Antidepressants - Detailed Overview

General Mechanism

Proposed mechanism of SNRI antidepressants (venlafaxine, duloxetine) blocking reuptake of serotonin and norepinephrine at the presynaptic terminal - Lippincott Illustrated Reviews: Pharmacology

Classification & Major Drug Classes

Class Dosage Reference Table

• Creasy & Resnik's Maternal-Fetal Medicine, Table 67.3

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

• Kaplan & Sadock's Synopsis of Psychiatry, Table 21-15

• All SSRIs are equally effective for depression; choice depends on pharmacokinetics, side effects, and individual response
• Fluvoxamine is NOT FDA-approved as an antidepressant in the US (marketing decision), but is used as such globally
• SSRIs are first-line for most indications due to favorable safety profiles vs. TCAs/MAOIs

• GI: Nausea, diarrhea, GI upset (most common, especially early)
• Sexual dysfunction: Anorgasmia, decreased libido (very common; up to 30-50%)
• CNS: Insomnia, agitation, restlessness, drowsiness
• Weight: Initial weight loss possible, but long-term weight gain with chronic use
• Anticholinergic (mainly paroxetine): Dry mouth, constipation, sedation
• Platelet dysfunction: Impaired aggregation - increased bleeding risk; avoid with NSAIDs/anticoagulants without GI protection
• Hyponatremia/SIADH: Especially in elderly or those on diuretics
• Endocrine: Increased prolactin, galactorrhea, mammoplasia (reversible)
• Glucose disturbance: Acute hypoglycemia; monitor diabetics
• Rash: About 4% of patients; rarely progresses to pulmonary involvement

2. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Major depressive disorder
• Generalized anxiety disorder
• Neuropathic pain and fibromyalgia (duloxetine)
• Chronic musculoskeletal pain (duloxetine)
• Stress urinary incontinence (duloxetine in some countries)
• PTSD, panic disorder (venlafaxine)

3. Tricyclic Antidepressants (TCAs)

• Tertiary amines (amitriptyline, imipramine, doxepin, clomipramine, trimipramine): Inhibit reuptake of both serotonin AND norepinephrine
• Secondary amines (desipramine, nortriptyline, amoxapine, maprotiline, protriptyline): Preferentially block norepinephrine reuptake

• Major depressive disorder (especially anergic depressions with early morning awakening, decreased appetite/libido)
• Neuropathic pain and chronic pain (amitriptyline is the most commonly used)
• OCD (clomipramine - gold standard)
• Enuresis (imipramine)

• Orthostatic hypotension
• Urinary retention
• Dry mouth
• Blurred vision
• Constipation
• Sedation and cognitive impairment
• Cardiac arrhythmia risk (QT prolongation) - most dangerous in overdose
• Lowering of seizure threshold

• Adams and Victor's Principles of Neurology, 12th Edition

4. Monoamine Oxidase Inhibitors (MAOIs)

• MAO-A inhibitors (phenelzine, tranylcypromine, isocarboxazid): Irreversible, non-selective
• MAO-B inhibitors (selegiline transdermal): Relatively selective; also used in Parkinson's disease

• Atypical depression (mood reactivity, hypersomnia, leaden paralysis, rejection sensitivity)
• Refractory depression
• Social anxiety disorder
• Panic disorder

• Orthostatic hypotension, urinary retention, skin rashes, tachycardia, sweating
• Significant weight gain
• Impotence, jaundice
• Risk of hypertensive crisis if combined with tyramine-containing foods or sympathomimetics

• Aged cheeses, red wine, beer
• Pickled herring, sardines, sausages
• Certain preserved meats/fish
• Sympathomimetic cold remedies, nasal sprays, nose drops

• TCAs or SSRIs (risk of serotonin syndrome)
• CNS stimulants
• Phenothiazines
• Meperidine (Demerol) - can cause respiratory depression, hyperpyrexia, profound hypotension

5. Atypical Antidepressants

Bupropion (Wellbutrin)

• Mechanism: Norepinephrine-dopamine reuptake inhibitor (NDRI); no serotonergic activity
• Key advantages: No sexual dysfunction (unlike SSRIs/SNRIs); promotes weight loss; approved for smoking cessation (Zyban)
• Contraindication: Seizure disorders, bulimia/anorexia (lowers seizure threshold); avoid in patients using MAOIs

Mirtazapine (Remeron)

• Mechanism: Alpha-2 adrenergic antagonist ("cuts the brake" on norepinephrine release) - increases NE and 5-HT by a different mechanism than reuptake inhibition
• Key advantages: Highly sedating - useful when insomnia or poor appetite is prominent; weight gain is a feature, not a bug, in malnourished patients
• Adverse effects: Sedation, weight gain, dry mouth

Trazodone (Desyrel)

• Mechanism: Serotonin reuptake inhibition + 5-HT2 antagonism
• Clinical use: Mainly used at low doses for insomnia rather than as primary antidepressant; also used in PTSD
• Adverse effect: Priapism (rare but serious)

Vortioxetine (Trintellix)

• Mechanism: Multimodal - SERT inhibition + 5-HT1A agonism + 5-HT3/5-HT7 antagonism; pro-cognitive actions via 5HT1B heteroreceptors on dopamine, acetylcholine, histamine, and NE terminals
• Advantage: Cognitive benefits especially in depression-related cognitive dysfunction

Nefazodone

• Mechanism: Multimodal - weak serotonin + norepinephrine reuptake inhibition + 5-HT2 postsynaptic antagonism
• Concern: Risk of hepatotoxicity (withdrawn from some markets)

Serotonin Syndrome

1. Diarrhea
2. Restlessness
3. Extreme agitation, hyperreflexia, autonomic instability, rapid vital sign fluctuations
4. Myoclonus, seizures, hyperthermia, shivering, rigidity
5. Delirium, coma, status epilepticus, cardiovascular collapse, death

• Kaplan & Sadock's Synopsis of Psychiatry

Discontinuation Syndrome

• "FINISH" symptoms: Flu-like symptoms, Insomnia, Nausea, Imbalance/dizziness, Sensory disturbances (electric-shock sensations/"brain zaps"), Hyperarousal/anxiety
• Onset within 1-3 days of stopping
• Usually self-limiting in 1-2 weeks but can last longer

Treatment Strategy

1. First-line: SSRIs (best tolerability, safety in overdose, broad spectrum)
2. Second-line: SNRIs, bupropion, mirtazapine
3. Third-line / augmentation: Add aripiprazole, buspirone, lithium, or combine antidepressants
4. Refractory: TCAs, MAOIs, or combination strategies
5. Special populations: TCAs preferred for neuropathic pain; clomipramine for OCD; bupropion when sexual side effects or weight gain are concerns

• Swanson's Family Medicine Review

Special Considerations

Pediatric Use

• Fluoxetine is the only SSRI FDA-approved for pediatric depression
• All antidepressants carry a black-box warning for increased suicidality in patients under 25 years old
• SSRIs approved for pediatric OCD: fluoxetine, fluvoxamine, sertraline

Pregnancy

• SSRIs are most frequently prescribed during pregnancy; information is greatest for SSRIs, venlafaxine, and TCAs
• MAOIs are rarely used in pregnancy
• Risks include: possible miscarriage association (absolute risk small), neonatal adaptation syndrome, persistent pulmonary hypertension (rare)
• Always weigh risk of untreated depression vs. medication exposure

Cardiovascular Disease

• SSRIs (sertraline, paroxetine, fluoxetine) are preferred; generally safe
• Avoid TCAs in recent MI or conduction disease (arrhythmia risk)
• Mirtazapine, bupropion, venlafaxine, duloxetine are alternatives for CVD patients

Elderly

• Use caution with SSRIs due to SIADH/hyponatremia risk
• Avoid TCAs (falls, arrhythmia, urinary retention, confusion)
• Start low, go slow