Antidepressants

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.

Antidepressants increase the risk of suicidal thoughts and suicidality in children, adolescents, and young adults < 24 years with major depressive disorder.

• Mechanism of action: inhibition of serotonin reuptake in synaptic cleft → ↑ serotonin levels
• Drugs
  • Fluoxetine
  • Paroxetine
  • Sertraline
  • Citalopram
  • Escitalopram
  • Fluvoxamine
• Indications
  • Major depressive disorder (first-line therapy)
  • Generalized anxiety disorder (GAD)
  • Obsessive-compulsive disorder (OCD)
  • Post-traumatic stress disorder (PTSD)
  • Panic disorder
  • Premature ejaculation
  • Premenstrual dysphoric disorder
  • Binge-eating disorder
  • Bulimia nervosa
  • Social anxiety disorder
  • Gambling disorder
  • Somatic symptom disorder
  • Irritable bowel syndrome
• Side effects
  • Early side effects (onset and resolution typically within 1 week of therapy start)
    • Headache
    • Diarrhea, nausea, vomiting
    • Activating effects (e.g., agitation, anxiety, insomnia)
  • Late side effects
    • Sexual dysfunction (e.g., anorgasmia, ↓ libido, erectile or ejaculatory dysfunction)
    • SIADH
    • Serotonin syndrome
      • Can be caused by any drug that increases serotonin levels (see “Serotonin syndrome”)
      • Serotonin syndrome caused by SSRIs alone typically manifests with mild symptoms (e.g., nausea, mild tremor).
      • Increased risk of occurrence and greater severity of symptoms when coadministered with another serotonergic agent (e.g., MAOIs)
      • Differential diagnosis: poisoning or overdose from concomitant use of substances (e.g., ethanol, salicylates) that may cause similar symptoms to serotonin syndrome (e.g., altered mental status)
    • Motor disorders (e.g., tremors, bruxism) ^[8]
• Drug interactions: increased risk of serotonin syndrome if used concomitantly with other serotonergic drugs (e.g., MAOIs, linezolid, St. John's wort, dextromethorphan, meperidine, methylene blue)
• Overdose: See “SSRI overdose.”
• Additional information
  • SSRIs typically take 4–6 weeks to significantly affect serotonin blood levels and, consequently, symptoms.
  • Contraindications: paroxetine in pregnant patients (may cause fetal cardiovascular malformations in the first trimester and fetal pulmonary hypertension in the third trimester)

The long-term side effects of SSRIs include: Serotonin syndrome, SIADH, Rocking (movement disorders), Insomnia (stimulating effects), and Sexual dysfunction.

To avoid serotonin syndrome, SSRIs should be discontinued at least two weeks before starting an MAOI. Particular caution is warranted with fluoxetine, which should be discontinued at least five weeks before starting a MAOI.

• Mechanism of action: inhibition of serotonin and norepinephrine reuptake in synaptic cleft → ↑ serotonin and norepinephrine levels
• Drugs
  • Venlafaxine
  • Duloxetine
  • Desvenlafaxine
  • Levomilnacipran
  • Milnacipran
• Indications
  • Major depressive disorder (second-line therapy)
  • Generalized anxiety disorder
  • Neuropathic pain (e.g. diabetic neuropathy)
  • Duloxetine and milnacipran specifically: fibromyalgia
  • Stress incontinence in women: duloxetine
  • Venlafaxine specifically: social anxiety disorder, OCD, panic disorder, and PTSD
• Side effects
  • Similar profile to SSRIs (see “Selective serotonin reuptake inhibitors” above)
  • Stimulant effect
  • Increased blood pressure
  • Insomnia, strange dreams, nightmares ^[9]
  • Can increase cholesterol and triglycerides
  • Nausea
• Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs
• Overdose: See “SNRI overdose.”
• Additional information: Blood pressure should be well-controlled before and after initiating SNRI therapy.

• Mechanism of action
  • Block postsynaptic type 2 serotonin receptors (5-HT₂) ^[10]
  • 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!

Mirtazapine ^[11]

• 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 is the likely cause of antidepressant action
  • H₁ antagonist
• Indications: : major depressive disorder, especially in patients who are underweight and/or who have insomnia
• Side effects
  • ↑ Appetite and weight gain: can also be a desired effect
  • Sedation (due to H₁ antagonism): can also be a desired effect
  • ↑ Serum cholesterol and triglyceride levels
  • Minimal sexual side effects
  • Dry mouth
• Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs

Mirtazzzapine makes you sleepy (Zzz...).

Bupropion ^[12]

• 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
  • Stimulant effect
  • Tachycardia, palpitations
  • Weight loss
  • Neuropsychiatric symptoms: insomnia, agitation, headache
  • 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).
  • Does not cause sexual side effects
  • Dry mouth
• Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs
• Overdose: See “Bupropion overdose.”

Buproprion is not associated with sexual dysfunction or weight gain. It should be avoided in patients at increased risk for seizure (e.g., history of epilepsy, anorexia/bulimia, alcohol or benzodiazepine withdrawal).

Vilazodone ^[13]

• Mechanism of action
  • Inhibition of serotonin reuptake in synaptic cleft → ↑ serotonin levels
  • 5-HT_1A receptor partial agonist
• Indications: major depressive disorder
• Side effects
  • Headaches
  • Nausea, diarrhea
  • Sleep disturbances
  • Sexual dysfunction
  • Anticholinergic effects (e.g., dry mouth)
• Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs

Vortioxetine ^[14]

• Mechanism of action
  • Inhibition of serotonin reuptake in synaptic cleft → ↑ serotonin levels
  • 5-HT_1A receptor agonist
  • 5-HT₃ receptor antagonist
• Indications: major depressive disorder
• Side effects
  • Sexual dysfunction
  • Nausea
  • Abnormal dreams
  • Sleep disturbance
  • Anticholinergic effects (e.g., dry mouth)
• Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs
• Additional information: Rare cases of pancreatitis have been reported.

Buspirone

• Mechanism of action
  • 5-HT_1A receptor stimulation
  • Requires consistent daily intake for at least two weeks because of its delayed onset of action
• Indication: anxiety disorders
• Side effects
  • Headaches, dizziness
  • Nausea
  • Seizures resulting from chronic use
• Additional information
  • Is not sedative
  • No risk of addiction or tolerance
  • No interaction with alcohol (as opposed to barbiturates and benzodiazepines)

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
  • Sleep disturbances
  • Seizures

VareniCliNe makes you Very Clean from Nicotine.

• Mechanism of action
  • Nonselective inhibition of monoamine oxidase → ↓ breakdown of epinephrine, norepinephrine, serotonin, and dopamine → ↑ levels of epinephrine, norepinephrine, serotonin, and dopamine
  • Selegiline: selective MAO-B inhibitor → mainly ↓ breakdown of dopamine → ↑ 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)
  • Anxiety
• Side effects
  • CNS stimulation
  • Sexual dysfunction
  • Orthostatic hypotension
  • Weight gain
  • Hypertensive crisis with ingestion of foods containing tyramine
    • Examples: aged cheeses, smoked/cured meats, alcoholic beverages (especially beer and red wine), dried fruits, fava beans, chocolate
    • Tyramine stimulates the sympathetic nervous system by releasing other neurotransmitters, such as noradrenaline, from vesicles into the synaptic cleft. ^[15]
• Drug interactions: risk of serotonin syndrome if used concomitantly with other serotonergic drugs, including linezolid, SSRIs, TCAs, meperidine, dextromethorphan, and St. John’s wort
• Overdose: See “MAOI poisoning.”
• Additional information
  • Before starting new serotonergic drugs or ceasing dietary restrictions (e.g., foods containing tyramine), MAOI therapy has to be stopped for at least 2 weeks.
  • 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).

• Mechanism of action: inhibition of serotonin and norepinephrine reuptake in synaptic cleft → ↑ serotonin and norepinephrine levels
• Drugs ^[16]
  • 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
  • Clomipramine specifically: OCD
  • Imipramine specifically: nocturnal enuresis (limited use due to side effects)
• 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
  • Anticholinergic symptoms due to blockage of muscarinic cholinergic receptors (more common with tertiary amines)
    • Cardiovascular: tachycardia, arrhythmia (including ventricular fibrillation), hypotension
    • CNS: confusion, hallucinations, sedation, seizures (confusion and hallucinations are most commonly seen in older patients)
    • Gastrointestinal: constipation
    • Genitourinary: urinary retention
    • General: xerostomia, mydriasis, hyperthermia, dry skin
  • Certain TCAs (e.g., clomipramine) are associated with hyperprolactinemia.
  • See also “Tricyclic antidepressant overdose.”
• Contraindications: Tertiary amines should be avoided in the elderly because of their side-effect profile; Secondary amines (e.g., nortriptyline) are less likely to cause anticholinergic side effects.
• 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)

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.

• 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 P450
  • Serotonin syndrome if taken with drugs that increase serotonin levels

For the management of toxic effects due to overdose, see “Antidepressant overdose.”

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.

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

Drug-induced hyperthermia

To differentiate between serotonin syndrome and the rest of drug-induced hyperthermia conditions remember that only SErotonin Shakes your Extremities (myoclonus and hyperreflexia, mostly of the lower limbs)