selective serotonin reuptake inhibitor

MECHANISM: SSRIs selectively inhibit the presynaptic serotonin reuptake transporter (SERT) in the raphe nuclei projections, raising synaptic serotonin. Clinical effect is delayed 4-8 weeks, likely due to downstream adaptations (desensitization of presynaptic 5-HT1A autoreceptors, increased BDNF/neuroplasticity) rather than the immediate rise in 5-HT.

INDICATIONS: Major depressive disorder (first-line), generalized anxiety disorder, panic disorder, social anxiety disorder, OCD (often requires higher doses), PTSD, bulimia nervosa (fluoxetine), premenstrual dysphoric disorder, and premature ejaculation (off-label/paroxetine).

ADVERSE EFFECTS: - Sexual dysfunction (decreased libido, anorgasmia, delayed ejaculation), the most common reason for nonadherence. - GI upset (nausea, diarrhea), headache, insomnia or somnolence, and weight changes (paroxetine causes the most weight gain). - Activation or increased suicidality early in treatment in patients under 25 (black box warning). Monitor closely. - Hyponatremia from SIADH, especially in older adults. - Increased bleeding risk (platelets depend on SERT for serotonin uptake), especially when combined with NSAIDs or anticoagulants. - QT prolongation (citalopram dose-dependent, max 40 mg/day, 20 mg in age >60). - Serotonin syndrome: altered mental status, autonomic instability (hyperthermia, tachycardia, diaphoresis), neuromuscular hyperactivity (clonus, hyperreflexia, tremor), and GI symptoms (diarrhea). It is precipitated by combining with MAOIs, TCAs, meperidine, tramadol, linezolid, triptans, dextromethorphan, St. John's wort, MDMA, or ondansetron. Treatment: stop the offending agents, give benzodiazepines, and give cyproheptadine (5-HT2A antagonist) if needed. - Discontinuation syndrome: dizziness, "brain zaps," flu-like symptoms, irritability, and paresthesias. It is most common with short half-life agents (paroxetine, fluvoxamine). Fluoxetine has the lowest risk because of its long half-life and active metabolite norfluoxetine.

KEY DRUG-SPECIFIC POINTS: - Fluoxetine: longest half-life, strong CYP2D6 inhibitor, and requires a 5-week washout before starting an MAOI (2 weeks for other SSRIs). It is activating, so give it in the morning. - Paroxetine: strongest anticholinergic activity, most sedating and weight-gaining, and a strong CYP2D6 inhibitor. It is associated with first-trimester cardiac malformations, so avoid it in pregnancy. It reduces tamoxifen activation (CYP2D6). - Sertraline: preferred in cardiac disease (e.g., post-MI) and often in pregnancy and lactation. It causes more GI side effects and diarrhea. - Citalopram/escitalopram: fewer CYP interactions, but QT risk (more with citalopram). - Fluvoxamine: used mainly for OCD, and a strong CYP1A2 inhibitor.

SPECIAL POPULATIONS: Late-pregnancy exposure is associated with neonatal adaptation syndrome and a small risk of persistent pulmonary hypertension of the newborn (PPHN). In bipolar disorder, SSRIs can precipitate mania, so use a mood stabilizer first.

COMPARISONS: SSRIs have a better safety profile in overdose than TCAs (no major anticholinergic, antihistaminic, or α1-blocking effects, and no fatal arrhythmias at typical overdose) and don't require dietary tyramine restriction like MAOIs. Bupropion and mirtazapine have less sexual dysfunction. SNRIs (venlafaxine, duloxetine) additionally block norepinephrine reuptake and are useful in neuropathic pain and fibromyalgia.