Sertraline

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Sertraline
Sertraline.svg
Sertraline-3D-balls.png
Systematic (IUPAC) name
(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine
Clinical data
Trade names Zoloft and others[1]
AHFS/Drugs.com monograph
MedlinePlus a697048
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • ℞ (Prescription only)
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 44%
Protein binding 98.5%
Metabolism Hepatic (N-demethylation mainly by CYP2B6)[2]
Biological half-life ~23-26 h (66 h [less-active[3] metabolite, norsertraline])[4]
Excretion Renal
Identifiers
CAS Number 79617-96-2 YesY
ATC code N06AB06 (WHO)
PubChem CID: 68617
IUPHAR/BPS 4798
DrugBank DB01104 YesY
ChemSpider 61881 YesY
UNII QUC7NX6WMB YesY
KEGG D02360 YesY
ChEBI CHEBI:9123 YesY
ChEMBL CHEMBL809 YesY
Chemical data
Formula C17H17Cl2N
Molecular mass 306.229 g/mol
  (verify)

Sertraline (trade names Zoloft and others) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily prescribed for major depressive disorder in adult outpatients as well as obsessive-compulsive disorder, panic disorder, and social anxiety disorder, in both adults and children. In 2013, it was the most prescribed antidepressant and second most prescribed psychiatric medication (after alprazolam) on the U.S. retail market, with over 41 million prescriptions.[5]

Differences with other newer antidepressants are subtle and mostly confined to side effects. It has a similar tolerability profile to other SSRIs, with the types of adverse events usually including diarrhea, nausea, trembling, sexual dysfunction and weight gain. The incidence of diarrhea was higher with sertraline in comparison to other SSRIs.[6]

Medical uses

Sertraline is used for a number of conditions including: major depression, obsessive-compulsive disorder (OCD), body dysmorphic disorder (BDD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder and social phobia (social anxiety disorder).[7] It has also been used for premature ejaculation and vascular headaches but evidence of the effectiveness in treating those conditions is not robust.[7]

Depression

A 2008 review concluded that 51% of studies of various SSRI's yielded positive outcomes.[8] The efficacy of sertraline is statistically similar to other SSRIs such as paroxetine, citalopram, escitalopram and venlafaxine (SNRI).[9][10][11][12] Evidence suggests that sertraline may be more effective than fluoxetine (Prozac) for some subtypes of depression.[13]

Evidence does not show a benefit in children with depression.[14]

With depression in dementia, there is no benefit compared to either placebo or mirtazapine.[15]

Comparison with other antidepressants

Tricyclic antidepressants (TCAs) as a group are considered to work better than selective serotonin reuptake inhibitors for melancholic depression[16] and in inpatients,[17] but not necessarily for simply more severe depression.[18] In line with this generalization, sertraline was no better than placebo in inpatients (see History) and as effective as the TCA clomipramine for severe depression.[9] The comparative efficacy of sertraline and TCAs for melancholic depression has not been studied. A 1998 review suggested that, due to its pharmacology, sertraline may be more efficacious than other SSRIs and equal to TCAs for the treatment of melancholic depression.[19]

A meta-analysis of 12 new-generation antidepressants showed that sertraline and escitalopram are the best in terms of efficacy and acceptability in the acute-phase treatment of adults with unipolar major depression. Reboxetine was significantly worse.[20]

Comparative clinical trials demonstrated that sertraline's efficacy in depression is similar to that of moclobemide,[21] nefazodone,[22] escitalopram, bupropion,[23] citalopram, fluvoxamine, paroxetine and mirtazapine.[24] There is low quality evidence that sertraline is more efficacious for the treatment of depression than fluoxetine.[25]

Elderly

Sertraline used for the treatment of depression in elderly (older than 60) patients was superior to placebo and comparable to another SSRI fluoxetine, and TCAs amitriptyline, nortriptyline (Pamelor) and imipramine. Sertraline had much lower rates of adverse effects than these TCAs, with the exception of nausea, which occurred more frequently with sertraline. In addition, sertraline appeared to be more effective than fluoxetine or nortriptyline in the older-than-70 subgroup.[26] A 2003 trial of sertraline vs. placebo in elderly patients showed a statistically significant (that is, unlikely to occur by chance), but clinically very modest improvement in depression and no improvement in quality of life.[27]

A meta-analysis on SSRIs and SNRIs that look at partial response (defined as at least a 50% reduction in depression score from baseline) found that sertraline, paroxetine and duloxetine were better than placebo. With respect to safety duloxetine and venlafaxine increased worsened dizziness, however not much safety data was reported.[28]

Obsessive-compulsive disorder

Sertraline is effective for the treatment of OCD in adults and children.[29] It was better tolerated and, based on intention to treat analysis, performed better than the gold standard of OCD treatment clomipramine.[30] It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression.[31] The onset of action is also slower for OCD than for depression. The treatment recommendation is to start treatment with a half of 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.[32]

Cognitive behavioral therapy alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments.[33][34] Sertraline may be useful for the treatment of OCD co-morbid with Tourette syndrome.[35]

Panic disorder

Treatment of panic disorder with sertraline results in a decrease of the number of panic attacks and an improved quality of life.[36] In four double-blind studies sertraline was shown to be superior to placebo for the treatment of panic disorder. 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 improvement of 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 placebo.[36][37] Sertraline was equally effective for men and women.[37] While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine, imipramine, clonazepam, alprazolam, fluvoxamine and paroxetine) indicates approximate equivalence of these medications.[36]

Social phobia

Sertraline is effective for the treatment of social phobia.[38] Improvement in scores on the Liebowitz Social Anxiety Scale were found with sertraline but not with placebo.[39] A combination of sertraline and cognitive behavioural therapy has a superior response rate when used in children.[40]

Premenstrual dysphoric disorder

SSRIs, including sertraline, reduce the symptoms of premenstrual syndrome.[41] Side effects such as nausea are common.[41]

Sertraline is effective in alleviating the symptoms of PMDD, a severe form of premenstrual syndrome. 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.[42][43] Taking sertraline only during the luteal phase, that is, the 12–14 days before menses, was shown to work as well as continuous treatment.[41]

Other indications

Sertraline when taken daily can be useful for the treatment of some aspects of premature ejaculation.[44] A disadvantage of SSRIs is that they require continuous daily treatment to delay ejaculation significantly,[45] and it is not clear how they affect psychological distress of those with the condition or the persons control over ejaculation timing.[46]

The benefit of sertraline in PTSD is not significant per the National Institute of Clinical Excellence.[47] Others, however, do feel that there is a benefit from their use.[48]

Adverse effects

Zoloft 50 mg & 25 mg tablets (US)
Zoloft 100 mg tablets (AU)

Compared to other SSRIs sertraline tends to be associated with a higher rate of psychiatric side effects and diarrhea.[49][50] It tends to be more activating (that is, associated with a higher rate of anxiety, agitation, insomnia, etc.) than other SSRIs, aside from fluoxetine.[51]

Over more than six months of sertraline therapy for depression, patients showed an insignificant weight increase of 0.1%.[52] Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg).[53] Although the difference did not reach statistical significance, the weight gain was lower for fluoxetine (Prozac) (1%) but higher for citalopram (Celexa), fluvoxamine (Luvox) and paroxetine (Paxil) (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.[53]

Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal fluency but did not affect word learning, short-term memory, vigilance, flicker fusion time, choice reaction time, memory span, or psychomotor coordination.[54][55] 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.[56] 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 under interference conditions decreased marginally. Because of the large number of measures taken, it is possible that these changes were still due to chance.[57] The unique effect of sertraline on dopaminergic neurotransmission may be related to these effects on cognition and vigilance.[58][59]

Sexual side effects

Like other SSRIs, sertraline is associated with sexual side effects, including sexual arousal disorder and difficulty achieving orgasm. The observed frequency of sexual side effects depends greatly on whether they are reported by patients spontaneously, as in the manufacturer's trials, or actively solicited by the physicians. There have been several double-blind studies of sexual side effects comparing sertraline with placebo or other antidepressants.[60] While nefazodone (Serzone), bupropion (Wellbutrin) and reboxetine (Edronax) did not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties vs. 18% before the treatment[60] (or 61% vs. 0% according to another paper).[23] Similarly, in a group of women who initially did not have difficulties achieving orgasm, 41% acquired this problem during treatment with sertraline.[23] A 40% rate of orgasm dysfunction (vs. 9% for placebo) on sertraline was observed in a mixed group in another study.[61] Sexual arousal disorder, defined as "inadequate lubrication and swelling for women and erectile difficulties for men", occurred in 12% of patients 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 that sexual 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.[61]

Suicide

The FDA requires all antidepressants, including sertraline, to carry a black box warning stating that antidepressants may increase the risk of suicide in persons younger than 25. This warning is based on statistical analyses conducted by two independent groups of FDA experts that found a twofold increase of suicidal ideation and behavior in children and adolescents, and a 1.5-fold increase of suicidal behavior in the 18–24 age group.[62][63][64]

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 in order to obtain statistically significant results. Considered separately, sertraline use in adults decreased the odds of suicidal behavior with a marginal statistical significance by 37%[64] or 50%[63] 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".[63] The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behavior.[65] Similarly, the analysis conducted by the UK MHRA 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.[66][67]

Overdose

Acute overdosage is often manifested by emesis, lethargy, ataxia, tachycardia and seizures. Plasma, serum or blood concentrations of sertraline and norsertraline, its major active metabolite, may be measured to confirm a diagnosis of poisoning in hospitalized patients or to aid in the medicolegal investigation of fatalities.[68] As with most other SSRIs its toxicity in overdose is considered relatively low.[49][69]

Pregnancy and lactation

The studies comparing the levels of sertraline and its principal metabolite, desmethylsertraline, in mother's blood to their concentration in umbilical cord blood at the time of delivery indicated that foetal exposure to sertraline and its metabolite is approximately a third of the maternal exposure.[70][71] The use of sertraline during the first trimester of pregnancy was associated with increased odds of the following birth defects: omphalocele (six-fold), anal atresia and limb reduction defects (four-fold), and septal defects (two-fold); however these specific defects themselves are rare and therefore the absolute risks are small.[72] Concentration of sertraline and desmethylsertraline in breast milk is highly variable and, on average, is of the same order of magnitude as their concentration in the blood plasma of the mother. As a result, more than half of breast-fed babies receive less than 2 mg/day of sertraline and desmethylsertraline combined, and in most cases these substances are undetectable in their blood.[73] No changes in serotonin uptake by the platelets of breast-fed infants were found, as measured by their blood serotonin levels before and after their mothers began sertraline treatment.[74]

Withdrawal syndrome

Interactions

Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro.[75] Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol, dextromethorphan, desipramine, imipramine and nortriptyline, as well as the CYP3A4/CYP2D6 substrate haloperidol.[76][77][78] 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.[79][80] In a placebo-controlled study, the concomitant administration of sertraline and methadone caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6.[81] Sertraline is often used in combination with stimulant medication for the treatment of co-morbid depression and/or anxiety in ADHD.[82] Amphetamine metabolism inhibits enzyme CYP2D6, but has not been known to interfere with Sertraline metabolism.[83]

Sertraline had a slight inhibitory effect on the metabolism of diazepam, tolbutamide and warfarin, which are CYP2C9 or CYP2C19 substrates; this effect was not considered to be clinically relevant.[79] As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam, carbamazepine, clonazepam, and terfenadine; neither did it affect metabolism of the CYP1A2 substrate clozapine.

Sertraline had no effect on the actions of digoxin and atenolol, which are not metabolized in the liver.[75][79][84][85] Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy,[86][87] and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.[88]

Clinical reports indicate that interaction between sertraline and the MAOIs isocarboxazid and tranylcypromine may cause serotonin syndrome. In a placebo-controlled study in which sertraline was co-administered with lithium, 35% of the subjects experienced tremors, while none of those taking placebo did.[79]

According to Pfizer, sertraline is contraindicated in individuals taking monoamine oxidase inhibitors or the antipsychotic pimozide (Orap). Sertraline concentrate contains alcohol, and is therefore contraindicated with disulfiram (Antabuse). 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.[84]

Grapefruit juice should be avoided, as this may increase the levels of Sertraline in the body ( see Grapefruit–drug interactions ).

Mechanism of action

Sertraline is primarily a serotonin reuptake inhibitor (SRI) with a binding affinity towards the serotonin transporter of Ki=2.0μM.[89] Therapeutic doses of sertraline (25–200 mg/day) taken by patients for four weeks resulted in 80–90% inhibition of serotonin transporter (SERT) in striatum as measured by positron emission tomography. A daily 9 mg dose was sufficient to inhibit 50% of SERT.[90]

Sertraline molecule

Sertraline is also a dopamine reuptake inhibitor, (<50 nmol/L). However, this is not considered a tight binding, and this action is only 10% of its potency as a monoamine reuptake inhibitor.[91] It is a σ1 receptor agonist with 5% of its SRI potency,[92] and an α1-adrenoreceptor antagonist with 1–10% of its SRI potency.[93] However, though confirming sertraline's high affinity for σ1 receptors, different studies suggest that the drug actually behaves as an antagonist at those.[94] In dopamine reuptake, sertraline is more potent than bupropion.[95]

Despite being a more potent dopamine reuptake inhibitor than bupropion, it is still a much more potent inhibitor of serotonin—it is about 60 times more potent at inhibiting serotonin reuptake than it is at inhibiting dopamine reuptake.[96] Regardless, sertraline could be considered a serotonin-dopamine reuptake inhibitor.[97][non-primary source needed][citation needed]

Pharmacokinetics

Norsertraline, sertraline's chief active metabolite

Sertraline is absorbed slowly when taken orally, achieving its maximal concentration in the plasma 4–6 hours after ingestion. In the blood, it is 98.5% bound to plasma proteins. Its half-life in the body is 13–45 hours and, on average, is about 1.5 times longer in women (32 hours) than in men (22 hours), leading to a 1.5-times-higher exposure in women.[79] According to in vitro studies, sertraline is metabolized by multiple cytochrome 450 isoforms: CYP2D6, CYP2C9, CYP2B6, CYP2C19 and CYP3A4. It appeared unlikely that inhibition of any single isoform could cause clinically significant changes in sertraline pharmacokinetics.[2][98] No differences in sertraline pharmacokinetics were observed between people with high and low activity of CYP2D6;[99] however, poor CYP2C19 metabolizers had a 1.5-times-higher level of sertraline than normal metabolizers.[100] In vitro data also indicate that the inhibition of CYP2B6 should have even greater effect than the inhibition of CYP2C19, while the contribution of CYP2C9 and CYP3A4 to the metabolism of sertraline would be minor. These conclusions have not been verified in human studies.[2] Sertraline can be deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo.[2] The major metabolite of sertraline, desmethylsertraline, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible.[93]

Non-amine metabolites may also contribute to the antidepressant effects of this medication. Sertraline deaminated is O-2098, a compound that has been found to inhibit the dopamine reuptake transporter proteins in spite of its lack of a nitrogen atom.[101]

Its chief active metabolite is norsertraline (N-desmethylsertraline) which is significantly less biologically active than its parent compound.[102]

History

Skeletal formulae of chlorprothixene and tametraline, from which sertraline was derived

The history of sertraline dates back to the early 1970s, when Pfizer chemist Reinhard Sarges invented a novel series of psychoactive compounds based on the structures of neuroleptics chlorprothixene and thiothixene.[103][104] Further work on these compounds led to tametraline, a norepinephrine and weaker dopamine reuptake inhibitor. Development of tametraline was soon stopped because of undesired stimulant effects observed in animals. A few years later, in 1977, pharmacologist Kenneth 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 a number of potent norepinephrine and triple reuptake inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared stereoisomers of this compound, which were tested in vivo by animal behavioral scientist Albert Weissman. The most potent and selective (+)-isomer 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 discovery of the sertraline molecule was serendipitous. 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.[103][105][106]

Sertraline was approved by the U.S. Food and Drug Administration (FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in the United Kingdom the previous year.[107] The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression.

Sertraline entered the Australian market in 1994 and became the most often prescribed antidepressant in 1996 (2004 data).[108] It was measured as among the top ten drugs ranked by cost to the Australian government in 1998 and 2000–01, having cost $45 million and $87 million in subsidies respectively.[109][110] Sertraline is less popular in the UK (2003 data) and Canada (2006 data)—in both countries it was fifth (among drugs marketed for the treatment of MDD, or antidepressants), based on the number of prescriptions.[111][112]

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 obsessive-compulsive disorder (OCD). In 2003, the UK Medicines and Healthcare products Regulatory Agency issued a guidance that, apart from fluoxetine (Prozac), SSRIs are not suitable for the treatment of depression in patients under 18.[113][114] However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents.[115] In 2005, the FDA added a black box warning concerning pediatric suicidal behavior to all antidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidal behavior in young adults ages 18 to 24.[116]

Society and culture

The U.S. patent for Zoloft expired in 2006,[117] and sertraline is now available in generic form.

Brand names

Brand names include Zoloft, Lustral, Asentra among others.[1]

See also

References

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