Current Clinical Strategies: Handbook of Psychiatric Drugs

Current Clinical Strategies
Handbook of Psychiatric
Drugs
2004 Edition
Lawrence J. Albers, MD
Assistant Clinical Professor
Department of Psychiatry and Human Behavior
University of California, Irvine, College of Medicine
Rhoda K Hahn, MD
Clinical Professor
Christopher Reist, MD
Associate Professor and Vice Chair
Current Clinical Strategies Publishing

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Indications for medications contained in this book

sometimes may not be approved by the FDA. Varying
degrees of empirical evidence exist for the effectiveness
of medications for non- FDA approved uses. The authors
have included those off-label indications where sufficient
research has been completed to warrant the
consideration of these agents as treatment alternatives.
Printed in USA ISBN 1929622-39-2

Antidepressants
Serotonin-Specific Reuptake
Inhibitors
I. Indications
A. Serotonin-Specific Reuptake Inhibitors (SSRIs) are
the most widely prescribed class of antidepressants.
SSRIs have proven efficacy in the treatment of
major depression, dysthymia, obsessive-compulsive
disorder (OCD), panic disorder, bulimia nervosa,
post-traumatic stress disorder, generalized anxiety
disorder and social phobia (social anxiety disorder).
B. SSRIs are also effective in the treatment of bipolar
depression and premenstrual dysphoric disorder.
They may have some efficacy in the treatment of
pain syndromes, such as migraine headaches and
chronic pain. There is some evidence that they be
effective in impulse control disorders. These agents
have also been used to treat behavioral compon-
ents of borderline personality disorder.
II. Pharmacology
A. SSRIs block serotonin reuptake into presynaptic
nerve terminals, leading to enhanced serotonergic
neurotransmission.
B. The half-life for these agents is approximately 24
hours for the parent compound. Fluoxetine,
however, has a half-life of 2-4 days, and its active
metabolite, norfluoxetine, has a 7-10 day half-life.
Thus it takes fluoxetine over a month to reach
steady-state plasma concentrations while the other
SSRIs take approximately 5 days.
C. With the exception of fluvoxamine, the SSRIs are
highly bound to plasma proteins. SSRIs have
significantly less effect on muscarinic, histaminic,
and adrenergic receptors, compared to tricyclic
antidepressants (TCAs), and the SSRIs are
generally better tolerated.
III.Clinical Guidelines
A. Dosage: SSRIs have the advantage of once-daily
dosing. The dosage of fluoxetine, citalopram, and
paroxetine is 20 mg per day; the dosage should be
decreased to 10 mg per day in the elderly. The
initial dose of escitalopram is 10 mg/day. Sertraline
and fluvoxamine are dosed at 50 mg per day, but
the dosage is decreased to 25 mg per day in elderly
patients. There is no linear relationship between
SSRI dose and response. For many patients, the
dosage does not need to be increased.
B. Obsessive-Compulsive Disorder and Bulimia:
Higher dosages of SSRIs, such as 60-80 mg of
fluoxetine or 200-300 mg of sertraline, have been
used to treat obsessive-compulsive disorder and
bulimia. While high doses may be necessary in
some patients, many patients will respond to
standard dosing after 6-12 weeks. When greater
than 40 mg a day of fluoxetine is given, the dosage
should be divided into two doses to minimize side
effects.
C. Panic Disorder: Patients with panic disorder should
be started at a low dosage to prevent exacerbation
of anxiety in the initial weeks of treatment. Patients
should start at 12.5- 25 mg of sertraline, 5-10 mg of
paroxetine, 10-20 mg of citalopram, 5-10 mg of
escitalopram, and 5 mg of fluoxetine. After 1-3
weeks, the dosage may be increased gradually to
standard dosages.
D. Response Time: SSRIs require 2-4 weeks to begin
to alleviate symptoms of depression and treatment
should continue for 6-8 weeks before a patient is
considered treatment refractory.
E. Plasma Levels: There is no correlation between
plasma concentrations of SSRIs and clinical
efficacy. Measuring plasma levels is not clinically
indicated.
F. Safety: SSRIs are much safer in overdose than
other antidepressants such as TCAs or MAOIs.
IV. Adverse Drug Reactions
A. Tolerability: SSRIs are better tolerated than TCAs
or MAOIs.
B. Alpha-1 Blockade: SSRIs do not produce
orthostatic hypotension because they do not block
alpha-1 adrenergic receptors as the tricyclic agents
do.
C. Histaminic Blockade: SSRIs produce markedly
less sedation or weight gain than TCAs or MAOIs
because of minimal effect on histamine receptors.
D. Muscarinic Blockade: SSRIs usually do not cause
dry mouth, constipation, blurred vision, and urinary
retention because they have minimal effect on
muscarinic cholinergic receptors.
E. Seizures: SSRIs have a seizure rate of
approximately 0.2%, which is slightly lower than the
rate for TCAs.
F. Serotonergic Side Effects: The side effects of
SSRIs are primarily mediated by their interaction
with serotonergic neurotransmission:
1. Gastrointestinal effects, such as nausea and
diarrhea, are the most common adverse
reactions. Nausea usually improves after the first
few days of treatment. Giving the medication with
food often alleviates the nausea.
2. Decreased appetite is common early in
treatment because of nausea, and this problem
usually improves after several days.
3. Insomnia may occur with any of the SSRIs, but
it is more common with fluoxetine. Insomnia
usually responds to treatment with trazodone 50-
100 mg qhs. The SSRI should be given in the
morning if insomnia occurs.
4. SSRIs are less sedating than tricyclic
antidepressants, but sedation can occur with
paroxetine or fluvoxamine. If sedation occurs, the
medication should be given at bedtime.
5. Headaches occur occasionally upon initiation of
treatment. In some patients, headaches are
more persistent.
6. Sexual dysfunction such as decreased libido,
delayed ejaculation and anorgasmia can occur,
and this problem may be treated with Sildenafil
(Viagra) 50-100 mg taken one hour before sex,
bupropion (75-150 mg bid), buspirone (BuSpar)
5-20 mg bid-tid, mirtazapine 15-30 mg one hour
before sex, nefazodone 100 mg one hour before
sex or switching the antidepressant to bupropion,
nefazodone or mirtazapine.
7. Serotonin syndrome, characterized by nausea,
confusion, hyperthermia, autonomic instability,
tremor, myoclonus, rigidity, seizures, coma and
death, can occur when SSRIs are combined with
MAOIs. SSRIs should not be used for 2 weeks
before or after the use of an MAOI. For
fluoxetine, 5-6 weeks should elapse after
discontinuation because of its long half-life.
G. Miscellaneous Side Effects: SSRIs may also
cause sweating, anxiety, dizziness, tremors, fatigue,
and dry mouth.
H. Mania: SSRIs, like all other antidepressants, can
induce mania or rapid cycling in bipolar patients.
I. SSRI Discontinuation Syndrome: On
discontinuation, some patients may experience
dizziness, lethargy, nausea, irritability, and
headaches. These symptoms are usually transient
and are more likely to occur with short- acting
agents such as paroxetine and fluvoxamine. These
symptoms can be prevented by slowly tapering the
medication over several weeks when discontinuing
the drug. Discontinuation of paroxetine may be
complicated by cholinergic rebound symptoms,
such as diarrhea.
J. Restlessness: An akathisia-like syndrome has
been reported with fluoxetine, and it can be treated
by reducing the dose of the SSRI. The agitation with
this syndrome can be profound and often requires
discontinuation of the medication.
K. Teratogenic Effects: All SSRIs are pregnancy
category C. However, there is no evidence that
SSRIs cause major birth defects in humans. The
impact of untreated depression on the mother and
fetus must be considered when determining these
risk benefit decisions. Lack of treatment during
pregnancy can lead to severe adverse
consequences for the woman and fetus. Data on
behavioral teratogenicity is limited.
L. Breast Feeding: SSRIs are secreted into breast
milk, and mothers should not breast feed while
taking an SSRI.
V. Drug Interactions
A. Cytochrome P450 Enzymes: SSRIs are
competitive inhibitors of a variety of cytochrome
P450 liver enzymes. This can result in elevated
plasma levels of medications metabolized by these
enzymes. Elevated plasma levels may lead to toxic
side effects.
B. Potential Toxicity: An example of these
interactions is the toxic side effects of the TCA,
desipramine, which can be seen when it is given
concomitantly with an SSRI such as fluoxetine.
Desipramine is metabolized by the liver enzyme
cytochrome P4502D6 (CYP2D6) and fluoxetine is a
potent inhibitor of cytochrome CYP2D6. Fluoxetine
can elevate plasma desipramine levels up to 400%,
with subsequent increased sedation, anticholinergic
effects, tremors and potential increased risk of
seizures or cardiotoxicity.
C. Substrates/Inhibitors
1. Table 1 lists the substrates of several P450 liver
enzymes, and table 2 indicates the degree of
inhibition of the enzymes by each SSRI. The
greater the inhibition, the greater the likelihood of
a drug-drug interaction.
2. Drugs that have a narrow therapeutic index are
more likely produce toxic symptoms when
combined with a strong inhibitor of their
metabolism. These drugs include
antiarrhythmics, anticonvulsants, warfarin, and
theophylline.
D. Warfarin: All the SSRIs can increase levels of
warfarin via P450 interactions as well as
competition for plasma protein binding sites.
Prothrombin times should be monitored when
combining these agents.
Table 1. Substrates of the P450 Enzymes
CYP1A Acetaminoph Haloperidol Tacrine

2 en Imipramine Theophyllin
Amitriptyline Methadone e
Caffeine Olanzapine Thioridazine
Clomipramin Paracetamo Thiothixene
e l R-Warfarin
Clozapine
CYP2D Amitriptyline Ethylmorphi Perphenazin

6 Amphetamin ne e
e Flecainide Propafenon
Bufaralol Haloperidol e
Clomipramin Imipramine Propranolol
e Metoprolol Nortriptyline
Clozapine Mexiletine Quinidine
Codeine MCPP Risperidone
Debrisoquine Molindone Sparteine
Desipramine Nortriptyline Thioridazine
Dextromethor Perhexiline Timolol
phan Tramadol
Donepezil
Encainide
CYP2C Diclofenac Naproxen Tolbutamide

9 Ibuprofen Phenytoin S-Warfarin
Mefenamic Piroxicam
acid
CYP2C Amitriptyline Hexobarbita Omeprazole

19 Clomipramin l Proguanil
e Imipramine Propranolol
Diazepam Mephenytoi
n
CYP3A Acetaminoph Dapsone Midazolam

4 en Disopyramid Nicardipine
Alfentanil e Nifedipine
Alprazolam Diltiazem Nisoldipine
Amiodarone Donepezil Omeprazole
Amitriptyline Estradiol Quetiapine
Buspirone Estrogen Quinidine
Carbamazepi Erythromyci Tamoxifen
ne n Testosteron
Cisapride Ethosuximid e
Clarithromyci e Triazolam
n Felodipine Verapamil
Clomipramin Imipramine Zolpidem
e Lidocaine
Clonazepam Loratadine
Clozapine Lovastatin
Cortisol
Cyclosporine
Degree of inhibition of Cytochrome P450 Enzymes by SSRIs
CYP1A CYP2C9 CYP2C19 CYP2D6 CYP3

2 A4
Escitalopram 0/+ 0/+ 0/+ + 0/+

(Lexapro)
Citalopram 0/+ 0/+ 0/+ + 0/+

(Celexa)
Fluoxetine (Prozac) 0/+ ++/+++ ++/+++ ++++ +/++
Fluvoxamine ++++ 0/+ ++++ 0/+ +++

(LuVox)
Paroxetine (Paxil) 0/+ 0/+ 0/+ ++++ 0/+
Sertraline (Zoloft) 0/+ 0/+ +/++ + 0/+
Citalopram (Celexa)
Indications: Effective for a variety of depressive and
anxiety disorders.
Preparations: 20 and 40 mg scored tablets.
Dosage:
Depression: 20 mg per day, usually given at bedtime.
The dosage may be increased to 40 mg per day after
one week. Maximum dosage is 60 mg/day and this
should be reserved for treatment refractory patients
who have had a 4-6 week trial at 40 mg/day.
Elderly: 10 mg per day for one week, then increase to
20 mg/day. Treatment refractory patients may require
40 mg/day after a trial of 4-6 weeks on 20 mg/day.
Half-life: 35 hr.
Adverse Drug Reactions: Cytochrome P450: Modest,
but significant inhibition of the hepatic enzyme, CYP2D6,
may lead to mild elevations TCAs and antiarrhythmics.
Clinical Guidelines: Of the SSRIs citalopram has low
overall effects on P450 enzymes (see table 2).
Escitalopram (Lexapro)
anxiety disorders.
Dosage:
Depression: 10 mg per day, usually given at bedtime.
The dosage may be increased to 20 mg per day after
one week. Maximum dosage is 30 mg/day, and this
dosage should be reserved for treatment refractory
patients who have had a 4-6 week trial at 20 mg/day.
Elderly: 10 mg per day. Treatment refractory patients
may require 20 mg/day after a trial of 4-6 weeks on 10
mg/day.
Half-life: 30 hr.
Adverse Drug Reactions: Cytochrome P450: Modest
inhibition of the hepatic enzyme, CYP2D6, may lead to
mild elevations of TCAs and antiarrhythmics.
Clinical Guidelines: Compared to the SSRIs,
escitalopram has low overall effects on P450 enzymes
(see table 2). Compared to racemate (citalopram),
escitalopram has an improved side-effect profile (less
sedation and GI upset). Sexual side effects are similar.
Fluoxetine (Prozac, Sarafem, Prozac

Weekly)
anxiety disorders.
Preparations: 10, 20 mg capsules; 20 mg/5 mL solution;
10 mg scored tablet; 90 mg weekly tablet.
Dosage:
Depression: 20 mg qAM is usually effective. May
increase to maximum dose of 80 mg/day. Increase
dose by 20 mg/day each month in partial
responders. Most patients respond at a dosage
between 20-40 mg/day.
Obsessive-compulsive disorder (OCD): 20
mg/day. Increase by 20 mg/day each month if
needed. Treatment of OCD may require a higher
dosage than depression. Maximum dose of 80
mg/day.
Panic Disorder: Begin with 5-10 mg qAM. Increase
gradually over several weeks to 10-20 mg/day.
Bulimia: Begin with 20 mg qAM and increase as
tolerated up to 60 mg per day over several days to
weeks.
Premenstrual Dysphoric Disorder (PMDD): Begin
with 20 mg q day throughout the month. May be
increased up to 60 mg/day.
Elderly: 5-80 mg/day. Due to the long half-life,
elderly patients require lower doses and every-other-
day dosing may be used.
Half-life: 2-5 days for fluoxetine and 7-10 days for its
active metabolite, norfluoxetine.
Adverse Drug Reactions
A. Fluoxetine is a potent inhibitor of the liver enzyme,
cytochrome CYP2D6. Use caution when combining
with a TCA or an antiarrhythmic agent. Can also
elevate levels of many neuroleptic agents and lead
to dystonias, akathisia, or other extrapyramidal
symptoms.
B. Benzodiazepines: Inhibition of the liver enzyme,
CYP3A4, can lead to moderate plasma elevations
of some benzodiazepines with increased sedation
and psychomotor impairment.
C. Carbamazepine: Inhibition of the liver enzyme,
CYP3A4, can elevate carbamazepine levels
moderately. Carbamazepine levels should be
monitored.
D. Phenytoin: Modest elevations of phenytoin via
inhibition of the liver enzyme CYP2C9. Phenytoin
levels should be monitored.
E. Codeine: Inhibition of the liver enzyme, CYP2D6,
prevents conversion of codeine to its active
metabolite and can prevent pain reduction.
F. Fluoxetine is more likely to produce anxiety and
insomnia than the other SSRIs.
G. Refer to tables 1 and 2 for other potential drug
interactions.
Clinical Guidelines: Long half-life permits daily dosing
and decrease withdrawal symptoms following abrupt
discontinuance of medication. Relatively safe in overdose.
The long half-life of fluoxetine/norfluoxetine requires
waiting at least 5 weeks after discontinuation before
starting an MAOI. Several weeks should also elapse
before beginning nefazodone, because nefazodone’s
metabolite is anxiogenic and its metabolism is impaired
by fluoxetine. Patients often require bid dosing above 40
mg per day. Typical dosing would be 40 mg in the
morning and 20-40 mg at noon. Late afternoon doses
often disrupt sleep.
Fluvoxamine (LuVox)
anxiety disorders.
Preparations: 25, 50, 100 mg scored tablets
Dosage:
Initial Dosage: 50 mg/day, then titrate to 300 mg/day
maximum, over several weeks
Elderly: 25-150 mg/day
Children: 25 mg/day initially, then increase by 25 mg
per week as needed to 50-200 mg/day
Half-life: 16-20 hours.
Adverse Drug Reactions:
A. Theophylline: Potent inhibition of the hepatic
enzyme, CYP1A2, can produce toxicity in
combination with theophylline and elevate plasma
levels of other CYP1A2 substrates.
B. Clozapine: Potent inhibition of CYP1A2 can lead to
markedly elevated clozapine levels with potential for
seizures and hypotension.
C. Benzodiazepines: Significant inhibition of the
hepatic enzyme, CYP3A4, can lead to elevated
levels of some benzodiazepines, such as
alprazolam, with subsequent increased sedation
and psychomotor impairment.
D. Beta-Blockers: Significant inhibition of the hepatic
enzyme, CYP2C19, can lead to elevated plasma
concentrations of propranolol, with further
reductions in heart rate and hypotension.
E. Calcium Channel Blockers: Inhibition of the
hepatic enzyme, CYP3A4, can produce elevated
levels of calcium channel blockers, such as
diltiazem, with subsequent bradycardia.
F. Methadone: Fluvoxamine can significantly raise
plasma methadone levels.
G. Carbamazepine: Fluvoxamine may elevate
carbamazepine levels via CYP3A4 inhibition,
leading to toxicity.
H. Refer to general discussion of SSRI adverse drug
interactions for side effects typical to all SSRIs and
tables 1 and 2 for further potential drug interactions.
Clinical Guidelines: Patients often require bid dosing at
dosages above 100-200 mg per day. Many drug
interactions with cytochrome P450 metabolized
medications have been reported. The other SSRIs are
just as effective; therefore, it is not commonly used.
Paroxetine (Paxil, Paxil CR)

anxiety disorders.
Preparations: 10, 20, 30, 40 mg tablets; (20 mg tablet is
scored); 10 mg/5 ml solution; 12.5, 25, and 37.5 mg
extended (continuous) release formulation
Dosage:
Depression: 10-20 mg qhs; may increase dose by 10-
20 mg/day each month if partial response occurs
(maximum 80 mg/day). For Paxil CR, begin at 25
mg/day and adjust upwards by 12.5 mg per week if
needed to a maximum dosage of 62.5 mg/day.
Obsessive-Compulsive Disorder: 20 mg per day to
start, then increase by 10-20 mg/day per month if
partial response occurs (maximum 80 mg/day).
Panic Disorder: Begin with 5-10 mg qhs, then
increase dose by 10 mg every 2-4 weeks as tolerated
until symptoms abate, up to 40 mg/day. For Paxil CR,
begin at 12.5 mg/day and increase by 12.5 mg per
week as need up to a maximum dosage of 75 mg per
day.
Social Anxiety Disorder: Begin with 20 mg qhs. In
some patients, an initial dosage of 10 mg qhs for one
week, then 20 mg qhs, may reduce side effects,
especially in highly anxious patients. If clinical
response is inadequate, increase the dosage by 10-20
mg/day every 4-6 weeks to a maximum dosage of 60
mg/day.
Elderly: 5-40 mg/day for immediate release and 12.5
to 50 mg per day for Paxil CR.
Half-life: 15-20 hours
Adverse Drug Reactions: Paroxetine is a potent
inhibitor of the liver enzyme, CYP2D6. Use caution when
combining with TCAs, or antiarrhythmics. Can also
elevate levels of some neuroleptics and increase the
incidence of EPS.
Clinical Guidelines: A reduction in anxiety often occurs
early in treatment due to sedating properties. Paroxetine
is less activating than fluoxetine and more sedating than
fluoxetine or sertraline for most patients. Paroxetine
should be taken at bedtime because it has sedative
properties, compared to fluoxetine of sertraline. Mild
anticholinergic effects (unlike other SSRIs) may occur
with paroxetine, and cholinergic rebound can occur with
discontinuation. Relatively safe in overdose. Patients may
require bid dosing at dosages above 40 mg per day. Paxil
CR at a dosage of 37.5 mg is bioequivalent to 30 mg or
immediate release Paxil. Paxil CR may have a decrease
in side effects such as nausea compared to immediate
release paroxetine.
Sertraline (Zoloft)
anxiety disorders.
Preparations: 25, 50, 100 mg scored tablets
Dosage:
Depression: 50 mg qAM, then increase by 50 mg/day
per month in patients with partial response (maximum
dose of 200 mg/day)
Obsessive-Compulsive Disorder: Begin with 50 mg
qAM and increase by 50 mg/day per month in partial
responders to a maximum of 200-300 mg/day
Panic Disorder/PTSD: Begin with 25 mg qAM and
increase dose by 25 mg every 2-4 weeks until
symptoms abate, to a maximum dose of 200 mg per
day. Patients with severe anxiety or sensitivity to
medication may be started at 12.5 mg for the first
week.
Premenstrual Dysphoric Disorder (PMDD): 50 mg
per day throughout the menstrual cycle or limited to
the luteal phase.
Children: 25 mg/day for ages 6-12 and 50 mg/day for
adolescents age 13-17.
Half-life: 24 hours for sertraline and 2-4 days for its
metabolite, desmethylsertraline
Adverse Drug Reactions: Cytochrome P450: Modest,
but significant inhibition of the hepatic enzyme, CYP2D6,
may lead to mild elevations of TCAs and antiarrhythmics.
Clinical Guidelines: Sertraline is less likely to cause
sedation compared to paroxetine or fluvoxamine. It is less
likely to produce restlessness or insomnia compared to
fluoxetine. Sertraline,escitalopram and citalopram have
the lowest overall P450 enzyme effects of the SSRIs (see
table 2).
References, see page 102.

Atypical Antidepressants
Atypical antidepressants are unique compounds that are

chemically unrelated to the SSRIs, TCAs and MAOIs.
They are indicated for depression and require the same
amount of time to achieve clinical efficacy. Like other
antidepressants, these agents may cause mania or rapid
cycling in bipolar patients. The use of MAOIs with these
agents can lead to a serotonergic syndrome, which may
be characterized by nausea, confusion, hyperthermia,
autonomic instability, tremor, myoclonus, rigidity,
seizures, coma and death. These antidepressants are
contraindicated for two weeks before or after the use of
an MAOI.
Bupropion (Wellbutrin, Zyban and

Wellbutrin SR)
I. Indications
A. Bupropion is effective in the treatment of major
depression, dysthymia, and bipolar depression.
Bupropion is also used for the treatment of
Attention-Deficit Hyperactivity Disorder.
B. Low-dose bupropion is used adjunctively to treat
the sexual dysfunction associated with SSRIs.
II. Pharmacology
A. Bupropion is a unicyclic aminoketone
antidepressant with a half-life of 4-24 hours. It is
thought to work via inhibition of norepinephrine
reuptake as well as its effect on dopaminegic
neurotransmission.
B. Therapeutic levels have not been established.
III. Clinical Guidelines
A. Preparations: 75 and 100 mg regular release
tablets and 100,150 and 200 mg sustained release,
non-scored, tablets.
B. Dosage
1. Initial Dosage: 100 mg bid, then increase to
100 tid after 4-5 days. Although bupropion has a
short half-life and is recommended for tid dosing,
many clinicians use bid dosing with the regular
release tablets as well as the sustained release.
Do not increase by more than 100 mg every 3
days.
2. Slow Release: Begin with 150 mg qAM for three
days, then increase to 150 mg bid for SR tabs.
Maximum dose of 200 mg SR tabs bid. The
sustained release bid preparation improves
compliance.
3. Average Dosage: 300 mg/day (divided doses).
Do not exceed 150 mg/dose for the regular
release or 200 mg/dose with sustained release,
with doses at least 6 hours apart.
4. Dosage Range: 75-450 mg/day (max 450
mg/day)
5. Elderly: 75-450 mg/day
C. Side-Effect Profile: Bupropion has fewer side
effects than TCAs and causes less sexual
dysfunction than the SSRIs. It does not produce
weight gain or orthostatic hypotension.
D. Cardiac Profile: Bupropion does not have
significant effects on cardiac conduction or
ventricular function and is a good choice in patients
with cardiac disease, such as congestive heart
failure.
IV.Adverse Drug Reactions
A. Most common side effects: Insomnia, CNS
stimulation, headache, constipation, dry mouth,
nausea, tremor.
B. Anorexia/Bulimia: Avoid bupropion in patients with
anorexia or bulimia, due to possible electrolyte
changes, potentiating seizures.
C. Liver/Renal Disease: Use caution in patients with
hepatic or renal disease, due to potential elevation
of plasma bupropion levels and toxicity.
D. Pregnancy/Lactation: Bupropion is not
recommend during pregnancy or while breast
feeding.
E. Seizures: Bupropion has a seizure rate of 0.4% at
doses less than 450 mg/day and 4% at doses of
450-600 mg/day. The sustained release preparation
has an incidence of 0.1% at doses up to 300 mg
per day. Bupropion is contraindicated in patients
with a history of seizure, brain injury or EEG
abnormality, or recent history of alcohol withdrawal.
A. Hepatically Metabolized Medications
1. Cimetidine may inhibit the metabolism of
bupropion and lead to elevated bupropion
plasma levels and subsequent toxicity.
2. Bupropion is a significant inhibitor of CYP2D6
and can lead to a two fold increase in maximum
concentration or five fold increase in AUC of
CYP2D6 substrates such as desipramine. If
bupropion is added to a treatment regimen of
medications metabolized by CYP2D6, the
dosage of the other medications may need to be
reduced. Examples would be certain tricyclic
antidepressants, Type 1C antiarrhythmics and
beta- blockers such as metoprolol.
3. Carbamazepine, phenobarbital, and
phenytoin may induce the enzymes responsible
for the metabolism of bupropion with a
subsequent decrease in plasma bupropion
levels.
4. Dopamine Agonists: Levodopa may cause
confusion or dyskinesias.
B. MAOIs: Combining bupropion with an MAOI can
lead to a serotonergic syndrome with severe
toxicity.
Duloxetine (Cymbalta)
I. Indications (FDA approval pending).
A. Duloxetine is effective for the treatment of major
depression.
II. Pharmacology
A. Duloxetine blocks serotonin and norepinephrine
transporters.
B. Half life is 12 hours.
A. Preparations: 20 mg capsules.
B. Dosage.
1. Initial dosage: 20 - 60 mg po q am.
2. Average dosage: 60 mg po q am.
C. Small increases in heart rate can be observed.
D. Abrupt discontinuation can be associated with
transient sleep disturbance and increases in HR.
A. Common Adverse Reactions: nausea, dry mouth,
dizziness, constipation, headache.
V. Drug Interactions: Not yet determined.
Gepirone ER
I. Indications (FDA approval pending).
A. Gepirone is effective in the treatment of major
depression.
II. Pharmacology
A. Gepirone is a pyridinyl piperazine 5HT1A agonist.
B. Gepirone has differential action at presynaptic
(agonist) and post-synaptic (partial agonist) 5-HT1A
receptors. Compared to buspirone, it has much
less D2 receptor affinity.
A. Preparations: Extended-release 20 mg tablets.
B. Dosage
1. Initial dosage: 20 mg PO qAM, increase every
4 days by 20 mg.
2. Average dosage: 60 mg/day is likely to be the
most common dosage.
3. Dosage range: 40-80 mg/day.
C. Gepirone has minimal effects on weight, sexual
function, or sedation.
A. Common Adverse Reactions: Dizziness, nausea,
insomnia, nervousness, dry mouth, and GI distress.
A. Gepirone does not inhibit P450 enzymes to a
significant extent.
B. Because it is metabolized through by the CYP3A4
enzyme primarily (CYP2D6 to a lesser extent),
inhibitors of CYP3A4 can alter kinetics.
Nefazodone (Serzone)
I. Indications
A. Nefazodone is effective in the treatment of major
depression, dysthymia, and the depressed phase of
bipolar disorder.
B. Nefazodone (Serzone) is also used clinically for
premenstrual dysphoric disorder, chronic pain, and
posttraumatic stress disorder.
II. Pharmacology
A. Nefazodone is the phenylpiperazine analog of
trazodone and has a half-life of 2-18 hours.
Nefazodone inhibits presynaptic serotonin reuptake
and blocks postsynaptic serotonin receptors (5HT-
2A).
B. Therapeutic levels have not been established.
A. Preparations: 50, 100, 150, 200, and 250 mg
tablets; the 100 and 150 mg tablets are scored.
B. Dosage
1. Initial dosage: 50-100 mg bid, then increase
gradually after several days to weeks by 50-100
mg per day.
2. Average dosage: 300-500 mg/day with bid
dosing.
4. Elderly: Start with 50 mg/day, range: 100-200
bid.
C. REM Sleep: Nefazodone does not suppress REM
sleep, unlike most antidepressants.
D. Sexual Functioning: Unlike other antidepressants,
nefazodone has no adverse effects on sexual
functioning.
A. Common Adverse Reactions: The most common
side effects are nausea, dry mouth, dizziness,
sedation, agitation, constipation, weight loss, and
headaches.
B. Hepatic Disease: Cases of life-threatening hepatic
failure have been reported at a rate of 1 case of
hepatic failure resulting in death or liver transplant
per 250,000-300,000 patient years of nefazodone
treatment. While there is no evidence that pre-
existing liver disease increases the likelihood of
liver failure ,nefazodone should not be initiated if
active liver disease or elevated transaminases are
present as it complicates monitoring. Patients who
develop increased transaminases more than three
times normal should be discontinued from
treatment.
C. Alpha Adrenergic Blockade: Nefazodone
produces less orthostatic hypotension than
trazodone or tricyclic antidepressants.
D. Histaminic Blockade: Nefazodone has little effect
on histamine receptors and produces less weight
gain than TCAs or trazodone.
E. Cardiac Effects: Nefazodone does not alter
cardiac conduction.
A. CYP3A4: Nefazodone is a significant inhibitor of the
hepatic CYP3A4 enzyme, and levels of all
medications metabolized by this enzyme may be
elevated. Levels of triazolam and alprazolam may
be increased.
B. Cytochrome P450 Inhibitors: A metabolite of
nefazodone, CPP, is inactivated by the cytochrome
P450 enzyme system. In the presence of a strong
inhibitor hepatic CYP2D6 enzyme, such as
fluoxetine, M-CPP is not broken down, resulting in
anxiety. When switching from fluoxetine or
paroxetine to nefazodone, a wash out period of 3-4
days for paroxetine and several weeks for fluoxetine
is recommended to avoid this adverse reaction.
C. Other Cytochrome P450 Enzymes: Nefazodone
does not appear to affect the metabolism of
medications metabolized by other P450 enzymes.
D. Digoxin: Nefazodone can produce modest
increases in digoxin levels.
E. MAOI: The combination of nefazodone with a MAOI
can lead to a serotonergic syndrome and severe
toxicity.
Trazodone (Desyrel)
I. Indications
A. Approved for use in depressive disorders. It is also
used clinically to reduce anxiety and decrease
agitation and aggression in elderly demented
patients.
B. Trazodone is commonly prescribed for insomnia,
and it is also effective in some patients with chronic
pain syndromes.
II. Pharmacology
A. Trazodone is a triazolopyridine with a half-life of 4-9
hours.
B. Its efficacy is related primarily to inhibition of
presynaptic serotonin reuptake, with possible mild
postsynaptic serotonergic agonism.
C. Plasma levels are not clinically useful.
A. Preparations: 50, 100, 150, and 300 mg tablets.
B. Dosage:
1. Initial dosage: 50-100 mg qhs, then increase by
50 mg/day as tolerated. May require bid dosing
initially.
2. Average dosage: 300-600 mg/day.
4. Elderly: 50-500 mg/day.
5. Insomnia: 25-200 mg qhs.
C. Tolerability: Many patients are unable to tolerate
the sedation and hypotension associated with an
antidepressant dosage. This significantly limits its
utility in the treatment of depression. It is therefore
most often used for insomnia, especially in patients
with SSRI-induced insomnia.
A. Histaminic Blockade: Trazodone is a potent
antihistamine and can lead to significant sedation
and weight gain.
B. Alpha-1 Adrenergic Blockade: Marked Inhibition
of alpha-1 adrenergic receptors often leads to
severe hypotension, especially at high doses.
Reflex tachycardia and dizziness may also occur.
C. Cholinergic Blockade: Trazodone has little impact
on muscarinic receptors and does not produce the
anticholinergic effects seen with TCAs.
D. Dry Mouth: Trazodone commonly causes dry
mouth.
E. Cardiac Effects: Trazodone has little effect on
cardiac conduction; however, there have been
reports of exacerbation of arrhythmias in patients
with preexisting conduction abnormalities. It should
be avoided in patients with recent myocardial
infarction.
F. Priapism: A prolonged, painful penile erection
occurs in 1/6000 patients, due to alpha-2 blockade.
Patients can be treated with intracavernal injection
of epinephrine.
G. Miscellaneous: Nausea, GI irritation and
headaches may occur.
H. Pregnancy/Lactation: Avoid use in pregnancy due
to potential teratogenicity. Patients should not
breast feed while using trazodone.
I. Overdose: Trazodone is much safer in overdose
than TCAs, but fatalities can occur with combined
overdose with alcohol or sedative/hypnotics.
J. ECT: Use of trazodone is not recommended during
ETC.
A. CNS Depressants: Trazodone may potentiate the
effects of other sedating medications.
B. Fluoxetine may elevate trazodone levels, but the
combination is generally safe and low-dose
trazodone is very effective in treating insomnia due
to fluoxetine.
C. Digoxin/Phenytoin: Trazodone may elevate
plasma levels of these drugs.
D. Warfarin: Trazodone has been reported to alter
prothrombin time in patients on warfarin.
E. MAOIs: Avoid combining trazodone with MAOIs
due to the potential of inducing a serotonergic
syndrome.
Venlafaxine (Effexor and Effexor

XR)
I. Indications
A. Venlafaxine is effective in the treatment of major
depression, dysthymia,other depressive disorders
and anxiety disorders such as generalized anxiety
disorder.
B. It may have some efficacy in Attention-Deficit
Hyperactivity Disorder as well as chronic pain
management.
II. Pharmacology
A. Venlafaxine is a phenylethylamine. The half-life is 5
hours for venlafaxine and 10 hours for its active
metabolite, O-desmethylvenlafaxine.
B. Venlafaxine is a selective inhibitor of norepinephrine
and serotonin reuptake.
C. Therapeutic plasma levels have not been
established.
A. Preparations: 25, 37.5, 50, 75, 100 mg scored
immediate release tablets; and 37.5, 75, and 150
mg extended release capsules.
B. Dosage
1. Immediate Release: 75 mg on the first day in
two or three divided doses with food. The dose
may be increased upward in increments of 75 mg
per day as clinically indicated with an average
dose between 75 to 225 mg per day in bid
dosing. Patients usually require several days on
a given dosage before it can be increased.
2. Extended Release: Begin with 37.5 to 75 mg
once a day with food, and increase the dosage
gradually up to 225 mg if needed with an average
dosage of 150 to 175 mg per day.
4. Elderly: 75-375 mg/day.
5. Generalized Anxiety Disorder: Begin with 75
mg Qod of Effexor XR; some patients may need
to begin with 37.5 mg Qod of Effexor XR for one
week and then increase to 75 mg Qod. The
dosage should then be titrated up as clinically
indicated to a maximum dosage of 225 mg/day.
A. Common Side Effects: Insomnia and nervousness
are the most common side effects with venlafaxine.
Nausea, sedation, fatigue, sweating, dizziness,
headache, loss of appetite, constipation and dry
mouth are also common. Some patients have
difficulty tolerating the GI distress and sedation.
B. Blood Pressure: Elevations of supine diastolic
blood pressure to greater than 90 mm Hg and by
more than 10 mm Hg above baseline occur in 3-7%
of patients. Blood pressure should be monitored
periodically in patients on venlafaxine, especially if
there is a history of hypertension.
C. Sexual: Abnormalities of ejaculation/orgasm occur
in approximately 10% of patients.
D. Seizures: Seizures occur in 0.3% of patients.
E. Discontinuation Syndrome: Venlafaxine can
produce dizziness, insomnia, dry mouth, nausea,
nervousness, and sweating with abrupt
discontinuation. It should be slowly tapered over
several weeks when possible.
F. Renal/Hepatic Disease: The clearance of
venlafaxine in patients with liver or renal disease is
significantly altered, and the dosage should be
decreased by approximately 50% in these patients.
G. Cardiac Disease: There is no systematic data on
the use of venlafaxine in patients with recent MI or
cardiac disease. It does not appear to have a
significant effect on patients with normal cardiac
conduction.
H. Pregnancy/Lactation: Avoid use in pregnant
patients due to potential teratogenic effects. Breast
feeding is contraindicated.
A. Cytochrome P450 Interactions: Venlafaxine does
not appear to produce clinically significant inhibition
of hepatic metabolism. It consequently should not
significantly inhibit the metabolism of medications
metabolized by these enzymes.
B. MAOIs: Venlafaxine should not be given
concomitantly with a MAOI because of the possibility
of producing a serotonergic syndrome with
characteristic toxicity.

H e t e r o c y c l i c
Antidepressants
Tertiary Amine Tricyclic

Antidepressants
I. Indications
A. The heterocyclic antidepressants are used in the
treatment of major depression, dysthymia, and the
depressed phase of bipolar disorder.
B. They have efficacy in anxiety disorders, such as
panic disorder, social phobia, generalized anxiety
disorder, and obsessive-compulsive disorder.
C. They are useful adjuncts in the treatment of bulimia
and chronic pain syndromes.
II. Pharmacology
A. The heterocyclic antidepressants are postulated to
work through their effects on monoamine
neurotransmitters such as serotonin, norepinephrine
and dopamine. These agents block the reuptake of
these neurotransmitters to varying degrees and also
interact with muscarinic cholinergic, alpha-1
adrenergic, and histaminic receptors which results
in their characteristic side-effect profile.
B. These antidepressants are rapidly absorbed from
the gut and undergo significant first pass clearance
by the liver. There is marked variability in plasma
levels among individuals, which correlates with
differences in cytochrome P450 isoenzymes.
C. These medications are highly protein bound and
lipid soluble. Their half-lives are usually greater than
24 hours, which allows for once-a-day dosing, and
steady-state levels are reached in approximately five
days.
D. The tertiary tricyclic antidepressant amines, such as
amitriptyline and imipramine, are demethylated to
secondary amine metabolites, nortriptyline and
desipramine, respectively. The tertiary tricyclic
amines have more side effects and greater lethality
in overdose because of greater blockade of
cholinergic, adrenergic and histaminic receptors
compared to secondary amines.
A. Choice of Drug: The selection of a heterocyclic
antidepressant should be based on a patient’s past
response to medication, family history of medication
response, and side-effect profile. For example, if a
patient has previously been effectively treated with
nortriptyline, there is a good chance of a positive
response if the same symptoms recur. Additionally,
if a patient is sensitive to the sedative properties of
medications, a secondary amine should be chosen
over a tertiary amine.
B. Dosage: The dosage of heterocyclic
antidepressants should be titrated upward over
several days to weeks to allow patients to adjust to
side effects. This is a major disadvantage compared
to SSRIs because it significantly increases the time
to reach therapeutic effect in most patients. In
general, most heterocyclics are started at a dose of
25-50 mg per day, and the daily dose is gradually
increased to an average of 150-300 mg per day.
Patients with anxiety disorders, such as panic
disorder, should receive a lower initial dosage, such
as 10 mg of imipramine. Patients with anxiety
disorders may require slow titration to avoid
exacerbation of anxiety symptoms, which is common
at the beginning of treatment. Anxiety and insomnia
may begin to improve within a few days with these
agents.
C. Time to Response: The most common reason for
lack of response is the use of a subtherapeutic dose
or lack of an adequate trial. A therapeutic trial of at
least 3-4 weeks at the maximum tolerated dosage
should be completed before a patient is considered
a nonresponder. Some patients may require 6-8
weeks of treatment before responding.
A. Elderly patients are much more sensitive to the
side effects of TCAs, and they may be unable to
tolerate therapeutic dosages.
B. Anticholinergic Effects: Cholinergic blockade can
produce dry mouth, blurred vision, constipation,
urinary retention, heat intolerance, tachycardia, and
exacerbation of narrow angle glaucoma.
Constipation may be alleviated by stool softeners.
Dry mouth can be improved with the use of
sugarless candy.
C. Alpha Adrenergic Effects: Alpha-1 adrenergic
receptor blockade can lead to orthostatic
hypotension, resulting in falls. Dizziness and reflex
tachycardia may also occur.
D. Histaminic Effects: Histaminic blockade can
produce sedation and weight gain. Many of these
agents should be given at bedtime to prevent
excess daytime sedation.
E. Cardiotoxicity: Heterocyclic antidepressants slow
cardiac conduction, leading to intraventricular
conduction delays, prolonged PR and QT intervals,
AV block, and T-wave flattening. These agents are
contraindicated in patients with preexisting
conduction delays, such as a bundle branch block,
or in patients with arrhythmias or recent myocardial
infarction. These effects can also be seen with
overdose. These agents can also cause tachycardia
and elevations of blood pressure.
F. Seizures: Seizures occur at a rate of approximately
0.3%, and they are more likely to occur with
elevated blood plasma levels, especially with
clomipramine, amoxapine, and maprotiline.
G. Neurotoxicity: Heterocyclics may produce tremors
and ataxia. In overdose, agitation, delirium,
seizures, coma and death may occur.
H. Serotonergic Effects: Erectile and ejaculatory
dysfunction may occur in males, and anorgasmia
may occur in females.
I. Overdose: Heterocyclic agents are extremely toxic
in overdose. Overdose with as little as 1-2 grams
may cause death. Death usually occurs from cardiac
arrhythmias, seizures, or severe hypotension.
J. Mania: Heterocyclic antidepressants can precipitate
mania or rapid cycling in patients with bipolar
disorder.
K. Liver/Renal Disease: Patients with hepatic or renal
disease may require a lower dosage. Severe
disease is a contraindication for TCAs.
L. Discontinuation Syndrome: Abrupt discontinuation
of these agents may lead to transient dizziness,
nausea, headache, diaphoresis, insomnia, and
malaise. These effects are mostly related to
cholinergic and serotonergic rebound. After
prolonged treatment with heterocyclic agents, they
should be tapered gradually over several weeks.
M. Teratogenic Effects: Heterocyclic antidepressants
are classified as pregnancy class C. However, there
is no evidence that TCAs cause major birth defects
in humans. The impact of untreated depression on
the mother and fetus must be considered when
determining these risk benefit decisions. Lack of
treatment during pregnancy can lead to severe
adverse consequences for the woman and fetus.
Data on behavioral teratogenicity is limited.
N. Breast Feeding: Heterocyclics are excreted in
breast milk, and mothers should not breast feed
when taking these agents.
A. Plasma Level Increases: Some of the new
generation antidepressants, such as fluoxetine, can
elevate heterocyclic antidepressants levels, leading
to marked toxicity.
B. Plasma Level Decreases: Oral contraceptives,
carbamazepine, barbiturates, chloral hydrate, and
cigarette smoking can induce hepatic enzymes and
lead to decreased levels of heterocyclics.
C. Antihypertensives: Heterocyclic agents can block
the effects of antihypertensive agents, such as
clonidine and propranolol.
D. MAOIs: The combination of heterocyclic agents with
monoamine oxidase inhibitors can lead to a
hypertensive crisis or a “serotonin syndrome,”
characterized by confusion, agitation, myoclonus,
hyperreflexia, autonomic instability, delirium, coma,
and even death. MAO inhibitors should be
discontinued for 2 weeks before or after the use of
a heterocyclic antidepressant.
E. Anticholinergic Toxicity: The combination of
heterocyclics with other medications with
anticholinergic properties can potentiate
anticholinergic effects and may lead to delirium.
Amitriptyline (Elavil, Endep)

Indications: Depressive disorders, anxiety disorders,
chronic pain, and insomnia.
Preparations: 10, 25, 50, 75, 100, 150 mg tablets; 10
mg/mL solution for IM injection.
Dosage:
Initial dosage: 25 mg qhs, then increase over 1-4
week period
Average dosage: 150-250 mg/day
Dosage range: 50-300 mg/day
Chronic Pain Syndromes: 25-300 mg qhs
Half-life: 10-50 hr.
Therapeutic Level: 100-250 ng/mL (amitriptyline +
nortriptyline)
Clinical Guidelines: Amitriptyline is widely used in the
treatment of chronic pain and is effective in the
prophylaxis of migraine headaches. Strong anticholinergic
effects are often difficult for patients to tolerate. It is useful
for insomnia, at a dosage of 25-100 mg qhs.
Clomipramine (Anafranil)
Indications: Depressive disorders and obsessive-
compulsive disorder.
Preparations: 25, 50, 75 mg capsules.
Dosage:
week period.
Average dose: 150-250 mg/day
Dosage Range: 50-250 mg/day
Panic disorder: 25-150 mg qhs
Therapeutic Level: 150-300 ng/mL
Clinical Guidelines: FDA approved for the treatment of
OCD. OCD symptoms may require a longer duration of
treatment (2-3 months) to achieve efficacy. Clomipramine
may be especially useful in depressed patients with
strong obsessional features. The side-effect profile
(sedation and anticholinergic effects) often prevents
patients from achieving an adequate dosage.
Clomipramine has a higher risk of seizures than other
TCAs.
Doxepin (Adapin, Sinequan)

insomnia, and chronic pain.
Preparations: 15, 25, 50, 75, 100, 150 mg tablets; 10
mg/mL liquid concentrate.
Dosage:
Initial dosage: 25 mg qhs or bid, then increase over 1-
4 week period
Insomnia: 25-150 mg Qhs
Half-Life: 8-24 hr.
Therapeutic Levels: 100-250 ng/mL
Clinical Guidelines: Doxepin may be used in the
treatment of chronic pain. It is one of the most sedating
TCAs. The strong antihistamine properties of doxepin
make it one of the most effective antipruritic agents
available. It is useful for insomnia at a dosage of 25-150
mg qhs.
Imipramine (Tofranil)
enuresis, chronic pain.
Preparations: 10, 25, 50 mg tablets; 75, 100, 125, 150
mg capsules; 25 mg/2 mL solution for IM injection.
Dosage:
week period
Elderly: 25-75 mg qhs (max 200 mg/day)
Half-Life: 5-25 hr.
Therapeutic Levels: 150-300 ng/mL (imipramine and
desipramine)
Clinical Guidelines: Imipramine has well-documented
effectiveness in the treatment of panic disorder.
Imipramine is effective in the treatment of enuresis in
children. The dosage for enuresis is usually 50-100 mg
per day.
Trimipramine (Surmontil)
Indications: Depressive disorders, anxiety disorders.
Preparations: 25, 50, 100 mg capsules
Dosage:
week period.
Dosage Range: 50-300 mg/day
Elderly: 25-50 mg qhs (max 200 mg/day)
Therapeutic Levels: Unknown
Clinical Guidelines: Trimipramine has no significant
advantages over other TCAs.

Secondary Amine
Tricyclic Antidepressants
Desipramine (Norpramin)
Indications: Depressive disorders, anxiety disorders, and
chronic pain.
Preparations: 10, 25, 50, 75, 100, 150 mg tablets; 25, 50
mg capsules.
Dosage:
week period
Elderly: 25-100 mg/day (max 200 mg/day)
Half-Life: 12-24 hr.
Clinical Guidelines: Desipramine is one of the least
sedating and least anticholinergic TCAs. It should be
considered a first-line heterocyclic agents in elderly
patients. Some patients may require AM dosing due to
mild CNS activation.
Nortriptyline (Pamelor, Aventyl)

Indications: Depressive disorders, anxiety disorders, and
chronic pain.
Preparations: 10, 25, 50, 75 mg capsules; 10 mg/5 m
liquid concentrate.
Dosage:
week period
Elderly: 10-75 mg/day (max 150 mg/day)
Clinical Guidelines: Nortriptyline is widely used in the
treatment of chronic pain. It is one of the least likely TCAs
to cause orthostatic hypotension and it is a good choice
for elderly patients who require a TCA. Nortriptyline is the
only antidepressant with known therapeutic serum levels.
Patients generally respond at serum levels between 50-
150 ng/mL.
Protriptyline (Vivactil)
Indications: Depressive disorders.
Preparations: 5, 10 mg tablets.
Dosage:
Initial dosage: 5 mg qAM, then increase over several
days to weeks.
Elderly: 5 mg tid (max 40 mg/day)
Clinical Guidelines: Protriptyline is the least sedating
and most activating TCA. Avoid giving near bedtime
because it can cause insomnia. It has no advantage over
other TCAs and is not commonly used.

T e t r a c y c l i c
Antidepressants
Amoxapine (Asendin)
Indications: Depressive disorders, especially major
depression with psychotic features.
Preparations: 25, 50, 100, 150 mg tablets.
Dosage:
Initial dosage: 25-50 mg qhs, then increase gradually
over 1-4 week period.
Average dosage: 200-250 mg/day.
Dosage range: 50-300 mg/day.
Elderly: Start with 25 mg qhs; increase to 50 mg bid-tid
(maximum 300 mg/day).
Half-Life: 8 hr.
Clinical Guidelines: Amoxapine is related to the
antipsychotic loxapine. Blockade of dopamine receptors
may produce extrapyramidal symptoms (EPS) due to
dopamine antagonism of its metabolite loxapine (eg,
dystonia, akathisia, Parkinsonian symptoms). Dopamine
receptor blockade can lead to hyperprolactinemia with
subsequent gynecomastia, galactorrhea, or amenorrhea.
Amoxapine is associated with higher rates of seizure,
arrhythmia, and fatality in overdose than many other
antidepressants. The antipsychotic properties of loxapine
may be useful in the treatment of major depression with
psychotic features. It has added risks of dopamine
antagonist side effects such as tardive dyskinesia.
Maprotiline (Ludiomil)
Preparations: 25, 50, 75 mg tablets.
Dosage:
Initial dosage: 75 mg qhs for 2 weeks, then increase
in 25 mg increments over the next few weeks.
Average dosage: 100-150 mg/day .
Elderly: Start with 25 mg qhs. Increase to 50-75 qhs
(max 100 mg/day).
Clinical Guidelines: Maprotiline is associated with higher
rates of seizure, arrhythmia, and fatality in overdose than
many other antidepressants. Avoid medications that lower
seizure threshold, and avoid use in patients with risk of
alcohol or sedative/hypnotic withdrawal syndrome. Do not
use in patients with a history of seizures. The long half-life
may necessitate a longer period of observation after
overdose. Maprotiline is rarely used.
Mirtazapine (Remeron)
Mechanism: Selective alpha-2 adrenergic antagonist that
e n h a n ce s n o r a d r e n e r g i c a n d se rotonergic
neurotransmission.
Soltabs: Orally disintegrating tablets (15,
30 and 45 mg).
Dosage:
Initial Dosage: Begin with 15 mg qhs and increase to
30 mg after several days to a maximum of 45 mg qhs.
Elderly: Begin with 7.5 mg qhs and increase by 7.5
mg each week to an average of 30 mg qhs.
Therapeutic levels: Not established.
Clinical Guidelines: Mirtazapine has little effect on
sexual function. It may have some efficacy in anxiety
disorders, and its antagonism of 5-HT3 receptors may
help in patients with stomach upset. It has little effect on
drugs metabolized by cytochrome P450 enzymes.
Sedation is the most common side effect and may be
marked initially, but usually decreases over the first week
of treatment. Increase in appetite is frequent with an
average weight gain of 2.0 kg after six weeks of
treatment. Dry mouth, constipation, fatigue, dizziness,
and orthostatic hypertension may occur. Agranulocytosis
has occurred in two patients, and neutropenia has
occurred in one patient during clinical trials with 2,800
patients. If a patient develops signs of an infection along
with a low WBC, mirtazapine should be discontinued.
Drug Interactions: Mirtazapine has a low liability for drug
interactions.

Monoamine Oxidase
Inhibitors
I. Indications
A. Monoamine oxidase inhibitors(MAOIs) are used in
the treatment of depressive and anxiety disorders.
MAOIs are particularly useful in the treatment of
major depression with atypical features, such as
mood reactivity, increased appetite, hypersomnia,
and sensitivity to interpersonal rejection.
B. These agents also have significant efficacy in
anxiety disorders such as social phobia and panic
disorder with agoraphobia and obsessive-
compulsive disorder.
C. Given the dietary restrictions and risk of
hypertensive crisis, most clinicians use MAOIs only
after more conventional treatments have failed.
II. Pharmacology
A. Monoamine oxidase inhibitors irreversibly inhibit the
enzyme, monoamine oxidase, located in the central
nervous system, gut and platelets, leading to lack of
degradation of monoamines.
B. The human body requires two weeks after
discontinuing an MAOI to replenish the body with
normal amounts of the monoamine oxidase enzyme.
C. MAOIs inhibit monamine oxidase in the gut wall
which leads to increased absorption of tyramine.
Tyramine can act as a false neurotransmitter and
elevate blood pressure.
A. Dietary Restrictions: These agents require
patients to adhere to a low tyramine diet in order to
avoid a hypertensive crisis.
B. Dose Titration: In order to minimize side effects,
these agents must be started at a low dose and
titrated upward over days to weeks. This is a major
disadvantage compared to SSRIs.
C. Response Time: These agents require at least 3-4
weeks for an adequate therapeutic trial and patients
may respond after 6-8 weeks.
D. Efficacy: May be slightly more effective than other
antidepressant treatments, especially with atypical
depression.
E. Clinical Utility: Given the side-effect profile and
dietary restrictions, these agents are generally
reserved for use in patients who are refractory to
other antidepressant treatments.
A. Alpha-1 Blockade: Alpha-1 adrenergic blockade
can lead to marked orthostatic hypotension. This is
actually the most common side effect despite the
fact that more clinical attention is focused on
hypertensive crisis. This can be treated with salt
supplements, support hose, or the
mineralocorticoid, fludrocortisone. Dizziness and
reflex tachycardia may also occur.
B. Histaminic Blockade: Antihistaminic properties can
lead to sedation and significant weight gain.
C. Hypertensive Crisis: Hypertensive crisis from
consuming tyramine containing foods is
characterized by markedly elevated blood pressure,
headache, sweating, nausea and vomiting,
photophobia, autonomic instability, chest pain,
cardiac arrhythmias, and even coma and death.
D. Treatment of Hypertensive Crisis: Treatment
involves the use of nifedipine, 10 mg sublingual,
while carefully monitoring blood pressure to make
sure it does not drop too far. Alternatively,
chlorpromazine, 50 mg orally, may be given. These
agents can be given to patients to keep with them if
they develop symptoms; however, they must be
careful not to take these agents when they may be
experiencing symptoms of hypotension. If patients
present to the emergency room, they can be given
phentolamine, 5 mg IV, followed by 0.25-0.5 mg IM
every 4 to six hours as indicated.
E. MAOI Diet: Foods to be avoided: Soy sauce,
sauerkraut, aged chicken or beef liver, aged
cheese, fava beans, air-dried sausage or other
meats, pickled or cured meat or fish, overripe fruit,
canned figs, raisins, avocados, yogurt, sour cream,
meat tenderizer, yeast extracts, caviar, and shrimp
paste. Beer and wine are generally contraindicated;
however, recent studies indicate that they contain
very little tyramine.
F. Pyridoxine Deficiency: Pyridoxine deficiency,
manifesting with paraesthesias, may occur and can
be treated with vitamin B6, 50 mg per day.
G. Overdose: Overdose can be fatal and acidification
of the urine or dialysis may be helpful along with
other supportive treatment. Death may occur from
arrhythmias, seizures or renal failure.
H. Surgery: Discontinue MAOIs 14 days before
surgery to prevent hypertensive crisis from
anesthetics.
I. Mania: MAOIs can induce mania or rapid cycling in
patients with bipolar disorder.
J. Comorbid Medical Illness: Use with caution in
patients with liver disease, abnormal liver function
tests, cardiovascular disease, migraine headaches,
renal disease, hyperthyroidism, or Parkinson’s
disease.
K. Pregnancy: Avoid use of MAOIs in pregnancy
secondary to teratogenic potential.
L. Miscellaneous: Other side effects include, liver
toxicity, agitation, dry mouth, constipation, seizures,
sexual dysfunction, insomnia, and edema.
A. Serotonergic Syndrome: A serotonergic syndrome
characterized by nausea, confusion, hyperthermia,
autonomic instability, tremor, myoclonus, rigidity,
seizures, coma and death, can occur when MAOIs
are combined with SSRIs, TCAs, or carbamazepine.
Wait fourteen days after discontinuing a MAOI
before starting a TCA or SSRI. Discontinue
sertraline, fluvoxamine and paroxetine for 14 days
before beginning an MAOI and wait 5-6 weeks after
discontinuing fluoxetine due to the long half-life of
norfluoxetine.
B. Opioids: Opiate analgesics, especially meperidine,
may lead to autonomic instability, delirium and
death.
C. Sympathomimetics: Sympathomimetic agents
such as amphetamines, cocaine, ephedrine,
epinephrine, norepinephrine, dopamine, isoproter-
e n o l , m e t h yl p h e n i d a t e , o xym e t a z o l i n e ,
phenylephrine, phenylpropanolamine metaraminol
can lead to a hypertensive crisis.
D. Antihypertensives: Antihypertensive agents can
further increase the likelihood of hypotension.
E. Oral Hypoglycemics: MAOIs can potentiate
decreases in blood glucose when combined with
oral hypoglycemics.
Phenelzine (Nardil)
Indications: Effective for atypical depression. Also used
for anxiety disorders such as panic disorder with
agoraphobia, social phobia, and obsessive-compulsive
disorder.
Preparations: 15 mg tablets.
Dosage:
Initial dosage: 15 mg bid; increase by 15 mg/day each
week.
Elderly: Start with 7.5-15 mg/day; max 60 mg/day.
Therapeutic Levels: Not established.
Clinical Guidelines: Major morbidity and mortality risks
are associated with MAOI use. Phenelzine is associated
with a higher incidence of weight gain, drowsiness, dry
mouth, and sexual dysfunction than tranylcypromine.
Tranylcypromine (Parnate)
Indications: Approved for atypical depression. Also used
for anxiety disorders, such as panic disorder with
agoraphobia, social phobia, and obsessive-compulsive
disorder.
Preparations: 10 mg tablets
Dosage:
Initial dosage: 10 mg bid. Increase by 10 mg/day each
week.
Elderly: Start with 5-10 mg/day; max 30-40 mg/day.
Therapeutic Levels: Not established.
Clinical Guidelines: Major morbidity and mortality risks
are associated with MAO-I use. Phenelzine is associated
with higher incidences of weight gain, drowsiness, dry
mouth, and sexual dysfunction than tranylcypromine.
Tranylcypromine is more likely to cause insomnia than
phenelzine.

Antipsychotics
Clinical Use of Antipsychotics

I. Indications: Antipsychotic agents (also referred to as
neuroleptics) are indicated for the treatment of
schizophrenia. Antipsychotics are also used for
schizoaffective disorder, mood disorders with psychotic
symptoms, and brief psychotic disorder. They often
improve functioning in patients with dementia or
delirium when psychotic symptoms are present. They
are also frequently used for treatment of substance
induced psychotic disorders and in psychotic symptoms
associated with certain personality disorders
(borderline).
II. Pharmacology: Typical and atypical antipsychotics
are distinguished by their unique receptor binding
profiles primarily with dopamine and serotonin
receptors. Typical antipsychotic agents have been the
first-line treatment for schizophrenia. New atypical
antipsychotics, however, are challenging this first-line
position because of their greater tolerability and
increased efficacy.
A. The efficacy of typical antipsychotic agents is
primarily related to their binding to dopamine D2
receptors.
1. Typical antipsychotic agents may be divided into
high-, moderate-, and low-potency categories
based on their level of dopamine receptor
antagonism.
2. All agents within the typical antipsychotic
category are equally effective.
a. High-potency agents have the highest affinity
for D2 receptors and are effective at relatively
lower doses.
b. Low-potency agents have lower D2 affinity
and require larger doses to elicit an
antipsychotic effect.
B. Atypical agents (serotonin-dopamine antagonists,
SDAs) are distinguished by their prominent
antagonism at the serotonin 2A receptor in addition
to D2 blockade. The ratio of serotonin to dopamine
blockade is generally high for these agents. These
agents are also unique in that there appears to be
more selectivity for the mesolimbic dopamine
pathway, which is thought to be a site of
antipsychotic action. There is relatively less action
on the nigrostriatal pathway where extrapyramidal
side effects are thought to originate. As a group
these drugs have a therapeutic dose range that
allows for the antipsychotic effect without inducing
significant extrapyramidal symptoms.
1. Clozapine is an antagonist of serotonin-2A,
alpha-1, dopamine-1, 2, and 4 receptors.
Clozapine also possesses significant
antihistamine and anticholinergic properties,
leading to a side-effect profile similar to that of
the typical low-potency agents.
2. SDAs include risperidone (Risperdal),
olanzapine (Zyprexa), ziprasidone (Geodon) and
quetiapine (Seroquel).
C. Pharmacokinetics
1. After oral absorption, peak plasma levels of
antipsychotics usually occur within 2-4 hours.
Liquid preparations are absorbed more quickly.
IM injections reach peak levels in 30-60 minutes.
2. Antipsychotic agents undergo extensive hepatic
metabolism. Typically 50% of the antipsychotic
is excreted via enterohepatic circulation and
50% through the kidneys.
3. Antipsychotics are 85-90% protein bound and
highly lipophilic.
4. Half-lives generally range from 5-50 hours.
Steady state plasma levels are established in 4-
10 days.
A. Choosing an Antipsychotic Agent
1. In general, the choice of neuroleptic should be
made based on past history of response to a
neuroleptic and side effects.
2. Atypical antipsychotics have gained acceptance
as first-line drugs for treatment of psychosis.
They can contribute to superior long-term
outcome in treatment of schizophrenia compared
to typicals. At least two weeks of treatment is
required before a significant antipsychotic effect
is achieved.
3. Poor response of negative symptoms (affective
flattening) is an indication for a trial of an atypical
agent. Negative symptoms can occur secondary
to treatment with typical neuroleptics.
4. Patients with tardive dyskinesia (TD) should be
considered for treatment with an atypical agent
to avoid progression of neurological impairment.
a. Clozapine is not associated with TD.
b. Olanzapine (Zyprexa), risperidone
(Risperdal), quetiapine (Seroquel) and
ziprasidone (Geodon) have significantly
reduced incidences of TD.
B. Efficacy
1. Positive Symptoms: With the exception of
clozapine, no differences have been clearly
shown in the efficacy of typical and atypical
agents in the treatment of positive symptoms
(eg, hallucinations, delusions, disorganization)
2. Negative Symptoms: Atypical agents may be
more effective in the treatment of negative
symptoms (eg, affective flattening, anhedonia,
avolition) associated with psychotic disorders.
The evidence, however, does not conclusively
support this view.
3. Treatment-Resistant Psychosis: Patients
failing to respond to adequate trials of typical
agents may respond to an atypical agent. Thirty
percent of poor responders to typical agents
show significant improvement when treated with
clozapine.
A. Tardive dyskinesia (TD) is a long-term, often
permanent, neurological impairment resulting from
extensive use of typical antipsychotics. Atypical
agents, however, have minimal risk of TD.
B. Neuroleptic malignant syndrome is an
uncommon, yet potentially fatal, adverse reaction to
typical antipsychotics. Although some risk of
neuroleptic malignant syndrome may be present
with risperidone use, this risk is minimal with
clozapine.
C. Side Effects
1. The older typical antipsychotics have traditionally
been classified according to their potency.
Chlorpromazine is an example of low- potency
drug where a dose fo 500-1000 mg is often used
while haloperidol is an example of high-potency
antipsychotic (5-10 mg is a usual dose). Low-
potency typical antipsychotic agents and
clozapine have more troublesome side effects
than high-potency agents because of greater
antagonism of cholinergic, adrenergic, and
histaminergic receptors. High-potency typical
agents, however, have more frequent
extrapyramidal side effects because of potent
antagonism of dopamine receptors. The atypical
agents generally have much lower antagonism of
cholinergic, adrenergic and histaminergic
receptors. Side-effect profiles resulting from
antagonism of these receptor pathways is
summarized as follows:
a. Muscarinic (cholinergic): Dry mouth,
constipation, urinary retention, blurred vision,
precipitation of narrow angle glaucoma, ECG
changes
b. Alpha-1 Adrenergic: Orthostatic
hypotension, lightheadedness, tachycardia,
sedation and sexual dysfunction.
c. Histamine-1: Sedation, weight gain, fatigue.
d. Dopamine-2: Extrapyramidal Parkinsonian
symptoms (eg, dystonic reactions, masked
facies, tremor, shuffling gait);
hyperprolactinemia (not with clozapine),
dystonic reaction, akathisia (restlessness).
e. Serotonin-1C: May mediate weight gain for
some atypical agents (olanzapine).
f. Non-specific Side Effects: Include
hyperthermia, hypothermia, hepatitis,
jaundice, photosensitivity, lowered seizure
threshold, hematologic changes, hepatitis,
and rash.
D. Management of Side Effects
1. Neuroleptic Malignant Syndrome (NMS) is an
uncommon side effect with possible fatal
outcome. NMS is marked by elevated
temperature, autonomic instability, delirium, and
rigid muscle tone, developing over 24-72 hours.
Risk factors for neuroleptic malignant syndrome
include dehydration, heat exhaustion, and poor
nutrition.
2. Agranulocytosis. Most common with clozapine
(1-2% incidence). Clozapine should be
discontinued if WBC drops below 3,000/mcL or
50% of the patient's normal level, or if the
absolute granulocyte count drops below
1,500/mcL.
3. Tardive Dyskinesia (TD) is a neurological
impairment, primarily limited to patients with a
history of chronic neuroleptic administration
(greater than two months). TDs are
characterized by involuntary dyskinetic
movements that may affect any striate muscle
and may result in permanent dysfunction of facial
(eg, lingual, perioral), truncal, esophageal, neck,
or extremity motor function. Risk for TD
increases by 1% with each year of antipsychotic
treatment. Treatment may include the following:
a. Quantify the degree of neurological
dysfunction by using a rating scale, such as
the abnormal involuntary movement scale
(AIMS).
b. Reduce or stop antipsychotic if possible.
c. If continued antipsychotic is necessary,
consider change to an atypi
c a l
age
nt.
d. Some studies suggest that vitamin E offers
modest benefits in prevention and treatment
of TD, particularly if initiated early.
4. Dystonic reactions are characterized by painful,
acute involuntary muscle spasms. They are
common side effects of typical antipsychotic
agents. Dystonic reactions commonly involve the
extremities, neck (torticollis), and ocular muscles
(oculogyric crisis). The muscle contractions are
not life threatening unless they involve airway
passages (eg, larynx) and lead to airway
obstruction. Treatment may include:
a. I n t r a m u s c u l a r or Intravenous
Antiparkinsonian Agent
(1) Benztropine (Cogentin), 1-2 mg PO, IM,
IV or
(2) Diphenhydramine (Benadryl), 50 mg PO,
IM, IV.
b. Consider change of antipsychotic to relieve
patient fears. Prophylaxis against further
episodes of dystonia is accomplished with an
oral anticholinergic agent such as
benztropine (Cogentin), 2 mg PO bid for one
to two months.
5. If dystonic reactions occur after discontinuing
anticholinergic agent, longer prophylactic
treatment should be provided (eg, 3-6 months).
6. Drug-induced parkinsonian symptoms include
bradykinesia, tremor, cogwheel rigidity, masked
facies, and festinating gait. Treatments include:
a. Decreasing antipsychotic dose.
b. Use of anticholinergic drug (eg, benztropine).
c. Changing to lower-potency or atypical agent.
d. Tremor can be treated with propranolol, 10-
40 mg PO bid to qid.
7. Akathisia is characterized by an intense sense of
restlessness or anxiety. Treatments include:
a. Decreasing antipsychotic dose.
b. Trial of anticholinergic agent (eg, benztropine
2 mg PO bid).
c. Trial of beta-adrenergic antagonist such as
propranolol, 10-40 mg PO bid to qid.
d. Trial of a benzodiazepine such as
clonazepam, 0.5 mg PO bid.
e. Consider changing to lower-potency or
atypical agent.
E. Overdose
1. Death is uncommon with antipsychotic overdose.
Risk of fatality is increased with concurrent use
of alcohol or other CNS depressants.
2. Mesoridazine, pimozide and thioridazine are
associated with a greatest risk of fatality because
of heart block and ventricular tachycardia.
3. CNS depression, hypotension, seizures, fever,
ECG changes, hypothermia, and hyperthermia
are possible.
4. Treatment may include gastric lavage, catharsis,
IV diazepam for treatment of seizure, and
medical treatment of hypotension.
F. Drug Interactions
1. Antacids and cimetidine. Absorption of
antipsychotics may be inhibited.
2. A n t i c h o l i n e r g i c s , antihistamines,
antiadrenergics. Additive effects.
3. Antihypertensives may potentiate hypotension
(eg, ACE Inhibitors and alpha-methyldopa); may
inhibit neuronal uptake of clonidine and alpha-
methyldopa.
4. Anticonvulsants may induce metabolism and
decrease level of antipsychotic; phenothiazines
may decrease metabolism/ increase level of
phenytoin.
5. Antidepressants tricyclics and SSRIs may
reduce metabolism and increase levels of
antipsychotics.
6. Antipsychotics may increase levels of tricyclics.
7. Barbiturates by enzyme induction levels of
antipsychotics may be reduced; may cause
respiratory depression.
8. Beta-blockers. Propranolol increases blood
levels of antipsychotics.
9. Bromocriptine may worsen psychotic
symptoms. Antipsychotics will decrease effect of
bromocriptine.
10. Cigarettes may increase metabolism and
decrease level of antipsychotics.
11. C N S depressants (including
benzodiazepines, narcotics, and alcohol)
enhance sedative effects of antipsychotics.
12. Digoxin absorption may be increased.
13. Isoniazid may increase risk of hepatic
toxicity.
14. L-Dopa. Effects blocked by dopamine
antagonists.
15. Lithium. Possible risk of neuroleptic-induced
encephalopathic syndrome or neurotoxicity.
16. MAO inhibitors will potentiate hypotensive
effects of antipsychotics.
17. Metrizamide decreases seizure threshold.
Avoid concomitant use with typical agents.
18. Oral Contraceptives may increase levels of
antipsychotics.
19. Stimulants. Amphetamine may worsen
psychotic symptoms. Antipsychotics will
lessen effects of stimulants.
20. Warfarin. Highly protein-bound, may alter
antipsychotic levels; levels may be decreased
leading to decreased bleeding time.
G. Preexisting Medical Conditions:
1. Cardiac History. Use high-potency agent (other
than pimozide) or atypicals (other than
clozapine) to avoid conduction abnormalities.
2. Elderly patients are more sensitive to side
effects; atypical drugs should be utilized initially.
Most experience is with risperidone, which can
be used in low doses (0.5 mg). If typical agents
are to be used, start with a low dose of a high-
potency agent (0.5 mg of haloperidol) and
increase slowly.
3. Hematologic Disorder. Clozapine is
contraindicated.
4. Hepatic, Renal, Cardiac, Respiratory Disease.
Use antipsychotics with caution; monitor renal,
cardiac, and liver function.
5. Parkinson's Disease. Atypical agents are
preferred due to selectivity for mesolimbic
dopamine tract.
6. Prostatic Hypertrophy. Agents with high
anticholinergic activity are contraindicated.
7. Seizure History. Some studies suggest that
molindone may have lower seizure risk more
than other antipsychotics. Atypicals are also
indicated for patients with a seizure disorder.
Avoid loxapine and clozapine.
8. Pregnancy. Phenothiazines may increase risk of
anomalies. Avoid low-potency agents.
Fluphenazine, haloperidol, trifluoperazine, and
perphenazine are associated with lower risks
during pregnancy.

Atypical Antipsychotics
I. Indications
A. Atypical antipsychotics are indicated for psychotic
disorders including schizophrenia, schizoaffective
disorder, brief psychotic disorders, and psychotic
symptoms associated with mood disorders,
substance abuse, organic brain syndromes,
dementia, and personality disorders.
B. Clozapine has been demonstrated to be more
effective for positive symptoms in treatment-
resistant psychotic patients.
II. Pharmacology
A. The primary distinguishing property of the currently
available atypical agents (serotonin-dopamine
antagonists, SDAs) is prominent antagonism at the
serotonin 2A receptor in addition to D2 blockade.
B. The ratio of serotonin to dopamine blockade is
generally high for these agents. These agents are
also unique in that there appears to be more
selectivity for the mesolimbic dopamine pathway,
which is thought to be important in mediating
antipsychotic action.
C. There is relatively less action on the nigrostriatal
pathway where extrapyramidal side effects are
thought to originate. As a group these drugs have a
therapeutic dose range that allows for the
antipsychotic effect without inducing significant
extrapyramidal symptoms.
D. Clozapine is an antagonist of serotonin-2A, alpha-1,
and dopamine-1, 2, and 4 receptors. Clozapine also
possesses significant antihistamine and
anticholinergic properties, resulting in a side-effect
profile that is similar to that of the typical low-
potency agents.
E. Aripiprazole (Abilify), risperidone (Risperdal),
olanzapine (Zyprexa), ziprasidone (Geodon) and
quetiapine (Seroquel) are available SDAs.
A. Although atypical agents have been reserved for
patients who have failed treatment with one typical
agent, clozapine should be reserved for patients
who have failed to respond to two different
antipsychotics. Atypical antipsychotics have gained
acceptance as first-line drugs for treatment of
psychosis. These agents produce superior long-
term outcomes compared to typicals in the
treatment of schizophrenia.
B. Atypical agents are clearly indicated if a patient
develops significant side effects when treated with
typical agents.
C. Poor response of negative symptoms of psychosis
is an indication for a trial of an atypical agent. Some
negative symptoms can be secondary to treatment
with typical neuroleptics. For example, neuroleptic
induced Parkinsonism being misinterpreted as flat
affect. Although not firmly established, the atypical
agents may be efficacious for primary negative
symptoms.
D. Patients with tardive dyskinesia (TD) should be
considered for treatment with an atypical agent to
avoid progression of neurological impairment.
1. Clozapine is not associated with TDs.
2. Aripiprazole (Abilify), olanzapine (Zyprexa),
risperidone (Risperdal), quetiapine (Seroquel)
and ziprasidone (Geodon) have a significantly
reduced incidence of TD.
IV. Treatment
A. Initial treatment should be continued for four to six
weeks. If there is no response after this period, a
change to an alternate medication is warranted.
B. Medically compromised patients. Atypical agents
are indicated in patients with conditions that
predispose them to increased sensitivity to side
effects of typical agents (eg, dementia, diabetes).
V. Adverse Drug Reactions
A. With the exception of clozapine the atypical agents
are very well tolerated. There is a much lower
occurrence of extrapyramidal symptoms.
B. The atypical agents are expected to have a very low
incidence of neuroleptic malignant syndrome and
tardive dyskinesia.
Aripiprazole (Abilify)
Class: Quinolinone
Mechanism: Aripiprazole is a new partial agonist at the
dopamine D2 and the serotonin 5-HT1A receptors, and it is
an antagonist of the serotonin 5-HT2A receptor.
Indications: Aripiprazole is indicated for psychotic
disorders that are refractory to treatment with typical
antipsychotics. They are indicated for patients with tardive
dyskinesia or severe side effects associated with other
neuroleptics.
Preparations: 10 mg, 15 mg, 20 mg, and 30 mg tablets;
no IM preparation is available.
Dosage:
Initial Dosage: 10-15 mg qAM and increased to 20
to 30 mg per day after 2-4 weeks if needed;
however, clinical trials have not found greater
efficacy for doses above 10-15 mg.
Maintenance: 10-30 mg per day.
Elderly: While aripiprazole clearance is reduced by
20% in patients over 65, no dosage adjustment is
required or recommended at this time. Begin with a
lower dosage in debilitated elderly patients.
Metabolism: Half-life is 75 hours for aripiprazole and 94
hours for its active metabolite, dehydro-aripiprazole.
Hepatic metabolism is mainly through CYP2D6 and
CYP3A4. Poor metabolizers who lack CYP2D6, have an
80% increase in aripiprazole plasma levels and a 30%
decrease in dehyro-aripiprazole levels compared to
normal.
Therapeutic Level: Not established.
Side-Effect Profile: The most common side effect is
nausea, with occasional vomiting, which usually resolves
within one week. The incidence of sedation is low, but can
occur especially at higher dosages. Anxiety and insomnia
may occur, especially early in treatment. Orthostatic
hypotension occurs rarely. The incidence of
extrapyramidal symptoms is comparable to placebo.
Aripiprazole does not appear to effect QTC intervals.
Clinical Guidelines: Aripiprazole should be given in the
morning due to lack of sedation compared to other
agents. It is recommended that aripiprazole can be added
to a current antipsychotic medication regimen with
tapering of the other antipsychotic gradually over time.
Early data seems to indicate a low liability for weight gain,
or changes in glucose or lipid levels. Aripiprazole does
not elevate serum prolactin.
Drug Interactions:
A. Coadminisration of aripiprazole with potent
inhibitors of CYP2D6, such as quinidine, fluoxetine
or paroxetine, can markedly increase blood levels
(112% with quinidine) and requires dosage
adjustment to one-half of its normal dosage.
B. Ketoconazole or other potent inhibitors of CYP3A4
require adjusting aripiprazole to one-half of its
normal dosage.
C. Carbamazepine, a CYP 3A4 inducer, can lower
plasma aripiprazole levels and the dose of
aripiprazole should be doubled when
coadministered.
D. Aripiprazole does not appear to effect levels of
other cytochrome P450 substrates metabolized by
CYP2D6,CYP2C9, CYP2C19, or CYP3A4.
Clozapine (Clozaril)
Class: Dibenzodiazepine
Mechanism: Multiple receptor antagonism: serotonin
5HT2A receptor, dopamine D1, D2, and D4 receptors.
Indications: Psychotic disorders which are refractory to
treatment with typical antipsychotics. They are indicated
for patients with tardive dyskinesia or severe side effects
associated with other neuroleptics.
Preparations: 25, 100 mg scored tablets; no IM
preparation available
Dosage:
Initial Dosage: 25 mg bid, then increase by 25-50
mg every 2-3 days to achieve total daily dose of
between 300-600 mg. Dose may need to be given tid
if side effects occur.
Maintenance: 400-600 mg/day; some patients may
require higher doses but rarely more than 900
mg/day.
Metabolism: Half-life 11 hours, hepatic metabolism,
CYP1A2.
Therapeutic Level: >350 ng/mL.
Side-Effect Profile: Orthostatic hypotension (high),
sedation (high), anticholinergic (high), extrapyramidal
symptoms (absent). Most common: sedation, dizziness,
hypotension, tachycardia, constipation, hyperthermia,
hypersalivation. Hypersalivation can be treated with
anticholinergic agents.
Clinical Guidelines: Clozapine does not cause tardive
dyskinesia or neuroleptic malignant syndrome. Clozapine
is often effective against symptoms that are resistant to
typical agents. It is more effective than typical agents in
treatment of the negative symptoms of schizophrenia.
Clozapine may decrease the risk of suicide in
schizophrenia and an FDA advisory panel has
recommended expanding the indications for clozapine to
include suicide prevention.
Drug Interactions:
A. Cimetidine (Tagamet) may increase clozapine
levels. Use ranitidine (Zantac) instead.
B. Fluvoxamine can double clozapine levels
C. TCAs can increase risk for seizures, cardiac
changes, sedation
Contraindications: Clozapine is contraindicated in
patients with granulocytopenia or a history of
agranulocytosis induced by clozapine. Do not use
clozapine with drugs that suppress bone marrow or have
a risk of agranulocytosis (eg, carbamazepine,
sulfonamides, captopril).
Adverse Effects:
A. Clozapine has a 1-2% incidence of agranulocytosis.
Patients should be instructed to report the onset of
fever, sore throat, weakness or other signs of
infection promptly. Discontinue the drug if the WBC
drops below 3,000/mcL, or 50% of patient's normal
count, or if granulocyte count drops below
1,500/mcL. Once the WBC normalizes, the patient
may be rechallenged. WBC should be monitored
weekly for the first 3 months of treatment.
Thereafter, monitoring can be reduced to every 2
weeks.
B. A 5% incidence of seizure has been noted in
patients taking more than 600 mg/day of clozapine.
If seizures develop, discontinue drug use and
consider restarting with concurrent use of
divalproex sodium (Depakote).
C. Rare myocarditis(5-100 cases/100,000 patient
years) has been seen especially during, but not
limited to the first month of clozapine treatment.
Consider myocarditis if patients present with
unexplained fatigue, dyspnea, tachypnea, fever,
chest pain, palpitations, other signs of heart failure,
or ECG changes such as ST-T wave abnormalities
or arrhythmias.
D. Use clozapine with caution and at low doses in
patients with hepatic or renal disease.
E. Monitor patients for hypotension and tachycardia.
When discontinuing clozapine, the dosage should
be tapered over two weeks because anticholinergic
rebound may occur.
Risperidone (Risperdal)
Class: Benzisoxazole.
Mechanism: Antagonist of serotonin-2A, dopamine-2 and
alpha-1 receptors.
Preparations: 0.25, 0.5, 1, 2, 3, 4 mg tablets (1 mg tablet
is scored); 1 mg/mL oral soln; the long-acting IM
preparation (Consta) is likely to be approved in 2003.
Dosage:
Initial Dosage: 1 mg bid, then increase by 1 mg every
2-3 days to 2-3 mg bid.
Acute agitation: No acute IM dose available.
Maintenance: 2-8 mg bid, many patients can be
treated with 4 mg given as a single dose.
Long-acting IM formulation (Consta)(FDA approval
pending):
25 - 50 mg IM every month (no evidence to increase
beyond 50 mg).
Elderly: reduced dosage (1-4 mg/day).
Metabolism: Half-life is 3-20 hours. Hepatic metabolism
to an active metabolite. Renal clearance. No risperidone-
specific drug interactions.
Side-Effect Profile: Orthostatic hypotension and reflex
tachycardia (alpha 1 receptor mediated, minimized with
slow upward titration), insomnia, and agitation are the
most frequent. Incidence of extrapyramidal symptoms is
very low. Risperidone can cause weight gain and increase
prolactin levels (usually not clinically significant). May
prolong QT interval.
Clinical Guidelines: Risperidone is generally very well
tolerated. A low incidence of extrapyramidal symptoms is
associated with doses less than 6 mg. Risperidone may
be given in once-a-day dose schedules. There is
increasing experience with successful use of risperidone
in elderly populations. There have been a number of
case reports of neuroleptic malignant syndrome.
Olanzapine (Zyprexa, Zydis)

Class: Thienobenzodiazepine
Mechanism: Antagonist of serotonin-2A, dopamine-1, 2,
3, 4, alpha-1, histamine-1, and muscarinic-1 receptors.
Preparations: Zyprexa: 2.5, 5, 7.5, 10, 15 mg tablets.
Zydis: 2.5, 5, 7.5 10, 15 mg orally disintegrating
tablets.
IM Zyprexa (for acute use): FDA approval pending.
Dosage:
Initial dosage: 10 mg/day.
Range: 5-20 mg/day, although some patients may
require higher doses.
IM: 5 -10 mg IM every 2 hours (maximum dose not
determined).
Metabolism: Half-life is 21-50 hours. Hepatic metabolism
(primarily through P450 1A2) to inactive metabolites.
Olanzapine levels may be decreased by tobacco use and
by carbamazepine (1A2 induction). Olanzapine levels
may be increased by fluvoxamine (1A2 inhibition). Dose
should be reduced in the elderly. Olanzapine levels tend
to be higher in females.
Side-Effect Profile: Most common side effects are
drowsiness, dry mouth, akathisia, and insomnia. Less
frequent are orthostatic hypotension, lightheadedness,
nausea, and tremor. Weight gain is common with
olanzapine. Increases in lipids and blood glucose are also
observed. There are reports of new onset diabetes and
diabetic ketoacidosis. Despite a similar chemical structure
to clozapine, there is no evidence of hemotoxicity.
Clinical Guidelines: Very well tolerated. No titration is
required and many patients can be treated with once a
day dosing. Weight gain can occur. Because of
pharmacokinetic variability, doses beyond 20 mg/day may
be required in some patients.
Quetiapine (Seroquel)
Class: Dibenzothiazepine.
Mechanism: Quetiapine (Seroquel) is an antagonist at
the serotonin-2A, dopamine-2, alpha-1 and 2, and
histamine-1 receptors.
Preparations: 25 mg, 100 mg, and 200 mg tablets.
Dosage:
Initial dosage: 25-50 mg bid, increased by 25-50 mg
every 1 to 3 days to a total daily dose of 400-600 mg.
Maintenance: Required daily dose can range
between 150-750 mg.
Elderly: Clearance is reduced by 40% in elderly;
dosage should be reduced in this population.
Metabolism: Half-life is 6 hours, hepatic metabolism
(P450 3A4), no active metabolites. Low potential for drug
interactions.
Side-Effect Profile: Orthostatic hypotension may occur
during initial dose titration due to alpha-blockade.
Somnolence and weight gain may occur due to H1
blockade. Dyspepsia, abdominal pain, and dry mouth may
also occur. There are reports of new onset diabetes or
diabetic ketoacidosis.
Clinical Guidelines:May be effective for primary negative
symptoms of schizophrenia. Minimal weight gain. Well
tolerated. No anticholinergic side effects. Very low
incidence of EPS. No sustained elevation of prolactin.
Requires bid or tid dosing.
Ziprasidone (Geodon)
Class: Benzisothiazolyl piperazine.
Indications: Psychotic disorders.
Mechanism: D2, D3, 5HT2A, 5HT1A antagonism; also
blocks reuptake of monoamines.
Preparations: 40 mg capsules, IM formulation: 20 mg/ml
dose vial.
Maintenance Dosage: Target dose is between 40-80 mg
bid;
IM Preparation: 10 mg IM every 2 hours or 20 mg IM
every 4 hours to maximum daily dose of 40 mg.
Metabolism: Inactive metabolites, half-life 4 hours. Low
potential for drug interactions.
Side-Effect Profile: Dizziness, nausea, and postural
hypotension are the most common side effects. Prolactin
elevation can occur. Sedation is more common with the
IM preparation.
Advantages/ Disadvantages: Very low incidence of
extrapyramidal symptoms. Minimal incidence of
cardiovascular problems. Prolactin elevation is minimal.
The incidence of weight gain, lipid abnormalities, and
glucose intolerance appears to be lower than other
atypical antipsychotics. Ziprasidone can increase QT
interval. While there are no reports linking this to cardiac
arrhythmias, caution should be exercised in patients with
pre-existing increased QT interval (from medications or
cardiac disease). These patients should have a baseline
ECG. QT prolongation has not been observed with the IM
formulation.

H i g h - P o t e n c y
Antipsychotics
Side-Effect Profile: Orthostatic hypotension (low),

sedation (low), anticholinergic (low). Extrapyramidal
symptoms are frequent.
Clinical Guidelines: High-potency agents have less
sedative, hypotensive, and anticholinergic side effects.
Many patients require concurrent use of an
antiparkinsonian agent (eg, benztropine) to control
extrapyramidal symptoms.
Fluphenazine (Prolixin)
Class: Piperazine
Preparations: 1, 2.5, 5, 10 mg tablets; 2.5, 5 mg/mL oral
solution; 2.5 mg/mL parenteral solution (IM); 25 mg/mL
decanoate (IM).
Dosage:
Initial: 2.5-10 mg/day, may be titrated to 40 mg/day.
Maintenance: 10-20 mg/day.
Acute agitation: 2.5-5 mg IM, should not exceed daily
dose of 10 mg IM
Elderly: 0.5-2mg bid/tid.
Chronic noncompliance: Switch to decanoate
formulation. Give 12.5 mg IM of decanoate every two
weeks for every 10 mg of oral dose.
Potency: (equivalent to 100 mg chlorpromazine): 2 mg.
Metabolism: Hepatic metabolism, half-life 10-20 hours.
The decanoate formulation has a typical duration of action
of 2 weeks.
Clinical Guidelines: Fluphenazine is a weak antiemetic.
Decanoate formulation available.
Haloperidol (Haldol)
Class: Butyrophenone
Indications: Psychotic disorders, Tourette’s Syndrome.
Preparations:
Haloperidol tablets: 0.5, 1, 2, 5, 10, 20 mg.
Haloperidol lactate: 2 mg/mL conc. (PO), 5 mg/mL soln.
(IM).
Haloperidol decanoate: 50, 100 mg/mL (IM - depot).
Dosage:
Initial: 5-10 mg/day.
Acute agitation: 5.0 - 10 mg IM. Should not exceed
daily dose of 20 mg IM.
Elderly: 0.5-2 mg bid/tid.
Chronic noncompliance: Switch to haloperidol
decanoate at 10-20 times the daily dose, given on
monthly basis. Maximum initial dose of 100 mg/day
IM. Give balance of dose 4-5 days later if necessary.
Do not give more than 3 mL per injection site.
Tourette’s disorder in children: 0.05- 0.1 mg/kg in
2 or 3 divided doses
Potency: (equivalent to 100 mg chlorpromazine): 2 mg
Metabolism: Hepatic metabolism to active metabolite.
Half-life 10–20 hours. Duration of action of decanoate is
approximately 4 weeks.
Therapeutic Level: 5-20 ng/mL..
Major Safety Concerns: High incidence of
extrapyramidal symptoms. May possibly lower seizure
threshold in patients with a history of seizures.
Pimozide (Orap)
Class: Diphenylbutylpiperdines.
Indications: Psychotic disorders, Tourette's Syndrome.
Preparations: 2.0 mg tablets.
Dosage:
Tourette's: 0.5-1 mg bid, then increase dose every
other day as needed (max 0.2 mg/kg/day or 10 mg).
Antipsychotic maintenance: 1-10 mg/day.
Potency: (equivalent to 100 mg chlorpromazine): 1 mg.
Metabolism: Hepatic metabolism. Half-life 55 hours.
Contraindications: Pimozide is contraindicated in
patients with a history of cardiac arrhythmia or with drugs
that prolong QT interval.
Major Safety Concerns: Pimozide may cause ECG
changes, including prolongation of QT interval, T-wave
inversion, and appearance of U waves and alter effects of
antiarrhythmic agents.
Cardiac side effects of pimozide make haloperidol safer
first-line treatment for Tourette's Syndrome. Use caution
in patients with a history of hypokalemia.
Thiothixene (Navane)
Class: Thioxanthene.
Preparations: Capsules: 1, 2, 5, 10, 20 mg.
Thiothixene hydrochloride: 5 mg/mL oral solution; 5
mg/mL parenteral (IM).
Dosage:
Initial dosage: 2-5 mg bid-tid. Titrate to 20-40 mg/day
(max 60 mg/day).
Acute agitation: 5 mg IM 4 hour prn.
Elderly: 1-15 mg/day.
Potency (equivalent to 100 mg chlorpromazine): 5 mg.
Metabolism: Hepatic metabolism. Half-life 10 – 20 hours.
Therapeutic Level: Not established. Some suggest 2-57
ng/mL.
Major Safety Concerns: May produce ocular pigmentary
changes. Periodic ophthalmological examination is
recommended.
Trifluoperazine (Stelazine)
Class: Piperazine.
Preparations: 1, 2, 5, 10 mg tablets; 10 mg/mL oral
solution, 2 mg/mL soln. (IM).
Dosage:
Initial: 2-5 mg bid-tid. Titrate to 20-40 mg/day (max 60
mg/day).
Acute agitation: 5 mg IM q 4 hour prn (max of 20
mg/day). Do not repeat dosage in less than 4 hrs.
Metabolism: Hepatic metabolism. Half-life 10–20 hours.
Clinical Guidelines: Associated with few ECG changes.

M i d - P o t e n c y
Antipsychotics
Side-Effect Profile: Orthostatic hypotension (moderate),

sedation (moderate), anticholinergic (moderate),
extrapyramidal symptoms (high). Anticholinergic side
effects of mid-potency agents lessen the need for
medication to control extrapyramidal side effects.
Neuroleptic malignant syndrome, tardive dyskinesia, and
dystonic reactions are possible.
Loxapine (Loxitane)
Class: Dibenzoxapine.
Preparations: 5, 10, 25, 50 mg capsules; 25 mg/mL oral
solution: 50 mg/mL parenteral solution (IM).
Dosage:
Initial dosage: 10 mg bid. Titrate as needed to max
of 250 mg/day in divided doses.
Acute agitation: 12.5-50 mg IM q4-6h prn.
Potency (equivalent to 100 mg chlorpromazine): 12.5 mg.
Metabolism: Hepatic metabolism to active metabolite.
Half-life 5-15 hours.
Clinical Guidelines: Loxapine may be associated with a
higher risk of seizure than other high- and mid-potency
agents. Concurrent use with medications that lower the
seizure threshold should be avoided.
Molindone (Moban)
Class: Dihydroindolones
Preparations: 5, 10, 25, 100 mg tablets; 20 mg/mL conc.
(PO)
Dosage:
Initial: 15-20 mg tid. Titrate to 10-40 mg tid-qid (max
225 mg/day)
Maintenance: 50-100 mg/day
Potency (equivalent to 100 mg chlorpromazine): 10 mg
Metabolism: Hepatic metabolism, half-life 10–20 hours.
Therapeutic Level: Not established
Clinical Guidelines: Studies suggest molindone is
associated with less weight gain, amenorrhea, and
impotence than other typical antipsychotics. Molindone
appears less likely to cause seizures than other
antipsychotics.
Perphenazine (Trilafon)
Class: Piperazine.
Preparations: 2, 4, 8, 16 mg tablets; 16 mg/5 mL oral
solution; 5 mg/mL parenteral solution (IM).
Dosage:
Initial: 4-8 mg tid, titrate to 8-16 mg bid-tid (max 64
mg/day).
Acute agitation: 5-10 mg IM q 6h. prn (max 30
mg/day).
Metabolism: Hepatic metabolism, half-life 10-20 hours.
Clinical Guidelines: Perphenazine has antiemetic
properties.

L o w - P o t e n c y
Antipsychotics
Side-Effect Profile: High potentiation of anticholinergic,

antihistamine, antiadrenergic agents. Orthostatic
hypotension (moderate), sedation (high), anticholinergic
(moderate), extrapyramidal symptoms (low). Neuroleptic
malignant syndrome, tardive dyskinesia, and dystonic
reactions are possible. Higher risk than most other
antipsychotics for ECG changes (including T-wave
changes), jaundice, decreased libido, and retrograde
ejaculation.
Chlorpromazine (Thorazine)
Class: Aliphatic Phenothiazine.
Preparations:
Tablets: 10, 25, 50, 100, 200 mg; Slow-release capsules:
30, 75, 100, 200, 300 mg. Oral liquid preparations: 30
mg/mL and 100 mg/mL conc; 10 mg/5 mL syrup.
Parenteral injection: 25 mg/mL (IM). Suppositories: 25,
100 mg (PR).
Dosage:
Initial: 10-50 mg PO bid-qid, titrate to 200-800 mg/day
in divided doses (max 2000 mg/day).
Acute agitation: 25-50 mg IM q 4-6h.
Elderly: Not recommended due to orthostatic
hypotension.
Metabolism: Hepatic metabolism to many metabolites.
Therapeutic Level: Not useful due to many active
metabolites.
Major Safety Concerns:
Higher risk than most other typical antipsychotics for
seizure, jaundice, photosensitivity, skin discoloration
(bluish), and granular deposits in lens and cornea.
Prolongation of QT and PR intervals, blunting of T-waves,
ST segment depression can occur. Associated with a high
incidence of hypotensive and anticholinergic side effects.
Chlorpromazine has high lethality in overdose. It has a
higher risk than many other antipsychotics for life-
threatening agranulocytosis. Use chlorpromazine with
caution in patients with a history of cardiovascular, liver,
or renal disease. Avoid use in pregnancy (especially in
first trimester).
Clinical Guidelines:
Can be used for treatment of nausea or vomiting (10-25
mg po qid; 25 mg IM qid; 100 mg suppository tid) and
intractable hiccups (25-50 mg qid).
Mesoridazine (Serentil)
Class: Piperidine
Preparations: 10-, 25-, 50-, 100-mg tablets; 25 mg/mL
oral solution; 25 mg/mL parenteral solution (IM).
Dosage:
Initial: 25-50 mg po tid. Titrate to 300 mg/day (max
400 mg/day).
Acute agitation: 25-50 mg IM. Dose may be repeated
q 4-6 hour.
Elderly: Avoid because of hypotension risk.
Metabolism: Hepatic metabolism to many metabolites.
Half-life 24-48 hours.
Major Safety Concerns: Because of its association with
QT prolongation and subsequent increased risk for fatal
arrhythmias, mesoridazine is reserved for only those
patients who have not responded to other antipsychotic
agents.
Thioridazine (Mellaril)
Class: Piperidine
Preparations: 10, 15, 25, 50, 100, 150, 200 mg tablets;
5 mg/mL, 30 mg/mL and 100 mg/mL oral solution.
Dosage:
Initial dosage: 25-100 mg tid; titrate to 100-400 mg
bid (max 800 mg/day)
Maintenance: 200-800 mg/day; never exceed 800
mg/day No IM form available.
Elderly: avoid because of hypotension risk.
Metabolism: Hepatic metabolism to active metabolites
including mesoridazine, half-life 10-20 hours.
Major Safety Concerns: Because of its association with
significant QT prolongation and subsequent increased
risk for fatal arrhythmias, thioridazine is reserved for only
those patients who have not responded to other
antipsychotic agents. Permanent pigmentation of retina
and potential blindness occurs with doses above 800
mg/day. Life-threatening agranulocytosis rarely occurs.
Retrograde ejaculation occurs more frequently with
thioridazine.
Anxiolytics
Anxiolytic medications are used for the treatment of

anxiety. Some have shown efficacy in the treatment of
specific anxiety disorders. Antidepressants are also used
in the treatment of anxiety disorders.
Benzodiazepines
I. Indications
A. Benzodiazepines are used for the treatment of
specific anxiety disorders, such as Panic Disorder,
Social Phobia, Generalized Anxiety Disorder, and
Adjustment Disorder with Anxious Mood (anxiety due
to a specific stressful life event). All anxiolytic
benzodiazepines can cause sedation.
II. Pharmacology
A. Benzodiazepines bind to benzodiazepine receptor
sites, which are part of the GABA receptor.
Benzodiazepine binding facilitates the action of
GABA at the GABA receptor complex, which
surrounds a chloride ion channel. GABA binding
causes chloride influx into the neuron, with
subsequent neuroinhibition.
B. The benzodiazepines differ in their absorption rates,
lipid solubility, metabolism and half-lives. These
factors will affect onset of action, length of action,
drug interactions and side-effect profile.
C. The long half-life of diazepam, chlordiazepoxide,
clorazepate, halazepam and prazepam (>100 hrs) is
due to the active metabolite desmethyldiazepam.
D. Most benzodiazepines are metabolized via the
microsomal cytochrome P450 system in the liver.
Hepatic metabolism involves discreet families of
isozymes within the cytochrome system and most
benzodiazepines are metabolized by the 3A3/4
isoenzyme family. Notable exceptions to this are
lorazepam, oxazepam, temazepam and
clonazepam.
A. Non-psychiatric causes of anxiety, including medical
disorders, medications and substances of abuse
should be excluded before beginning
benzodiazepine treatment.
B. Choosing a benzodiazepine should be based on the
patient’s past response to medication, family history
of medication response, medical conditions, current
medications (drug interactions), and whether or not
to choose a long half-life or short half-life drug. Long
half-life drugs can be given less frequently, and they
have less serum fluctuation and less severe
withdrawal. These agents have a higher potential for
drug accumulation and daytime sedation.
C. The initial dosage should be low and titrated up as
necessary, especially when using long half-life
drugs, since these may accumulate with multiple
dosing over several days. The therapeutic dose for
benzodiazepines is far below the lethal dose. Long-
term use of benzodiazepines is associated with
tolerance and dependence. Continued use of
benzodiazepines for more than 3 weeks is
associated with tolerance, dependence and a
withdrawal syndrome.
1. Tolerance develops most readily to the sedative
side effect of benzodiazepines.
2. Cross-tolerance may develop between
benzodiazepines and other sedative hypnotic
drugs, including alcohol.
3. Withdrawal symptoms include heightened
anxiety, tremor, shakiness, muscle twitching,
sweating, insomnia, tachycardia, hypertension
with postural hypotension, and seizures.
D. Avoidance of an abstinence syndrome requires
gradual tapering upon discontinuation. One-fourth of
the dose per week is a good general guideline.
A. Side Effects: The most common side effect is
sedation. Dizziness, ataxia and impaired fine motor
coordination can also occur. Some patients
complain of cognitive impairment.
B. Anterograde amnesia has been reported, especially
with benzodiazepines that reach peak levels quickly.
C. Respiratory depression is rarely an issue even in
patients who overdose on benzodiazepines alone.
However, patients who overdose with
benzodiazepines and other sedative-hypnotics
(commonly alcohol) may experience respiratory
depression. Patients with compromised pulmonary
function are more sensitive to this effect and even
therapeutic doses may cause respiratory
impairment.
D. Diazepam (Valium) and chlordiazepoxide (Librium)
should not be used in patients with hepatic
dysfunction because their metabolism will be
impaired and toxicity risk increases.
E. Clonazepam should be avoided in patients with
renal dysfunction because its metabolism will be
impaired and the risk of toxicity will be high.
V.Drug Interactions
A. The concomitant use of benzodiazepines and other
CNS depressant agents, including sedative-
hypnotics, will enhance sedation and increase the
risk of respiratory depression. Alcohol use should be
limited.
B. Most benzodiazepines are metabolized via the liver
enzyme CYP3A4; therefore, any other drug also
metabolized via this pathway may increase the level
of the benzodiazepine (except lorazepam,
oxazepam, temazepam and clonazepam). Other
agents that increase benzodiazepine levels include
cimetidine, fluoxetine, ketoconazole, metoprolol,
propranolol, estrogens, alcohol, erythromycin,
disulfiram, valproic acid, nefazodone, and isoniazid.
Benzodiazepine levels may be decreased by
carbamazepine, rifampin (enzyme induction), and
antacids (absorption).

A n x i o l y t i c
Benzodiazepines
Alprazolam (Xanax)
Indications: Panic Disorder, Social Phobia. Can be used
in Generalized Anxiety Disorder (GAD) and Adjustment
Disorder with Anxious Mood.
Preparations: 0.25, 0.5, 1, 2 mg tablets.
Dosage: 0.25-2 mg tid-qid.
Elderly: reduce dosage.
Half-Life: Up to 12 hrs.
The clinical duration of action is short despite moderate
serum half-life.
Clinical Guidelines: Fast onset provides quick relief of
acute anxiety. Alprazolam has a relatively short duration
of action and multiple dosing throughout the day is
required (some patients require as much as Qid dosing).
It is associated with less sedation but a high incidence of
inter-dose anxiety. Dependence and withdrawal are
serious problems with this drug. Since SSRIs and other
antidepressants are as effective in anxiety disorders,
Alprazolam is no longer a first-line drug for the treatment
of anxiety disorders.
Chlordiazepoxide (Librium,
Libritabs)
Indications: Anxiety and alcohol withdrawal.
Preparations: 5, 10, 25 mg capsules.
Dosage:
Anxiety: 5-25 mg tid-qid.
Alcohol withdrawal: 25-50 mg every 2-4 hours
(maximum 400 mg/day) prn.
Dose range: 10-100 mg/day.
Elderly: Avoid use
Half-Life: >100 hrs.
Clinical Guidelines: This drug will accumulate with
multiple dosing. Because this drug is metabolized by
P450 isoenzymes. Metabolism can be slowed in the
elderly and patients with hepatic impairment. If used for
anxiety, once-a-day dosing may be possible. Slower
onset of action than Valium.
Clonazepam (Klonopin)
Indications: Approved as anticonvulsant. Used in Panic
Disorder, Social Phobia and general anxiety. Useful in
acute treatment of Mania.
Preparations: 0.5, 1, 2 mg tablets.
Dosage:
Anxiety: 0.25-6 mg Qod, in divided dose bid-tid.
Mania: 0.25-10 mg Qod, in divided dose bid-tid.
Elderly: 0.25-1.5 mg Qod.
Half-Life: 20-50 hrs. No active metabolites.
Clinical Guidelines: Rapid onset provides prompt relief.
Clonazepam, with its long half-life, may be substituted for
shorter acting benzodiazepines, such as alprazolam, in
the treatment of benzodiazepine withdrawal and panic
disorder. Its long half-life allows for once-a-day dosing.
Clorazepate (Tranxene)
Indications: Anxiety
Preparations: 3.75, 7.5, 11.25, 15, 22.5 mg tablets; 3.75,
7.5, 15 mg capsules
Pharmacology: Clorazepate is metabolized to
desmethyldiazepam in the GI tract and absorbed in this
active form.
Dosage:
Anxiety: 7.5 mg tid or 15 mg qhs. Increase as needed.
Dose range: 15-60 mg/day (maximum 90 mg/day).
Elderly: Avoid use in the elderly.
Half-Life: >100 hrs.
Clinical Guidelines: This drug will accumulate with
multiple dosing and over time. Because this drug is
metabolized by P450 isoenzymes, metabolism can be
slowed in the elderly and patients with hepatic
impairment. If used for anxiety, once-a-day dosing may be
possible.
Diazepam (Valium)
Indications: Anxiety, alcohol withdrawal.
Preparations: 2, 5, 10 mg tablets; 15 mg capsules
(sustained release); 5 mg/mL solution for IV use. IM
administration not recommended due to erratic
incomplete absorption.
Dosage:
Anxiety: 2-40 mg/day divided bid-tid.
Alcohol withdrawal: 5-10 mg q 2-4 hr prn withdrawal
signs for first 24 hrs, then slow taper. Maximum of 60
mg/day.
Dose range: 2-60 mg/day.
Elderly: Use with caution because metabolism is
significantly delayed.
Half-Life: 100 hrs.
Clinical Guidelines: Diazepam is the most rapidly
absorbed benzodiazepine. Due to its long half-life, it may
accumulate with multiple dosing. Because this drug is
metabolized by P450 isoenzymes, metabolism can be
slowed in the elderly and patients with hepatic
impairment. If used for anxiety, once-a-day dosing may be
possible.
Halazepam (Paxipam)
Indications: Anxiety.
Dosage:
Anxiety: 20-80 mg/day (divided doses).
Dose range: 40-160 mg/day. Use with caution in
elderly.
Half-Life: >100 hrs .
Clinical Guidelines: This medication has no unique
advantages over other benzodiazepines that have long
half-lives and are metabolized by P450 isoenzymes.
Lorazepam (Ativan)
Indications: Anxiety, alcohol withdrawal, and adjunct in
the treatment of acute psychotic agitation.
Preparations: 0.5, 1, 2 mg tablets; 2 mg/mL, 4 mg/mL
soln (IV, IM).
This is the only benzodiazepine available in IM form that
has rapid, complete, predictable absorption.
Dosage:
Anxiety: 0.5-6 mg/day (divided doses).
Alcohol withdrawal: 0.5-2 mg q 2-4 hr prn signs of
alcohol withdrawal; or 0.5-1.0 mg IM to initiate
treatment. Maximum dose of 10 mg/day.
Elderly: Metabolism is not significantly affected by age;
elderly may be more susceptible to side effects.
Half-Life: 15 hrs. No active metabolites
Clinical Guidelines: Metabolism is not P450 dependent
and will only be affected when hepatic dysfunction is
severe. The inactive glucuronide is renally excreted; it is
the benzodiazepine of choice in patients with serious or
multiple medical conditions. It is the only benzodiazepine
available in IM form with rapid and complete absorption.
Its metabolism is not affected by age. These properties
make it ideal for alcohol withdrawal in a patient with liver
dysfunction or who is elderly. Since the half-life is
relatively short, accumulation with multiple dosing usually
does not occur. The IM form is useful in rapid control of
agitation, resulting from psychosis, or drug-induced
agitation. It is also widely used on a PO basis as a prn
adjunct to fixed doses of antipsychotic medication.

Non-Benzodiazepine
Anxiolytics
Buspirone (BuSpar)
Category: Non-benzodiazepine, non-sedative hypnotic
anxiolytic.
Mechanism: Serotonin 1A agonist.
Indications: Generalized Anxiety Disorder (GAD). May
be used to augment antidepressant treatment of Major
Depressive Disorder and Obsessive- Compulsive
Disorder (OCD). Often useful in the treatment of
aggression and agitation in dementia and in patients with
developmental disabilities.
Preparations: 5, 10, 15 and 30 mg tablets (15 mg and 30
mg tablet is scored so that it can be either bisected or
trisected).
Dosage:
Initial Dosage: 7.5 mg bid, then increase by 5 mg
every 2-3 days as tolerated.
Dose Range: 30-60 mg/day (maximum 60 mg/day).
Antidepressant Augmentation: 15-60 mg/day if a
patient has a suboptimal response to a 4-6 week trial of
an antidepressant.
Half-Life: 2-11 hours. No active metabolites.
Side Effects: Dizziness, headache, GI distress, fatigue.
Clinical Guidelines: Buspirone lacks the sedation and
dependence associated with benzodiazepines, and it
causes less cognitive impairment than the
benzodiazepines. It is less effective in patients who have
taken benzodiazepines in the past because it lacks the
euphoria and sedation that these patients may expect
with anxiety relief. Unlike benzodiazepines, buspirone
does not immediately relieve anxiety. Onset of action may
take 2 weeks. The patient may be started on a
benzodiazepine and buspirone for two weeks, followed by
slow tapering of the benzodiazepine.
Hydroxyzine (Atarax, Vistaril)

Category: Antihistamine, mild anxiolytic.
Mechanism: Histamine receptor antagonist, mild
anticholinergic activity.
Indications: Anxiety (short-term treatment), sometimes
used to augment the sedative side effects of
antipsychotics when given for acute agitation.
Preparations: 10, 25, 50, 100 mg tablets; 10 mg/5 mL
syrup; 50 mg/mL solution (IM, not IV).
Dosage:
Anxiety: 50-100 PO q 4-6 hrs.
Acute agitation: 50-100 mg IM q 4-6 hrs.
Side Effects: Dry mouth, dizziness, drowsiness, tremor,
thickening of bronchial secretions, hypotension,
decreased motor coordination.
Drug Interactions: The sedative effect of hydroxyzine will
be enhanced by the concomitant use of other sedative
drugs. Similarly, the mild anticholinergic properties may
be enhanced if another medication with anticholinergic
properties is also taken.
Clinical Guidelines: Hydroxyzine is not associated with
dependence. It is a weak anxiolytic and only effective for
short-term treatment of anxiety. It can be helpful as an
adjunct to antipsychotic medications since it will potentiate
the sedative side effects and reduce the risk of
extrapyramidal side effects.

Benzodiazepine Hypnotics
Hypnotic medications are used for the treatment of
insomnia. Choice of agent is determined by half-life.
Short-acting hypnotics are best for the treatment of initial
insomnia or difficulties with sleep onset. They are
associated with less morning sedation. Long-acting
agents are more useful for the treatment of late insomnia
or difficulties in maintaining sleep. These agents are more
likely to be associated with daytime sedation.
I. Indications. Insomnia.
II. Pharmacology
A. The major difference between the anxiolytic and
hypnotic benzodiazepines is the rate of absorption.
B. Benzodiazepine hypnotics are rapidly absorbed from
the GI tract and achieve peak serum levels quickly,
resulting in rapid onset of sedation.
A. Hypnotics are recommended for short-term use only.
Insomnia treatment should include exercise, stress
reduction, sleep hygiene, and caffeine avoidance.
B. Prolonged use of benzodiazepines (generally
greater than 3 weeks) is associated with tolerance,
dependence and withdrawal syndromes.
C. The choice of benzodiazepine hypnotic is usually
dictated by the need for sleep onset or sleep
maintenance, half-life, and drug interactions.
A. Daytime sedation or morning “hangover” is a major
complaint when patients take hypnotics with long
half-lives. Dizziness and ataxia may occur during the
daytime or if the patient awakens during the night.
Anterograde amnesia has been reported.
B. Benzodiazepines may depress respiration at high
doses. Patients with compromised pulmonary
function are more sensitive to this effect.
V.Drug Interactions
A. Other CNS depressant agents, including the
sedative-hypnotics will enhance the sedative effect
of hypnotic benzodiazepines. Alcohol use should
also be determined.
B. Since triazolam, estazolam, flurazepam and
quazepam are metabolized via the liver enzyme,
CYP3A4, concomitant use of other medications with
similar metabolism will increase the half-life effect
and potential for toxicity.
Flurazepam (Dalmane)
Indications: Insomnia.
Dosage: Insomnia: 15-30 mg qhs, less in elderly.
Half-Life: 100 hrs.
Clinical Guidelines: Fast onset is useful in treatment of
early insomnia. Long duration is useful in treatment of late
insomnia but may result in morning sedation. Shorter half-
life medications are preferable to flurazepam.
Estazolam (ProSom)
Dosage:
Insomnia: 1-2 mg qhs
Elderly: 0.5-1.0 mg qhs.
Half-Life: 17 hrs.
Clinical Guidelines: Fast onset of action is useful for
treatment of early insomnia. Medium half-life should help
patients stay asleep throughout the night. Estazolam
offers no real advantage over temazepam (Restoril). More
clinicians are familiar with the use of estazolam.
Estazolam is not commonly used.
Quazepam (Doral)
Preparations: 7.5, 15 mg tablets.
Dosage:
Insomnia: 7.5-30 mg qhs.
Elderly: 7.5 mg qhs.
Half-Life: 100 hrs.
Clinical Guidelines: Long duration of action may result
in morning sedation. It has no unique properties; it is not
commonly used.
Temazepam (Restoril)
Indication: Insomnia.
Preparations: 7.5, 15, 30 mg capsules.
Dosage: Insomnia: 7.5-30 mg qhs (less for elderly).
Half-Life: 10-12 hrs.
Clinical Guidelines: Short duration of action limits
morning sedation.
Triazolam (Halcion)
Indication: Insomnia.
Preparations: 0.125, 0.25 mg tablets.
Dosage: Insomnia: 0.125-0.25 mg qhs. Reduce dosage
in elderly.
Half-life: 2-3 hrs.
Clinical Guidelines: Ultra-short half-life results in
minimal AM sedation. It is best for sleep initiation.
Patients may report waking up after 3-4 hours when blood
level drops. It is not recommended for patients who have
trouble maintaining sleep throughout the night. Use
should be limited to 10 days.
Non-Benzodiazepine
Hypnotics
Zolpidem (Ambien)
Category: Non-benzodiazepine hypnotic.
Mechanism: Binds to the GABA receptor, but is a non-
benzodiazepine.
Dosage: 10 mg qhs (5.0 mg for elderly).
Half-Life: 2-3 hrs.
Side Effects: Dizziness, GI upset, nausea, vomiting.
Anterograde amnesia and morning “hangover” occur at
dosages.
Drug–Drug Interactions: Potentiation of other CNS
depressants (eg, alcohol). Higher serum levels reported
in patients with hepatic insufficiency, but not with renal
insufficiency.
Clinical Guidelines: Zolpidem has a rapid onset. It is
especially useful for initiating sleep. Zolpidem is not
associated with dependence or withdrawal. Zolpidem is
rated a pregnancy category B.
Zaleplon (Sonata)
Category: Non-benzodiazepine hypnotic.
Mechanism: Binds to the GABA receptor, but is a non-
benzodiazepine.
Preparations: 5-, 10-mg tablets.
Dosage: 10 mg qhs (5.0 mg for elderly).
Half-Life: 1 hr.
Side Effects: Dizziness, dyspepsia, and diarrhea.
Drug–Drug Interactions: Potentiation of other CNS
depressants (eg, alcohol). Higher serum levels reported
in patients with hepatic insufficiency, but not with
moderate renal insufficiency. Cimetidine can increase
serum levels.
Clinical Guidelines: Zaleplon has a rapid onset. It is
especially useful for initiating sleep and is not associated
with dependence or withdrawal. Because of its short half-
life, a repeat dose may be given. It is rated pregnancy
category
Diphenhydramine (Benadryl)
Category: Antihistamine.
Mechanism: Histamine receptor antagonist (sedation),
acetylcholine receptor antagonist (extrapyramidal
symptom control).
Indications: Mild insomnia, neuroleptic-induced
extrapyramidal symptoms, antihistamine.
Preparations: 25, 50 mg tablets; 25, 50 mg capsules; 10
mg/mL and 50 mg/mL soln. (IM, IV), 12.5 mg/5 mL elixir
(PO).
Dosage:
Insomnia: 50 mg PO qhs.
Extrapyramidal symptoms: 25-50 mg PO bid, for acute
extrapyramidal. symptoms 25-50 mg IM or IV.
Half-Life: 1-4 hrs.
decreased motor coordination, GI distress.
Interactions: Diphenhydramine has an additive effect
when used with other sedatives and other medications
with anticholinergic activity. May cause exacerbation of
narrow angle glaucoma and prostatic hypertrophy. MAO
inhibitor use is contraindicated within 2 weeks of
diphenhydramine.
Clinical Guidelines: Diphenhydramine is a very weak
sedative, and it is minimally effective as a hypnotic. It is
non-addicting.
Chloral Hydrate (Somnote)

Category: Sedative-hypnotic.
Mechanism: CNS depression, specific mechanism is
unknown.
Preparations: 500 mg capsules.
Dosage: 500-1000 mg qhs (short-term only).
Half-Life: 8 hrs.
Side Effects: Nausea, vomiting, diarrhea, daytime
sedation and impaired coordination.
Interactions: IV furosemide may cause flushing and
labile blood pressure. Additive effects when given with
other CNS depressants.
Clinical Guidelines: Tolerance and dependence
regularly develop with consistent use. It is highly lethal in
overdose and can cause hepatic and renal damage. Its
use has decreased since benzodiazepines are equally
effective and are much safer.

Barbiturates
Barbiturate use has diminished since the introduction of
benzodiazepines due to their lower therapeutic index and
high abuse potential.
I. Indications
A. There are very few psychiatric indications for
barbiturates since benzodiazepines are safer and
just as effective. The phenobarbital challenge test is
also used to quantify sedative-hypnotic abuse in
patients abusing multiple sedative hypnotics,
including alcohol.
B. Given the availability of equally effective and safer
benzodiazepines, it is difficult to justify the long-term
use of barbiturates.
II. Pharmacology
A. Barbiturates bind to barbiturate receptor sites, which
are part of the GABA receptor. Barbiturate binding
facilitates the action of GABA at the GABA receptor
complex, resulting in inhibition.
B. Barbiturates induce hepatic microsomal enzymes
and may reduce levels of other medications with
hepatic metabolism.
A. Continued use of barbiturates for more than 3-4
weeks is associated with tolerance, dependence and
withdrawal syndrome.
1. Tolerance develops to the sedative side effects.
Cross-tolerance between barbiturates and other
sedative hypnotic drugs, including alcohol, may
develop.
2. Withdrawal symptoms include: heightened
anxiety, tremor, muscle twitching, sweating,
insomnia, tachycardia, hypertension with postural
hypotension and seizures.
3. The severity of withdrawal is determined by the
rate of decreasing serum level. Faster rates of
decline are associated with more sever
withdrawal.
B. Avoidance of an abstinence syndrome requires
gradual tapering upon discontinuation. A long half-
life benzodiazepine (eg, clonazepam) helps to
reduce the severity of withdrawal.
C. Barbiturates should not be used in pregnancy.
Infants born to habituated mothers may have
respiratory depression at birth and will go into
withdrawal.
A. The most common side effect is sedation and
impaired concentration. Dizziness, ataxia and
impaired fine motor coordination can also occur.
B. Barbiturates should not be used in patients with
hepatic dysfunction since their metabolism will be
impaired and toxicity may occur. Barbiturates are
contraindicated in patients with acute intermittent
porphyria since they may cause the production of
porphyrins.
V.Drug Interactions
A. The concomitant use of benzodiazepines and CNS
depressant agents, including sedative-hypnotics, will
enhance sedation and increase the risk of
respiratory depression. Alcohol use should be
limited.
B. Barbiturates enhance the metabolism of a number of
commonly used medications because they induce
hepatic enzymes. Reduced effectiveness of these
medications can occur. These include
anticoagulants, tricyclic antidepressants,
propranolol, carbamazepine, estrogen (oral
contraceptives), corticosteroids, quinidine, and
theophylline.
C. The effect of barbiturates on phenytoin metabolism
is unpredictable, phenytoin levels should be
monitored. Valproate inhibits barbiturate
metabolism.
Amobarbital (Amytal)
Preparations: 30, 50, 100 mg tablets; 65, 200 mg
capsules; 250 mg/5 mL, 500 mg/5 mL solution (IM, IV).
Dosage:
Sedation: 50-100 PO or IM.
Hypnosis: 50-200 mg IV (max 400 mg/day).
Half-life: 8-42 hrs.
Clinical Guidelines: Lorazepam has largely replaced the
use of amobarbital for emergent control of psychotic
agitation. The use of amobarbital in clinical diagnosis has
also decreased.
Pentobarbital (Nembutal)
Preparations: 50, 100 mg capsules.
Dosage: 200 mg PO.
Half-Life: 15-48 hrs.
Pentobarbital Challenge Test: The pentobarbital
challenge test is a useful method of quantifying the daily
intake of sedative hypnotics so that patients can be
detoxified. Patients are given 200 mg orally and after one
hour, the level of intoxication is assessed. If no signs of
intoxication, 100 mg is given, and the patient is
reassessed after one hour. Repeat procedure every two
hours until signs of intoxication occur (Nystagmus is the
most sensitive sign and sleep is the most obvious sign).
Maximum dose 600 mg. The dose required to show signs
of intoxication is the equivalent dose to the daily habit of
sedative hypnotics. Substitute a long half-life drug in
divided doses and gradually taper by 10% per day.

Mood Stabilizers
Mood stabilizers are used for the treatment of mania,

depression, and bipolar disorder and schizoaffective
disorder. They are also used for the treatment of severe
cyclothymia and unipolar depression. They can be helpful
in the treatment of impulse control disorders, severe
personality disorders, and behavioral disorders. Mood
stabilizers include lithium, anticonvulsants, and calcium
channel blockers.
Lithium Carbonate (Eskalith,

Lithobid, Lithonate, Eskalith CR)
I. Indications
A. Lithium is effective in the treatment of the acute
manic phase of bipolar disorder as well as
maintenance treatment of bipolar disorder. It is more
effective in the treatment of the manic episodes of
bipolar disorder than in the depressed episodes.
Antidepressants are often added to lithium when
treating bipolar depressed patients. Antidepressant
medication can trigger manic episodes in bipolar
patients has been shown to enhance the risk of
rapid cycling patterns.
B. Lithium is also used clinically for schizoaffective
disorder and severe cyclothymia.
C. In depressed patients who have not responded to
antidepressants, lithium augmentation may enhance
response. Lithium augmentation may be a useful
treatment strategy in some patients with
schizophrenia that does not respond adequately to
antipsychotics.
D. Lithium may be helpful in treating borderline
personality disorder, certain impulse control
disorders such as intermittent explosive disorder and
behavioral disturbances.
II. Pharmacology
A. Lithium may act by blocking inositol-1-phosphatase
in neurons with subsequent interruption of the
phosphatidylinositol second messenger system.
B. Lithium is excreted by the kidneys. Impaired renal
function or decreased fluid and salt intake can lead
to toxicity. An age-related reduction in creatinine
clearance will lead to reduced lithium clearance in
the elderly. Lower doses and close monitoring are
required in the elderly.
C. Preparations
1. Rapid absorption - Eskalith caps (300 mg),
lithium carbonate caps and tabs (300 mg),
Lithonate caps (300 mg), Lithotabs tabs (300
mg).
2. Slow release - Lithobid tabs (300 mg), Eskalith
CR (450 mg).
3. Lithium citrate syrup: 8 mEq/5 mL (rapid
absorption).
D. Half-Life: 20 hrs.
A. Lithium is the first-line drug in the treatment of
bipolar disorder. Valproate may also be used.
Approximately 30% of patients with bipolar disorder
will not respond to lithium.
B. Pre-Lithium Work-up: Non-psychiatric causes of
mood disorder or manic symptoms should be
excluded before initiating lithium, including medical
disorders, medications and substances of abuse. In
the absence of clinical symptoms of a medical
disorder, screening laboratory studies should be
ordered to monitor the effects of lithium. These
include a basic chemistry panel, thyroid function
tests, CBC, and an EKG in patients who are over 40
years old or with pre-existing cardiac disease. In
females of childbearing age, pregnancy should be
excluded.
IV. Dosage and Administration
A. Lithium is given in divided doses. Bid dosing with a
slow-release formula is recommended. The starting
dose for most adults is 300 mg bid-tid. The average
dose rage is 900-2100 mg/day.
B. Single daily dosing can be used if the daily dose is
less than 1200 mg/day. Divided doses cause less GI
upset and tremor.
C. Upward titration of lithium should occur until a serum
level of 0.8-1.2 mEq/L is obtained. Some patients on
long-term maintenance can be managed at lower
serum levels between 0.5-0.8 mEq/L.
D. Serum lithium levels can be obtained after five days
at any given dosage. Serum levels should be drawn
12 hours after the previous dose and are usually
done in the morning before the AM dose. Serum
levels should be monitored weekly for the first 1-2
months, then biweekly for another 2 months. A
patient who has been stable on lithium for a year can
be monitored every 3-4 months.
E. Therapeutic Response: Therapeutic effect may
take 4-6 weeks. True prophylactic effect may take >2
months.
F. Pregnancy and Lactation: Pregnancy category D.
Lithium should not be administered to pregnant
women in the first trimester when it is associated
with an increased incidence of birth defects,
especially Ebstein’s anomaly. After the first
trimester, lithium treatment may be initiated on a
risk-benefit basis. Breast feeding in contraindicated.
V.Adverse Drug Reactions
A. Side Effects: The most common side effects are GI
distress, weight gain, fine tremor, and cognitive
impairment (“fuzzy thinking”). Nausea, vomiting and
tremor can be alleviated by dividing the dose, taking
it with food or switching to a slow-release
preparation. Small doses of propranolol (eg, 10 mg
bid-tid) can also reduce or even eliminate tremor.
B. Renal: Polyuria with secondary polydipsia occurs in
20%. Lithium-induced diabetes insipidus may be
treated with the diuretic amiloride (5-10 mg/day).
Renal function should be monitored.
C. Thyroid: Hypothyroidism may occur, and it may be
treated with levothyroxine. Monitor TSH several
times per year.
D. Cardiovascular: Cardiovascular side effects include
T-wave flattening or inversion and, rarely,
arrhythmias which usually require discontinuation.
Edema may respond to spironolactone 50 mg/day,
or a reduction of the lithium dose.
E. Dermatological: Side effects include rash and
acne. Both problems may respond to dose
reductions, and acne can be treated with benzoyl
peroxide or topical antibiotics. Lithium can induce or
exacerbate psoriasis, which usually responds to
discontinuation of lithium. Alopecia will also respond
to discontinuation of lithium.
F. Hematologic: A benign leukocytosis can occur with
lithium. No treatment is indicated, but infection
should be excluded.
G. Neurologic: Muscle weakness, fasciculations, clonic
movements, slurred speech and headaches have
been reported. These symptoms may subside with
time.
H. Lithium Toxicity
1. Reduced fluid intake, increased fluid loss
(excessive sweating) or reduced salt intake may
lead to toxicity.
2. Symptoms of lithium toxicity include nausea,
vomiting, and diarrhea, coarse tremor (in contrast
to the fine tremor seen at therapeutic doses).
Ataxia, headache, slurred speech, confusion,
arrhythmias may also occur.
3. Mild-to-moderate toxicity occurs at 1.5-2.0
mEq/L. Severe toxicity occurs at levels over 2.5
mEq/L. Death may occur at levels >4.0 mEq/L.
VI. Drug Interactions
A. The most common cause of drug interactions is a
change in the renal clearance of lithium.
B. Medications that decrease lithium levels include:
1. Xanthines (theophylline, aminophylline, caffeine).
2. Increased dietary sodium and sodium
bicarbonate (antacids).
3. Carbonic anhydrase inhibitors (acetazolamide).
4. Osmotic diuretics (mannitol).
C. Medications that increase lithium levels and increase
the risk of toxicity include the following:
1. Potassium sparing diuretics (spironolactone),
loop diuretics (furosemide), NSAIDS.
D. Neurotoxicity is a frequent consequence of lithium
toxicity, and a number of medications will enhance
the risk of lithium neurotoxicity. These medication
include methyldopa, typical antipsychotics,
carbamazepine, phenytoin calcium channel
blockers. Close monitoring for symptoms of
neurotoxicity is recommended. These symptoms
include tremor, disorientation, confusion, ataxia, and
headaches.
E. The action of neuromuscular-blocking agents,
especially succinylcholine, will be prolonged by
lithium. Prolonged recovery from electroconvulsive
therapy, often requiring ventilatory assistance, may
occur. Lithium should be discontinued prior to
electroconvulsive therapy.

Anticonvulsants
Anticonvulsants are primarily used for the treatment of
bipolar disorder. Increasingly; they are replacing lithium
as a first-line treatment in acute mania and the long-term
prophylaxis of mood episodes in bipolar disorder. The
prophylactic action of anticonvulsants in bipolar disorder
is based on the theory of kindling, whereby repeated
subthreshold stimulation of a neuron will eventually result
in the spontaneous firing of the neuron. Anticonvulsants
are more effective than lithium in the treatment of rapid-
cycling and mixed bipolar states, impulse control
disorders, treatment resistant depressive disorder,
borderline personality disorder and other disorders with
impulsive, unpredictable and/or aggressive behavior.
Some newer anticonvulsants such as pregabalin are
being studied primarily for the treatment of anxiety
disorders.
Carbamazepine (Tegretol)
I. Indications
A. Carbamazepine is used for the treatment of the
acute manic phase of bipolar disorder and for
maintenance treatment of bipolar disorder. It may
be used alone or in combination with lithium. It is
more effective than lithium in treating rapid-cycling
bipolar disorder and mixed episodes.
B. Carbamazepine is more effective in the treatment
and prophylaxis of manic episodes than the
depressed episodes of bipolar disorder. When
treating the depressed episode of bipolar disorder
with an antidepressant, it is necessary to maintain
carbamazepine treatment to prevent an
antidepressant-induced manic episode or rapid
cycling.
C. Carbamazepine is also used in the treatment of
cyclothymia and schizoaffective disorder. It is
frequently used with antipsychotics and/or lithium in
schizoaffective disorder.
D. Carbamazepine augmentation of antipsychotic
medication can be useful in patient with
schizophrenia when there is inadequate response
to antipsychotics alone. It is particularly helpful for
aggressive or impulsive behavior.
E. Carbamazepine may be helpful in treating certain
impulse control disorders, such as those seen in
patients with developmental disabilities. It may also
be helpful to reduce symptoms of impulsivity and
affective instability in patients with severe
personality disorders.
F. Augmentation of antidepressant treatment with
carbamazepine might be helpful in depressed
patients who are treatment-resistant.
II. Pharmacology
A. The mechanism of carbamazepine in psychiatric
disorders is unknown.
B. Carbamazepine is metabolized by the liver
(CYP3A4) and its metabolites are excreted renally.
It will induce it’s own metabolism and serum levels
tend to decrease with time, requiring an increase in
the dosage. Initially, the half-life can be 25-65
hours. After several weeks, the serum half-life can
decrease to 12-17 hours.
C. Preparations: 100, 200 mg tablets; 100 mg/5 ml oral
suspension.
A. Pre-Carbamazepine Work-Up
1. Non-psychiatric causes of mood disorder or
manic symptoms, including medical disorders,
medications and substances of abuse should be
excluded before beginning carbamazepine
treatment.
2. Screening labs should include a basic chemistry
panel, CBC and an EKG in patients over 40 years
old or with pre-existing cardiac disease.
Pregnancy should be excluded in women of
childbearing age.
B. Carbamazepine should not be given to patients with
pre-existing liver, cardiac, or hematological disease.
It is not recommended for patients with renal
dysfunction because it has active metabolites that
are renally excreted.
C. If carbamazepine is used in patients who have not
responded to lithium, the carbamazepine should be
added to the drug regimen. If the patient responds,
the lithium should be withdrawn in an attempt to
manage the patient with a single mood stabilizer.
D. Dosage and Administration
1. Starting dose is 200 mg Bid. The average dose
range is 600–1200 mg/day. The dosage should
be reduced by one-half in the elderly.
2. Dosage increases, especially when initiating
treatment, can cause proportionally larger
increases in serum level; therefore, the dosage
should not be increased by more than 200
mg/day at a time.
3. Carbamazepine should be titrated to a serum
level of 8-12 :g/mL. Serum carbamazepine levels
should be obtained after five days at any given
dosage. Serum levels should be drawn 12 hours
after the previous dose, usually in the morning
before the AM dose.
4. Serum levels should be monitored weekly for the
first 1-2 months, then biweekly for another 2
months. Carbamazepine will induce its own
metabolism, decreasing the serum level. The
dosage may need to be increased in order to
maintain a serum level within therapeutic range
after initial stabilization. Frequent monitoring of
serum level is recommended during the first three
months of treatment.
5. A patient who has been stable on carbamazepine
for a year can be monitored every 3-4 months.
CBC and liver function, electrolytes and renal
function should be checked after one month, then
quarterly for the first year.
take 2-4 weeks.
F. Pregnancy and Lactation: Pregnancy category C.
Carbamazepine is contraindicated during pregnancy
or lactation. There may be an association between
use of carbamazepine in pregnancy and congenital
malformations, including spina bifida.
IV. Adverse Drug Effects
A. Side Effects: The most common side effects are GI
complaints (nausea, vomiting, constipation,
diarrhea, loss of appetite) and CNS complaints
(sedation, dizziness, ataxia, confusion). These can
be prevented or significantly reduced by increasing
the daily dosage slowly.
B. Hematological
1. Carbamazepine causes life-threatening
thrombocytopenia, agranulocytosis, and aplastic
anemia in 0.005% of patients. Patients should
contact their physician immediately with any signs
of infection (fever, sore throat) or bleeding
abnormality (easy bruising, petechiae, pallor). A
CBC should be drawn immediately.
Carbamazepine should be discontinued if the
WBC declines to less than 3000 mm3, absolute
neutrophil count <1500 mm3 or platelet count
decreases to <100,000 per mm3.
2. Transient and minor decreases in blood cell
indices can occur in the early phase of treatment
and do not warrant discontinuation of
carbamazepine.
C. Hepatic: Hepatitis and cholestatic jaundice may
occur. The medication should be discontinued
immediately.
D. Dermatological: Rash and urticaria are relatively
common. Photosensitivity reactions may rarely
occur. Potentially dangerous, but extremely rare,
dermatological side effects include exfoliative
dermatitis, toxic epidermal necrolysis and Stevens-
Johnson syndrome, requiring immediate
discontinuation of the drug.
E. Anticholinergic: Carbamazepine has mild
anticholinergic activity and may exacerbate
glaucoma and prostatic hypertrophy.
F. Cardiac: Uncommon side effects include AV
conduction defects, arrhythmias, and congestive
heart failure.
G. Metabolic/Endocrine: SIADH with hyponatremia
has been reported.
H. Genitourinary: Urinary frequency, urinary retention,
azotemia, renal failure and impotence are
uncommon.
I. Toxicity: Signs of toxicity include confusion, stupor,
motor restlessness, ataxia, mydriasis, muscle
twitching, tremor, athetoid movements, nystagmus,
abnormal reflexes, oliguria, nausea and vomiting.
Cardiac arrhythmias do not generally occur unless
very large doses are ingested.
A. The following medications inhibit the metabolism of
carbamazepine with resultant increase in serum
levels and neurotoxicity:
1. Verapamil and diltiazem.
2. Danazol.
3. Erythromycin.
4. Fluoxetine.
5. Cimetidine (transient effect). Not seen with
ranitidine or famotidine.
6. Isoniazid.
7. Ketoconazole.
8. Loratadine.
B. The following medications cause cytochrome P450
enzyme induction and decreased carbamazepine
levels:
1. Rifampin.
2. Cisplatin.
C. Anticonvulsant Interactions with Carbamazepine
1. Phenobarbital will lower carbamazepine levels
due to microsomal enzyme induction.
2. When phenytoin and carbamazepine are given at
the same time, the levels of both drugs may be
decreased.
3. Decreased ethosuximide levels due to
cytochrome P450 enzyme induction.
4. Felbamate can decrease carbamazepine levels
but increase the active metabolite, which has
been implicated in toxicity.
5. Lamotrigine and valproate can increase the
active metabolite. Patients may have signs of
toxicity with normal carbamazepine levels.
Carbamazepine will cause decreased valproate
levels.
D. Carbamazepine will induce hepatic microsomal
enzymes and enhance the metabolism, decrease
serum levels and decrease the effectiveness of the
following medications:
1. Acetaminophen (may also enhance
hepatotoxicity in overdose).
2. Clozapine and haloperidol.
3. Benzodiazepines (especially alprazolam,
triazolam).
4. Oral contraceptives.
5. Corticosteroids.
6. Cyclosporine.
7. Doxycycline.
8. Mebendazole.
9. Methadone.
10. Theophylline (can also decrease
carbamazepine levels).
11. Thyroid supplements (may mask compensatory
increases in TSH).
12. Valproate.
13. Warfarin.
E. Diuretics should be used with caution since
hyponatremia can occur with carbamazepine alone.
F. A minimum 14-day washout should elapse before
beginning an MAOI due to the molecular similarity
between tricyclic antidepressants and
carbamazepine.
Valproic Acid (Depakene) and

Divalproex (Depakote, Depakote
ER)
I. Indications
A. Valproate may be used with lithium or alone in
bipolar disorder and schizoaffective disorder.
B. It is more effective in rapid cycling and mixed
episode bipolar disorder than lithium.
C. Recent evidence suggests that valproate may be
more effective in treating depressive episodes
compared to lithium and carbamazepine. However,
it remains more effective in the treatment
prophylaxis of manic episodes than the depressed
episodes of bipolar disorder.
D. Valproate augmentation may be a useful treatment
strategy in patients with schizophrenia who have not
responded adequately to antipsychotics alone. It is
particularly helpful in patients with aggressive or
impulsive behavior.
E. There have been reports that it may be helpful in
treating certain impulse control disorders such as
intermittent explosive disorder and aggressive,
impulsive behavior in patients with developmental
disabilities. It may also be helpful to reduce
symptoms of impulsivity and affective instability in
patients with severe personality disorders.
II. Psychopharmacology
A. Valproate causes decreased GABA metabolism with
secondary increased CNS GABA concentrations.
Valproate may also impact signal transduction
through actions on protein kinase C. It is unknown
if these mechanisms are involved in the treatment
of psychiatric disorders.
B. The average half-life is 8-10 hours, making bid-tid
dosing necessary.
C. Pharmacokinetics and Metabolism of Valproate
1. Valproate is metabolized by the liver via
mitochondrial beta-oxidation, glucuronidation and
the P450 microsomal system. Unlike many other
psychotropic medications, cytochrome P450 is
relatively unimportant in valproate metabolism
and medications that affect P450 have little effect
on valproate serum levels.
2. The relationship between dose and blood level at
the higher end of the therapeutic range is less
helpful. Serum levels can be helpful to establish
minimum dosages at the low end of the
therapeutic range, but at higher levels, it is
probably more important to monitor clinical
symptoms of toxicity and side effects.
3. Valproate is highly protein bound and, at higher
concentrations, this system becomes saturated
and there is more unbound drug available. This
actually enhances the metabolism of the drug
and lowers the serum concentration.
4. Decreased protein binding (higher serum levels)
is seen in the elderly and patients with hepatic
and renal disease. These patients are at greater
risk for toxicity.
D. Preparations: Valproic acid – 250 mg capsules;
250 mg/5 mL oral susp.
Divalproex – 125 mg, 250 mg, 500 mg tablets.
Extended release (Depakote ER) – 500 mg tablets
A. Valproate may be used as a first-line drug in the
treatment of bipolar disorder, especially in patients
with rapid cycling bipolar disorder or mixed mood
episode.
B. Pre-Valproate Work-Up
1. Non-psychiatric causes of mood disorder or
manic symptoms, including medical disorders,
excluded before beginning valproate treatment.
2. Screening laboratory exams should include liver
function tests and a CBC. In females of
childbearing age, pregnancy should be excluded.
C. Valproate should not be given to patients with pre-
existing hepatic or hematological disease.
D. Dosage and Administration
1. Initiation of treatment begins with 20 mg/kg/day
or approximately 500 mg tid or 750 mg Bid, then
titrating up or down, depending on the serum
level. The average daily dose is between 1500
and 2500 mg/day. The extended release
formulation allows once daily dosing and the
bioavailability is 80-90 % compared to Depakote.
The elderly will require doses nearly half that of
younger adults.
2. A serum level of 50-125 µg/mL is usually
adequate for symptom relief. Serum levels in the
low range are more accurate and more clinically
useful compared to the high end of the
therapeutic range. Patients can often tolerate
levels up to 150 µg/mL.
3. Serum valproate levels can be obtained after 3
days at any given dosage. Serum levels should
be drawn 12 hours after the previous dose and
are usually done in the morning before the AM
dose.
4. Serum levels should be monitored weekly for the
first 1-2 months, then biweekly for another 2
months. A patient who has been stable for a year
can be monitored every 3-4 months. CBC and
liver function tests should be drawn after one
month then quarterly for the first year.
take 2-4 weeks.
F. Pregnancy and Lactation: Pregnancy Category D.
Valproate should not be used in pregnancy or
breast-feeding. An increased incidence of neural
tube defects and other birth defects has been
reported. Fatal clotting abnormalities and hepatic
failure have occurred in infants.
A. Side Effects: The most common side effects are
sedation, dizziness, nausea and vomiting
(divalproex has lower incidence of GI side effects).
GI side effects tend to decrease over time,
especially if the drug is taken with food.
B. Pancreatitis: A rare but serious adverse effect is
pancreatitis. It usually occurs early in treatment.
C. Hepatic
1. Hepatitis, which can be fatal, occurs in 0.0005%
of patients. It is most common in children.
Symptoms include lethargy and malaise,
vomiting, loss of appetite, jaundice and
weakness, usually occurring in the first 6 months
of treatment. Valproate should be discontinued
immediately if hepatitis is suspected.
2. A transient early increase in liver enzymes may
occur in up to 25% of patients but does not
predict the development of hepatitis. Close
monitoring of liver enzymes is important to
distinguish the benign temporary increase in
hepatic enzymes from more dangerous hepatitis.
D. Hematological: Thrombocytopenia and platelet
dysfunction can occur with secondary bleeding
abnormalities.
E. Neurological: Tremor, ataxia, headache, insomnia,
agitation
F. Other GI side effects: Changes in appetite and
weight, diarrhea or constipation.
G. Dermatological: Alopecia, maculopapular rash.
H. Overdose: Symptoms of toxicity/overdose include
somnolence, heart block and coma.
I. Urea Cycle Disorders: Hyperammonemic
encephalopathy, sometimes fatal, can occur in
patients with urea cycle disorders. These disorders
are uncommon genetic diseases such as ornithine
transcarbamlyase deficiency.
A. The following medications inhibit the metabolism of
valproate with resultant increases in serum levels
and increased potential for toxicity:
1. Aspirin inhibits metabolism and decreases bound
fraction
2. Felbamate
3. Rifampin
B. Anticonvulsant Interactions
1. Phenobarbital causes non-P450 enzyme
induction and lowers valproate levels. Valproate
inhibits phenobarbital metabolism.
2. Phenytoin causes non-P450 enzyme induction
and lowers valproate levels. Levels of both drugs
should be monitored.
3. Carbamazepine causes non-P450 enzyme
induction and lowers valproate levels. Valproate
may not affect carbamazepine levels but will
increase serum levels of the active metabolite.
Patients should be monitored for symptoms of
carbamazepine toxicity.
4. Valproate inhibits the metabolism of lamotrigine
and ethosuximide.
5. The combination of valproate and clonazepam
has been reported to cause absence seizures.
C. Other Interactions
1. Valproate inhibits the metabolism of diazepam,
resulting in increased levels.
2. Valproate inhibits the metabolism of AZT.
3. Valproate can displace warfarin from protein
binding. Careful monitoring of clotting times is
recommended.
Gabapentin (Neurontin)
I. Indications
A. While initial studies with gabapentin showed
promise in the treatment of cyclic affective illness,
data does not currently indicate significant efficacy
for this medication in monotherapy or as an
adjunctive agent.
B. Gabapentin is still often used as an adjunctive agent
in cyclic affective illness and other psychiatric
conditions to alleviate anxiety and assist with sleep
and low-grade iritability.
II. Pharmacology
A. Gabapentin is chemically related to the
neurotransmitter GABA, but it does not act on GABA
receptors. It is not converted into GABA and does
not effect GABA metabolism or reuptake. The
mechanism in psychiatric disorders is unknown.
B. Gabapentin is excreted renally in an unchanged
state. Reduced clearance of gabapentin with age is
largely caused by reduced renal function.
C. Half-life: 5-7 hrs.
D. Preparations: 100, 300, 400, 600, 800 mg capsules
A. Pre-Gabapentin Work-Up: Non-psychiatric causes
of mood disorder or mood symptoms (mania and
depression), including medical disorders,
excluded before beginning gabapentin treatment.
Screening laboratory exams should be ordered to
monitor renal function. In females of childbearing
age, pregnancy should be excluded.
B. Dosage and Administration
1. Starting dose can be 300 mg qhs, then
increasing by 300 mg each day. The average
daily dose is between 900 and 1800 mg/day, but
doses up to 2400 have been used.
2. Monitoring of serum levels is not necessary.
There is no information available regarding a
therapeutic window.
3. Significantly lower doses should be given to
patients with impaired renal function or reduced
creatinine clearance.
C. Therapeutic Response: 2-4 weeks
D. Pregnancy and Lactation: Pregnancy category C.
There are no controlled studies in pregnant women.
Gabapentin should be avoided during the first
trimester. Use after the first trimester must be on a
risk-benefit basis. Mothers should be encouraged
not to breast feed since the risks are unknown.
A. Side Effects
1. The most common side effects are somnolence,
fatigue, ataxia, nausea and vomiting and
dizziness.
2. Metabolic: Weight gain, weight loss, edema.
3. Cardiovascular: Hypertension.
4. GI: Loss of appetite, increased appetite,
dyspepsia, flatulence, gingivitis.
5. Hematological: Easy bruising.
6. Musculoskeletal: Arthralgia.
7. CNS: Nystagmus, tremor, diplopia, blurred vision.
8. Psychiatric: Anxiety, irritability, hostility,
agitation, depression.
A. There are no interactions with other anticonvulsants.
B. Gabapentin has reduced absorption with antacids,
and it should be taken at least 2 hours after antacid
administration.
Lamotrigine (Lamictal)
I. Indications
A. Lamotrigine has efficacy in the treatment of bipolar
depression as an adjunctive agent or as
monotherapy. It has also been shown to decrease
relapse to depression in stable bipolar patients by
itself. Its efficacy in the treatment of bipolar mania
or rapid cycling is not supported by current data. It
is recommended that lamotrigine be used primarily
as an adjunctive agent due to lack of proven efficacy
in the treatment or prevention of mania.
B. It is more effective in depression compared to other
mood stabilizers, prompting use in treatment-
resistant unipolar depression. Controlled studies are
currently underway.
II. Pharmacology
A. The mechanism of action is unknown. It may have
an effect on sodium channels that modulate release
of glutamate and aspartate. It also has a weak
inhibitory effect on 5-HT3 receptors.
B. Lamotrigine is hepatically metabolized via
glucuronidation with subsequent renal excretion of
the inactive glucuronide.
C. Half-Life: 25 hours.
D. Preparations: 25, 100, 150, 200 mg scored tablets.
A. Non-psychiatric causes of mood disorder or mood
symptoms (mania and depression), including
medical disorders, medications and substances of
abuse should be excluded before beginning
lamotrigine treatment.
B. Screening laboratory exams should be ordered to
monitor renal and hepatic function. In females of
C. Dosage and Administration
1. The initial dose is 25 mg/day increased weekly to
50 mg/day, 100mg/ day, and then 200 mg/day.
2. In patients taking valproate, the dosage is 25 mg
every other day for two weeks, then 25 mg per
day for the next two weeks. In patients taking
phenytoin, carbamazepine, phenobarbital or
primidone without valproate, the dosage is 50
mg/day for two weeks, then 50 mg bid for the
next two weeks. Average daily dose: 100-200
mg/day. Antidepressant effect may require up to
400 mg/day which may be given in a divided
dose.
3. Renal dysfunction does not markedly affect the
half-life of lamotrigine. However, caution should
be used when treating patients with renal disease
since there is very little data in this population.
D. Therapeutic Response: Clinical effect: 2-4 weeks.
E. Pregnancy and Lactation
1. Pregnancy category C. There are no controlled
studies in pregnant women. Lamotrigine should
be avoided during the first trimester.
2. Use after the first trimester must be on a risk-
benefit basis. Lamotrigine is excreted in breast
milk. Mothers should be encouraged not to breast
feed because the risks are unknown.
IV. Adverse Drug Effects
dizziness, sedation, headache, diplopia, ataxia, and
decreased coordination.
B. Dermatological: The side effect most likely to
cause discontinuation of the drug is rash (10%
incidence), which can be quite severe – Stevens-
Johnson syndrome (toxic epidermal necrolysis).
Rash is most likely to occur in the first 4-6 weeks.
C. Metabolic: Weight gain.
D. GI: Nausea and vomiting.
E. Psychiatric: Agitation, irritability anxiety, depression
and mania.
A. Carbamazepine-induced enzyme induction will
enhance lamotrigine metabolism, with subsequent
lower levels than expected. Lamotrigine will
increase the levels of carbamazepine and its
metabolites.
B. Valproate will increase lamotrigine levels (as much
as two times), and lamotrigine will decrease
valproate levels slightly.
C. Phenobarbital-induced enzyme induction will lower
lamotrigine levels.
D. Phenytoin will decrease lamotrigine levels.
E. No interaction with lithium has been reported.
F. Alcohol may enhance the side effects of lamotrigine.
G. Lamotrigine can be used with MAO inhibitors.
Topiramate (Topamax)
I. Indications
A. Open label studies suggest that it may have efficacy
as a mood stabilizer in patients with bipolar disorder.
One recent double-blind, placebo controlled study
was discontinued, however, due to lack of efficacy.
B. Other open label clinical studies have suggested
potential effectiveness of topiramate in bulimia,
migraine, and post traumatic stress disorder.
II. Pharmacology
A. The mechanism of action is unknown.
B. Topiramate is not extensively metabolized and is
mostly excrete unchanged in the urine.
C. Half-life: approximately 21 hours.
D. Preparations: 25, 100 and 200 mg tablets; 15 and
25 mg sprinkle capsules.
A. Non-psychiatric causes of mood disorder or mood
symptoms (mania and depression), including
medical disorders, medications and substances of
abuse should be excluded before beginning
topiramate treatment.
B. Screening laboratory exams should be ordered to
monitor renal and hepatic function. In females of
C. Topiramate is associated with appetite suppression
and possible weight loss, a side effect that may be
considered in a positive light by both the patient and
the treating physician. Minimal hepatic metabolism
may make it preferable over other anticonvulsants.
D. Dosage and administration (adults)
1. Initial dose: 25-50mg q hs then increase in 25-
50mg increments per week up to 400 mg/day in
divided doses.
2. Patients with renal impairment should take ½ the
recommended dose.
3. No adjustments are necessary for the elderly
based on age alone.
E. Pregnancy and Lactation: Pregnancy category C.
IV. Adverse Effects
A. The most common side effects are fatigue,
somnolence, dizziness, nausea, anorexia,
decreased concentration, ataxia, anxiety, and
paresthesias.
B. The potential for appetite suppression and weight
loss may be welcome side effects, since a significant
number of psychotropic medications can cause
weight gain.
V.Drug Interactions
A. Carbamazepine-induced enzyme induction will
reduce topiramate levels.
B. When given with valproic acid, topiramate and
valproic acid levels may decrease.
C. When given with phenytoin, topiramate levels were
decreased and phenytoin levels were increased.
D. Concomitant use of phenobarbital can decrease
topiramate levels.
E. Concomitant use of acetazolamide will increase the
risk of nephrolithiasis and should be avoided.
F. Topiramate may decrease serum digoxin levels.
G. Topiramate may reduce the effectiveness of oral
contraceptives by reducing estrogen availability.
Pregabalin
I. Indications (FDA approval pending): Pregabalin is
currently under investigation for the treatment of
epilepsy, neuropathic pain, generalized anxiety
disorder, social phobia, and panic disorder. Recent
studies indicate comparable efficacy to
benzodiazepines, venlafaxine and SSRIs in the
reduction of generalized anxiety.
II. Pharmacology
A. Pregabalin binds to calcium channels, not GABA
receptors, and modulates calcium influx, resulting in
anxiolytic, analgesic and anticonvulsant activity.
A. Dosage and Administration. The dosage of
pregabalin in anxiety studies has ranged from 300 to
600 mg per day, usually given tid. The optimal
dosage has yet to be determined.
B. Response Time. Time to response is likely similar
to antidepressants, but some preliminary data
indicates that pregabalin may have a more rapid
onset of action.
C. Adverse Drug Reactions: Not fully established, but
dizziness and drowsiness are common.
IV. Drug Interactions: Not established to date.

Psychostimulants
Dextroamphetamine (Dexedrine)
I. Indications
A. Dextroamphetamine has been approved for the
treatment of narcolepsy symptoms and Attention-
Deficit Hyperactivity Disorder deficit hyperactivity
disorder (ADHD). It is used in the treatment of
ADHD in children and adults.
B. Dextroamphetamine is used as an adjunct to
antidepressants in patients who have had an
inadequate response to antidepressants. It has also
been used effectively in depressed medically ill or
elderly patients who have not been able to tolerate
antidepressants.
II. Pharmacology
A. Dextroamphetamine is the d-isomer of
amphetamine. It is a centrally acting
sympathomimetic amine and causes the release of
norepinephrine from neurons. At higher doses, it
will also cause dopamine and serotonin release. It
inhibits CNS MAO activity.
B. Peripheral effects include increased blood pressure
and pulse, respiratory stimulation, mydriasis, and
weak bronchodilation.
C. Preparations: Dextroamphetamine sulfate
(Dexedrine) – 5, 10, 15 mg tabs; elixir 5 mg/5 mL;
Dexedrine Spansule (sustained release) - 5, 10, 15
mg caps.
D. Half-Life: 8-12 hrs
A. Dextroamphetamine is a schedule II controlled
substance, requiring a triplicate prescription.
Dextroamphetamine has a high potential for abuse
since it increases energy and productivity.
Tolerance and intense psychological dependence
develop.
B. Symptoms upon discontinuation may include
fatigue and depression. Chronic users can become
suicidal upon abrupt cessation of the drug.
C. Pre-Dextroamphetamine Work-Up
1. Blood pressure and general cardiac status
should be evaluated prior to initiating
dextroamphetamine.
2. Since dextroamphetamine can precipitate tics
and Tourette’s syndrome, careful screening for
movement disorders should be completed prior
to beginning treatment.
D. Dextroamphetamine is contraindicated in patients
with hypertension, hyperthyroidism, cardiac disease
or glaucoma. It is not recommended for psychotic
patients or patients with a history of substance
abuse.
E. Dosage and Administration
1. Attention-Deficit Hyperactivity Disorder: Initial
Dosage 2.5-5.0 mg bid-tid. Increase gradually in
divided doses (7 am, 11 am or noon, 3 pm) until
optimal response. Maximum dose approximately
1.0 mg/kg/day for children. Maximum 40 mg/day
for adults. Spansule preparation can be given
bid.
2. Depression (medically ill): 5-20 mg/day.
3. Narcolepsy: 10-60 mg/day in divided doses.
4. Children under the age of 3 should not be given
dextroamphetamine.
F. Weight and growth should be monitored in all
children. Weight loss and growth delay are reasons
to discontinue medication.
G. Pregnancy and Lactation: Pregnancy category C.
There is an increased risk of premature delivery
and low birth weight in infants born to mothers
using amphetamines. Dextroamphetamine is
contraindicated in pregnancy or breast feeding.
psychomotor agitation, insomnia, loss of appetite,
and dry mouth. Tolerance to loss of appetite tends
to develop. Effect on sleep can be reduced by
making sure no drug is given after 12 pm.
B. Cardiovascular: Palpitations, tachycardia,
increased blood pressure
C. CNS: Dizziness, euphoria, tremor, precipitation of
tics, Tourette’s syndrome, and, rarely, psychosis.
D. GI: Anorexia and weight loss, diarrhea,
constipation.
E. Growth inhibition: Chronic administration of
psychostimulants has been associated with growth
delay in children. Growth should be monitored
during treatment.
F. Toxicity/Overdose: Symptoms include insomnia,
irritability, hostility, psychomotor agitation,
psychosis with paranoid features, hypertension,
tachycardia, sweating, hyperreflexia, tachypnea. At
very high doses, patients can present with
arrhythmias, nausea, vomiting, circulatory collapse,
seizures and coma.
A. High blood levels of propoxyphene can enhance the
CNS stimulatory effects of dextroamphetamine,
causing seizures and death
B. Dextroamphetamine will enhance the activity of
tricyclic and tetracyclic antidepressants, and will
also potentiate their cardiovascular effects.
C. Dextroamphetamine may antagonize the effects of
antihypertensives.
D. Typical antipsychotics and lithium can inhibit the
CNS stimulatory effects of dextroamphetamine
E. Fatal reactions are likely if psychostimulants are
given with MAOIs. Hypertensive crisis and seizures
may occur. MAOIs should be discontinued for at
least 14 days prior to the initiation of
dextroamphetamine.
F. Dextroamphetamine will delay the absorption of the
anticonvulsants ethosuximide, phenobarbital and
phenytoin.
Dextroamphetamine and
Amphetamine (Adderall, Adderall
XR)
I. Indications
A. Adderall is indicated for the treatment of Attention-
Deficit and Hyperactivity Disorder (ADHD) and
Narcolepsy.
II. Pharmacology
A. Adderall is a combination of two closely related
amphetamines and has a similar pharmacology to
Dexedrine.
B. Preparations: Adderall 5-, 7.5-, 10-,12.5-, 15-, 20-
,30-mg tablets; Adderall XR 5-, 10-, 15-, 20-, 25-,
30-mg capsules
C. Dosing: 5-10 mg/day with the average dose of 20-
30 mg/day for ADHD and 5-60 mg for narcolepsy.
Maximum dose is 40 mg for children and 60 mg for
adults.
A. Adderall is a schedule II controlled substance,
requiring a triplicate prescription. Adderall has a
high potential for abuse since it increases energy
and productivity. Tolerance and intense
psychological dependence develop.
fatigue and depression. Chronic users can become
suicidal upon abrupt cessation of the drug.
C. Pre-Adderall Work-Up
should be evaluated prior to initiating
dextroamphetamine.
2. Since Adderall can precipitate tics and
Tourette’s syndrome, careful screening for
D. Adderall is contraindicated in patients with
hypertension, hyperthyroidism, cardiac disease or
glaucoma. It is not recommended for psychotic
patients or patients with a history of substance
abuse.
E. Weight and growth should be monitored in all
F. Pregnancy and Lactation: Pregnancy category C.
There is an increased risk of premature delivery
and low birth weight in infants born to mothers
using amphetamines. Adderall is contraindicated in
pregnancy or breast feeding.
psychomotor agitation, insomnia, loss of appetite,
and dry mouth. Tolerance to loss of appetite tends
to develop. Effect on sleep can be reduced by
making sure no drug is given after 12 pm.
B. Cardiovascular: Palpitations, tachycardia,
increased blood pressure
C. CNS: Dizziness, euphoria, tremor, precipitation of
tics, Tourette’s syndrome, and, rarely, psychosis.
D. GI: Anorexia and weight loss, diarrhea,
constipation.
E. Growth inhibition: Chronic administration of
during treatment.
F. Toxicity/Overdose: Symptoms include insomnia,
irritability, hostility, psychomotor agitation,
psychosis with paranoid features, hypertension,
tachycardia, sweating, hyperreflexia, tachypnea. At
very high doses, patients can present with
arrhythmias, nausea, vomiting, circulatory collapse,
seizures and coma.
A. High blood levels of propoxyphene can enhance the
CNS stimulatory effects of Adderall, causing
seizures and death
B. Adderall will enhance the activity of tricyclic and
tetracyclic antidepressants, and will also potentiate
their cardiovascular effects.
C. Typical antipsychotics and lithium can inhibit the
CNS stimulatory effects of dextroamphetamine.
D. Fatal reactions are likely if psychostimulants are
given with MAOIs. Hypertensive crisis or seizures
may occur. MAOIs should be discontinued for at
least 14 days prior to the initiation of Adderall.
E. Adderall will delay the absorption of the
anticonvulsants ethosuximide, phenobarbital and
phenytoin.
Methylphenidate (Ritalin, Ritalin SR,

Ritalin LA, Concerta, Metadate ER,
Metadate CD, Focalin)
I. Indications
A. Methylphenidate is the most commonly used in the
treatment of Attention-Deficit Hyperactivity Disorder
(ADHD) in children and adults. It is also used in the
treatment of narcolepsy.
B. Methylphenidate is also used for depression as an
adjunct to antidepressants in patients who have an
inadequate response to antidepressants. It has also
been used effectively in depressed medically ill or
elderly patients who have not been able to tolerate
antidepressants.
II. Pharmacology
A. Methylphenidate is a CNS stimulant, which is
chemically related to amphetamine.
Methylphenidate is metabolized by hydroxylation
and then renally excreted.
B. Preparations: 5, 10, 20 mg tabs; sustained release
20 mg tabs; LA 20, 30 and 40 mg capsules. The
sustained release tablet should be swallowed whole
and not crushed or chewed. Concerta comes in 18
and 36 mg extended release tablets. Metadate CD
20 mg capsules. Metadate ER 10- and 20-mg tabs.
Focalin 2.5-, 5-, 10-mg tabs.
C. Half-Life: 3-4 hrs; 6-8 hrs for sustained release.
A. Methylphenidate is a schedule II controlled
substance, requiring a triplicate prescription. It has
a high potential for abuse. Tolerance and
psychological dependence can develop.
severe fatigue and depression. Chronic users can
become suicidal upon abrupt cessation of the drug.
C. Pre-Methylphenidate Work-Up
should be evaluated prior to initiating treatment.
The cardiac risk with methylphenidate is less
than that for dextroamphetamine.
2. Leukopenia, anemia and elevated liver enzymes
have been reported; therefore, baseline and
periodic blood counts and liver function tests are
recommended.
3. Since methylphenidate can precipitate tics and
Tourette’s syndrome, careful screening for
D. Patients with hypertension, seizure disorder and
symptomatic cardiac disease should not take
methylphenidate. Methylphenidate is not
recommended for psychotic patients or patients
with a history of substance abuse.
E. Weight and growth should be monitored in children.
Weight loss and growth failure are reasons to
discontinue medication.
F. Dosage and Administration
1. Attention-Deficit Hyperactivity Disorder:
Initiate with 5 mg bid. Increase by 5-10 mg each
week until optimal response achieved. Usual
dose: 10-60 mg/day (max 2.0 mg/kg/day). The
initial dosage of Concerta is 18 mg/day, with an
average dose of 18 -54 mg/day. Ritalin LA
releases an immediate dose of methylphenidate
with a second release(via enteric-coated,
delayed release beads) four hours later. The
recommended starting dosage of Ritalin LA is 20
mg, titrated by 10 mg per week as needed up to
60 mg/day. Focalin is th d-isomer
(dexmethylphenidate) of methlphenidate and,
the recommended conversion is half the dose of
racemic methylphenidate.
2. Depression (medically ill): 10-20 mg/day.
3. Augmentation of Antidepressant: 10-40
mg/day.
4. Safety and efficacy in children under the age of
6 has not been established.
G. Pregnancy and Lactation: Methylphenidate is
contraindicated in pregnant or lactating women.
nervousness and insomnia. These can be reduced
by decreasing dose.
B. Cardiovascular: Hypertension, tachycardia,
arrhythmias
C. CNS: Dizziness, euphoria, tremor, headache,
precipitation of tics and Tourette’s syndrome and,
rarely, psychosis
D. GI: Decreased appetite, weight loss. Case reports
of elevated liver enzymes and liver failure.
E. Hematological: Leukopenia and anemia have
been reported.
F. Growth inhibition: Chronic administration of
during treatment.
G. Toxicity/Overdose: Symptoms include agitation,
tremors, hyperreflexia, confusion, psychosis,
psychomotor agitation, tachycardia, sweating and
hypertension. At very high doses, patients can
present with seizures, arrhythmias, and coma.
A. Methylphenidate may antagonize the effects of
antihypertensives.
B. Methylphenidate decreases metabolism and
increases level of the following medications:
1. Tricyclic and tetracyclic antidepressants.
2. Warfarin.
3. Phenytoin, phenobarbital and primidone.
4. Phenylbutazone.
C. Sudden Death: There have been recent case
reports of sudden cardiac death when
methylphenidate and clonidine have been used
together.
Pemoline (Cylert)
Pemoline is chemically unrelated to amphetamine and its
mechanism and site of action is unknown. It has
pharmacological activity similar to the psychostimulants.
Because of its association with life threatening hepatic
failure, pemoline should not be used as first-line therapy
for Attention-Deficit Hyperactivity Disorder.
I. Indications: Attention-Deficit Hyperactivity Disorder.

II. Pharmacology
A. Pemoline is metabolized by the liver and excreted
renally. Fifty percent of the drug is excreted
unchanged.
B. Preparations: 18.75, 37.5, 75 mg tablets; 37.5
chewable tablets.
C. Half-Life: 12 hrs.
A. Cylert has reduced abuse potential compared to
other psychostimulants, but psychological
dependence is still possible.
B. Pre-Pemoline Work-Up: Liver function tests and
CBC should be ordered prior to beginning
pemoline. Pemoline is contraindicated if liver
function tests are abnormal or if there is a history of
liver disease. Since pemoline can precipitate tics
and Tourette’s syndrome, careful evaluation of
patients for movement disorders should be
completed prior to beginning treatment. Pemoline is
not recommended for psychotic patients or patients
with a history of substance abuse.
C. Dosage and Administration: Initial dosage, 18.75-
37.5 mg/day (8 am) Increase weekly by 18.75
mg/day until optimal response is achieved.
Maximum dose: 3 mg/kg/day or 112.5 mg/day.
Safety and efficacy in children under the age of 6
has not been established.
D. Weight and growth should be monitored in all
E. Liver function should be monitored and serum ALT
levels should be determined at baseline, and every
two weeks thereafter. Pemoline should be
discontinued if ALT levels increase $2 times the
upper limit of normal.
F. Therapeutic Response: 3-4 weeks.
G. Pregnancy and Lactation: Pregnancy Category B.
A. Side Effects: The most common side effect is
insomnia. It may resolve over time; however, dose
reduction may be necessary.
B. Hepatic: Liver enzymes, and hepatic failure may
occur. If biweekly monitoring reveals elevated liver
enzymes, the drug should be discontinued.
C. CNS: Tremor, headache, irritability, precipitation of
tics and Tourette’s syndrome, decreased seizure
threshold and, rarely, psychosis
D. GI: Loss of appetite and weight loss, which tends to
be transient and usually resolves after the first few
months of treatment.
E. Minimal effect on cardiovascular status occurs,
particularly in comparison to Dexedrine and
methylphenidate.
F. Toxicity/Overdose: Symptoms include nausea and
vomiting, psychomotor agitation, tremor,
hyperreflexia, sweating, headache, tachycardia,
hypertension, confusion, hallucinations.
V. Drug Interactions. Decreased seizure threshold has
been reported when pemoline is given with
anticonvulsants.
Modafinil (Provigil)
I. Indications: Excessive Daytime Sleepiness
associated with Narcolepsy. Some evidence exists for
the effectiveness of modafinil (300 mg q am) for
ADHD.
II. Pharmacology
A. Modafinil is metabolized by the liver (3A4 enzyme).
3A4 inhibitors or inducers may affect the
metabolism of modafinil.
B. Preparations: 100 and 200 mg tablets.
C. Absorption is delayed by food.
D. Half-Life: 15 hrs.
A. Modafinil is generally well tolerated, with little effect
on nighttime sleep. It has less side effects and less
abuse potential than amphetamine-like stimulants.
B. Limited data suggests that modafinil may be useful
in antidepressant augmentation.
C. Dosage and Administration: Initial dosage is 200
mg/day (8 AM). Elderly and patients with hepatic
impairment require lower dose. Some patients may
benefit from a mid-afternoon dose (100-200 mg).
The maximum recommended daily dose is 400
mg/day.
D. Pregnancy and Lactation: Pregnancy Category C.
headache, nausea, diarrhea, and anorexia.
Anxiety, nervousness, and insomnia have been
reported but are less frequent compared to
methylphenidate.
B. Toxicity/Overdose: Symptoms include
nausea/diarrhea, palpitations, tremor, sleep
disturbance, irritability, aggressiveness, and
confusion.
V. Drug Interactions. Potential interactions exist with
inducers, substrates, or inhibitors of 3A4 hepatic
enzyme. Other potential interactions may exist with
the 2D6 and 2C19, enzymes. Use with monoamine
oxidase inhibitors should be avoided.
Atomoxetine (Strattera)
I. Indications: Attention-Deficit Hyperactivity Disorder.
II. Pharmacology
A. Atomoxetine is a newly approved medication that
works via presynaptic norepinephrine transporter
inhibition with subsequent enhancement of
noradrenergic function. Atomoxetine is not
considered a psychostimulant and is not a
controlled substance.
B. Metabolism: Atomoxetine is metabolized via the
CYP2D6 enzyme.
C. Half-Life: Approximately 4 hours.
D. Preparations: 10, 18, 25, 40, and 60 mg capsules.
E. Dosage:
1. In children (<70 kg) the dose should be initiated
at 0.5 mg/kg and increased to target a dose of
1.2 mg/kg/day. The dose should not exceed 1.4
mg/kg or 100 mg/day, whichever is less.
2. In adults (>70 kg), initial dose is 40 mg/day,
which is increased to 80 mg/day. Dose can be
increased to 100 mg/day after 2-4 weeks. The
dose should not exceed 100 mg.
3. The dose can be given in the morning or divided
between morning and late afternoon/early
evening.
A. Dividing the dose may reduce some side effects.
B. Dose reductions are necessary in the presence of
moderate hepatic insufficiency.
C. Atomoxetine should not be used within 2 weeks of
discontinuation os a MAO inhibitor.
D. Atomoxetine should be avoided in patients with
narrow angle glaucoma and, it should be used with
caution in patients with tachycardia, hypertension or
cardiovascular disease.
E. Atomoxetine can be discontinued without taper.
F. Pregnancy and Lactation: Pregnancy Category C.
A. Cardiovascular: Increased blood pressure and
heart rate (similar to those seen with conventional
psychostimulants).
B. Gastrointestinal: Anorexia, weight loss, nausea,
abdominal pain.
C. Miscellaneous: Fatigue, dry mouth, constipation,
urinary hesitancy and erectile dysfunction.
V. Drug Interactions: Individuals with decreased activity
of the CYP2D6 enzyme or who are taking CYP2D6
inhibitors (eg, fluoxetine, paroxetine) will have
significantly greater plasma levels (fivefold) and the
drug will have a longer half-life (24 hours).

Substance Dependence
M a n a gem e nt of Substance
Dependence
I. Clinical Guidelines for the Management of
Substance Dependence
A. Alcohol Dependence/Withdrawal: Prolonged use
of large amounts of alcohol leads to dependence
and withdrawal upon discontinuation. If untreated,
withdrawal can be fatal in cases where a patient
develops delirium tremens and subsequent
electrolyte abnormalities or cardiac arrhythmias.
Benzodiazepines, such as lorazepam and
chlordiazepoxide, are used to prevent withdrawal
symptoms.
B. Alcohol Relapse: Disulfiram and naltrexone are
used to help prevent relapse once a patient has
been detoxified. These agents in conjunction should
be used with a behavior modification program, such
as Alcoholics Anonymous, in order to yield
maximum benefit.
C. Opioid Dependence/Withdrawal: Opioid
withdrawal can lead to severe symptoms and
discomfort. Typical signs and symptoms of opioid
withdrawal include nausea, emesis, stomach
cramps, diarrhea, sweating, rhinorrhea, anxiety,
muscle cramps, bone pain, and severe craving.
Detoxification with methadone can alleviate the
withdrawal syndrome. Clonidine is also helpful in
reduction of withdrawal, but is not as effective as
methadone. Adjunctive prochlorperazine (5-10 mg
PO/IM q 6-8hr prn) for nausea/emesis; dicyclomine
(20 mg PO q6hr.) for stomach cramps/diarrhea;
ibuprofen (600 mg po q6hr prn) for muscle/bone
pain; and methocarbamol (500-750 mg q6hr prn)
can help during the initial days of detoxification.
D. Nicotine Dependence: Sustained release of
bupropion has been approved for smoking
cessation. Up to 50% of patients taking bupropion
will achieve abstinence from tobacco after 12 weeks
of treatment. This rate is twice the rate of placebo.
Success of bupropion is increased by combining
bupropion with a smoking cessation program.
E. Sedative/Hypnotic Withdrawal: Marked
withdrawal symptoms can occur with abrupt
discontinuation of sedative/hypnotic medications.
F. Psychostimulant Abstinence Syndrome:
Discontinuation of psychostimulants such as
amphetamines, methylphenidate, and cocaine can
produce fatigue, depression, hypersomnia, and
irritability. Treatment usually consists of supportive
care. Benzodiazepines can be used to treat
irritability.
Buprenorphine (Subutex, Suboxone)

Category: Synthetic opioid.
Mechanism: Buprenorphine is a partial agonist at the
mu-opioid receptor and an antagonist at the kappa-opioid
receptor.
Indications: Treatment of opioid dependence.
Preparations:
Suboxone: Tablets contain 2 mg of buprenorphine with
0.5 mg of naloxone, or tablets contain 8 mg of
buprenorphine with 2 mg of naloxone.
Subutex: 2 mg or 8 mg tablets of buprenorphine alone.
Dosage:
Induction: To avoid precipitating withdrawal, Subutex
should be used for induction when signs of withdrawal
are present. Patients may be given Subutex, 8 mg, on
day one and 16 mg of Subutex on day two. On day
three and thereafter, Suboxone at a dosage of 16 mg
per day is recommended.
Maintenance: Suboxone is preferred for maintenance
because it contains naloxone. The recommended
target dose of Suboxone is 16 mg per day. This
should be accomplished by increasing the dosage by
2-4 mg per day, titrated to suppress opioid withdrawal
symptoms. The range is between 4-24 mg per day.
Half-life: 37 hours for buprenorphine; 1.1 hours for
naloxone.
A. Respiratory/CNS depression can occur with
buprenorphine, especially if used intravenously.
The risk of respiratory depression, including
possible death, is increased if buprenorphine is
combined with alcohol, benzodiazepines or other
CNS depressants. Caution should be used in
patients with compromised respiratory function (eg,
COPD, hypercapnea, cor pulmonale).
B. Buprenorphine produces opioid dependence,
characterized by withdrawal if the drug is abruptly
discontinued. The naloxone in Suboxone can
produce marked opioid withdrawal if used
intravenously or sublingually by opioid dependent
patients.
C. Buprenorphine may cause hepatocellular injury,
and cases of hepatic failure, hepatic
encephalopathy and other hepatic disease have
been reported. Liver enzymes should be measured
at baseline and periodically during treatment.
D. Allergic reactions characterized by rashes, hives,
and pruritis may occur. Bronchospasm,
angioneurotic edema and anaphylactic shock have
been seen. Hypersensitivity to naloxone is a
contraindication to Suboxone.
Drug Interactions
A. CYP3A4 inhibitors, such as azole antifungals and
protease inhibitors, increase the plasma levels of
buprenorphine, and a decrease in the dosage of
Subutex or Suboxone may be required.
B. CYP3A4 inducers, such as carbamazepine and St.
John’s wort, have not been systematically studied
with buprenorphine but will likely decrease plasma
levels and require a higher dosage of
buprenorphine.
Clinical Guidelines
A. In order to prescribe buprenorphine, clinicians will
need to have specialty certification in addiction
medicine and complete separate training on the
treatment of opioid-dependent patients. In addition,
clinicians must not treat more than 30 patients in
their practice, and they should be able to refer
patients for adjunct services, such as psychosocial
therapy.
B. Subutex should be administered at least four hours
after use of heroin or other short-acting opioids,
and it should ideally be administered when early
opioid withdrawal signs appear.
C. There is minimal experience with transferring
patients on methadone maintenance to
buprenorphine, and withdrawal symptoms may
occur during induction.
D. Suboxone is preferred to Subutex for maintenance
due to the inclusion of naloxone.
Clonidine (Catapres, Catapres-TTS)

Category: Antihypertensive agent.
Mechanism: Alpha-2-adrenergic receptor agonist.
Indications: Used for opioid withdrawal. It may also be
used adjunctively for other withdrawal syndromes, such
as alcohol or sedative/hypnotic withdrawal, to dampen
noradrenergic symptoms.
Preparations: 0.1, 0.2, 0.3 mg tablets; clonidine TTS
patch - 2.5 mg/ 3.5 cm. (0.1 mg/day), 5.0 mg/ 7.0 cm(0.2
mg/day), 7.5 mg/ 10.5 cm (0.3 mg/day).
Dosage:
Opioid withdrawal: 0.1-0.2 mg po bid-qid with 0.1 mg
q4hr prn (max 2.4 mg/day) or use a TTS patch along
with po prn.
Methadone withdrawal: 0.1-0.2 mg PO bid-tid.
Half Life: 12-16 hr.
Adverse Drug Reactions: Hypotension, sedation, and
dizziness may be severe. Fatigue, dry mouth, nausea,
constipation, sexual dysfunction, insomnia, anxiety,
depression, photophobia, rash, and weight gain may
occur.
Drug-Drug Interactions
A. Potentiates the sedation with alcohol, barbiturates,
and other sedative/hypnotics.
B. TCAs inhibit the hypotensive effects of clonidine.
C. Antihypertensive agents increase the hypotensive
effects of clonidine.
Clinical Guidelines: Clonidine reduces the autonomic
signs of opioid withdrawal. It is less effective for craving.
The abrupt cessation of clonidine can lead to rebound
hypertension, which can be fatal in rare instances.
Clonidine should be tapered gradually over several days
when discontinuing use. Use caution in patients with a
history of cardiac disease or Raynaud's Syndrome.
Disulfiram (Antabuse)
Category: Aldehyde dehydrogenase inhibitor.
Mechanism: Leads to elevated levels of acetaldehyde
with subsequent toxic effects.
Indications: Alcohol dependence.
Dosage: 250-500 mg qhs.
A. Sedation, fatigue, headaches, acne, impotence,
rash, metallic aftertaste, and irritability are relatively
common, but usually disappear during the first few
weeks of treatment.
B. Hepatotoxic effects can occur, and disulfiram
should not be used in patients with preexisting liver
disease.
C. Peripheral neuropathy, optic neuritis, and psychosis
are rare complications of treatment.
D. If alcohol is consumed, patients will usually
experience flushing, headache, nausea, vomiting,
dyspnea, thirst, diaphoresis, hypotension,
palpitations, chest pain, anxiety, blurred vision, and
confusion. In severe cases, respiratory depression,
arrhythmias, heart failure, seizures, and death may
follow. Treatment of a disulfiram-alcohol interaction
consists of supportive therapy. The disulfiram-
alcohol reaction may occur for up to 14 days after
discontinuing disulfiram.
Drug Interactions:
A. Isoniazid may cause ataxia with mental status
changes.
B. Metronidazole may precipitate psychosis.
C. Disulfiram may increase levels of: diazepam,
paraldehyde, phenytoin, tricyclic antidepressants,
anticoagulants, barbiturates, benzodiazepines, or
anticoagulants.
Clinical Guidelines
A. The combination of disulfiram with an alcohol
recovery program decreases the risk of relapse.
Patients must be motivated to stop drinking,
otherwise, they usually stop taking the drug or drink
while taking it.
B. A risk of severe alcohol reaction remains for two
weeks after the last dose of disulfiram. Use caution
in patients with a history of renal or hepatic disease,
CNS disorder, hypothyroidism, or over age 50.
Baseline liver function tests and an ethanol level
are recommended.
C. Periodic monitoring of liver function tests is advised.
Warn patients about dietary and over the counter
preparations that may contain alcohol. Disulfiram is
contraindicated in patients with severe
cardiovascular or pulmonary disease.
Methadone (Dolophine)
Category: Synthetic opioid.
Mechanism: Opioid receptor agonist.
Indications: Detoxification and maintenance treatment of
opioid addiction. Methadone can only be prescribed in a
federally approved treatment center. The drug may be
continued if the patient is hospitalized for another reason.
Preparations: 5, 10, 40 mg tablets; 5 mg/5 mL solution,
10 mg/5 mL solution, 10 mg/mL solution. (PO); 10 mg/mL
solution. (IV, IM)
Dosage:
Detoxification: Short-term use (21 days maximum).
Initial dosage, 10-20 mg po on the first day. Increase
by 5-10 mg per day over the next few days, up to 40
mg per day in a single or divided dosage. Maintain at
this dosage for 2-5 days and then decrease by 5 mg
qod.
Maintenance: Treatment with methadone after 21
days is considered maintenance. A dosage of 60-80
mg is usually effective in preventing relapse.
A. Methadone produces tolerance along with
physiological and psychological dependence.
Tolerance to the euphoric effects may lead to
overdose. Overdose can lead to respiratory and
cardiovascular depression, coma, and death.
B. The most common adverse reactions include
sedation, nausea, emesis, dizziness, sweating,
constipation, euphoria or dysphoria, dry mouth,
urinary retention, and depression.
Drug Interactions:
A. CNS Depressants can potentiate the effects of
alcohol, sedative/hypnotics, other narcotics, general
anesthetics, tricyclic antidepressants.
B. Desipramine may increase desipramine plasma
concentrations.
C. Carbamazepine may lower plasma levels of
methadone.
D. MAOIs: The combination of an MAOI and the
opiates meperidine and fentanyl have led to
fatalities.
Clinical Guidelines
A. Use caution in patients with a history of respiratory
disease, hepatic or renal abnormalities, seizure
disorder, or head injury.
B. Women who conceive while on methadone should
continue taking the drug; however, the newborn will
require medical care for withdrawal symptoms.
Naltrexone (ReVia)
Category: Opioid antagonist.
Mechanism: Antagonist of opioid receptors.
Indications: Alcohol dependence (reduce craving),
opioid dependence (blocks euphoric effects of alcohol).
Preparations: 50 mg tablets.
Long-acting IM preparation is under development
(150-300 mg q 4 weeks).
Dosage:
Alcohol craving: 50 mg/day.
Opioid abuse: Start with 25 mg on first day; then 50
mg/day.
Half-life: 13 hrs (including active metabolite)
A. Naltrexone may precipitate acute opiate withdrawal
in patients who are still using opiates. Nausea is the
most common adverse effect, which is minimized by
starting with 25 mg Qod or administering with food.
Other adverse effects include insomnia, headache,
anxiety, fatigue, dizziness, weight loss, and joint
and muscle pain.
B. Naltrexone may cause hepatocellular injury when
given in excessive dosages. It is contraindicated in
patients with significant liver disease. Liver
enzymes should be monitored.
Drug Interactions
A. Patients who are currently using opioids will
experience withdrawal due to the antagonist effect
of naltrexone. If continued opioid use is suspected,
a naloxone challenge may be used, and the patient
is observed for signs of opiate withdrawal. Patients
should be opioid free for at least 14 days before
initiation of naltrexone.
B. Naltrexone will block the analgesic effects of
opioids, and higher than average doses of
analgesics may be needed for pain relief.
C. Disulfiram and naltrexone should not be combined
because of the hepatotoxic potential of both of
these agents.
Clinical Guidelines
A. Naltrexone decreases the euphoria associated with
alcohol consumption when used in combination with
an alcohol treatment program. It reduces craving,
and there are fewer relapses. Naltrexone also
lowers consumption of alcohol when a patient does
relapse.
B. Naltrexone’s utility in opiate dependent patients is
more controversial. Some heroin dependent
patients will attempt to use high dose of heroin in
order to overcome the Mu receptor blockade. This
can lead to accidental overdose and death by
respiratory depression.
Bupropion (Zyban)
Category: Unicyclic aminoketone antidepressant.
Mechanism: Bupropion may work via alteration of
dopaminergic and noradrenergic neurotransmission.
Indications: Smoking cessation.
Preparations: 150 mg sustained release tablets.
Dosage: 150 mg Qod for several days, then increase
dosage to 150 mg bid
Half-life: 4-21 hr.
A. Most common side effects: Dry mouth, insomnia,
dizziness, and arthralgias.
B. Seizures: Rate of seizures at doses up to 300
mg/day is 0.1%. Bupropion is contraindicated in
patients with history of seizures, head trauma, brain
tumor or who are taking medications that
significantly lower seizure threshold. Avoid use in
patients with anorexia or bulimia, due to possible
electrolyte imbalances leading to seizures.
C. Mania: Bupropion can precipitate mania or rapid
cycling and should be used with caution in patients
with bipolar disorder.
D. Use caution in patients with hepatic, renal, or
cardiac disease.
E. Neuropsychiatric: In depressed patients,
bupropion has been associated with psychosis and
confusion. These symptoms abate with reduction or
discontinuation of bupropion.
F. Bupropion is not recommended during pregnancy
or while breast feeding.
Drug Interactions
A. Enzyme Inducers: Enzyme-inducing agents, such
as carbamazepine, phenobarbital, and phenytoin,
may induce lower plasma bupropion levels.
B. Cimetidine may inhibit the metabolism of bupropion,
leading to higher plasma levels.
Clinical Guidelines: Bupropion is generally well
tolerated. Efficacy compared to nicotine patches or gum
is unknown.

Cognitive Enhancers
I. Indications: Reversible acetylcholinesterase inhibitors

are indicated for the treatment of cognitive impairment
associated with early Alzheimer’s disease.
II. Pharmacology: Cognitive impairment associated with
Alzheimer’s disease is thought to be secondary to
deficiency of cholinergic neurotransmission. These
medications inhibit cholinesterase, resulting in
increased synaptic concentrations of acetylcholine.
While these drugs do not alter the overall course of the
disease, they can prolong functional status in
demented patients early in the course while there are
still sufficient numbers of cholinergic neurons present.
A. These medications improve cognitive performance
in patients with mild to moderate dementia of the
Alzheimer’s type. Prior to treatment, patients should
undergo a thorough medical examination to rule out
treatable causes of dementia.
B. Cognitive function should be evaluated using
standardized testing (ex: Mini-Mental Status Exam
MMSE) prior to treatment and periodically thereafter
to provide an objective measure of treatment
response. Improvement of 1-2 points on the MMSE
can be observed in patients with mild to moderate
cognitive impairment. Mild to moderate is defined
on the MMSE as a score between 10-26.
C. Clinical studies indicate that improvement is
temporary. Decline often is evident by 30 weeks.
The rate of decline appears to be slower with
acetylcholinesterase inhibitor treatment.
D. Tacrine was the first acetylcholinesterase inhibitor,
and it has largely been replaced by newer
medications which do not carry the risk of
hepatoxicity.
A. Due to increased cholinergic activity, gastric acid
secretion can be increased, resulting in increased
risk of ulcer development.
B. Other predictable adverse effects caused by the
cholinergic mechanism of action include: nausea
and vomiting, diarrhea, anorexia, weight loss,
dizziness, syncope, and bradycardia. These tend
to be dose related and can also be minimized by
following manufacturer’s guidelines regarding slow
upward dose titration.
C. Cholinomimetics may reduce seizure threshold, and
exacerbate obstructive pulmonary disease.
D. Tacrine is associated with liver toxicity.
Donepezil (Aricept)
Class: Piperidine.
Mechanism: Reversible selective acetylcholinesterase
inhibitor.
Indications: Mild-to-moderate dementia of the
Alzheimer’s type. Donepezil does not have the potential
for hepatotoxicity associated with tacrine.
Dosage:
Initial Dosage: 5 mg/day for four weeks.
Maintenance Dosage: Increase dose to 10 mg Qod
after 4 weeks if tolerated.
Metabolism: Half-life is 70 hours; hepatic metabolism
through CYP2D6 and 3A4 hepatic isoenzymes, followed
by glucuronidation.
Side-Effect Profile: Most common are nausea, vomiting,
diarrhea, insomnia, muscle cramps, fatigue and anorexia,
which often resolve with continued treatment.
Clinical Guidelines: The 10-mg dose is associated with
a higher incidence of side effects, but may be more
effective. May cause syncope and exacerbate
bradycardia; therefore, beta-blockers should be avoided
or be given in a reduced dosage.
Galantamine (Reminyl)
Class: Tertiary alkaloid.
Indications: Treatment of mild-to-moderate Alzheimer’s
dementia.
Pharmacology
Mechanism of action: Reversible, competitive
acetylcholinesterase inhibitor with subsequent
enhancement of cholinergic function.
Half-life: Approximately 7 hours.
Preparations: 4, 8, and 12 mg tablets; 4 mg/ml oral
solution.
Clinical Guidelines
Dosage and Administration:
The recommended starting dose is 4 mg bid,
increasing to 8 mg twice a day (16 mg/day) after 4
weeks of treatment. A further increase to 12 mg twice
a day (24 mg/day) may be attempted after a minimum
of 4 weeks at the previous dose. The recommended
therapeutic dose for most patients is 16-24 mg/day.
Pregnancy and Lactation: Pregnancy category B.

Adverse Drug Effects: Bradycardia, nausea, vomiting,
diarrhea, anorexia, weight loss, dizziness, syncope. Side
effects tend to be caused by the cholinergic mechanism
of action and are dose related.
Drug Interactions: Since galantamine is metabolized via
CYP2D6 and CYP3A4, inhibitors of either of these
cytochrome enzymes will reduce galantamine clearance,
such as paroxetine (2D6), erythromycin, nefazodone
(3A4) and ketoconazole (both). No clinically significant
effects on digoxin levels or prothrombin time (in patients
receiving warfarin) has been noted.
Rivastigmine (Exelon)
Class: Phenyl Carbamate.
Mechanism: Reversible selective acetylcholinesterase
inhibitor.
Indications: Mild-to-moderate dementia of the
Alzheimer’s type. Rivastigmine does not have the
potential for hepatotoxicity associated with tacrine.
Preparations: 1.5, 3, 4.5, 6 mg tablets; 2 mg/mL oral
solution
Dosage:
Initial Dosage: 1.5 mg bid, after 2 weeks increase to
3 mg bid
Maintenance Dosage: 3 mg bid may be effective.
The dose can be increased if necessary to 4.5 mg
bid, and then to 6 mg bid at two week intervals if
required and if tolerated. May be given with food to
reduce GI side effects.
Metabolism: Half-life is 1.5 hours. Rivastigmine is
metabolized and eliminated by the kidneys. Because the
dose is adjusted based on tolerability, adjustments in
renally impaired patients are not always necessary.
Side Effects: Most common are nausea, vomiting,
diarrhea, dizziness, anorexia, headache, abdominal pain,
and sedation. Rivastigmine has more peripheral effects
than donepezil, which may result in more gastrointestinal
side effects.
Tacrine (Cognex)
Class: Acridine
Mechanism: Reversible non-specific cholinesterase
inhibitor (inhibits both acetyl and butyl cholinesterase
increasing occurrence of systemic side effects).
Indications: Mild-to-moderate dementia of Alzheimer’s
type. Tacrine can be hepatotoxic and is infrequently used.
Preparations: 10, 20, 30, 40 mg capsules.
Dosage:
Initial Dosage: 10 mg qid. After four weeks, the dose is
increased to 20 mg qid. Daily dose is raised by 40 mg
increments every four weeks to 120-160 mg/day.
Maintenance Dosage: 120-160 mg/day in divided doses
or qid. Tacrine should be administered at least one hour
before meals as food impairs absorption.
Metabolism: Half-life is 2-4 hours, extensive hepatic
metabolism, principally by CYP 1A2 isoenzyme. Smoking
reduces tacrine levels by induction of the CYP 1A2
isoenzyme. Women develop blood levels by 50% higher
than men.
Side-Effect Profile: Elevation of serum transaminases is
the most frequent side effect (30%). This appears to be
reversible if tacrine is discontinued. Other side effects
include nausea, vomiting, diarrhea, dizziness, agitation,
anorexia, and confusion.
Clinical Guidelines: Serum liver function (ALT/SGPT)
should be monitored every two weeks for the first 4
months of treatment. If elevation is three times normal,
dose should be reduced. Elevations of more than five
times normal, bilirubin above 3 mg/dL, hypersensitivity, or
jaundice require immediate discontinuation.
Memantine (Axura, Ebixa)

Class: Dimethyladamantane
Mechanism: Memantine is an uncompetative antagonist
of the N-methyl-D-aspartate receptor. It reduces
glutamate mediated excitotoxicity.
Indications: Mild-to-moderate dementia of Alzheimer’s
type (FDA approval is pending).
Preparations: 10, 20, 30, 40 mg capsules.
Initial Dosage: 5 mg po qAM.
Maintenance Dosage: Increase at weekly intervals to 10
mg bid.
Metabolism: No dosage adjustment is required for
patients over 65. In patients with moderate renal
impairment, reduce dose to 5 mg bid. There are no active
metabolites.
Side-Effect Profile: Memantine is fairly well tolerated.
Side effects include dizziness, constipation and
hallucinations in a small proportion of patients.
Clinical Guidelines: Memantine does not have the
undesirable side effects associated with cholinesterase
inhibitors. Cognitive improvement in patients with
dementia treated with memantine is modest. Animal
models suggest it may have neuroprotective benefits.
Drug Interactions: Memantine does not significantly
interact with CYP450 enzymes. Drugs such as cimetidine,
ranitidine, procainamide, quinidine and nicotine use the
same renal cationic transport system and may increase
blood levels of memantine. Coadministration of NMDA
antagonists (amantadine, ketamine, dextromethorphan)
should be avoided. Such combinations could result in
development of psychosis. The actions of dopaminergic
agonists and anticholinergic agents may be enhanced by
memantine.
Antiparkinsonian Drugs
Psychiatric Side-Effect
Management
I. Indications: Parkinsonian side effects are frequently
encountered during treatment with typical antipsychotic
agents and to a lesser degree with some of the atypical
antipsychotics. Parkinsonian side effects includes
tremor, rigidity, dystonias, and akathisia.
II. Pharmacology
A. Parkinsonian side effects are thought to be
mediated by blockade of nigrostriatal dopamine D2
receptors. They typically occur early after initiation
of treatment with dopamine antagonists.
B. Antiparkinsonian drugs fall into two major
categories:
1. Anticholinergic drugs.
a. Benztropine (Cogentin).
b. Trihexyphenidyl (Artane).
c. Biperiden (Akineton).
d. Procyclidine (Kemadrin).
2. Dopamine agonists.
a. Amantadine (Symmetrel).
A. Anticholinergic agents are frequently required when
treating patients with mid- and high-potency typical
antipsychotics.
B. For patients being treated for the first time with mid-
and high-potency antipsychotics, prophylactic
treatment with an antiparkinsonian is recommended
to prevent unpleasant extrapyramidal side effects.
Prevention of these side effects can improve
compliance with antipsychotic medication. Patients
who have past exposure to antipsychotic agents will
frequently be able to report on the occurrence of
extrapyramidal side effects, and the patient should
receive anticholinergic agents.
A. Anticholinergic agents can cause blurred vision, dry
mouth, constipation, urinary retention, tachycardia
and, less frequently, hyperthermia.
B. Elderly patients are more sensitive to anticholinergic
agents and are at risk for developing anticholinergic
induced delirium.
C. Anticholinergic are contraindicated in patients with
glaucoma, prostatic hypertrophy, myasthenia gravis,
duodenal or pyloric obstruction. Benztropine is the
least sedating anticholinergic agent.
D. Anticholinergic intoxication can occur if drugs with
strong anticholinergic effects are combined.
Confusion, agitation, hallucinations, ataxia,
tachycardia, blurred vision, mydriasis, increased
blood pressure, hyperpyrexia, hot and dry skin,
nausea and vomiting, seizures, coma, and
respiratory arrest can occur.
Benztropine (Cogentin)
Category: Anticholinergic (muscarinic receptor
antagonist).
Indications: Neuroleptic induced extrapyramidal
symptoms.
Preparations: 0.5, 1, 2 mg tablets; 1 mg/mL soln. (IM).
Dosage:
Acute dystonia: 1-2 mg IM (max 6 mg/day).
Chronic Extrapyramidal Symptoms: 1-2 mg PO bid-
tid. Perform trial off benztropine in 4 to 8 weeks to
determine if continued use is necessary. Taper
medication over 2 weeks.
Side Effects: Drowsiness, dry mouth, blurred vision,
nausea, weakness, confusion, constipation, urinary
retention, sedation, drowsiness, depression, psychosis.
Interactions: Anticholinergics (eg, low-potency
neuroleptics, tricyclics, over-the-counter sleep
preparations); anticholinergic intoxication may develop.
Clinical Guidelines: Avoid using this medication with low
potency neuroleptics because of additive anticholinergic
effects. Benztropine is contraindicated in glaucoma,
prostatic hypertrophy, myasthenia gravis, duodenal or
pyloric obstruction. Benztropine is the most widely used
agent for extrapyramidal symptoms.
Trihexyphenidyl (Artane)
antagonist).
symptoms (Extrapyramidal symptoms).
Preparations: 2, 5 mg tablets, 5 mg capsules.
Dosage: Initially 1 mg Qod, then increase to 2 mg bid-qid
(max 15 mg/day). Perform trial off trihexyphenidyl in 4 to
8 weeks to determine if continued use is necessary.
Taper medication over 2 weeks when discontinuing.
retention, sedation, drowsiness, depression, psychosis.
May cause restlessness and euphoric symptoms.
neuroleptics, tricyclics, over the counter sleep
preparations) may cause anticholinergic intoxication.
Clinical Guidelines: Avoid this medication with low-
potency neuroleptics (additive anticholinergic effects).
Trihexyphenidyl is contraindicated in glaucoma, prostatic
hypertrophy, myasthenia gravis, and duodenal or pyloric
obstruction.
Biperiden (Akineton)
antagonist).
symptoms.
Preparations: 2 mg tablets; 5 mg/mL (IV, IM).
Dosage:
Acute dystonia: 2 mg IM. Repeat in 20 minutes, if
needed.
Chronic extrapyramidal symptoms: 2 mg PO bid-tid
(max 6 mg/day).
Perform trial off biperiden after 4 to 8 weeks to
determine if continued use is necessary. Taper
medication over 2 weeks when discontinuing.
Half-life: 4–6 hours
retention, sedation, drowsiness, depression, psychosis. IV
form is associated with orthostatic hypotension.
neuroleptics, tricyclics, over-the- counter sleep
preparations) may cause anticholinergic intoxication.
Clinical Guidelines: Avoid using this medication with
low-potency neuroleptics (additive anticholinergic effects).
Biperiden is contraindicated in glaucoma, prostatic
hypertrophy, myasthenia gravis, and duodenal or pyloric
obstruction.
Amantadine (Symmetrel)
Category: Dopamine agonist
symptoms.
Preparations: 100 mg capsules; 50 mg/5 mL syrup.
Dosage:
Initial treatment: 100 mg bid (max 400 mg/day).
Perform trial off amantadine after 4 to 8 weeks to
assess the need for continued use. Taper drug when
discontinuing use.
Half-life: 24 hours, increased in elderly.
Side Effects: Nausea (common), dry mouth, blurred
vision, constipation, anorexia, hypotension, dizziness,
anxiety, tremor, insomnia, irritability, impaired
concentration, psychosis, seizure.
Use caution in patients with a history of congestive heart

failure and liver disease. Neuroleptic malignant syndrome
has been reported with dose reduction or discontinuation
of amantadine. Reduce dose in elderly. Contraindicated
in pregnancy and lactation. Alcohol should not be used.
Amantadine is contraindicated with renal disease or
seizures.
Interactions:
A. Anticholinergics may rarely cause potentiation.
B. CNS stimulants may cause irritability, seizure,
arrhythmia.
C. Thiazides may increase level of amantadine.
D. Sympathomimetics may cause potentiation.
Clinical Guidelines: Amantadine is associated with less
memory impairment than anticholinergics. It is useful
when anticholinergics must be avoided. Amantadine is
less effective than anticholinergics in treatment of acute
dystonias.
Diphenhydramine (Benadryl)
Category: Histamine receptor (H1) antagonist,
muscarinic receptor antagonist
Indications: Neuroleptic-induced extrapyramidal
symptoms (Extrapyramidal symptoms), mild insomnia.
Preparations: 25, 50 mg tablets; 25, 50 mg capsules; 10
mg/mL & 50 mg/mL soln. (IM, IV), 12.5 mg/5 mL elixir
(PO).
Dosage:
Extrapyramidal symptoms: 25-50 mg PO Bid, for
acute Extrapyramidal symptoms 25-50 mg IM or IV.
Half-Life: 1-4 hrs.
decreased motor coordination, GI distress.
Interactions.
A. The major concern about concomitant medication
use with diphenhydramine is the additive effect of
other sedatives and other medications with
anticholinergic activity.
B. Medical conditions that are sensitive to
anticholinergic action such as narrow angle
glaucoma and prostatic hypertrophy may worsen.
C. MAOI use can prolong and intensify anticholinergic
effects. Opiate addicts commonly add
antihistamines to enhance the subjective effect of
the illicit drug.
Clinical Guidelines: Diphenhydramine is non-addicting
and available over the counter.
References
References are available at www.ccspublishing.com

Selected DSM-IV Codes
ATTENTION-DEFICIT AND DISRUPTIVE BEHAVIOR
DISORDERS
314.xx Attention-Deficit/Hyperactivity Disorder
.01 Combined Type
.00 Predominantly Inattentive Type
.01 Predominantly Hyperactive-Impulsive
Type
DEMENTIA
290.xx Dementia of the Alzheimer's Type, With
Early Onset (also code 331.0 Alzheimer's
disease on Axis III)
.10 Uncomplicated
290.xx Dementia of the Alzheimer's Type, With
Late Onset (also code 331.0 Alzheimer's
disease on Axis III)
.0 Uncomplicated
290.xx Vascular Dementia
.40 Uncomplicated
MENTAL DISORDERS DUE TO A GENERAL

MEDICAL CONDITION NOT ELSEWHERE
CLASSIFIED
310.1 Personality Change Due to... [Indicate the
General Medical Condition]
ALCOHOL-RELATED DISORDERS
303.90 Alcohol Dependence

305.00 Alcohol Abuse
291.8 Alcohol-Induced Mood Disorder
291.8 Alcohol-Induced Anxiety Disorder
AMPHETAMINE (OR AMPHETAMINE-LIKE)-

RELATED DISORDERS
304.40 Amphetamine Dependence
305.70 Amphetamine Abuse
COCAINE-RELATED DISORDERS
304.20 Cocaine Dependence
305.60 Cocaine Abuse
OPIOID-RELATED DISORDERS
304.00 Opioid Dependence
305.50 Opioid Abuse
SEDATIVE-, HYPNOTIC-, OR ANXIOLYTIC-RELATED

DISORDERS
304.10 Sedative, Hypnotic, or Anxiolytic
Dependence
305.40 Sedative, Hypnotic, or Anxiolytic Abuse
POLYSUBSTANCE-RELATED
DISORDER
304.80 Polysubstance Dependence
SCHIZOPHRENIA AND OTHER PSYCHOTIC

DISORDERS
295.xx Schizophrenia
.30 Paranoid Type
.10 Disorganized Type
.20 Catatonic Type
.90 Undifferentiated Type
.60 Residual Type
295.40 Schizophreniform Disorder
295.70 Schizoaffective Disorder
297.1 Delusional Disorder
298.8 Brief Psychotic Disorder
297.3 Shared Psychotic Disorder
293.xx Psychotic Disorder Due to...
.81 With Delusions
.82 With Hallucinations
298.9 Psychotic Disorder NOS
DEPRESSIVE DISORDERS
296.xx Major Depressive Disorder
.2x Single Episode
.3x Recurrent
300.4 Dysthymic Disorder
311 Depressive Disorder NOS
BIPOLAR DISORDERS
296.xx Bipolar I Disorder,
.0x Single Manic Episode
.40 Most Recent Episode Hypomanic
.4x Most Recent Episode Manic
.6x Most Recent Episode Mixed
.5x Most Recent Episode
Depressed
.7 Most Recent Episode Unspecified
296.89 Bipolar II Disorder
301.13 Cyclothymic Disorder
296.80 Bipolar Disorder NOS
293.83 Mood Disorder Due to...
[Indicate the General Medical Condition]
ANXIETY DISORDERS
300.01 Panic Disorder Without Agoraphobia
300.21 Panic Disorder With Agoraphobia
300.22 Agoraphobia Without History of Panic
Disorder
300.29 Specific Phobia
300.23 Social Phobia
300.3 Obsessive-Compulsive Disorder
309.81 Posttraumatic Stress Disorder
308.3 Acute Stress Disorder
300.02 Generalized Anxiety Disorder
EATING DISORDERS
307.1 Anorexia Nervosa
307.51 Bulimia Nervosa
307.50 Eating Disorder NOS
ADJUSTMENT DISORDERS
309.xx Adjustment Disorder
.0 With Depressed Mood
.24 With Anxiety
.28 With Mixed Anxiety and Depressed Mood
.3 With Disturbance of Conduct
.4 With Mixed Disturbance of Emotions and
Conduct
.9 Unspecified
PERSONALITY DISORDERS
301.0 Paranoid Personality Disorder
301.20 Schizoid Personality Disorder
301.22 Schizotypal Personality Disorder
301.7 Antisocial Personality Disorder
301.83 Borderline Personality Disorder
301.50 Histrionic Personality Disorder
301.81 Narcissistic Personality Disorder
301.82 Avoidant Personality Disorder
301.6 Dependent Personality Disorder
301.4 Obsessive-Compulsive Personality Disorder
301.9 Personality Disorder NOS

Current Clinical Strategies: Handbook of Psychiatric Drugs

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Current Clinical Strategies

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Current Clinical Strategies Publishing

Indications for medications contained in this book

Printed in USA ISBN 1929622-39-2

Table 1. Substrates of the P450 Enzymes

CYP1A Acetaminoph Haloperidol Tacrine

CYP2D Amitriptyline Ethylmorphi Perphenazin

CYP2C Diclofenac Naproxen Tolbutamide

CYP2C Amitriptyline Hexobarbita Omeprazole

CYP3A Acetaminoph Dapsone Midazolam

CYP1A CYP2C9 CYP2C19 CYP2D6 CYP3

Escitalopram 0/+ 0/+ 0/+ + 0/+

Citalopram 0/+ 0/+ 0/+ + 0/+

Fluoxetine (Prozac) 0/+ ++/+++ ++/+++ ++++ +/++

Fluvoxamine ++++ 0/+ ++++ 0/+ +++

Paroxetine (Paxil) 0/+ 0/+ 0/+ ++++ 0/+

Sertraline (Zoloft) 0/+ 0/+ +/++ + 0/+

Fluoxetine (Prozac, Sarafem, Prozac

Paroxetine (Paxil, Paxil CR)

References, see page 102.

Atypical antidepressants are unique compounds that are

Bupropion (Wellbutrin, Zyban and

Venlafaxine (Effexor and Effexor

References, see page 102.

Tertiary Amine Tricyclic

Amitriptyline (Elavil, Endep)

Doxepin (Adapin, Sinequan)

References, see page 102.

Nortriptyline (Pamelor, Aventyl)

References, see page 102.

References, see page 102.

References, see page 102.

Clinical Use of Antipsychotics

References, see page 102.

Olanzapine (Zyprexa, Zydis)

References, see page 102.

Side-Effect Profile: Orthostatic hypotension (low),

References, see page 102.

Side-Effect Profile: Orthostatic hypotension (moderate),

References, see page 102.

Side-Effect Profile: High potentiation of anticholinergic,

References, see page 102.

Anxiolytic medications are used for the treatment of

References, see page 102.

References, see page 102.

Hydroxyzine (Atarax, Vistaril)

References, see page 102.

Chloral Hydrate (Somnote)

References, see page 102.

References, see page 102.

Mood stabilizers are used for the treatment of mania,

Lithium Carbonate (Eskalith,

References, see page 102.

Valproic Acid (Depakene) and

References, see page 102.

Methylphenidate (Ritalin, Ritalin SR,

I. Indications: Attention-Deficit Hyperactivity Disorder.