Sertraline was developed by scientists atPfizer and approved for medical use in the United States in 1991. It is on theWorld Health Organization's List of Essential Medicines[16] and available as ageneric medication.[10] In 2016, sertraline was the most commonly prescribed psychotropic medication in the United States.[17] It was also the eleventh most commonly prescribed medication in the United States, with more than 39million prescriptions in 2022,[18][19] and sertraline ranks among the top 10 most prescribed medications in Australia between 2017 and 2023.[20]
For alleviating the symptoms of depression and anxiety, the drug is usually second in potency to another SSRI,escitalopram. Sertraline'seffectiveness is similar to that of other antidepressants in its class, such asfluoxetine andparoxetine, which are also considered first-line treatments and are better tolerated than the oldertricyclic antidepressants.
Inmeta-analyses, sertraline displays similar efficacy to other SSRI antidepressants, with anodds ratio for response in clinical depression of between 1.44 and 1.67.[22][23] However, as with other antidepressants, the nature and clinical significance of this effect remain disputed.[24][25] A major study of sertraline in a broad primary care population found improvements in general mental health, quality of life, and anxiety.[26] However, it failed to find significant effects on depression in either the mildly or severely depressed, and the clinical relevance and accuracy of the positive effects found have been questioned.[27][28]
In severaldouble-blind studies, sertraline was consistently more effective thanplacebo fordysthymia, a more chronic variety of depression, and comparable toimipramine in that respect. Sertraline also improves the functional impairments of dysthymia to a similar degree whether group Cognitive-Behavioral Therapy is undergone or not.[29]
Limited pediatric data also demonstrates a reduction in depressive symptoms in the pediatric population though remains a second-line therapy after fluoxetine.[30][31]
In general, sertraline efficacy is similar to that of other antidepressants.[32] For example, a meta-analysis of 12 new-generation antidepressants showed that sertraline andescitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with depression.[33] Comparative clinical trials demonstrated that sertraline is similar in efficacy against depression tomoclobemide,[34]nefazodone,[35]escitalopram,bupropion,[36]citalopram,fluvoxamine,paroxetine,[33]venlafaxine,[37] andmirtazapine.[38] Sertraline may be more efficacious for the treatment of depression in the acute phase (first four weeks) thanfluoxetine.[39]
There are differences between sertraline and some other antidepressants in their efficacy in the treatment of different subtypes of depression and in their adverse effects. For severe depression, sertraline is as good asclomipramine but is better tolerated.[37] Sertraline appears to work better inmelancholic depression than fluoxetine,paroxetine, andmianserin and is similar to thetricyclic antidepressants such asamitriptyline andclomipramine.[32] In the treatment of depression accompanied byOCD, sertraline performs significantly better thandesipramine on the measures of both OCD and depression.[29][40] Sertraline is equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it is better tolerated.[41] Compared with amitriptyline, sertraline offered a greater overall improvement inquality of life of depressed patients.[32]
Sertraline used for the treatment of depression in elderly (older than 60) patients is superior to placebo and comparable to another SSRI fluoxetine, andtricyclic antidepressants (TCAs) amitriptyline,nortriptyline andimipramine. Sertraline has much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurs more frequently with sertraline. In addition, sertraline appears to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup.[42] Accordingly, a meta-analysis of antidepressants in older adults found that sertraline,paroxetine andduloxetine were better than placebo.[43] However, in a 2003 trial theeffect size was modest, and there was no improvement inquality of life as compared toplacebo.[44] With depression in dementia, there is no benefit of sertraline treatment compared to either placebo ormirtazapine.[45]
Sertraline is effective for the treatment of OCD in adults,[21] adolescents and children.[46][47][48] It was better tolerated and, based onintention-to-treat analysis, performed better than the gold standard of OCD treatmentclomipramine.[49] Continuing sertraline treatment helps prevent relapses of OCD with long-term data supporting its use for up to 24 months.[50] The sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression.[51] The onset of action is also slower for OCD than for depression. The treatment recommendation is to start treatment with half of the maximal recommended dose for at least two months. After that, the dose can be raised to the maximal recommended in the cases of unsatisfactory response.[52]
Cognitive behavioral therapy alone is not more effective than sertraline in adolescents and children; however, a combination of these treatments is effective.[48]
Sertraline is superior to placebo for the treatment ofpanic disorder.[21] The response rate was independent of the dose. In addition to decreasing the frequency of panic attacks by about 80% (vs. 45% for placebo) and decreasing general anxiety, sertraline resulted in an improvement in quality of life on most parameters. The patients rated as "improved" on sertraline reported better quality of life than the ones who "improved" on placebo. The authors of the study argued that the improvement achieved with sertraline is different and of a better quality than the improvement achieved with a placebo.[53][54] Sertraline is equally effective for men and women,[54] and for patients with or without agoraphobia.[55] Previous unsuccessful treatment withbenzodiazepines does not diminish its efficacy.[56] However, the response rate was lower for the patients with more severe panic.[55] Starting treatment simultaneously with sertraline andclonazepam, with subsequent gradual discontinuation of clonazepam, may accelerate the response.[57]
Double-blind comparative studies found sertraline to have the same effect on panic disorder asparoxetine orimipramine.[58] While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine,imipramine, clonazepam,alprazolam, andfluvoxamine) indicates approximate equivalence of these medications.[53]
Sertraline has been successfully used for the treatment ofsocial anxiety disorder.[59][60] All three major domains of the disorder (fear, avoidance, and physiological symptoms) respond to sertraline.[29] Maintenance treatment, after the response is achieved, prevents the return of the symptoms.[61] The improvement is greater among the patients with later, adult onset of the disorder.[62] In a comparison trial, sertraline was superior toexposure therapy, but patients treated with the psychological intervention continued to improve during a year-long follow-up, while those treated with sertraline deteriorated after treatment termination.[63] The combination of sertraline andcognitive behavioral therapy appears to be more effective in children and young people than either treatment alone.[64]
Sertraline has not been approved for the treatment ofgeneralized anxiety disorder; however, several guidelines recommend it as a first-line medication referring to good quality controlled clinical trials.[65][41][50]
Sertraline is effective in alleviating the symptoms ofpremenstrual dysphoric disorder, a severe form ofpremenstrual syndrome.[66] Significant improvement was observed in 50–60% of cases treated with sertraline vs. 20–30% of cases on placebo. The improvement began during the first week of treatment, and in addition to mood, irritability, and anxiety, improvement was reflected in better family functioning, social activity, and general quality of life. Work functioning and physical symptoms, such as swelling, bloating, and breast tenderness, were less responsive to sertraline.[67][68] Taking sertraline only during theluteal phase, that is, the 12–14 days before menses is not as effective as continuous treatment.[66] Continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50–100 mg) is also effective.[69]
Sertraline is approved for the treatment ofpost-traumatic stress disorder (PTSD).[21] TheNational Institute for Clinical Excellence recommends it for patients who prefer drug treatment to a psychological one.[70] Other guidelines also suggest sertraline as a first-line option forpharmacological therapy.[71][41] When necessary, long-term pharmacotherapy can be beneficial.[71] There are both negative and positive clinical trial results for sertraline, which may be explained by the types ofpsychological traumas, symptoms, andcomorbidities included in the various studies.[50] Positive results were obtained in trials that included predominantly women (75%) with a majority (60%) having physical or sexual assault as the traumatic event.[71] Somewhat contrary to the above suggestions, a meta-analysis of sertraline clinical trials for PTSD found it to be statistically superior to placebo in the reduction of PTSD symptoms but the effect size was small.[12] Another meta-analysis relegated sertraline to the second line, proposingtrauma focused psychotherapy as a first-line intervention. The authors noted thatPfizer had declined to submit the results of a negative trial for inclusion in the meta-analysis making the results unreliable.[13]
Sertraline, when taken daily, can be useful for the treatment ofpremature ejaculation.[72] A disadvantage of sertraline is that it requires continuous daily treatment to delay ejaculation significantly.[73]
Sertraline is contraindicated in individuals takingmonoamine oxidase inhibitors or the antipsychoticpimozide. Sertraline concentrate containsethanol and is therefore contraindicated withdisulfiram. The prescribing information recommends that treatment of the elderly and patients with liver impairment "must be approached with caution". Due to the slower elimination of sertraline in these groups, their exposure to sertraline may be as high as three times the average exposure for the same dose.[21]
Nausea, ejaculation failure, insomnia, diarrhea, dry mouth, somnolence, dizziness, tremor, headache, excessive sweating, fatigue,restless legs syndrome and decreasedlibido are the common adverse effects associated with sertraline with the greatest difference fromplacebo. Those that most often result in interruption of the treatment are nausea, diarrhea, and insomnia.[21] The incidence of diarrhea is higher with sertraline – especially when prescribed at higher doses – in comparison with otherSSRIs.[75]
Over more than six months of sertraline therapy for depression, people showed no significant weight increase.[76] A 30-month-long treatment with sertraline for OCD also resulted in no significant weight gain.[77] Although the difference did not reachstatistical significance, the average weight gain was lower forfluoxetine (1%) but higher forcitalopram,fluvoxamine andparoxetine (2.5%). Of the sertraline group, 4.5% gained a large amount of weight (defined as more than 7% gain). This result compares favorably with placebo, where, according to the literature, 3–6% of patients gained more than 7% of their initial weight. The large weight gain was observed only among female members of the sertraline group; the significance of this finding is unclear because of the small size of the group.[77]
Over a two-week treatment of healthy volunteers, sertraline slightly improved verbalfluency but did not affect word learning,short-term memory,vigilance,flicker fusion time, choicereaction time,memory span, orpsychomotor coordination.[78][79] In spite of lower subjective rating, that is, feeling that they performed worse, no clinically relevant differences were observed in the objective cognitive performance in a group of people treated for depression with sertraline for 1.5 years as compared to healthy controls.[80] In children and adolescents taking sertraline for six weeks for anxiety disorders, 18 out of 20 measures of memory, attention, and alertness stayed unchanged.Divided attention was improved and verbal memory underinterference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance.[81] The unique effect of sertraline ondopaminergicneurotransmission may be related to these effects on cognition and vigilance.[82][83]
Sertraline has a low level of exposure of an infant through the breast milk and is recommended as the preferred option for the antidepressant therapy of breast-feeding mothers.[84][85] There is 29–42% increase incongenital heart defects among children whose mothers were prescribed sertraline during pregnancy,[14][15] with sertraline use in the first trimester associated with 2.7-fold increase inseptal heart defects.[14]
Abrupt interruption of sertraline treatment may result inwithdrawal or discontinuation syndrome. Dizziness, insomnia, anxiety, agitation, and irritability are common symptoms.[86] It typically occurs within a few days from drug discontinuation and lasts a few weeks.[87] The withdrawal symptoms for sertraline are less severe and frequent than for paroxetine, and more frequent than forfluoxetine.[86][87] In most cases symptoms are mild, short-lived, and resolve without treatment. More severe cases are often successfully treated by temporary reintroduction of the drug with a slower tapering-off rate.[88]
Like other SSRIs, sertraline is associated with sexual side effects, includingsexual arousal disorder,erectile dysfunction and difficulty achievingorgasm. Whilenefazodone andbupropion do not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties versus 18% before the treatment.[92]Sexual arousal disorder, defined as "inadequate lubrication and swelling for women and erectile difficulties for men", occurred in 12% of people on sertraline as compared with 1% of patients on placebo. The mood improvement resulting from the treatment with sertraline sometimes counteracted these side effects, so thatsexual desire and overall satisfaction with sex stayed the same as before the sertraline treatment. However, under the action of placebo the desire and satisfaction slightly improved.[93] Some people continue experiencing sexual side effects after they stop taking SSRIs.[94]
The USFood and Drug Administration (FDA) requires all antidepressants, including sertraline, to carry aboxed warning stating that antidepressants increase the risk of suicide in persons younger than 25 years.[95][96][97] This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a 100% increase of suicidal thoughts and behavior in children and adolescents, and a 50% increase in the 18–24 age group.[98][99][100]
Suicidal ideation and behavior in clinical trials are rare. For the above analysis, the FDA combined the results of 295 trials of 11 antidepressants for psychiatric indications to obtainstatistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidal behavior with a marginal statistical significance of 37%[100] or 50%[99] depending on the statistical technique used. The authors of the FDA analysis note that "given the large number of comparisons made in this review, chance is a very plausible explanation for this difference".[99] The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behavior.[101] Similarly, the analysis conducted by the UKMHRA found a 50% increase of odds of suicide-related events, not reaching statistical significance, in the patients on sertraline as compared to the ones on placebo.[102][103]
Acute overdosage is often manifested byemesis,lethargy,ataxia,tachycardia andseizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its majoractive metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities.[104] As with most other SSRIs its toxicity in overdose is considered relatively low.[105][106]
Sertraline is a moderateinhibitor ofCYP2D6 andCYP2B6in vitro.[7] Accordingly, in human trials it caused increased blood levels of CYP2D6substrates such asmetoprolol,dextromethorphan,desipramine,imipramine andnortriptyline, as well as theCYP3A4/CYP2D6 substratehaloperidol.[109][110][111] This effect is dose-dependent; for example, co-administration with 50 mg of sertraline resulted in 20% greater exposure to desipramine, while 150 mg of sertraline led to a 70% increase.[8][112] In a placebo-controlled study, the concomitant administration of sertraline andmethadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.[113]Bupropion is metabolized by CYP2B6, which is inhibited by sertraline, and this may result in an interaction between sertraline and bupropion.[114][115][116]
Sertraline did not affect the actions ofdigoxin andatenolol, which are not metabolized in the liver.[5]Case reports suggest that taking sertraline withphenytoin orzolpidem may induce sertraline metabolism and decrease its efficacy,[118][119] and that taking sertraline withlamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.[120]
CYP2C19 inhibitoresomeprazole increased sertraline concentrations in blood plasma by approximately 40%.[121]
Clinical reports indicate that interaction between sertraline and theMAOIsisocarboxazid andtranylcypromine may causeserotonin syndrome. In a placebo-controlled study in which sertraline was co-administered withlithium, 35% of the subjects experienced tremors, while none of those taking placebo did.[8]
Sertraline also shows relatively high activity as an inhibitor of thedopamine transporter (DAT) occupying ~20% of DAT receptors at doses 200mg and above,[123][133][134] and antagonist of thesigmaσ1 receptor (but not theσ2 receptor).[129][130][135] However, sertraline affinity for its main target (SERT) is much greater than its affinity for σ1 receptor and DAT.[122][123][130][129] Although there could be a role for the σ1 receptor in thepharmacology of sertraline, the significance of this receptor in its actions is unclear.[32] Similarly, the clinical relevance of sertraline's blockade of the dopamine transporter is uncertain.[123]
Following a single oral dose of sertraline, mean peak blood levels of sertraline occur between 4.5 and 8.4 hours.[5]Bioavailability is likely linear and dose-proportional over a dose range of 150 to 200 mg.[5] Concomitant intake of sertraline with food slightly increases sertraline peak levels and total exposure.[5] There is an approximate 2-fold accumulation of sertraline with continuous administration andsteady-state levels are reached within one week.[5]
Sertraline is highlyplasma protein bound (98.5%) across a concentration range of 20 to 500 ng/mL.[5] Despite the high plasma protein binding, sertraline and itsmetabolitedesmethylsertraline at respective tested concentrations of 300 ng/mL and 200 ng/mL were found not to interfere with the plasma protein binding ofwarfarin andpropranolol, two other highly plasma protein-bound drugs.[5]
Theelimination half-life of sertraline is on average 26 hours, with a range of 13 to 45 hours.[5][8] The elimination half-life of desmethylsertraline is 62 to 104 hours.[5]
In a small study of two males, sertraline wasexcreted to similar degrees inurine andfeces (40 to 45% each within 9 days).[5] Unchanged sertraline was not detectable in urine, whereas 12 to 14% of unchanged sertraline was present in feces.[5]
Skeletal formulae of thiothixene, lometraline and tametraline, from which sertraline was derived. Commonalities to the structure of sertraline are highlighted in red.
The history of sertraline dates back to the early 1970s whenPfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds, includinglometraline, based on the structures of the neurolepticsthiothixene andpinoxepin.[141][142] Further work on these compounds led totametraline, anorepinephrine and weakerdopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesiredstimulant effects observed in animals. A few years later, in 1977, pharmacologistKenneth Koe, after comparing the structural features of a variety of reuptake inhibitors, became interested in the tametraline series. He asked another Pfizer chemist, Willard Welch, to synthesize some previously unexplored tametraline derivatives. Welch generated several potent norepinephrine andtriple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactivecis-analogs was a serotonin reuptake inhibitor. Welch then preparedstereoisomers of this compound, which were testedin vivo by animalbehavioral scientist Albert Weissman. The most potent and selective (+)-isomer[a] was taken into further development and eventually named sertraline. Weissman and Koe recalled that the group did not set up to produce an antidepressant of the SSRI type—in that sense their inquiry was not "very goal driven", and the invention of the sertraline molecule wasserendipitous. According to Welch, they worked outside the mainstream at Pfizer, and even "did not have a formal project team". The group had to overcome initial bureaucratic reluctance to pursue sertraline development, as Pfizer was considering licensing an antidepressant candidate from another company.[141][145][146]
Sertraline was approved by the USFood and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in theUnited Kingdom the previous year.[147] The FDA committee achieved a consensus that sertraline was safe and effective for the treatment ofmajor depression. During the discussion, Paul Leber, the director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a "tough decision", since the treatment effect onoutpatients with depression had been "modest to minimal". Other experts emphasized that the drug's effect on inpatients had not differed fromplacebo and criticized the poor design of the clinical trials by Pfizer.[148] For example, 40% of participants dropped out of the trials, significantly decreasing theirvalidity.[149]
Until 2002, sertraline was only approved for use in adults ages 18 and over; that year, it was approved by the FDA for use in treating children aged 6 or older with severe OCD. In 2003, the UKMedicines and Healthcare products Regulatory Agency issued guidance that, apart fromfluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18.[150][151] However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents.[152] In 2005, the FDA added aboxed warning concerning pediatric suicidal behavior to allantidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidal behavior in young adults ages 18 to 24.[153]
Sertraline has been the most sought-after antidepressant worldwide before, during, and after theCOVID-19 pandemic, according toGoogle Trends data. The pandemic has led to an increase in searches for antidepressants, with sertraline,fluoxetine,duloxetine, andvenlafaxine showing the highest search volumes, whereas searches ofcitalopram decreased during the pandemic.[158]
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