Depressive Disorders: Pathophysiology
Depressive Disorders: Pathophysiology
Depressive Disorders: Pathophysiology
68 Depressive Disorders
• The essential feature of major depressive disorder (MDD) is a clinical course char-
acterized by one or more major depressive episodes without a history of manic or
hypomanic episodes.
• Refer to guidelines published by the American Psychiatric Association, the British
Association of Psychopharmacology, and the Canadian Network for Mood and Anxi-
ety Treatments (CANMAT) because they have similarities in their recommendations.
PATHOPHYSIOLOGY
• Monoamine hypothesis: Decreased brain levels of the neurotransmitters norepinephrine
(NE), serotonin (5-HT), and dopamine (DA) may cause depression.
• Postsynaptic changes in receptor sensitivity: Studies have demonstrated that desensi-
tization or downregulation of NE or 5-HT1A receptors may relate to onset of antide-
pressant effects.
• Dysregulation hypothesis: Failure of homeostatic neurotransmitter regulation, rather
than absolute increases or decreases in their activities.
• Inflammatory hypothesis: Chronic stress and inflammation may alter glutamatergic
and GABA transmission. Brain-derived neurotrophic factor (BDNF) is a primary
mediator of neuronal changes as well as synaptogenesis whose expression is reduced
due to stress and may be associated with depression.
• Neuroactive steroids are a growing area of research for depression.
CLINICAL PRESENTATION
• Emotional symptoms: Diminished ability to experience pleasure, loss of interest in
usual activities, sadness, pessimism, crying, hopelessness, anxiety, feelings of worth-
lessness or guilt, and psychotic features (eg, auditory hallucinations and delusions).
Recurrent thoughts of death, suicidal ideation without a specific plan, suicide
attempt, or a plan for committing suicide.
• Physical symptoms: Weight gain or loss, fatigue, pain (especially headache), sleep dis-
turbance, decreased or increased appetite, loss of sexual interest, and gastrointestinal
(GI) and cardiovascular complaints (especially palpitations).
• Cognitive symptoms: Decreased ability to concentrate, poor memory for recent
events, confusion, and indecisiveness.
• Psychomotor disturbances: Psychomotor retardation (slowed physical movements,
thought processes, and speech) or psychomotor agitation.
DIAGNOSIS
• MDD is characterized by one or more major depressive episodes, as defined by the
Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Five or more of the
above symptoms must have been present nearly every day during the same 2-week
period and cause significant distress or impairment. Depressed mood or loss of
interest or pleasure must be present in adults (or irritable mood in children and
adolescents). Table 68-1 outlines a common acronym for MDD diagnostic criteria.
• The depressive episode must not be attributable to physiological effects of a substance
or medical condition.
• There must not be a history of manic-like or hypomanic-like episodes unless they
were induced by a substance or medical condition.
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TREATMENT
• Goals of Treatment: Resolution of current symptoms (ie, remission), prevention of
further episodes of depression (ie, relapse or recurrence), and prevention of suicide.
NONPHARMACOLOGIC TREATMENT
• Psychotherapy (eg, cognitive therapy, behavioral therapy, or interpersonal psycho-
therapy) is recommended as primary treatment for mild to moderately severe major
depressive episode. For severe depression, it may be used in combination with medi-
cations as its effect is considered additive. Psychotherapy alone is not recommended
for acute treatment of severe and/or psychotic MDD.
• Electroconvulsive therapy (ECT) may be considered when a rapid response is
needed, risks of other treatments outweigh potential benefits, there is history of a
poor response to drugs, and the patient prefers ECT. A rapid therapeutic response
(10–14 days) has been reported.
• Repetitive transcranial magnetic stimulation has demonstrated efficacy and does not
require anesthesia as does ECT.
• Recent data suggest the benefit of physical activity in patients with MDD, and the
American Psychiatry Association has endorsed inclusion of exercise into MDD
treatment plans.
PHARMACOLOGIC THERAPY
General Approach
• Figure 68-1 shows an algorithm for treatment of uncomplicated MDD. Table 68-2
guides adult dosing of antidepressants.
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contraindication to a specific class of antidepressants
Consider augmentation
Ensure medication adherence (non-SSRI antidepressant, lithium, Maintain for at least 4–9 months
thyroid hormone, atypical antipsychotic) for continuation, and, if
-or- necessary, 12–36 months
Switch to alternative agent for maintenance
Switch to alternative agent
(different SSRI, non-SSRI (different SSRI or non-SSRI
antidepressant) antidepressant)
Switch to alternative Consider augmentation Maintain for at least Consider augmentation Maintain for at least 4–9
Switch to alternative
agent (non-SSRI antidepressant, 4–9 months for continuation, (non-SSRI antidepressant, months for continuation, and,
agent (non-SSRI
(non-SSRI lithium, thyroid hormone, and, if necessary, 12–36 lithium, thyroid hormone, if necessary, 12–36 months
Depressive Disorders |
antidepressant)
antidepressant) atypical antipsychotic) months for maintenance atypical antipsychotic) for maintenance
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TABLE 68-2 Adult Dosing Guidance for Currently Available Antidepressant Medications
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Usual Dosage
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Drug Initial Dose Range Comments (eg, Maximum Daily Dosage, Suggested Therapeutic Plasma
(Brand Name) (mg/day) (mg/day) Concentration)a
Selective serotonin reuptake inhibitors (SSRIs)
Citalopram (Celexa) 20 20–40 Doses >40 mg/day not recommended due to QT prolongation risk; maximum 20 mg/day
for CYP2C19 poor metabolizers or coadministration with CYP2C19 inhibitors; 20 mg/
day recommended for patients older than 60 years of age
Escitalopram 10 10–20 Maximum 20 mg/day; dose may be increased to maximum daily dose after at least 1 week
(Lexapro) if needed; 5 mg tablet available for unique circumstances
SECTION 13 | Psychiatric Disorders
Fluoxetine (Prozac) 20 20–60 Maximum 80 mg/day; dose may be increased in 20 mg increments; doses of 5 or 10 mg/
day have been used as initial therapy; doses >20 mg/day may be given in a single daily
dose or divided twice daily
Fluvoxamine (Luvox) 50 50–300 Maximum 300 mg/day; daily doses >100 mg total dose should be divided twice daily,
with the larger dose given at night
Maximum 300 mg/day (ER formulation)
Paroxetine (Paxil) 20 20–50 Maximum 50 mg/day (IR formulation); titrate 10 mg/day increments weekly
Maximum 62.5 mg/day (CR formulation); titrate 12.5 mg/day increments weekly
Sertraline (Zoloft) 50 50–200 Maximum 200 mg/day; titrate 25 mg/day increments weekly
Serotonin–norepinephrine reuptake inhibitors (SNRIs)
Newer-generation SNRIs
Desvenlafaxine 50 50 Doses up to 400 mg/day have been studied; however, AEs are increased and no
(Pristiq) additional benefit has been shown at doses exceeding 50 mg/day. Dose reductions or
discontinuation may be required if sustained hypertension occurs
Duloxetine 30 30–90 Maximum 120 mg/day (given once or twice daily); doses exceeding 60 mg/day not
(Cymbalta) shown to provide increased efficacy for the treatment of MDD
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Venlafaxine (Effexor) 37.5–75 75–225 Maximum 375 mg/day (IR); maximum 225 mg/day (ER); may increase in increments up to
75 mg/day at a minimum of every 4 days. Dose reductions or discontinuation may be
required if sustained hypertension occurs
Levomilnacipran 20 40–120 Initial dose (20 mg) for 2 days before dose increases is recommended at intervals of 2 or
(Fetzima) more days. Dose adjustment or discontinuation may be required if sustained elevated
heart rate or hypertension occurs
Tricyclic antidepressants (TCAs)
Amitriptyline (Elavil) 25 100–200 Maximum 300 mg/day for MDD; depending on the total dose, it may be given as a single
daily dose at bedtime or in divided doses throughout the day; therapeutic serum level
100–250 ng/mL (mcg/L; 370–925 nmol/L); parent drug plus metabolite (nortriptyline)
Desipramine 25 100–200 Maximum 300 mg/day; suggested therapeutic concentration range for combined
(Norpramin) imipramine + desipramine: 150–300 ng/mL (mcg/L; 550–1100 nmol/L)
Doxepin (Sinequan) 25 100–200 Maximum 300 mg/day; may be given in a single daily dose at bedtime (if tolerated) or in
divided doses throughout the day; a single dose should not exceed 150 mg
Imipramine (Tofranil) 25 100–200 Maximum 300 mg/day; may be given in a single daily dose at bedtime (if tolerated) or
in divided doses throughout the day; suggested therapeutic concentration range for
combined imipramine + desipramine: 150–300 ng/mL (mcg/L; 550–1100 nmol/L)
Nortriptyline 25 50–150 Maximum 150 mg/day; total daily may be given as a single daily dose (if tolerated) or
(Pamelor) 25 mg doses given three to four times daily; therapeutic serum level 50–150 ng/mL
(mcg/L; 190–570 nmol/L)
Norepinephrine and dopamine reuptake inhibitor (NDRI)
Bupropion 150 (75 mg given 150–450 Maximum 450 mg/day (IR, ER), 400 mg/day (SR); ER dosed once daily; SR dosed once or
(Wellbutrin) twice daily) twice daily; IR may be dosed up to three times daily. Adhering to labeled maximum
Depressive Disorders |
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TABLE 68-2 Adult Dosing Guidance for Currently Available Antidepressant Medications (Continued )
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Usual Dosage
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Drug Initial Dose Range Comments (eg, Maximum Daily Dosage, Suggested Therapeutic Plasma
(Brand Name) (mg/day) (mg/day) Concentration)a
Trazodone (Desyrel; 50 150–300 Maximum 600 mg/day; IR daily dose should be divided three times daily and may increase
Oleptro) by 50 mg/day increments every 3–7 days; ER dose titration initiated at 150 mg at
bedtime and can be increased 75 mg/day every 3 days
Vilazodone (Viibryd) 10 20–40 Target dose 20–40 mg/day unless coadministered with CYP3A4 inhibitor (dose not to
exceed 20 mg/day). Dose titration: 10 mg/day for 7 days, 20 mg/day for 7 days, and
then may increase to 40 mg/day. Dose must be taken with food to ensure adequate
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Second-generation antipsychotics (SGA) as augmentation (5HT2A and D2 modulators)
Aripiprazole (Abilify) 2 2–15 FDA-approved for augmentation; CANMAT Level 1 evidence, 1st line
Brexpiprazole 1 1–3 Not FDA-approved for augmentation; CANMAT Level 1 evidence, 2nd line
(Rexulti)
Olanzapine (Zyprexa) 2.5 2.5–10 Not FDA-approved for augmentation; CANMAT Level 1 evidence, 2nd line
Quetiapine 50 150–300 FDA-approved for augmentation; CANMAT Level 1 evidence, 1st line
(Seroquel)
Risperidone 1 1–3 Not FDA-approved for augmentation; CANMAT Level 1 evidence, 1st line
(Risperdal)
Alternative augmentation agents (not FDA-approved for antidepressant augmentation)
Buspirone (Buspar) 10 10–60 Divided dosing 2–3 times daily
5HT1A partial agonist
Lithium 300 600–1200 Dose based on therapeutic levels (target 0.6–1 mEq/L [mmol/L])
Depressive Disorders |
Mechanism in depression not fully understood
Triiodothyronine 0.025 0.025–0.05 Once daily dosing; monitor free T3 levels
(Cytomel)
a
SI conversion for cases where reference ranges are for a mixture of parent drug and active metabolite is calculated based on a 1:1 ratio.
AE, adverse effects; CR, continuous release; ER, extended release; IR, immediate release; MDD, major depressive disorder; SR, sustained release; CANMAT, Canadian Network for Mood and
Anxiety Treatments.
CHAPTER 68
AL G R A W A N Y
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TABLE 68-3 Relative Potencies of Norepinephrine and Serotonin Reuptake Blockade and
Selected Receptor Antagonism Profile of Antidepressants
Reuptake Antagonism
NE 5-HT M1 H1 α1
Selective serotonin reuptake inhibitors (SSRIs)
Citalopram 0 ++++ 0 + 0
Escitalopram 0 ++++ 0 0 0
Fluoxetine + ++++ 0 0 0
Fluvoxamine 0 ++++ 0 + 0
Paroxetine ++ ++++ + + 0
Sertraline 0 ++++ 0 0 0
Serotonin–norepinephrine reuptake inhibitors (SNRIs)
Duloxetine +++ ++++ + 0 +
Levomilnacipran ++++ +++ + 0 0
Venlafaxinea and +++ ++++ + + 0
desvenlafaxine
Tricyclic antidepressants (TCAs)
Amitriptyline ++ ++++ ++++ ++++ +++
Desipramine ++++ ++ ++ ++ ++
Doxepin ++ ++ +++ ++++ ++
Imipramine ++ ++++ +++ +++ ++++
Nortriptyline ++++ ++ ++ ++ +
Mixed serotonergic (mixed 5-HT)
Nefazodone 0 ++ 0 +++ +++
Trazodone 0 ++ 0 ++++ +++
Vilazodone 0 ++++ 0 + 0
Vortioxetine 0 ++++ 0 + 0
Norepinephrine and dopamine reuptake inhibitor (NDRI)
Bupropionb + 0 + 0 0
Serotonin and α2-receptor antagonist
Mirtazapine 0 0 0 ++ ++
Venlafaxine: primarily 5-HT at lower doses, NE at higher doses, and DA at very high doses.
a
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Drug ADR(s) Monitoring Comments
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Antidepressants from each pharmacologic class
Common to all
antidepressants
Suicidality Behavioral changes (US black box warning) for all antidepressants; caregivers
Mental status should be alerted to monitor for acute changes in behavior
(especially early in treatment)
Selective serotonin reuptake inhibitors (SSRIs)
Common to all SSRIs
Anxiety or Assess severity and impact on Most prominent on initial treatment; lower initial doses
SECTION 13 | Psychiatric Disorders
nervousness patient functioning and quality recommended in patients with prominent anxiety
of life
Hyponatremia Serum sodium More likely in older females; sodium may decrease within
72 hours of initiating antidepressant
Nausea Frequency and severity May improve with slower dose titration
Sleep changes Sleep patterns Among SSRI class: fluoxetine may be more activating;
(insomnia and fluvoxamine and paroxetine may be more sedating
somnolence)
Sexual Assess severity and impact on Spontaneous self-reporting may be low; clinician should
dysfunction patient functioning and quality assess symptoms; reversible on drug discontinuation
of life
SSRI-specific
Citalopram (possibly QTc interval Electrocardiogram; electrolytes (eg, Caution use in “at-risk” patients (eg, electrolyte disturbance);
escitalopram) prolongation potassium, magnesium) discontinue if QTc persistently >500 msec or increased >5
msec over baseline
Fluoxetine Anorexia Weight (over time) SSRIs are generally considered weight neutral
Paroxetine Anticholinergic Symptoms: dry mouth, constipation, Paroxetine possesses relatively more anticholinergic effects
effects urinary retention, mental status than other SSRIs
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Serotonin–norepinephrine reuptake inhibitors (SNRIs)
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Common to all SNRIs
Cardiovascular Increases in blood pressure; Possibly less likely with duloxetine; may need to lower/
changes heart rate discontinue dose
Insomnia Sleep patterns Possibly less likely with duloxetine
Nausea Frequency and severity May improve with slower dose titration
Sexual Assess severity and impact on Spontaneous self-reporting may be low; clinicians should
dysfunction patient functioning and quality assess symptoms; reversible on drug discontinuation
of life
Sweating Frequency and severity May require change in therapy
SNRI-specific
Desvenlafaxine Dose-related Lipid profile Elevations in total cholesterol, low-density lipoproteins, and
hyperlipidemia triglycerides
Duloxetine Liver toxicity Liver function tests May be transient upon initiation or sustained
Mixed serotonergic effects (mixed 5-HT)
Nefazodone Liver toxicity Liver function tests Nefazodone black box warning in the United States for
hepatotoxicity
Trazodone Orthostatic Blood pressure, pulse May be more severe as compared with other antidepressants;
hypotension rate-limiting side effect
Priapism Patient report of sexual side effects, Patient should seek medical attention for prolonged erection
especially painful erection (ie, >4 hours)
Vilazodone and vortioxetine Nausea Frequency and severity Most common dose-limiting side effect
Serotonin and α2-adrenergic antagonist
Mirtazapine Weight gain Body weight Frequently occurring and significant (>7% over baseline)
Depressive Disorders |
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TABLE 68-6 Second- and Third-Generation Antidepressants and Cytochrome (CYP) P450
Enzyme Inhibitory Potential
CYP Enzyme
Drug 1A2 2C 2D6 3A4
Bupropion 0 0 +++ 0
Citalopram 0 0 + NA
Duloxetine 0 0 +++ 0
Escitalopram 0 0 + 0
Fluoxetine 0 ++ ++++ ++
Fluvoxamine ++++ ++ 0 +++
Mirtazapine 0 0 0 0
Nefazodone 0 0 0 ++++
Paroxetine 0 0 ++++ 0
Sertraline 0 ++ + +
(des)-Venlafaxine 0 0 0/+ 0
++++, high; +++, moderate; ++, low; +, very low; 0, absent.
• Vilazodone and vortioxetine are other antidepressants with mixed serotonin effects
that are a combination SSRI and 5-HT1A presynaptic receptor partial agonists. Vilazo-
done may be particularly useful for depressed patients with anxiety, and vortioxetine
may be helpful for depressed patients with cognitive difficulties.
✓ Vilazodone is associated with nausea, diarrhea, dizziness, insomnia, and decreased
libido, especially in men.
✓ Vortioxetine causes nausea and constipation and sexual dysfunction in men at the
highest dose (20 mg/day).
Bupropion
• Bupropion inhibits both the NE and DA reuptake that makes it one of the most
activating antidepressants.
✓ The occurrence of seizures with bupropion is dose related and may be increased by
predisposing factors (eg, history of head trauma or central nervous system [CNS]
tumor). At the ceiling dose (450 mg/day), the incidence of seizures is 0.4%.
✓ Other side effects are nausea, vomiting, tremor, insomnia, dry mouth, and skin
reactions. It is contraindicated in patients with bulimia or anorexia nervosa, as these
patients have a higher risk for seizures. It causes less sexual dysfunction than SSRIs.
Tricyclic Antidepressants
• Tricyclic antidepressant (TCA) use has diminished because of the availability of
equally effective therapies that are safer on overdose and better tolerated. They
inhibit the reuptake of NE and 5-HT and have affinity for adrenergic, cholinergic,
and histaminergic receptors.
• TCAs cause anticholinergic side effects (eg, dry mouth, blurred vision, constipation,
urinary retention, tachycardia, memory impairment, and delirium) and sedation.
Additional adverse effects include weight gain, orthostatic hypotension, cardiac con-
duction delay, and sexual dysfunction.
• Desipramine carries an increased risk of death in patients with a family history of
sudden cardiac death, cardiac dysrhythmias, or cardiac conduction disturbances.
• Abrupt withdrawal of TCAs (especially high doses) may result in cholinergic
rebound (eg, dizziness, nausea, diarrhea, insomnia, and restlessness).
• Maprotiline, a tetracyclic drug, causes seizures at a higher incidence than do stan-
dard TCAs and is contraindicated in patients with a history of seizure disorder.
• Metabolism of the TCAs appears to be linear within the usual dosage range. Dose-
related kinetics cannot be ruled out in older patients. Factors reported to influence
TCA plasma concentrations include renal or hepatic dysfunction, genetics, age, ciga-
rette smoking, and concurrent drug administration.
• In acutely depressed patients, there is a correlation between antidepressant effect and
plasma concentrations for some TCAs (eg, amitriptyline, nortriptyline, imipra-
mine, and desipramine). The best-established therapeutic range is for nortriptyline,
and data suggest a therapeutic window (Table 68-2).
• Some indications for TCA plasma level monitoring include inadequate response;
relapse; serious or persistent adverse effects; use of higher than standard doses;
suspected non-adherence, toxicity, pharmacokinetic interactions; elderly, pediatric,
and adolescent patients; pregnant patients; patients of African or Asian descent
(because of slower metabolism); cardiac disease; and changing brands. Plasma
concentrations should be obtained at steady state, usually after a minimum of
1 week at constant dosage, during the elimination phase, and usually in the morning
12 hours after the last dose.
• TCAs may interact with other drugs that modify hepatic cytochrome P450 (CYP450)
enzyme activity or hepatic blood flow. TCAs also are involved in interactions through
displacement from protein-binding sites.
• Increased plasma concentrations of TCAs and symptoms of toxicity may occur when
fluoxetine or paroxetine (both inhibitors of CYP2D6) are added.
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Ketamine
• Ketamine is an older anesthetic agent, which modulates glutamate activity via extra-
synaptic N-methyl-D-aspartate (NMDA) receptor antagonism resulting in increased
BDNF activity and synaptogenesis.
• Ketamine has rapid antidepressant effects when used in intravenous doses of 0.5mg/
kg for treatment refractory MDD.
• Esketamine is the single s-isomer of ketamine that has a higher affinity for the
NMDA receptor than the r-isomer. Intranasal esketamine is FDA-approved and
requires supervised, in-clinic self-administration (2–6 sprays per session) followed
by 2 hours of in-clinic observation. In trials, patients received doses twice weekly for
4 weeks and variable dosing thereafter.
• Side effects include transient psychotomimetic/dissociative effects and blood pres-
sure elevation (10–20 mm Hg) with both agents.
Brexanolone
• Brexanolone (exogenous allopregnanolone) is thought to exert antidepressant
effect by allosteric modulation of GABAA receptors, which may increase 5HT and
NE transmission and is FDA-approved for postpartum depression. Administration
involves a 60-hour stepped dose, intravenous infusion.
• Common adverse effects are headache, dizziness, and somnolence. It has a manda-
tory Risk Evaluation and Mitigation Strategies (REMS) program with Elements
to Ensure Safe Use (ETASU) due to the incidence of excessive sedation or loss of
consciousness.
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TABLE 68-7 Dietary and Medication Restrictions for Patients Taking Monoamine Oxidase
Inhibitorsa
Approximate Tyramine
Foods to Avoid Completely Content (mg) Per Ounce
Aged cheeses (eg, cheddar, blue, Swiss, Camembert) 25–45
Chicken liver 60
Dry aged meats (eg, mortadella, salami, prosciutto) 2–45
Fava beans Unknown
Kim chee Unknown
Red wine Variable
Sauerkraut 1–3
Smoked or pickled fish (eg, lox, caviar, pickled herring) 0–80
Soy sauce, fermented soy, miso Varies
Tap beer 20–40
Yeast extract 2–60
Foods to Eat in Moderation
American cheese, Parmesan cheese <2
Canned, filtered beer <2 per 12 oz (355 mL)
Havarti, brie Thought to be low
Pepperoni <2
Pizza (large commercial chains generally safe; avoid gourmet 2 slices
with aged cheeses and meats)
White wine <1 per 4 oz (120 mL)
Foods Without Restrictions
Fresh dairy products (cottage cheese, cream cheese,
fresh milk, ice cream, ricotta, sour cream, yogurt)
Fresh meats (including fresh sausage)
Processed meats (eg, lunch meat, hot dogs, ham)
Spirits (eg, bourbon, gin, rum, vodka)
Yeast bread products
Medications to Avoid Completely
Antidepressantsa Dopamine Methylphenidate
Amphetamines Ephedrine Reserpine
Appetite suppressants Epinephrine Sympathomimetics
Asthma inhalants Guanethidine Tryptophan
Buspirone Levodopa
Carbamazepine Local anestheticsb
Decongestants Meperidine
Dextromethorphan Methyldopa
a
Tricyclic antidepressants may be used with caution by experienced clinicians in treatment-refractory
populations.
b
Those containing sympathomimetic vasoconstrictors.
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SPECIAL POPULATIONS
Older Patients
• In older patients, depressed mood may be less prominent than other symptoms, such
as loss of appetite, cognitive impairment, sleeplessness, fatigue, physical complaints,
and loss of interest in usual activities.
• The SSRIs are often considered first-choice antidepressants for older patients.
Bupropion, venlafaxine, and mirtazapine are also effective and well tolerated.
• Hyponatremia is more common in older patients.
Pediatric Patients
• Symptoms of depression in childhood include boredom, anxiety, failing adjustment,
and sleep disturbance.
• Data supporting efficacy of antidepressants in children and adolescents are sparse.
Fluoxetine and escitalopram are the only FDA-approved antidepressants for patients
below 18 years of age.
• All antidepressants carry a black box warning for caution when using antidepressants
in this population, and the FDA recommends specific monitoring parameters.
• Several cases of sudden death have been reported in children and adolescents taking
desipramine and baseline electrocardiogram (ECG) is recommended.
Pregnancy
• Approximately 14% of pregnant women develop depression during pregnancy and
women who discontinued antidepressant therapy were five times more likely to have
a relapse during their pregnancy than were women who continued treatment.
• The absolute risk of antidepressant use in pregnancy is unknown.
• Risks reported with SSRIs use in pregnancy include low birth weight, respiratory
distress, and congenital heart defects.
• The risks and benefits of drug therapy during pregnancy must be weighed, including
concerns about untreated depression.
• Lack of current data exists regarding antidepressant exposure to infants during
breastfeeding; however, sertraline may be preferred. The Motherisk program has the
most up-to-date information.
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See Chapter 85, Major Depressive Disorder, authored by Amy M. Vandenberg, for a more
detailed discussion of this topic.
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• Opioid use disorder (OUD) consists of intoxication and withdrawal from the sub-
stance for which there is no cure. Since 1999, the number of overdose deaths contrib-
uted to OUD has more than tripled. These deaths have involved opioid substances
including prescription opioids (ie, natural opioids, semisynthetic opioids, and metha-
done), as well as heroin and synthetic opioids (ie, illicitly manufactured fentanyl).
PATHOPHYSIOLOGY
• The true etiology behind substance use disorders (SUD) is unknown. In general, it is
felt that there needs to be a triad of the right patient, with the right genetic risk fac-
tors, being exposed to the right medication or substance in order for a SUD to occur.
CLINICAL PRESENTATION
• Signs and symptoms of opioid intoxication include euphoria, dysphoria, slurred
speech, miosis, apathy, sedation, and attention impairment. Signs and symptoms of
withdrawal include lacrimation, mydriasis, piloerection, diaphoresis, diarrhea, yawn-
ing, muscle aches, and insomnia. Pinpoint pupils, decreased breathing, pulmonary
edema, loss of consciousness, and death may occur with opioid intoxication.
• The onset of withdrawal ranges from a few hours after stopping heroin to 3–5 days
after stopping methadone. Duration of withdrawal ranges from 3–14 days. Occur-
rence of delirium suggests withdrawal from another drug (eg, alcohol).
• Symptoms can be scored on the Clinical Opiate Withdrawal Symptoms (COWS)
assessment tool to assess severity of opioid withdrawal.
• Laboratory tests to obtain include a comprehensive metabolic panel to monitor serum
electrolyte concentrations in the setting of significant vomiting or diarrhea; check
liver function tests if using buprenorphine. Arterial blood gases, pulse oximetry, and
capnography are useful to assess respiratory depression in opioid intoxication.
DIAGNOSIS
• The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5)
defines SUD as “problematic pattern of substance use leading to clinically significant
impairment or distress as manifested by at least two of eleven criteria occurring in
the preceding 12-month period.”
• These behaviors fall into the categories of: (1) impaired control, (2) social impairment,
(3) risky use, and (4) pharmacological criteria, including tolerance and withdrawal,
and are outlined in Table 69-1.
• SUDs occur in a broad range of severity from mild (2–3 symptoms) to moderate (4–5
symptoms) to severe (6 or more symptoms).
• DSM-5 does not separate the diagnoses of substance abuse and substance dependence.
Criteria are provided for SUD, accompanied by criteria for intoxication, withdrawal,
substance-induced disorders, and unspecified substance-related disorders in some cases.
• Addiction: A primary chronic neurobiologic disease characterized by the inability to
consistently abstain, impairment in behavioral control, craving, dysfunctional emo-
tional response, and diminished recognition of significant problems with behaviors
and interpersonal relationships.
• Intoxication: Development of a substance-specific syndrome after recent ingestion and
presence in the body of a substance; it is associated with maladaptive behavior during
the waking state caused by effects of the substance on the central nervous system (CNS).
• Physical dependence: A state of adaptation manifested by a drug-class–specific with-
drawal syndrome that can be produced by abrupt cessation, rapid dose reduction,
decreasing blood level of the drug, and/or administration of an antagonist.
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