Sertraline

Indications

• FDA-approved for major depressive disorder in adults, typically at 50-200 mg/day, with efficacy comparable to other first-line antidepressants.
• FDA-approved for obsessive-compulsive disorder in adults and in children from age 6, where doses at the top of the range are usually needed.
• FDA-approved for panic disorder, post-traumatic stress disorder, and social anxiety disorder, all started at 25 mg/day to limit early activation.
• FDA-approved for premenstrual dysphoric disorder using either continuous daily dosing or luteal-phase-only dosing each cycle.
• Off-label for generalized anxiety disorder, binge-eating disorder, and premature ejaculation, with generalized anxiety the most common use.
• Frequently chosen off-label for depression or anxiety in pregnancy, in lactation, and in cardiac disease because of its reassuring safety record.

Mechanism of action

• Blocks the presynaptic serotonin transporter with high potency and selectivity, increasing synaptic 5-HT throughout cortical and limbic circuits.
• Downstream desensitization of 5-HT1A somatodendritic autoreceptors restores raphe firing and underlies the delayed onset of antidepressant effect.
• Has modest dopamine transporter affinity, weak among clinical effects but possibly contributing to its slightly activating quality at higher doses.
• Binds sigma-1 receptors, an action of uncertain clinical meaning that has driven research interest in psychosis and in antiviral repurposing.
• Essentially devoid of muscarinic, histaminic, and alpha-adrenergic blockade, so anticholinergic load and orthostasis are minimal.

Pharmacokinetics

• Oral absorption is slow, with peak levels at 4 to 6 hours; food raises exposure modestly, so consistent dosing with or without meals is advised.
• Half-life averages 26 hours, supporting once-daily dosing, and steady state is reached in about one week in most adults.
• Metabolized mainly by CYP2B6 with contributions from 2C19, 2C9, 3A4, and 2D6, so no single enzyme dominates and interaction risk stays low.
• N-desmethylsertraline has a 62 to 104 hour half-life but is 10 to 20 times less potent, contributing little to clinical effect.
• Only a weak to moderate CYP2D6 inhibitor below 150 mg/day, though inhibition becomes clinically relevant near the 200 mg/day ceiling.

Dosing

• Start 50 mg PO daily for depression or OCD; start 25 mg daily for panic disorder, PTSD, or social anxiety, then raise after one week.
• Titrate by 25 to 50 mg no more often than weekly; usual effective range is 50 to 200 mg/day and the label maximum is 200 mg/day.
• Pediatric OCD starts at 25 mg/day in ages 6 to 12 and 50 mg/day in ages 13 to 17, with the same 200 mg/day adult ceiling.
• Available as 25, 50, and 100 mg tablets, a 20 mg/mL oral concentrate that must be diluted before use, and 150 and 200 mg capsules.
• No renal adjustment is required; in mild hepatic impairment use a lower dose or longer interval, and avoid in moderate to severe impairment.
• Taper over two to four weeks when stopping, since abrupt withdrawal produces dizziness, paresthesia, irritability, and flu-like symptoms.

Adverse effects

• Diarrhea and loose stools occur in about 20 percent and are more frequent with sertraline than with any other SSRI, often improving over weeks.
• Nausea, insomnia, somnolence, tremor, headache, and diaphoresis are common early and generally settle within the first two weeks of treatment.
• Sexual dysfunction affects roughly 30-50 percent of patients, including delayed orgasm, reduced libido, and erectile difficulty.
• Hyponatremia from SIADH, increased bleeding with NSAIDs or anticoagulants, and bruxism are the notable non-serotonergic safety issues.
• Serotonin syndrome, treatment-emergent mania in undiagnosed bipolar disorder, and rare akathisia are the serious effects that change prescribing.
• Modest weight gain of 1 to 2 kg is typical over a year of treatment, less than with paroxetine or mirtazapine.

Monitoring

• Reassess suicidality, activation, and agitation weekly for four weeks and after each dose increase, with the closest attention under age 25.
• Check sodium at baseline and within two to four weeks in older adults, diuretic users, or anyone developing confusion, falls, or lethargy.
• Use PHQ-9, GAD-7, PCL-5, or Y-BOCS at baseline and every two to four weeks to guide titration rather than global impression.
• No routine ECG, plasma levels, or laboratory monitoring is required in otherwise healthy adults taking sertraline alone.
• Screen for bipolar disorder before starting and recheck sleep, energy, and impulsivity if response looks unusually rapid or excessive.

Interactions

• Contraindicated with MAOIs and within 14 days either side, and with pimozide because of additive QT prolongation and raised pimozide levels.
• The oral concentrate contains alcohol and is contraindicated in patients taking disulfiram; the tablets carry no such restriction.
• Additive serotonin syndrome risk with triptans, tramadol, linezolid, methylene blue, fentanyl, and St. John's wort.
• Inhibits CYP2D6 meaningfully only near 200 mg/day, when tricyclic, metoprolol, and atomoxetine levels may rise and warrant reassessment.
• Increases bleeding risk with aspirin, NSAIDs, and anticoagulants, and modestly raises warfarin INR, so recheck INR after any dose change.

Special populations

• Among the best-studied antidepressants in pregnancy, with no consistent teratogenic signal and low placental transfer relative to other SSRIs.
• Preferred SSRI in lactation because relative infant dose is under 2 percent and infant serum levels are usually undetectable.
• Approved from age 6 for OCD; pediatric depression use is off-label and requires close monitoring for activation and suicidality.
• In older adults start at 25 mg/day given hyponatremia, falls, and bleeding risk, but sertraline remains a preferred geriatric SSRI.
• No dose change is needed in renal impairment, including dialysis, because clearance is almost entirely hepatic.

Clinical pearls

• Diarrhea is the signature early side effect; take with food and it usually resolves in two weeks.
• Preferred SSRI in pregnancy and breastfeeding, and the safest choice after myocardial infarction.
• 2D6 inhibition only matters near 200 mg/day, so it is easy to combine with other psychotropics.