Sertraline
Sertraline is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class, sold under brand names including Zoloft and Lustral. Developed by Pfizer and approved for medical use in 1991, it is prescribed for major depressive disorder, anxiety disorders, obsessive-compulsive disorder, panic disorder, and other psychiatric conditions.citation needed Sertraline became one of the most commonly prescribed psychotropic medications worldwide and is included on the World Health Organization's List of Essential Medicines.
Dosage & Duration
Dosage
Doses are population estimates that vary widely between individuals.
Typical initial dosing is 25-50 mg per day, with maintenance dosing usually 50-200 mg per day adjusted to treatment response; a maximum maintenance dose of 200 mg per day is generally recommended. Doses of 250-400 mg per day have been used in patients unresponsive to standard lower-dose treatment. Higher doses are associated with a greater incidence of diarrhea, and dopamine transporter occupancy becomes appreciable at 200 mg and above. Overdose reports include ingestions of 400 mg to 8 g, with somnolence, vomiting, tachycardia, nausea, dizziness, agitation, and tremor being the most common features; serotonin syndrome, cardiac conduction changes including QT prolongation, seizures, delirium, and coma have been reported.
Subjective Effects
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Sertraline is a prescription antidepressant whose effects emerge gradually rather than acutely; several weeks of daily use are typically required before benefit is noticed, with some improvement in the first one to two weeks and the greatest effect over the first couple of months. The central subjective change is one of altered mood, reduced anxiety, reduced depression, a more positive outlook, and greater ease and assertiveness with others. In a subset of people, anxiety and agitation are temporarily worsened during the initial phase of treatment before giving way to anxiolysis. Adverse effects are generally mild in medical settings, and its effects on cognitive performance are slight.
Physical
Mild sedation and drowsiness are common alongside dizziness, tremor, fatigue, dry mouth, sweating, and gastrointestinal upset including nausea and diarrhea. Insomnia is one of the more consistently reported complaints, and sexual dysfunction — reduced libido, delayed or absent orgasm, and arousal difficulty — is frequent and tends to persist rather than fade with continued use.
Cognitive
The headspace is characterized by lowered anxiety and improved mood rather than any distortion of thought, with cognitive performance largely unchanged and verbal fluency slightly improved in healthy volunteers. Agitation, restlessness, and irritability occur in some people, particularly early in treatment or on discontinuation.
Emotional
Impairment
Visual
Visual disturbance is uncommon and largely confined to rare reports and overdose states.
Auditory
Tactile
Pharmacology
Pharmacodynamics
Sertraline is a selective serotonin reuptake inhibitor (SSRI) that acts primarily by binding to the serotonin transporter (SERT), inhibiting neuronal reuptake of serotonin and potentiating serotonergic activity in the central nervous system.citation needed The therapeutic benefits typically emerge after 4-6 weeks of administration, believed to result from neuroadaptations including downregulation of presynaptic 5-HT1A autoreceptors and downstream increases in brain-derived neurotrophic factor expression. Sertraline also displays affinity for sigma-1 receptor binding sites and exhibits relatively high activity as a dopamine transporter inhibitor, occupying approximately 20% of DAT receptors at doses of 200mg and above, though the clinical relevance of these secondary actions remains uncertain. The drug shows weak inhibitory effects on norepinephrine reuptake and has been observed to increase extracellular dopamine in the nucleus accumbens and striatum at clinically relevant doses in animal studies. Sertraline exhibits little to no affinity for GABA, histamine, acetylcholine, benzodiazepine, or serotonergic receptors (5-HT1A, 5-HT1B, 5-HT2), and does not exert significant anticholinergic, antihistamine, or adrenergic blocking activity.
Pharmacokinetics
Sertraline undergoes extensive first-pass metabolism in the liver, with bioavailability estimated above 44%.citation needed The primary metabolic pathway is N-demethylation to desmethylsertraline (N-desmethylsertraline), which is substantially weaker (5-50 fold less potent) as a serotonin reuptake inhibitor. CYP2C19 appears to play the most important role in metabolism, followed by CYP2B6, with additional contributions from CYP3A4 and CYP2D6. Secondary metabolic pathways include N-hydroxylation, oxidative deamination, and glucuronide conjugation. Sertraline is highly plasma protein bound (98-99%) and widely distributed with a volume of distribution exceeding 20 L/kg. Excretion occurs to similar degrees in urine and feces, with unchanged sertraline representing only 12-14% of fecal elimination and being undetectable in urine.1 CYP2C19 poor metabolizers show 2.7-fold higher sertraline levels compared to normal metabolizers.2
Dangerous
Highest riskThese combinations are considered extremely harmful and should always be avoided. Reactions to these drugs taken in combination are highly unpredictable and have a potential to cause death.
Caution
Use cautionThese combinations are not usually physically harmful, but may produce undesirable effects, such as physical discomfort or overstimulation. Extreme use may cause physical health issues. Synergistic effects may be unpredictable. Care should be taken when choosing to use this combination.
Tolerance
Tolerance timelines are rules of thumb, not exact schedules, and vary widely between individuals and use patterns.
Harm Potential
Addiction & Dependence
Psychological
LowSertraline is not considered to have significant abuse potential or psychological addiction liability.citation needed It does not produce euphoria or reinforcing effects that typically drive compulsive use patterns.
Physical
ModeratePhysical dependence develops with regular use, and discontinuation syndrome is common in medical settings.citation needed Withdrawal symptoms typically appear within a few days of stopping or reducing dose and include flu-like symptoms, dizziness, electric shock sensations, anxiety, insomnia, irritability, and headache.3 Symptoms usually resolve within 1-3 weeks, though a minority experience prolonged or severe symptoms lasting more than 6 weeks.citation needed Restarting the medication can usually eliminate withdrawal symptoms within 24 hours.
Toxicity
The drug is largely safe in fairly large overdose. No cases of fatal overdose with sertraline alone have been reported; most fatal cases involve co-ingestion with other drugs.citation needed Analysis of 52 sertraline-only overdoses with a mean dose of 727 mg showed no significant symptoms in 34 cases, with symptomatic patients experiencing only mild CNS, cardiovascular, and gastrointestinal effects.4 Another analysis of 40 overdoses with doses up to 8000 mg found that among 17 sertraline-only ingestions, 10 were asymptomatic.5 The manufacturer reported ingestions up to 2600 mg in four patients with suicidal intent, all requiring minimal treatment.
LD50 Data
| Species | Route | Value |
|---|---|---|
| rat | oral | 2000 mg/kg |
| mouse | oral | 419 mg/kg |
| rat | oral | 1327 mg/kg |
Rare cases of hepatotoxicity have been reported, typically presenting as elevated transaminases, jaundice, and fatigue; this appears to be an idiosyncratic reaction occurring in a very small proportion of users regardless of dose, though doses over 100 mg may carry slightly higher risk.citation needed
Cardiovascular effects are generally less problematic than with tricyclic antidepressants; tachycardia is the primary effect seen during overdose, and ECG changes have occasionally been recorded.citation needed Hypotension may occur transiently when treatment first begins but appears quite rare.
Gastrointestinal effects including nausea and diarrhea are common adverse effects; the incidence of diarrhea is higher with sertraline compared to other SSRIs, especially at higher doses.citation needed
Rare reports of abnormal bleeding have been documented; SSRIs inhibit serotonin uptake into platelets, significantly reducing platelet serotonin concentrations and impairing aggregation.citation needed
Psychosis Risk
Rare reports of psychotic symptoms including auditory hallucinations and paranoid ideation have been documented. Mania and hypomania have been reported relatively rarely, including in children and adolescents, sometimes triggered by doses as low as 25-50 mg daily. Hallucinations and delirium have been observed in overdose cases and as part of serotonin syndrome.citation needed
Seizure Risk
Seizures are listed among manifestations of acute overdose but appear to be uncommon.citation needed In documented overdose cases involving very high doses, seizures were not a prominent feature, with most symptomatic patients experiencing only mild effects.5
History & Culture
Discovery and Development
The history of sertraline traces back to the early 1970s when Pfizer chemist Reinhard Sarges developed a series of psychoactive compounds, including lometraline, based on the structures of the neuroleptics thiothixene and pinoxepin. This work led to tametraline, a norepinephrine and weaker dopamine…
Legality
International
1961 Single Convention: sertraline is not scheduled.
1971 Convention on Psychotropic Substances: sertraline is not scheduled.
1988 Convention: sertraline is not listed in precursor Tables I or II.
By Country
United StatesPrescription only
AustraliaPrescription only
IrelandPrescription only
JapanPrescription only
New ZealandPrescription only
SingaporePrescription only
SwedenPrescription only
References
Citations
- ZOLOFT- sertraline hydrochloride tablet, film coated ZOLOFT- sertraline hydrochloride solution, concentrate. DailyMed (n.d.). https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=fe9e8b7d-61ea-409d-84aa-3ebd79a046b51234567891011
- Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients. (2020). https://pmc.ncbi.nlm.nih.gov/articles/PMC6969041/1
- Warner CH, Bobo W, Warner C, Reid S, & Rachal J. (August 2006). Antidepressant discontinuation syndrome. American Family Physician, 74(3), 449–56. https://pubmed.ncbi.nlm.nih.gov/16913164/1
- Analysis of sertraline-only overdoses. 14(5), 456–458 (1996). https://pubmed.ncbi.nlm.nih.gov/8765108/1
- Sertraline overdose. 3(2), 132–6 (1996). https://pubmed.ncbi.nlm.nih.gov/8808373/12
- Mitochondrial Dysfunction Induced by Sertraline, an Antidepressant Agent. (2012). https://pmc.ncbi.nlm.nih.gov/articles/PMC5736306/1
- Wide spectrum of inhibitory effects of sertraline on cardiac ion channels. 16(5) (2012). https://synapse.koreamed.org/articles/10258211
- The Architect of Zoloft. Reed Magazine, Reed College (2015). https://www.reed.edu/reed-magazine/articles/2015/koe-zoloft-chemistry.html1
- Top 25 Psychiatric Medications for 2016. Psych Central (12 October 2017). https://psychcentral.com/blog/top-25-psychiatric-medications-for-2016/1
- Sertraline Drug Usage Statistics, United States, 2014 - 2023. ClinCalc (n.d.). https://clincalc.com/DrugStats/Drugs/Sertraline1
Article Status
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Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
Josie Kins · Updated the article · also 1,4-Butanediol, 1B-LSD, 1cP-AL-LAD and 573 more
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