Sertraline: Difference between revisions

| brand            = Zoloft

| structure        =

| classes          = SSRI, Anxiolytic, Antidepressant

| uses              = <vote slug="depression-use">Depression</vote>, <vote slug="anxiety-use">Anxiety</vote>, <vote slug="gad-use">Generalized anxiety</vote>, <vote slug="ocd-use">OCD</vote>, <vote slug="panic-use">Panic disorder</vote>, <vote slug="ptsd-use">PTSD</vote>, <vote slug="social-anxiety-use">Social anxiety</vote>, <vote slug="pmdd-use">PMDD</vote>, <vote slug="premature-ejaculation-use">Premature ejaculation</vote>

| pill_id           =

| onset            = Anxiolysis classically 3-4 weeks, continuing improvement to 8-12 weeks

| duration          = Long

| halflife          = ~26 h (sertraline; range 13-45 h, longer in females); ~62-104 h (N-desmethylsertraline, weakly active)

| bioavailability  = Absolute bioavailability not precisely characterized; food modestly increases exposure

| pregnancy        = Category C<ref name="lactmed-sert">S0</ref>

| legal            = Rx-only in US

| mechanism        = TrkB/BDNF<ref name="trkb-sert">S1</ref> <vote slug="ssri-claim-sert">Sertraline is a selective serotonin reuptake inhibitor.</vote>

| intro            = Sertraline, marketed as Zoloft, is the most widely prescribed psychiatric medicine in the United States, accounting for roughly 40 million prescriptions annually as of recent years. It is the second selective serotonin reuptake inhibitor brought to market, approved by the United States Food and Drug Administration on 30 December 1991 and launched by Pfizer as Zoloft in the first quarter of 1992.<ref name="koe1983">Koe BK, Weissman A, Welch WM, Browne RG. Sertraline, 1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin. Journal of Pharmacology and Experimental Therapeutics. 1983;226(3):686-700. PMID: 6310078.</ref> It was discovered at Pfizer Central Research in Groton, Connecticut by a team led by the biochemist Kenneth Koe and the chemist Willard Welch, who in 1977 reopened a compound series their employer had previously discarded. Sertraline carries the broadest FDA-approved indication set of any SSRI, covering major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, social anxiety disorder, and premenstrual dysphoric disorder; it is also widely prescribed off-label for generalized anxiety disorder, where multiple international guidelines recommend it as a first-line choice.

| history          = The compound that became sertraline emerged from a Pfizer compound series that had been discarded. In the early 1970s the Pfizer chemist Reinhard Sarges synthesized a series of psychoactive tetrahydronaphthalenamines whose initial members, including lometraline, were modeled on the structural skeletons of the neuroleptics thiothixene and pinoxepin. Further work on the series produced tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Tametraline was set aside because its candidates produced an undesired stimulant effect in animals. In 1977 the biochemist Kenneth Koe took an interest in the discarded series and proposed that it might be modified to act selectively on serotonin reuptake rather than on the catecholamines. Koe and the chemist Willard Welch synthesized a second generation of compounds incorporating chlorine substituents on the phenyl ring. One of the otherwise inactive cis-analogs proved to be a serotonin reuptake inhibitor; Welch then prepared the stereoisomers, and the animal behavioral scientist Albert Weissman performed the in vivo screening that identified the most potent and selective candidate, the (1S,4S)-cis enantiomer of N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine. The team published the founding paper on the compound, then designated sertraline, in 1983.<ref name="koe1983"/> The discovery was characterized at the time as emerging from a working group that operated outside Pfizer's mainstream research priorities, without a formal project team, and that had to overcome internal company reluctance to pursue sertraline because Pfizer was simultaneously considering licensing an antidepressant candidate from another firm.

Koe's biographical arc is worth recording. He was born in 1925 to Chinese immigrant parents in Astoria, Oregon. The family moved to Portland, where he attended Lincoln High School and washed dishes at the Hung Far Low restaurant in the city's Chinatown district to help support the family. He won a full scholarship to Reed College, completed a master's degree at the University of Washington, and earned his doctorate at the California Institute of Technology. He joined Pfizer in 1955, initially working on antibiotics in the company's Brooklyn laboratory, and was at Pfizer Central Research in Groton, Connecticut when the sertraline work took place. He died in 2015.

Sertraline reached the Food and Drug Administration as the second SSRI to be reviewed, four years behind Lilly's fluoxetine. The FDA approved sertraline for major depressive disorder on 30 December 1991 on the recommendation of the Psychopharmacological Drugs Advisory Committee; the medicine had already been available in the United Kingdom for a year by that point. The FDA approval was a closer call than the medicine's eventual commercial success would suggest. The treatment effect on outpatients with depression was characterized during committee discussion as modest, the effect on inpatients had not differed from placebo, and the trial design had been criticized for a 40 percent dropout rate that materially weakened the validity of the results. The committee nonetheless reached consensus that the medicine was safe and effective.<ref name="cipriani2018">Cipriani A, Furukawa TA, Salanti G, Chaimani A, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391(10128):1357-1366. PMID: 29477251.</ref>

Pfizer's US patent on sertraline expired in June 2006. Generic versions became available immediately, with Teva, Roxane, and several other manufacturers entering the market in the months that followed. Zoloft had been Pfizer's seventh-best-selling medicine in its final patent year, with sales of approximately $3.1 billion. The transition to generic supply reduced the cost per pill substantially without disrupting prescribing patterns; sertraline remained the leading SSRI through the 2010s and into the 2020s. Roughly 40 million prescriptions for sertraline were dispensed in the United States in 2019, and prescribing has continued to rise, with sertraline ranking as the most prescribed psychiatric medicine and the eleventh most prescribed medicine of any kind in the United States. The branded Zoloft franchise was transferred from Pfizer to Viatris following the Upjohn spinoff in 2020 and is now marketed under that label.

The serotonergic framing under which sertraline was discovered, marketed, and prescribed reflects the dominant model of depression pharmacology in the 1980s and 1990s. That framing has not aged uniformly well. The acute pharmacological action of sertraline, blockade of the serotonin transporter, occurs within hours, while the clinical antidepressant response classically requires weeks; the gap is the central puzzle in the modern mechanistic literature. The most consequential recent challenge to the orthodox account is the PANDA trial, a 655-patient pragmatic primary-care randomized controlled trial led by Gemma Lewis and colleagues and published in 2019. PANDA found that sertraline did not significantly reduce depression scores at six weeks in primary care patients with depressive symptoms, regardless of baseline severity or duration; secondary outcomes (anxiety, quality of life, self-rated mental health) did show improvement.<ref name="panda2019">Lewis G, Duffy L, Ades A, Amos R, et al. The clinical effectiveness of sertraline in primary care and the role of depression severity and duration (PANDA): a pragmatic, double-blind, placebo-controlled randomised trial. The Lancet Psychiatry. 2019;6(11):903-914. PMID: 31543474.</ref> The PANDA finding is consistent with the larger 21-drug network meta-analysis by Cipriani and colleagues showing modest absolute effects across the antidepressant class.<ref name="cipriani2018"/> Work in the 2000s and 2010s on BDNF-TrkB signaling and synaptic plasticity, and the 2021 demonstration by Casarotto and colleagues that fluoxetine and several other antidepressants bind directly to the TrkB neurotrophin receptor,<ref name="casarotto2021">Casarotto PC, Girych M, Fred SM, Kovaleva V, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. 2021;184(5):1299-1313.e19. PMID: 33606976.</ref> have moved the field toward a mechanistic account in which SERT inhibition is the initiating event but downstream effects on neuronal plasticity are the therapeutically active mechanism.<ref name="castren2013">Castren E. Neuronal network plasticity and recovery from depression. JAMA Psychiatry. 2013;70(9):983-989. PMID: 23842648.</ref> The page treats SERT inhibition as the canonical claim and the BDNF-TrkB account as the contemporary working model; the mechanism field above reflects this.

Sertraline is a prescription-only medicine in the United States; it is not a scheduled controlled substance. It is on the World Health Organization's Model List of Essential Medicines and is broadly available as a low-cost generic in essentially all major markets worldwide.

 

Including generalized anxiety, panic, and social anxiety.

<problem ref="social-anxiety" author="MDElliottMD"/>

<problem ref="ocd" author="MDElliottMD"/>

First SSRI approved for this indication (FDA 1999); subsequent meta-analyses suggest modest effect sizes, with trauma-focused psychotherapy first-line in several guideline frameworks.

Continuous or luteal-phase dosing; continuous is more reliable, luteal-phase works for many patients with fewer overall pill-days.

 

 

| dosing            = <titration slug="standard" author="MDElliottMD" title="Standard adult: depression, GAD, social anxiety">

Start at 25-50 mg daily. Increase by 25-50 mg every 1-2 weeks based on response and tolerability, up to a typical effective range of 50-200 mg. Absolute max: 200 mg. Many patients respond at 50-100 mg.

 

<titration slug="anxiety-panic-ptsd" author="MDElliottMD" title="Anxiety-prone, panic disorder, PTSD">

Start at 25 mg daily for one week to minimize early activation and nausea. Then increase to 50 mg, and titrate from there as above. Many anxiety patients respond at 50-100 mg.

 

<titration slug="ocd" author="MDElliottMD" title="OCD">

</titration>

 

Two strategies. Continuous: 50-150 mg daily throughout the cycle. Luteal-phase: 50-100 mg daily starting 14 days before menstruation, stopping at menses onset. Continuous dosing is more reliable; luteal works for many patients with fewer overall pill-days. Sub-therapeutic continuous dosing (25 mg) is also effective for some.

 

 

Start at 25 mg daily and titrate cautiously. Sertraline exposure may be approximately threefold higher in mild cirrhosis; use is not recommended in moderate-to-severe hepatic impairment.

 

* <effect ref="persistent-sexual-dysfunction" author="MDElliottMD">Historically [https://pmc.ncbi.nlm.nih.gov/articles/PMC11450419/ associated with SSRIs].</effect>

 

| pk_absorption    = Oral bioavailability is not precisely characterized in humans (intravenous sertraline has not been administered for absolute bioavailability measurement). Absorption is essentially complete, with extensive first-pass metabolism limiting systemic availability. Peak plasma concentrations occur between 4.5 and 8.4 hours post-dose. Concomitant food modestly increases peak plasma levels and total exposure. Steady-state is reached within approximately one week of continuous dosing.<ref name="zoloft-label">U.S. Food and Drug Administration. Zoloft (sertraline hydrochloride) prescribing information. NDA 019839.</ref>

| pk_metabolism    = Sertraline undergoes extensive hepatic metabolism by N-demethylation, predominantly via CYP2C19 in vivo with secondary contribution from CYP2B6; CYP2C9, CYP3A4, and CYP2D6 also contribute. The principal metabolite, N-desmethylsertraline, is approximately 10- to 50-fold weaker than the parent compound as a serotonin reuptake inhibitor and is not thought to contribute meaningfully to clinical effect.<ref name="zoloft-label"/> CYP2C19 poor metabolizers have approximately 2.7-fold higher sertraline exposure than normal metabolizers, and intermediate metabolizers approximately 1.4-fold higher,<ref name="braten2020">Bråten LS, Haslemo T, Jukic MM, Ingelman-Sundberg M, et al. Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients. Neuropsychopharmacology. 2020;45(3):570-576. PMID: 31649299.</ref> with dose-relevant implications particularly in East Asian populations where CYP2C19 poor metabolism is more common. Sertraline itself is a moderate inhibitor of CYP2D6 (weaker than fluoxetine or paroxetine) and a moderate inhibitor of CYP2B6.<ref name="cpic2015">Hicks JK, Bishop JR, Sangkuhl K, Müller DJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clinical Pharmacology & Therapeutics. 2015;98(2):127-134. PMID: 25974703.</ref>

| pk_elimination    = Elimination is renal and biliary in approximately equal proportions (40-45% each), almost entirely as metabolites. Less than 0.2% of an oral dose is recovered unchanged in urine; approximately 12-14% of a dose appears unchanged in feces.<ref name="zoloft-label"/>

| pharmacodynamics  = Sertraline inhibits the serotonin transporter (SERT) with high affinity (Ki 0.15-3.3 nM) and high selectivity over the norepinephrine transporter (Ki 420-925 nM). The dopamine transporter (DAT) is bound at intermediate affinity (Ki 22-315 nM); at doses of 200 mg daily and above, sertraline occupies approximately 20% of DAT receptors in human imaging studies, an effect that distinguishes it from other SSRIs and may contribute to motivational and cognitive effects. Sertraline is also an antagonist at sigma-1 receptors (Ki 32-57 nM in rat tissue). Affinity at histamine, acetylcholine, GABA, and benzodiazepine receptors is negligible. The acute mechanism, blockade of synaptic 5-HT reuptake, does not by itself explain the delayed clinical response, which classically begins at 2-4 weeks and continues to improve for 2-3 months. The contemporary mechanistic account places downstream effects on BDNF-TrkB signaling and synaptic plasticity at the center of the antidepressant response; on this view, SERT inhibition is the initiating event but not the therapeutically active one.<ref name="castren2013"/><ref name="casarotto2021"/>

 

Sertraline has additional in vitro and ex vivo activities that have generated active research interest but whose clinical significance remains uncertain: REDD1-dependent mTOR inhibition with autophagy induction, antifungal activity (particularly against Candida species), antiparasitic effects against Leishmania and Trypanosoma species, and photosensitizing activity against some bacteria. None of these is part of the medicine's approved use; they are noted here for completeness.

 

 

* '''MAO inhibitors and pimozide: contraindicated.''' Combination with non-selective MAOIs (isocarboxazid, phenelzine, tranylcypromine) or with linezolid or intravenous methylene blue may produce serotonin syndrome, which can be life-threatening. A 14-day washout is required in both directions. Combination with pimozide is contraindicated because of QT-prolongation risk.

* '''Methadone: sertraline increases methadone plasma levels by approximately 26% over six weeks via CYP2B6 inhibition,''' with stereoselective accumulation of the (S)-methadone enantiomer that carries the QT-prolongation risk.<ref name="hamilton2000">Hamilton SP, Nunes EV, Janal M, Weber L. The effect of sertraline on methadone plasma levels in methadone-maintenance patients. The American Journal on Addictions. 2000;9(1):63-69. PMID: 10914294.</ref> Clinically significant; monitor when starting sertraline in methadone-maintained patients.

* '''Tamoxifen, codeine, tramadol, metoprolol: sertraline is a moderate CYP2D6 inhibitor''' (weaker than fluoxetine or paroxetine but not negligible). Tamoxifen efficacy depends on CYP2D6 activation to endoxifen; sertraline is among the less problematic SSRIs in this context but is not preferred. Codeine analgesia depends on CYP2D6 activation; sertraline blunts this. Tramadol carries both a CYP2D6-substrate consideration and a serotonergic-toxicity consideration.

* '''Warfarin: small clinically uncertain effect on INR.''' Monitor INR more frequently when starting or stopping sertraline.

* '''Levothyroxine: sertraline may decrease the efficacy of levothyroxine''' through an incompletely characterized mechanism. Monitor TSH when starting sertraline in patients on thyroid replacement.

 

| pregnancy_details = Sertraline is among the most extensively studied SSRIs in pregnancy, and the modern evidence base is broadly reassuring once depression and other confounders are accounted for. The largest and most rigorously confounding-adjusted study is the Huybrechts and colleagues 2014 cohort in the New England Journal of Medicine, which examined 949,504 Medicaid-enrolled pregnancies and was specifically designed to address concerns about a sertraline-cardiac-defect association. Unadjusted analyses showed a modest excess of cardiac defects in antidepressant-exposed pregnancies; once the analysis was restricted to women with depression and adjusted with propensity scores for severity of illness and other confounders, the association with major cardiac malformations was no longer statistically significant.<ref name="huybrechts2014">Huybrechts KF, Palmsten K, Avorn J, Cohen LS, et al. Antidepressant use in pregnancy and the risk of cardiac defects. New England Journal of Medicine. 2014;370(25):2397-2407. PMID: 24941178.</ref> Older meta-analyses that pooled mostly unadjusted cohorts have reported a 29-42% increased odds of congenital heart defects and a roughly 2.7-fold increase in septal defects with first-trimester sertraline exposure,<ref name="gao2018">Gao SY, Wu QJ, Sun C, Zhang TN, et al. Selective serotonin reuptake inhibitor use during early pregnancy and congenital malformations: a systematic review and meta-analysis of cohort studies of more than 9 million births. BMC Medicine. 2018;16(1):205. PMID: 30415641.</ref><ref name="devries2021">De Vries C, Gadzhanova S, Sykes MJ, Ward M, Roughead E. A Systematic Review and Meta-Analysis Considering the Risk for Congenital Heart Defects of Antidepressant Classes and Individual Antidepressants. Drug Safety. 2021;44(3):291-312. PMID: 33354752.</ref> but these estimates are largely attenuated by the better-adjusted evidence and should be interpreted with caution. The absolute risk is low. Use late in the third trimester may produce a neonatal adaptation syndrome (jitteriness, feeding difficulties, respiratory distress) lasting days to a few weeks. Untreated depression in pregnancy carries its own substantial risks for mother and infant. Sertraline is excreted in breast milk at low levels and is generally considered the first-choice SSRI in lactation. On the present evidence, sertraline is one of the preferred SSRIs for use in pregnancy and in breastfeeding.

 

| seealso          = [[Fluoxetine]], [[Escitalopram]], [[Paroxetine]], [[Duloxetine]], [[Methadone]]

 

[[Category:Antidepressants]]