10/16/2020 Antidepressants - AMBOSS

Antidepressants
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Summary

Antidepressants are used primarily to treat major depressive disorder (MDD), although they are also indicated for the treatment of
many other neuropsychiatric conditions. The most widely used classes of antidepressants are selective serotonin reuptake
inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic
antidepressants (TCAs). Most of these drugs work by increasing levels of serotonin, norepinephrine, or dopamine within the
synaptic cleft. SSRIs are the first-line treatment for the vast majority of patients with depression because of their efficacy and
favorable side-effect profile. While MAOIs and TCAs also have a high degree of efficacy, they are no longer widely used because of
their undesirable side-effect profiles. Serotonin syndrome may occur as a complication of serotonergic antidepressant use; TCA
toxicity is also possible, as is antidepressant discontinuation syndrome, which is caused by abrupt withdrawal or dose reduction of
an antidepressant taken for ≥ 4 weeks.

Overview

Selective serotonin reuptake inhibitors

Mechanism of action: inhibition of serotonin reuptake in synaptic cleft → ↑ serotonin levels

Drugs
Fluoxetine
Paroxetine
Sertraline
Citalopram
Escitalopram
Fluvoxamine
Indications
Side effects
Drug interactions:
Additional information
Typically takes 4–6 weeks before SSRIs begin to reduce symptoms
In the first trimester of pregnancy, paroxetine increases the risk of fetal cardiovascular malformations; in the third
trimester, it increases the risk of pulmonary hypertension in the fetus.

The side effects of SSRIs are: Serotonin syndrome, Stimulation of the CNS (agitation), Reproductive dysfunctions in males,
and Insomnia.
To avoid serotonin syndrome, SSRIs should be discontinued at least two weeks before starting an MAOI. Particular caution
should be observed with fluoxetine, which should be discontinued at least five weeks before MAOI treatment begins.
References:[1]

Serotonin-norepinephrine reuptake inhibitors

Mechanism of action: inhibition of serotonin and norepinephrine reuptake in synaptic cleft → ↑ serotonin and
norepinephrine levels

Drugs
Venlafaxine
Duloxetine
Desvenlafaxine
Levomilnacipran
Milnacipran

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Indications
Major depressive disorder (second-line therapy)
Generalized anxiety disorder
Neuropathic pain
Fibromyalgia: duloxetine and milnacipran
Stress incontinence in women: duloxetine

Social anxiety disorder, OCD, panic disorder, and PTSD: venlafaxine

Side effects
Similar profile to SSRIs (see selective serotonin reuptake inhibitors above)
Increased blood pressure
Sedation
Nausea
Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs
Additional information: Blood pressure should be well-controlled before initiating SNRI therapy.

References:[2]

Serotonin antagonist and reuptake inhibitors

Mechanism of action

Block postsynaptic type 2 serotonin receptors (5-HT2) [3]

Weak inhibition of serotonin reuptake → ↑ serotonin levels
Antagonist of H1 and α1-adrenergic receptors
Drugs
Trazodone
Nefazodone
Indications
Insomnia
Major depressive disorder (high doses required)
Side effects
Priapism
Sedation (due to H1 antagonism)
Orthostatic hypotension
Nausea
Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs
Additional information
Mainly used as an adjunct to other antidepressants for treating insomnia associated with depression

Two-week washout period before starting other serotonergic drugs

Think “traZzzoBONE” to remember the adverse effects of sedation (Zzz...) and priapism!
References:[4][3]

Atypical antidepressants

Mirtazapine [5][6]
Mechanism of action

Selective α2-adrenergic antagonist → ↑ serotonin and norepinephrine release

5-HT2 and 5-HT3 receptor antagonists → ↑ effect of serotonin on free 5-HT1 receptor → likely causes antidepressant
effects
H1 antagonist
Indications: major depressive disorder, especially in patients who are underweight and/or who have insomnia
Side effects
↑ Appetite and weight gain
Sedation (due to H1 antagonism)
↑ Serum cholesterol and triglyceride levels
Minimal sexual side effects
Dry mouth

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Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs

Mirtazzzapine makes you sleepy (Zzz...).

Bupropion [7]
Mechanism of action: not fully understood, but thought to increase dopamine and norepinephrine levels via reuptake
inhibition

Indications
Smoking cessation: used in conjunction with counseling and nicotine replacement (see nicotine use disorder)
Major depressive disorder
Side effects
Reduction of seizure threshold: Bupropion should be avoided in patients at increased risk for seizure (e.g., history of
epilepsy, anorexia/bulimia, alcohol or benzodiazepine withdrawal).
Tachycardia, palpitations
Dry mouth
Weight loss
Neuropsychiatric symptoms: insomnia, agitation, headache
Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs

Buproprion is not associated with sexual dysfunction or weight gain. It is contraindicated in patients with seizure and eating
disorders.

Vilazodone [8]
Mechanism of action
Inhibition of serotonin reuptake in synaptic cleft → ↑ serotonin levels
5-HT1A receptor partial agonist
Indications: major depressive disorder
Side effects
Headaches
Nausea, diarrhea
Sleep disturbances
Sexual dysfunction
Dry mouth
Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs

Vortioxetine [9]
Mechanism of action
Inhibition of serotonin reuptake in synaptic cleft → ↑ serotonin levels
5-HT1A receptor agonist
5-HT3 receptor antagonist
Indications: major depressive disorder
Side effects
Sexual dysfunction
Nausea
Abnormal dreams
Sleep disturbance
Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs

Varenicline
Mechanism of action
Nicotinic ACh receptor partial agonist
Stimulates dopamine activity → decreases nicotine cravings and withdrawal
Indications: smoking cessation (see nicotine use disorder)
Side effects
Mood disturbances
Sleep disturbances
Seizures

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VareniCliNe makes you Very Clean from Nicotine.

References:[5][6][10][7][8][9]

Monoamine oxidase inhibitors

Mechanism of action

Inhibition of monoamine oxidase → ↓ breakdown of epinephrine, norepinephrine, and serotonin → ↑ levels of

epinephrine, norepinephrine, and serotonin
Selegiline: selective MAO-B inhibitor → ↑ levels of dopamine
Drugs
Tranylcypromine
Phenelzine
Selegiline
Isocarboxazid
Indications
Major depressive disorder (third- or fourth-line therapy); particularly effective treatment for atypical depression
Parkinson disease: selegiline (as an adjunct to carbidopa-levodopa)
Side effects
CNS stimulation
Sexual dysfunction
Orthostatic hypotension
Weight gain
Hypertensive crisis with ingestion of foods containing tyramine (e.g., aged cheeses, smoked/cured meats, alcoholic
beverages, dried fruits)
[11]
Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs
Additional information
Rarely used due to poor side-effect profile
For the treatment of depression, selegiline is available as a transdermal patch (the oral form is only used for Parkinson
disease).

To remember the members of the MAO inhibitor class, think: “MAO thought capitalism was the PITS” (Phenelzine,
Isocarboxazid, Tranylcypromine, Selegiline).
References: [12]

Tricyclic antidepressants

Mechanism of action: inhibition of serotonin and norepinephrine reuptake in synaptic cleft → ↑ serotonin and
norepinephrine levels

Drugs
Secondary amines

Nortriptyline
Desipramine
Protriptyline
Amoxapine
Tertiary amines

Amitriptyline
Clomipramine
Doxepin
Imipramine
Trimipramine
Indications
Major depressive disorder (third- or fourth-line therapy)
Neuropathic pain (e.g., peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia)
Chronic pain (including fibromyalgia)
Migraine prophylaxis
OCD: clomipramine
Nocturnal enuresis: imipramine

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Side effects
Orthostatic hypotension

Cardiotoxicity due to Na+ channel inhibition in the myocardium: changes in cardiac conductivity velocity, arrhythmias,
prolonged QT interval (predisposes to torsades de pointes), wide QRS complex
Tremor
Respiratory depression
Hyperpyrexia
Anticholinergic symptoms (more common with tertiary amines)
Cardiovascular: tachycardia, arrhythmia (including ventricular fibrillation), hypotension
CNS: confusion, hallucinations, sedation, coma, seizures
Gastrointestinal: intestinal ileus, constipation
Genitourinary: urinary retention
General: xerostomia, mydriasis, hyperthermia, dry skin
Certain TCAs (e.g., clomipramine) are associated with hyperprolactinemia.

See tricyclic antidepressant toxicity.

Contraindications: Tertiary amines should be avoided in the elderly because of their side-effect profile.
Drug interactions
Risk of serotonin syndrome if used concomitantly with other serotonergic drugs
Risk of anticholinergic toxicity
Additional information: rarely used as a first- or second-line antidepressant today because of extensive side-effect profile and
risk of lethal overdose (ingestion of a one-week supply can be fatal)

Physostigmine should not be given to patients with suspected TCA overdose because it can precipitate cardiac arrest!

Secondary amines are generally better tolerated than tertiary amines, especially in elderly patients.

The side effects of TCAs are: Tremor, Cardiovascular adverse effects, Anticholinergic adverse effects, Sedation, and Seizures.
References:[13][14][15][16]

St. John's wort

Description
A flowering plant (Hypericum perforatum) used as a medicinal herb for depression
Because of its over-the-counter availability and significant drug interactions, it is important to be familiar with this
dietary supplement.
Indication: Although not approved by the FDA, which considers it a dietary supplement, there are some studies that support
St. John's wort is superior to placebo in treating mild depression.
Drug interactions
Inducer of cytochrome P-450
Serotonin syndrome if taken with drugs that increase serotonin levels

Complications

Antidepressant discontinuation syndrome [17][18]

Description: symptoms caused by abrupt withdrawal or dose reduction of antidepressants taken for ≥ 4 weeks
Clinical features
Flu-like symptoms (fatigue, lethargy, malaise, muscle aches, headaches, diarrhea, sweating)
Insomnia (vivid dreams, nightmares)
Nausea
Imbalance (gait instability, dizziness, lightheadedness, vertigo)
Sensory disturbances (paresthesias, electric shock sensations)
Hyperarousal (anxiety, agitation)
Dysphoria, irritability
Psychosis (especially with MAOI discontinuation)
Timing
Typically occurs within 3 days after drug cessation
Symptoms usually subside within 1–2 weeks
Diagnosis is primarily based on history and clinical features.
Treatment
Restart antidepressant therapy at the original dose and begin tapering slowly.

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To remember the main clinical features of antidepressant discontinuation syndrome, think: FINISH (Flu-like symptoms,
Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal).

Serotonin syndrome [19][20]

Description: a life-threatening condition caused by serotonergic overactivity
Cause: can be caused by any drug that increases serotonin levels
Psychiatric drugs: MAOIs, SSRIs, SNRIs, TCAs, vortioxetine, vilazodone, trazodone
Other drugs: tramadol, ondansetron, MDMA, dextromethorphan, meperidine, St. John's wort, triptans, linezolid
Increased risk with:
Concurrent use of two or more serotonergic drugs
Switching from one serotonergic drug to another without tapering
Clinical features [20]
Classic triad: neuromuscular excitability, autonomic dysfunction, altered mental status
General: diaphoresis, hyperthermia
Cardiovascular: hypertension, tachycardia

Gastrointestinal: nausea, vomiting, diarrhea

Psychiatric: delirium, psychomotor agitation, anxiety
Neurological: hypertonia (especially in the lower extremities), hyperreflexia, myoclonus, tremor, horizontal ocular
clonus, ataxia, mydriasis, seizure, coma
Diagnosis is primarily based on patient history and clinical features.
Treatment [20]
Immediate discontinuation of serotonergic drugs
Supportive care
Antihypertensives, fluid replacement
Benzodiazepines for sedation
Cyproheptadine: H1, 5-HT1A, and 5-HT2A receptor antagonists
Used for cases of serotonin syndrome that do not respond to supportive care
Cooling measures: ice packs and cold compresses

Serotonin syndrome causes HARM: Hyperthermia, Autonomic instability, Rigidity, and Myoclonus.

Tricyclic antidepressant toxicity [14]

Mechanism
Cardiac fast sodium channel inhibition
Muscarinic ACh receptor inhibition
A1-adrenergic receptor inhibition
H1 receptor inhibition
GABAA inhibition
Clinical features: Most signs and symptoms are related to anticholinergic effects.

See anticholinergic syndrome.

Prolonged QTc, arrhythmias
Seizures
Coma
Respiratory depression
Hyperpyrexia
Diagnosis is primarily based on history and clinical features.
ECG: prolonged QRS

, prolonged QTc
Urine immunoassay: for detection of TCA

Management
Activated charcoal within 2 hours of ingestion
Sodium bicarbonate for treatment and prevention of cardiac arrhythmia

Benzodiazepines for seizures

The clinical features of TCA overdose can be remembered with the three Cs of Tri-cyclic poisoning: Convulsions, Coma, and
Cardiac conduction abnormalities.

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Differential diagnosis of drug-induced hyperthermia

Characteristics Neuroleptic malignant Malignant

Serotonin syndrome syndrome hyperthermia Anticholinergic toxicity

Causative Serotonergic drugs D2 receptor antagonists Volatile anesthetics Belladonna poisoning

agents (e.g., SSRIs, Typical (e.g., halothane) Medications
MAOIs, TCAs, antipsychotics Succinylcholine Anticholinergic
MDMA, triptans) Haloperidol agents
Trifluoperazine Atropine
Fluphenazine Benztropine
Metoclopramide Trihexyphenidyl
Carbamazepine TCAs (tertiary
Promethazine amines)
Venlafaxine Antipsychotics
Clozapine
Quetiapine
First-generation
antihistamines
Promethazine
Dimenhydrinate

Onset < 24 h Days to weeks Minutes–24 h < 24 h

Clinical Autonomic Autonomic dysfunction Autonomic Autonomic dysfunction

features dysfunction Hyperthermia dysfunction Tachycardia,
Hyperthermia Hypertension Hyperthermia arrhythmias
Hypertension Tachycardia Hypertension Dry mouth
Diarrhea and Tachypnea Tachycardia Warm, dry, flushed
↑ bowel Neuromuscular Mottled skin skin
sounds hypoactivity (livedo Mydriasis
Mydriasis (parkinsonism) reticularis) ↓ Bowel sounds
Diaphoresis Hyporeflexia with areas of Urinary retention
Neuromuscular Severe rigidity flushing and Neuromuscular stability
excitability (lead-pipe rigidity) cyanosis Normal reflexes and
Hyperreflexia Altered mental status Neuromuscular tone!
Tremor Confusion hypoactivity Possibly altered mental
Clonus Delirium (parkinsonism) status
Hypertonia Hyporeflexia Delirium
(especially in Rigidity
the lower Possibly altered
extremities) mental status
Altered mental Confusion
status
Agitation
Coma

Laboratory Nonspecific Elevated creatine kinase Increased end-tidal Nonspecific

findings Low serum iron levels CO2
Leukocytosis Metabolic acidosis
Hyperkalemia

Treatment Discontinuation of Discontinuation of the Discontinuation of Physostigmine

serotonergic drugs causative drugs the causative
Benzodiazepines Dantrolene drugs
Cyproheptadine Dantrolene
Bromocriptine
Cooling

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