression. Therapeutic effects may be achievable in micro doses that
HT are sub-psychedelic (i.e., do not cause hallucinations). Even at
psychedelic strength, LSD has minimal potential for addiction and may
have potential as a treatment of addiction to other substances.
The effect of LSD is felt to be due entirely to prolonged stimulation of

5-HT2A serotonin receptors, which is the same mechanism of other
classic hallucinogens like DMT, psilocybin and mescaline. These are
the receptors blocked by many second generation antipsychotics
(SGAs). Endogenous serotonin binds these receptors briefly, while LSD
is essentially locked onto the receptor for hours. LSD is mostly cleared
from the bloodstream within 6 hours, but the hallucinogenic effect
Although John Lennon denied that it is a drug song, continues for an average of 12 hours because this is how long LSD is
the Beatles' '"Lucy in the Sky with Diamonds" is stuck to a 5-HT2A receptor. Unsurprisingly, LSD can be a contributor to
obviously about LSD.
serotonin syndrome.
Picture yourself in a boat on a river
With tangerine trees and marmalade skies Overdose deaths on LSD alone are essentially non-existent, but are
Somebody calls you, you answer quite slowly possible with 100–200x the usual dose. Terrifying “bad trips” are
A girl with kaleidoscope eyes… possible. Due to LSD’s effects on the hypothalamus, it may elevate
body temperature, raise blood pressure and make it virtually impossible
Follow her down to a bridge by a fountain to fall asleep while it is in effect.
Where rocking horse people eat marshmallow pies
Everyone smiles as you drift past the flowers Following cessation of LSD, the user may experience persisting
That grow so incredibly high perceptual disturbances as “LSD flashbacks”, for instance seeing trails
of moving objects, afterimages, or misperceptions of images as too
large (macropsia) or too small (micropsia). Flashbacks may occur in
individuals with minimal exposure to LSD. Flashbacks only constitute a
disorder (Hallucinogen Persisting Perception Disorder, DSM-5) if they
cause clinically significant distress or impairment.
LSD is regulated by the DEA as a Schedule I (illegal) controlled

substance. Lysergic acid (without the ‘D’), commonly known as ergine
from morning glory seeds, has milder psychedelic properties and is
Schedule III. Other lysergic acid derivatives include the dopaminergic
agonist bromocriptine, and the headache medications ergotamine and
methysergide.
For context, LSD’s stimulation of 5-HT2A receptors is the opposite of

what second-generation antipsychotics (SGAs) do. Mnemonic: 2A for
2nd Gen Antipsychotics, which block 5-HT2A receptors.
Dilated pupils are seen with LSD use page

LSD has and with serotonin syndrome, which 16
serotonin can be caused by LSD .
essentially
embedded in Dynamic interactions:
its structure. ❖ Serotonergic (strong)
❖ LSD is metabolized by 3A4
LSD Serotonin and other CYP enzymes. 3A4 substrate

Chapter 8 –Serotonin Antagonists
- #91
1991
Ondansetron (ZOFRAN) ❖ Antiemetic ODT tab
283
4 4
$3–$76 tab
on DAN se tron / ZO fran ❖ Serotonin 5-HT3
8 8
receptor antagonist
$3–$76 ODT “On Dancer Tron! (Go) so frantic!” mg mg
FDA-approved for: Used off-label for: On Dancer Tron!

❖ Prevention of ❖ Nausea/vomiting (other) On Prancer Tron!
nausea/vomiting ❖ Irritable bowel syndrome Go, so frantic!
associated with: ❖ Tourette’s syndrome
❖ Chemotherapy ❖ Schizophrenia (adjunct)
❖ Radiating therapy ❖ Tardive dyskinesia
❖ Surgery ❖ Obsessive-compulsive
disorder (OCD)
❖ Alcoholism
Ondansetron (Zofran) is the first-line medication for

nausea/vomiting. It blocks the 5-HT3 serotonin receptor, which
is involved in antidepressant-induced nausea. Ondansetron’s
receptor binding profile is “clean”, i.e., it does not bind off-target
receptors like other antiemetics. Ondansetron exerts its effect
in the gastrointestinal tract and in the brain’s chemoreceptor
trigger zone.
QT prolongation
Ondansetron is a more effective antiemetic than dopamine (intravenous route)
blockers such as metoclopramide (Reglan). Another advantage
over metoclopramide is ondansetron’s lack of extrapyramidal
effects (EPS) and sedation. It does not work well for nausea
due to motion sickness, which is better treated with an Ondansetron may have value in the treatment of schizophrenia, as
anticholinergic like diphenhydramine, promethazine, or an adjunct to haloperidol (Zhang et al, 2006). Ondansetron has
scopolamine. been proposed as a possible treatment for psychosis associated
with Parkinson’s disease (Zoldan et al, 1995). The mechanism of
Ondansetron is very well-tolerated. It can be somewhat ondansetron’s purported antipsychotic effect is unknown. It does
constipating. Otherwise, no side effects are expected. not block dopamine receptors like traditional antipsychotics. It does
not significantly block the 5-HT2A receptor that is targeted by
In 2011 the FDA issued a warning about ondansetron causing second generation antipsychotics and pimavanserin (Nuplazid). If
QT prolongation, although this is not a black box warning. QT ondansetron is proven to truly benefit schizophrenia, the etiology of
prolongation is not much of an issue with oral ondansetron. In psychosis may need to be reconsidered.
2012 the 32 mg IV dose was withdrawn due to QT
prolongation. The maximum IV dose is now 16 mg. The Ondansetron could possibly improve tardive dyskinesia (Zullino et
maximum PO dose is 24 mg. al, 2001).
Ondansetron is available as an orally disintegrating tablet Similar serotonin receptor antagonist (“-setron”) antiemetics
(ODT), branded as ONDISSOLVE, which costs no more than include granisetron (Kytril), palonosetron (Aloxi), and dolasetron
the swallowed tablet. The ODT formulation can be taken (Anzemet). Other chemicals that have antiemetic properties due to
sublingually for faster onset of action. blocking 5-HT3 receptors are ginger and mirtazapine (Remeron).
The antidepressant vortioxetine (Trintellix) blocks 5-HT3 receptors
An effective regimen for preventing vomiting from cancer but may cause nausea by other serotonergic mechanisms.
chemotherapy is a combination of a “-setron” and the
corticosteroid dexamethasone (Decadron). How corticosteroids Dosing: The orally disintegrating tablet (ODT) formulation is
prevent vomiting is unclear. preferred. The standard dose for nausea/vomiting is around 4 mg q
4 hr PRN or 8 mg q 8 hr PRN. Scheduled dosing usually starts at 4
mg TID before meals. The maximum IV dose is 16 mg, limited due
to QT prolongation. The maximum PO dose is 24 mg. For
experimental psychiatric uses such as OCD and alcoholism, very
low doses were used, for instance 0.25 mg BID for two weeks,
then increased to 0.5 mg BID (Pallanti et al, 2013 for OCD).
Antidepressant-induced nausea
Nausea is one of the most common reasons patients
stop medications prematurely. Nausea tends to be a
transient side effect that usually resolves Dynamic interactions: page
spontaneously. Nausea can often be avoided ❖ QT prolongation 16
altogether with slow titration. Other tips for ❖ Anti-serotonergic - potential
medication-induced nausea is to take the pill after for profound hypotension in
food—not with food, but immediately after a meal. Also combination with apomorphine
effective for nausea is ginger extract (one 550 mg (Apokyn)
capsule) taken 1 hour before a meal, for a maximum of
3 caps/day (Bodagh et al, 2019; Rajnish Mago, MD; Kinetic interactions:
The Carlat Psychiatry Report, Jun/Jul 2019). Ginger ❖ 3A4 substrate
ale does not suffice. 3A4 substrate

Cyproheptadine (PERIACTIN) ❖ 1st Generation antihistamine
1961 ❖ Anticholinergic 4
si pro HEP tuh deen / pear e ACT in
$14–$30 ❖ 5-HT2 serotonin receptor
mg
“Perry actin’…help to dine” antagonist

❖ Allergic rhinitis ❖ Appetite stimulation
❖ Urticaria ❖ Serotonin syndrome
“help to dine”
❖ Female anorgasmia
—used as an
❖ Nightmares appetite We’re not going to
❖ Akathisia stimulant show another penis,
❖ SSRI-induced sweating but cyproheptadine
improves sexual
functioning
Perry
Cyproheptadine (Periactin), released in 1961, is a first
generation antihistamine with antiserotonergic properties. As
Perry Actin’—In the cartoon Phineas and Ferb, Perry the
with all first generation antihistamines, cyproheptadine is highly Platypus is a crime-fighting spy, but is often undercover actin'
anticholinergic. like a docile pet. For Perry to act like a pet, it would help to
dine on pet food.
Cyproheptadine is FDA-approved as an antihistamine for
allergic rhinitis and urticaria but is not used for these conditions
because it causes a lot of weight gain. Cyproheptadine is useful Anticholinergic with CNS
as an appetite stimulant off-label. effects—“mad as a hatter”
Cyproheptadine’s antiserotonergic effects can oppose the action

of antidepressants, potentially rendering them ineffective.
Nonetheless, it has been used to counteract SSRI-induced night
sweats. Cyproheptadine can be used as a treatment for
serotonin syndrome, though the main intervention is stopping
the serotonergic culprit(s).
Cyproheptadine is used off-label to treat nightmares. Unless the Dosing: To stimulate appetite start 2 mg QID and increase to
patient needs to gain weight, prazosin (Minipress) and target dose of 8 mg QID over 3 weeks. For serotonin syndrome
gabapentin (Neurontin) should be tried before resorting to give 12 mg x 1, then 2 mg q 2 hr until response (max 32
cyproheptadine. mg/day). To treat female anorgasmia, the dose is 4–12 mg PRN
1–2 hr prior to sex. For nightmares, start 4 mg HS but may need
Cyproheptadine is also used off-label for treatment of female to go as high as 24 mg HS; Although cyproheptadine is no
anorgasmia. Serotonergics (e.g., SSRIs) may cause longer used for the FDA-approved indications of allergic rhinitis
anorgansmia, so it makes sense that an antiserotonergic could and urticaria, the dose would be 4 mg TID.
facilitate orgasm.
The structure of cyproheptadine is closely related to Dynamic interactions:

tricyclic antidepressants (TCAs), but cyproheptadine is ❖ Antiserotonergic effects can page
antiserotonergic, not serotonergic like a TCA. oppose therapeutic effects of 18
serotonergic antidepressants.
❖ Sedative
❖ Anticholinergic PERIACTIN
– constipation
– confusion
– urinary retention
– dry mouth
cyproheptadine (Periactin) amitriptyline (Elavil) - TCA ❖ None significant

About the author:
Dr Jason Cafer is Medical Director for Behavioral Health Services at SSM Health/St. Mary's
Hospital in Jefferson City, Missouri where he serves as attending physician for a bustling 20-bed
acute inpatient psychiatric ward. He graduated from University of Missouri-Columbia School of
Medicine in 2003 and completed Psychiatric Residency at the same institution in 2007. He is a
diplomate of the American Board of Psychiatry and Neurology and is also board-certified in
Addiction Medicine by the American Board of Preventive Medicine. Prior to St. Mary’s, he
practiced inpatient psychiatry at Fulton State Hospital and outpatient at Comprehensive Health
Systems. In 2007 he founded Iconic Health, a medical informatics startup that obtained angel
round funding. He was Principal Investigator for Phase I and II Small Business Innovation
Research (SBIR) grants for “Online Rural Telepsychiatry Platform” (2007-2009) funded by the
United States Department of Agriculture. He is the inventor of United States Patent
US8255241B2 which was the subject of an SBIR grant awarded by the Department of Health
and Human Services for "Medication IconoGraphs: Visualization of Complex Medication
Regimens". He completed Cafer’s Psychopharmacology while serving as preceptor for
Stephens College Master of Physician Assistant Studies program.

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First Edition, 2020

Author: Jason Cafer, MD

Editor: Julianna Link, PA-C

Cafer’s Psychopharmacology | cafermed.com 1

Copyright 2020, CaferMed LLC

Author: Jason Cafer, MD

Editor: Julianna Link, PA-C

Illustrations: Coccus from 99Designs

Cover design: BengsWorks from 99Designs

Licensed images: Shutterstock and Wikimedia Commons

2 Cafer’s Psychopharmacology | cafermed.com

Cafer’s Psychopharmacology | cafermed.com 3

Price range for a month’s supply of A representative pill of the underlined

Boxes like this contain contextual

Antidepressant (rain cloud) QT interval-prolonging

Anticholinergic with CNS effects

MAOI inhibitor (Chairman MAO) Antihistamine (push pin)

4 Cafer’s Psychopharmacology | cafermed.com

PHARMACODYNAMICS VS PHARMACOKINETICS PHARMACOKINETIC INTERACTIONS

In the liver, kinetic interactions predominantly involve CYtochrome P450

antihypertensive orthostasis as side effect

Fighting “dynos” involved in an antagonistic interaction. 1A2 - One Axe To (grind)

3A4 - Three A’s For (fishing)

serotonergic antihistamine with

Cafer’s Psychopharmacology | cafermed.com 5

Each CYP enzyme can metabolize several substrates and most

2B6 inhibitor - thick calf

1A2 substrate - tree 2C19 inhibitor - watering can

2D6 inhibitor - air pump

2C9 substrate - eyeball 3A4 inhibitor - fishing hook & bobber

2D6 substrate - beach ball

Some substrates are also competitive inHibitors of the same CYP

The magnitude to which an inHibitor increases the serum concentration

The last two are “cone”-azole antifungals.

6 Cafer’s Psychopharmacology | cafermed.com

The D is for Down, i.e., Decreased serum concentrations of victim

D for Down and Delayed (2–4 weeks) bone shredding machine

3A4 inducer - anvil “3 A’s for

An example of reversal of inDuction involves tobacco, which is a 1A2

Although reversal of inHibition is typically faster than reversal of

Cafer’s Psychopharmacology | cafermed.com 7

Phase I metabolism typically involves biotransformation of an active

Phase I Phase II glucuronic

Interactions affecting renal clearance of

With prodrugs, the opposite effect is observed clinically. Induction

About 5% of the population have extra copies of 2D6 genes, resulting in

8 Cafer’s Psychopharmacology | cafermed.com

An example of a relevant P-gp interaction involves the OTC opioid

“1 Axe to 2 Grind” “1 Axe 2 Grow”

First Generation Antipsychotics Second Generation Antipsychotics “-pine” trees Antidepressant

NAVANE HALDOL STELAZINE

Melatonin agonists Methylxanthines Spasmolytic

ROZEREM HETLIOZ NOURIANZ ZANAFLEX

up to 100-fold 3-fold increase > 10-fold increase

Conclusion: Keep in mind that 52% of individuals have a 1A2 ultrarapid

10 Cafer’s Psychopharmacology | cafermed.com

Fluvoxamine, a strong 1A2

Kinetic interactions can be more complicated than simply