Sertraline (Zoloft)
SSRI • Last reviewed 2025-09-23
General information
Sertraline is an SSRI approved for major depressive disorder, obsessive-compulsive disorder, panic disorder, PTSD, social anxiety disorder, and PMDD, and is frequently co-prescribed with antipsychotics or mood stabilisers to treat comorbid mood and anxiety symptoms (sertraline_label_2024, stein2006).
Formulations include tablets (25, 50, 100 mg) and oral solution (20 mg/mL). Standard initiation for depression is 50 mg once daily; panic disorder usually starts at 25 mg once daily for one week to limit activation before increasing to 50 mg/day (sertraline_label_2024).
Sertraline selectively inhibits SERT while exerting modest sigma-1 receptor agonism and weak DAT inhibition, which may support anxiolytic and energising effects (arnold2016).
Metabolism involves CYP2B6, CYP2C19, CYP2C9, and CYP3A4 with minimal CYP2D6 inhibition; the parent half-life is ~26 hours and active metabolite desmethylsertraline has a half-life up to 104 hours, allowing once-daily dosing and a relatively mild discontinuation profile (sertraline_label_2024, mandrioli2013).
Dosing & administration
MDD/OCD/PTSD/SAD: 50 mg once daily; titrate by 25–50 mg at weekly intervals to 200 mg/day.
Panic disorder: 25 mg once daily for 1 week, then 50 mg/day; titrate to 100–200 mg/day as needed.
PMDD: 50 mg/day continuously or luteal-phase dosing (50 mg from day 14 to menses).
Hepatic impairment: reduce dose or extend dosing interval.
Dose considerations
- Hepatic impairment
- Sertraline exposure doubles in cirrhosis; use half dose or alternate-day dosing.
- Elderly
- Start 25 mg/day; monitor sodium and fall risk.
- Drug interactions
- Monitor CYP2D6/CYP2B6 substrates though inhibition is modest; watch for additive serotonergic effects.
- Switching from MAOI
- Observe 14-day washout before and after sertraline.
Mechanism of action
Sertraline inhibits SERT, increasing serotonin in limbic structures to alleviate depressive and anxiety symptoms (arnold2016).
Sigma-1 receptor agonism and weak dopamine transporter inhibition may contribute to anxiolytic and pro-cognitive properties, differentiating sertraline from other SSRIs (stein2006).
- SERT Ki ≈ 0.29 nM.
- Sigma-1 receptor agonist (Ki ≈ 30 nM).
- Weak DAT inhibition relative to SERT; minimal muscarinic or histaminergic activity.
Metabolism & pharmacokinetics
Peak concentrations occur 4–6 hours post-dose; bioavailability increases modestly with food but adjustment is not required (sertraline_label_2024).
Sertraline is ~98% protein bound and extensively metabolised to desmethylsertraline, which accumulates but has substantially lower serotonin reuptake inhibition (mandrioli2013).
Drug interactions
Serotonergic agents (MAOIs, linezolid, triptans) raise serotonin syndrome risk; adhere to washouts and monitor closely.
Sertraline is a weak CYP2D6 inhibitor but can modestly increase concentrations of risperidone, aripiprazole, and TCAs; consider dose adjustments in sensitive patients (mandrioli2013).
Combination with anticoagulants or NSAIDs increases bleeding risk due to platelet serotonin depletion.
| Mechanism | Agents / factors | Management |
|---|---|---|
| Serotonergic toxicity | MAOIs, linezolid, triptans | Avoid or monitor closely; educate on symptoms. |
| CYP2D6 inhibition | Risperidone, aripiprazole, TCAs | Monitor for increased adverse effects; adjust dose if needed. |
| Bleeding risk | NSAIDs, anticoagulants, antiplatelets | Monitor for bruising/bleeding; consider gastroprotection. |
Monitoring & safety checks
Mood and suicidality
Baseline and each visit • Detect manic switch or emergent suicidality.
Serum sodium
Baseline and if confusion/lethargy develops • Hyponatremia risk, especially in older adults.
Weight and gastrointestinal tolerance
During titration and quarterly • Monitor for weight change or persistent GI effects.
Advise consistent daily dosing and set expectations for 2–4 week onset of benefit.
Take with food if nausea occurs; morning dosing may mitigate insomnia while evening dosing can help if sedation develops.
Discontinuation guidance
Taper over 1–2 weeks to minimise withdrawal symptoms (dizziness, irritability), although discontinuation syndrome is less common than with paroxetine.
Observe a 14-day washout before starting an MAOI to prevent serotonin syndrome.
Special populations
Pregnancy: sertraline is one of the better-studied SSRIs during pregnancy; consider lowest effective dose and monitor neonates for adaptation syndrome (apa_ptsd_2017).
Breastfeeding: typically preferred SSRI due to low infant serum concentrations; monitor for irritability.
Hepatic impairment: reduce dose or dosing frequency because clearance is reduced.
Adverse effects
Common: diarrhea, nausea, insomnia, sexual dysfunction, tremor.
Less common: sweating, dizziness, restlessness; consider dose adjustment or adjunctive therapy if persistent.
Rare: QT prolongation, SIADH, serotonin syndrome—obtain ECG in high-risk patients and monitor sodium when indicated.
References
- ZOLOFT (sertraline) prescribing information — DailyMed (2024)
- APA guideline for the treatment of patients with PTSD — American Psychiatric Association (2017) DOI: 10.1176/appi.books.9781615371099
- Pharmacology of sertraline — CNS Drugs (2016) DOI: 10.1007/s40263-016-0332-y
- Sertraline for post-traumatic stress disorder — Current Opinion in Psychiatry (2006) DOI: 10.1097/01.yco.0000194376.01650.5c
- Pharmacokinetic drug interactions involving sertraline — Expert Opinion on Drug Metabolism & Toxicology (2013) DOI: 10.1517/17425255.2013.776330
Educational use only — verify details in current prescribing information and authoritative clinical guidelines before making prescribing decisions.