Sertraline

Sertraline
"Lustral" redirects here. For the electronic music band, see Lustral (band).
Sertraline
Systematic (IUPAC) name
(1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine
Clinical data
Trade names Zoloft
AHFS/Drugs.com monograph
MedlinePlus a697048
Pregnancy cat. C
Legal status ℞ Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 44%
Protein binding 98.5%
Metabolism Hepatic (N-demethylation mainly by CYP2B6)[1]
Half-life Approximately 26 hours
Excretion Renal
Identifiers
CAS number 79617-96-2 YesY
ATC code N06AB06
PubChem CID 68617
DrugBank DB01104
ChemSpider 61881 YesY
UNII QUC7NX6WMB YesY
KEGG D02360 YesY
ChEBI CHEBI:9123 N
ChEMBL CHEMBL809 YesY
Chemical data
Formula C17H17Cl2N 
Mol. mass 306.229 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Sertraline hydrochloride (brand names Zoloft and Lustral) is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in both adults and children. In 2007, it was the most prescribed antidepressant on the U.S. retail market, with 29,652,000 prescriptions.[2]

The efficacy of sertraline for depression is similar to that of older tricyclic antidepressants, but its side effects are much less pronounced. Differences with newer antidepressants are subtler and also mostly confined to side effects. Evidence suggests that sertraline may work better than fluoxetine (Prozac) for some subtypes of depression.[3] Sertraline is highly effective for the treatment of panic disorder, but cognitive behavioral therapy in combination with sertraline is a better treatment for obsessive-compulsive disorder than sertraline alone.[4] Although approved for social phobia and posttraumatic stress disorder, sertraline leads to only modest improvement in these conditions.[5][6] Sertraline also alleviates the symptoms of premenstrual dysphoric disorder and can be used in sub-therapeutic doses or intermittently for its treatment.

Sertraline shares the common side effects and contraindications of other SSRIs, with high rates of nausea, diarrhea, insomnia, and sexual side effects; however, has relatively mild effects on both cognition and vigilance. The unique effect of sertraline on dopaminergic neurotransmission may be related to these favorable effects on cognition and vigilance.[7][8] In pregnant women taking sertraline, the drug was present in significant concentrations in fetal blood, and was also associated with a higher rate of various birth defects. Similarly to other antidepressants, the use of sertraline for depression may be associated with a higher rate of suicidal behavior. Due to the rarity of this side effect, statistically significant data are difficult to obtain, and suicidal behavior continues to be a subject of controversy.

Contents

Medical uses

Sertraline is used for a number of conditions including: major depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder and social phobia (social anxiety disorder).[9] It has also been used for premature ejaculation and vascular headaches but evidence of the effectiveness in treating those conditions is less robust.[9]

Depression

The original pre-marketing clinical trials demonstrated only weak-to-moderate efficacy of sertraline for depression.[10] Nevertheless, a considerable body of later research established it as one of the drugs of choice for the treatment of depression in outpatients. Despite the negative results of early trials, sertraline is often used to treat depressed inpatients as well.[11] Sertraline is effective for both severe depression[12] and dysthymia, a milder and more chronic variety of depression. In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia[13][14][15][16] and comparable to imipramine (Tofranil) in that respect.[14] Sertraline also improved the depression of dysthymic patients to a greater degree than group cognitive behavioral therapy or interpersonal psychotherapy, and adding psychotherapy to sertraline did not seem to enhance the outcome.[15][16] These results also held up in a two-year follow-up of sertraline-treated and interpersonal-therapy-treated groups.[17] In the treatment of depression accompanied by OCD, sertraline performed significantly better than desipramine (Norpramine) on the measures of both OCD and depression.[18] Sertraline was equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it was better tolerated.[19] Sertraline treatment of depressed patients with co-morbid personality disorders improved their personality traits, and this improvement was almost independent from the improvement of their depression.[20]

Comparison with tricyclic antidepressants

The effect of sertraline on the core symptoms of depression is similar to that of tricyclic antidepressants (TCAs); however, it is better tolerated and results in a better quality of life. Similar improvement of depression scores was seen in studies comparing sertraline with clomipramine (Anafranil)[12] and amitriptyline (Elavil).[21][22] At the same time, sertraline resulted in a much lower rate of side effects than amitriptyline (49%, vs. 72% for amitriptyline and 32% for placebo), particularly dry mouth, somnolence, constipation and increased appetite.[22] However, there were more cases of nausea and sexual dysfunction in the sertraline group.[21][22] Participants taking sertraline showed a greater improvement of the subjective quality of life on such measures as work satisfaction, subjective feeling, perceptions of health and cognitive function.[22]

A large and thorough double-blind study compared sertraline—prescribed for chronic (longer than two years) depression or depression with dysthymia—to the "gold standard" of depression treatment, the TCA imipramine (Tofranil). Sertraline was equivalent to imipramine for both of these indications during the first 12 weeks of the study[23][24][25] and the 16-week continuation phase.[26] Only 11% of patients on sertraline suffered from severe side effects vs. 24% on imipramine. Constipation, dizziness, tremor, dry mouth, micturition disorder and sweating were observed more often with imipramine, and diarrhea and insomnia with sertraline.[24] Patients on sertraline also reported significantly better social and physical functioning. The 30% of the patients treated with sertraline or imipramine who achieved a remission during the trial did not differ from the healthy population on the measures of marital, parental, physical and work functioning and were close to normal on social adjustment and other measures of interpersonal functioning.[25]

TCAs as a group are considered to work better than selective serotonin reuptake inhibitors for melancholic depression[27] and in inpatients,[28] but not necessarily for simply more severe depression.[29] 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.[12] 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.[30] A later open-label study of general practice patients, funded by Pfizer, found that sertraline had equal efficacy in melancholic vs. non-melancholic patients, as well as in previous TCA non-responders vs. all other patients.[31]

Comparison with other antidepressants

According to a meta-analysis of 12 new-generation antidepressants, 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.[32]

Comparative clinical trials demonstrated that sertraline's efficacy in depression is similar to that of moclobemide (Aurorix),[33] nefazodone (Serzone),[34] escitalopram (Lexapro),[35] bupropion (Wellbutrin),[36] citalopram (Celexa), fluvoxamine (Luvox), paroxetine (Paxil) and mirtazapine (Remeron).[37] Compared to patients on bupropion, those taking sertraline had much higher rates of sexual dysfunction (61% vs. 10% for men and 41% vs. 7% for women), nausea, diarrhea, somnolence and sweating, as well as a higher rate of discontinuation due to side effects (13% vs. 3%).[36] Meta-analysis by the independent Cochrane Collaboration indicated that sertraline is more effective for the treatment of depression than fluoxetine (Prozac), with a 1.4 times higher probability of response, and is possibly better tolerated.[38] The greatest advantage of sertraline over fluoxetine was seen among severely depressed and melancholic patients with low anxiety.[3] Comparative studies of sertraline and venlafaxine (Effexor) found marginal differences in favor of venlafaxine[39][40][41] or no differences.[42]

Depression in the 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.[43] 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.[44] The authors were sharply criticized by Bernard Carroll, a one-time chairman of the FDA Psychopharmacological Drugs Advisory Committee,[45] for presenting these results as positive: "The study has all the hallmarks of an 'experimercial,' a cost-is-no-object exercise driven by a corporate sponsor to create positive publicity for its product in a market niche. ... Thus does the corporate mandate to put lipstick on the pig prevail over the academic duty to communicate independent analyses of the data."[46]

Obsessive-compulsive disorder

Placebo-controlled studies have demonstrated sertraline to be efficacious for the treatment of OCD in adults and children.[47][48][49][50] It was better tolerated and, based on intention to treat analysis, performed better than the gold standard of OCD treatment clomipramine.[51] Sertraline was also marginally more efficacious than fluoxetine (Prozac).[52] It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression.[53] 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.[54] If the patient was completely non-responsive to the maximal recommended dose of sertraline (200 mg), further increasing the dose did not significantly improve the response rates. However, patients with a partial but incomplete response to sertraline at 200 mg did see a clinically significant reduction in symptoms, when the dose was titrated up to a maximum of 400 mg. Incidence of side effects at 400 mg was found to be comparable to 200 mg.[55]

The patients who responded to sertraline during a short-term trial sustained their improvement when the treatment continued for a year[56] and longer.[57] At the same time, the prolonged treatment may not be necessary for everyone. In a double-blind study, half of the subjects who had been successfully treated for a year were discontinued from sertraline. Only 48% of the patients in the discontinuation group were able to complete the study; however, these completers fared as well as the subjects who continued taking sertraline.[58]

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.[59][60] A review mentions that sertraline can be used for the treatment of OCD co-morbid with Tourette syndrome;[61] however, sertraline may cause exacerbation of tics in Tourette syndrome.[62]

Panic disorder

In four large 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 (50–200 mg). 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.[63][64] Sertraline was equally effective for men and women[64] and for patients with or without agoraphobia.[65] Previous unsuccessful treatment with benzodiazepines did not diminish its efficacy.[66] However, the response rate was lower for the patients with more severe panic.[65] Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine (Paxil)[67] or the gold standard of panic disorder treatment alprazolam (Xanax).[68] While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (clomipramine (Anafranil), imipramine (Tofranil), clonazepam (Klonopin), alprazolam, fluvoxamine (Luvox) and paroxetine) indicates approximate equivalence of these medications.[63] Although panic disorder is considered to be a chronic condition, continuous treatment may not be necessary for everyone. In a double-blind discontinuation trial, abruptly stopping sertraline after one year of successful treatment resulted in relapse of the disorder in 33% of the patients vs. 13% of those who continued taking sertraline over the following 28 weeks. The patients experienced distinct withdrawal syndrome, expressed primarily as insomnia and dizziness, and the authors noted that a significant part of the relapse rate among the discontinued patients could possibly be accounted for by the withdrawal syndrome.[69] Confirming these hypotheses, in another study, gradual discontinuation of sertraline after 12 weeks of treatment did not lead to the return of panic symptoms. In the same study, discontinuation of paroxetine caused exacerbation of panic in about a fifth of the previously responding patients. The authors attributed this difference to the more severe withdrawal syndrome with paroxetine, which even discontinuation over three weeks could not remedy.[67]

Social phobia

Sertraline has been successfully used for the treatment of social phobia (social anxiety disorder).[70] In a flexible dosing study, it appeared that a higher dose range was needed for adequate response. Furthermore, improvement was achieved slowly, separating from the placebo response only by week six, and continuing to increase until week 12.[71] The response was higher among the patients with later onset, especially adult onset, of the disorder.[5] Among the different rating scales, the clinician-rated global improvement demonstrated the highest difference vs. placebo, while the patient self-rated quality of life differed from placebo only modestly. The greatest improvement of quality of life was observed among the most impaired patients.[71] In addition to psychological components of social phobia, such as fear and avoidance, sertraline also ameliorated some physiological components, such as blushing and palpitations but not sweating and trembling.[72] In a four-way placebo-controlled comparison trial of sertraline and exposure therapy, sertraline performed significantly better than placebo, while the exposure therapy resulted in only marginal improvement. The combination of sertraline and exposure therapy was not significantly better than sertraline alone; however, it appeared that the response was achieved faster with the combined treatment.[73]

Premenstrual dysphoric disorder

According to several double-blind studies, 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.[74][75][76] Despite the well-known sexual side effects of sertraline, significantly higher improvement of sexual functioning was achieved by the sertraline group as compared to the placebo group.[77] A three-way comparison of sertraline, norepinephrine reuptake inhibitor tricyclic antidepressant desipramine, and placebo demonstrated the superiority of sertraline, while desipramine fared no better than placebo.[78] Taking sertraline only during the luteal phase, that is, the 12–14 days before menses, was shown to work as well as continuous treatment.[77][79][80] Although the luteal-phase treatment may be more acceptable to patients, there have been indications that by the end of a three-month period it is less well-tolerated than the continuous treatment. The study authors suggested that the continuous treatment may allow the tolerance to side effects of sertraline to develop faster.[77] The most recent (2006) trial findings indicate that continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50–100 mg) may both afford the highest effectiveness and minimize the side effects.[81]

Posttraumatic stress disorder

Two double-blind placebo-controlled studies confirmed the efficacy of sertraline for severe chronic PTSD in civilians, with the mean duration of the illness more than ten years. Physical or sexual assault was the traumatic event for more than 60% of the subjects, and 75% of them were women. Over the 12-week period, 53–60% of the patients treated with sertraline were much or very much improved vs. 32–38% for placebo.[6][82] The treatment was continued for another year with some participants from both trials. The condition of the responders further improved; some of the patients who did not respond to the initial 12-week trial slowly improved as well, so that about half of them were classified as responders by the end of the following 24 weeks. The authors noted that the medication worked more slowly for those with more severe symptoms.[83][84] Discontinuation of the successful treatment after six months resulted in the return of the PTSD symptoms in 52% of the patients vs. 16% in those who continued taking sertraline.[85] Longer-term treatment has been advocated in such cases.[84]

Three-way (placebo–sertraline–third antidepressant) comparison trials of sertraline for PTSD found it to be better than placebo and equivalent to venlafaxine (Effexor)[86] or citalopram (Celexa),[87] and in a two-way comparison it had the same efficacy as nefazodone (Serzone).[88] Sertraline was not effective for veterans with combat-related PTSD.[89][90]

Other indications

Two large placebo-controlled clinical trials of sertraline for generalized anxiety disorder have been conducted. While one trial demonstrated highly significant improvements on all measures used, including anxiety, depression and quality of life,[91] the other showed only marginal improvement of anxiety, and insignificant improvement of quality of life.[92] Small double-blind studies of sertraline for eating disorders, such as binge eating disorder,[93][94] night eating syndrome[95] and bulimia nervosa[96] indicated its effectiveness.

Although sertraline can be used for the treatment of premature ejaculation[97] a comparative study found it to be inferior to another SSRI, paroxetine.[98] A general disadvantage of SSRIs is that they require continuous daily treatment to delay ejaculation significantly.[99] For the occasional "on-demand", a few hours before coitus, treatment, clomipramine gave better results than paroxetine in one study,[100] while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine.[101] The most recent research, conducted in 2007, suggests that on-demand treatment with sildenafil (Viagra) offers a dramatic improvement in ejaculation delay and sexual satisfaction as compared with daily paroxetine,[102] with on-demand sertraline, paroxetine or clomipramine,[101] and with the pause–squeeze technique.[101][102]

A small study suggested that sertraline may help some children and adolescents with refractory syncope.[103] Subsequent case reports indicated that sertraline may itself cause syncope in adolescents[104] and that sertraline treatment of syncope may make it more frequent.[105][106]

Adverse effects

Zoloft 25 mg & 50 mg tablets (US)
Zoloft 100 mg tablets (SE)
Selectra 50 mg capsules (TR)

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.[107]

Among the common adverse effects associated with sertraline and listed in the prescribing information, those with the greatest difference from placebo are nausea (25% vs. 11% for placebo), ejaculation failure (14% vs. 1% for placebo), insomnia (21% vs. 11% for placebo), diarrhea (20% vs. 10% for placebo), dry mouth (14% vs. 8% for placebo), somnolence (13% vs. 7% for placebo), dizziness (12% vs. 7% for placebo), tremor (8% vs. 2% for placebo) and decreased libido (6% vs. 1% for placebo).[107] Those that most often resulted in interruption of the treatment were nausea (3%), diarrhea (2%) and insomnia (2%).[107] Sertraline appears to be associated with microscopic colitis, a rare condition of unknown etiology.[108]

Akathisia—that is, "inner tension, restlessness, and the inability to stay still"—caused by sertraline was observed in 16% of patients in a case series.[109] This and other reports[110][111][112] note that akathisia begins soon after the initiation of treatment or a dose increase; often, several hours after taking the medication. Akathisia usually disappears within several days after sertraline is stopped or its dose is decreased. In some cases, clinicians confused akathisia with anxiety and increased the dose of sertraline, causing further worsening of the patients' symptoms.[112] Experts note that because of the possible link of akathisia with suicide and the distress it causes to the patient, "it is of vital importance to increase awareness amongst staff and patients of the symptoms of this relatively common condition".[113][114]

Over more than six months of sertraline therapy for depression, patients showed an insignificant weight increase of 0.1%.[115] Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg).[116] 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%). Only 4.5% of the sertraline group 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.[116]

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.[117][118] 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.[119] 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.[120]

Overdosage

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.[121]

In 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 fetal exposure to sertraline and its metabolite is approximately a third of the maternal exposure.[122][123] 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.[124] 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.[125] 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.[126]

Sexual side effects

Like other SSRIs, sertraline is associated with sexual side effects, including 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.[127] While nefazodone (Serzone) and bupropion (Wellbutrin) did not have negative effects on sexual functioning, 67% of men on sertraline experienced ejaculation difficulties vs. 18% before the treatment[127] (or 61% vs. 0% according to another paper).[36] Similarly, in a group of women who initially did not have difficulties achieving orgasm, 41% acquired this problem during treatment with sertraline.[36] A 40% rate of orgasm dysfunction (vs. 9% for placebo) on sertraline was observed in a mixed group in another study.[128] 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 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.[128]

Genital anesthesia,[129] loss of or decreased response to sexual stimuli, and ejaculatory anhedonia are also possible. Although usually reversible, these sexual side effects can last for months or years after the drug has been completely withdrawn.[130] This is known as Post SSRI Sexual Dysfunction.

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 2-fold 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.[131][132][133]

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%[133] or 50%[132] 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".[132] The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidal behavior.[134] 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.[135][136]

Discontinuation syndrome

Main article: SSRI discontinuation syndrome

Abrupt interruption of sertraline treatment may result in withdrawal or discontinuation syndrome. This syndrome occurred in 60% of the remitted depressed patients taking sertraline in a blind discontinuation study, as compared to 14% of patients on fluoxetine and 66% of patients on paroxetine.[137] During the 5–8-day period when sertraline was temporarily replaced by placebo, the most frequent symptoms (reported by more than a quarter of patients) were irritability, agitation, dizziness, headache, nervousness, crying, emotional lability, bad dreams and anger. Around a third experienced mood worsening to the level generally associated with a major depressive episode.[137] In a double-blind study of remitted panic disorder patients, abrupt discontinuation of sertraline treatment resulted in insomnia and dizziness (both 16–17% vs. 4% for continuing treatment), although headache, depression and malaise did not increase significantly.[69] In another double-blind study of recovered panic disorder patients, the withdrawal syndrome was completely avoided when sertraline was gradually discontinued over three weeks, while patients stopping paroxetine treatment still suffered from it.[67]

Interactions

Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro.[138] 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.[139][140][141] 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.[142][143] 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.[144] Sertraline is often used in combination with stimulant medication for the treatment of co-morbid depression and/or anxiety in ADHD[145] Studies have shown there was an increase in the concentration of amphetamine in the brain in rats pretreated with 5 mg/kg sertraline. Sertraline has been shown to augment the locomotor stimulatory effect of amphetamine by decreasing the metabolism of amphetamine, perhaps via actions on cytochrome P450 isozymes.[146]

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.[142] 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.[107][138][142][147] Case reports suggest that taking sertraline with phenytoin or zolpidem may induce sertraline metabolism and decrease its efficacy,[148][149] and that taking sertraline with lamotrigine may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.[150]

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.[142]

Mechanism of action

Sertraline is primarily a serotonin reuptake inhibitor (SRI), with a binding affinity (Ki) of 3.3 nM.[151] Therapeutic doses of sertraline (50–200 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.[152]

Sertraline is also a dopamine reuptake inhibitor, with a Ki=315 nM,[153] a σ1 receptor agonist with 5% of its SRI potency,[154] and an α1-adrenoreceptor antagonist with 1–10% of its SRI potency.[151] However, though confirming sertraline's high affinity for σ1 receptors, different studies suggest that the drug actually behaves as an antagonist at those.[155]

Sertraline has shown antibacterial activity mainly against gram-positive bacteria.[156] Sertraline demonstrated anti-fungal activity against Candida species in vivo.[157]

Sertraline also inhibits dynamin 1 dependent endocytosis.[158]

Pharmacokinetics

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.[142] 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.[159][1] No differences in sertraline pharmacokinetics were observed between people with high and low activity of CYP2D6;[160] however, poor CYP2C19 metabolizers had a 1.5-times-higher level of sertraline than normal metabolizers.[161] 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.[1] Sertraline can be deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo.[1] The major metabolite of sertraline, desmethylsertraline, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible.[151]

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.[162]

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.[163][164] 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.[163][165][166]

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.[167] The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of major depression. During the discussion, Paul Leber, Director of the FDA Division of Neuropharmacological Drug Products, noted that granting approval was a "tough decision", since the treatment effect on outpatients with depression had been "modest to minimal". Other experts emphasized that the drug's effect on inpatients had not differed from placebo and criticized poor design of the trials by Pfizer.[168] For example, 40% of participants dropped out of the trials, significantly decreasing their validity.[169]

Sertraline entered the Australian market in 1994 and became the most often prescribed antidepressant in 1996 (2004 data).[170] 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.[171][172] 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.[173][174]

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.[175][176] However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents.[177] 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.[178]

The U.S. patent for Zoloft expired in 2006,[179] and sertraline is now available in generic form.

In 1999, Zoloft came under great public scrutiny after it was discovered that Eric Harris, one of the two shooters involved in the Columbine High School massacre, had been taking the drug before switching to Luvox. Many[who?] immediately pointed fingers at sertraline and fluvoxamine.

Controversy

Further information: Chemical imbalance and Biology of depression#Monoamine hypothesis

The brand-name form of sertraline, Zoloft, was advertised to consumers by Pfizer using the following wording: "While the cause is unknown, depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance. You just shouldn't have to feel this way anymore." An essay published in the journal PLoS Medicine noted that there is no scientific support for the "serotonin imbalance" theory of depression, and criticized Pfizer and manufacturers of other SSRIs for using it. When asked to comment on this apparent breach of federal regulations, the FDA answered that such "reductionist statements" are acceptable to explain the neurochemistry of depression "to the fraction of the public that functions at no higher than a 6th-grade reading level."[180] However, the FDA reacted promptly with a Warning Letter when a Zoloft advertisement omitted information about the risk of suicidal behavior.[181]

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  152. ^ Meyer JH, Wilson AA, Sagrati S, Hussey D, Carella A, Potter WZ, Ginovart N, Spencer EP, Cheok A, Houle S (2004). "Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study". The American Journal of Psychiatry 161 (5): 826–35. doi:10.1176/appi.ajp.161.5.826. PMID 15121647. 
  153. ^ Owens JM, Knight DL, Nemeroff CB (2002). "Second generation SSRIS: human monoamine transporter binding profile of escitalopram and R-fluoxetine". Encephale 28 (4): 350–5. PMID 12232544. 
  154. ^ Narita N, Hashimoto K, Tomitaka S, Minabe Y (1996). "Interactions of selective serotonin reuptake inhibitors with subtypes of sigma receptors in rat brain". Eur. J. Pharmacol. 307 (1): 117–9. doi:10.1016/0014-2999(96)00254-3. PMID 8831113. 
  155. ^ Hashimoto, K (2009). "Sigma-1 Receptors and Selective Serotonin Reuptake Inhibitors: Clinical Implications of their Relationship". Central Nervous System Agents in Medicinal Chemistry 2009 (Sept): 197–204.  [1]PDF
  156. ^ Mikrobiyol Bul. 2009 Oct;43(4):651-6.[Investigation of antibacterial activity of sertralin].[Article in Turkish]Coban AY, Tanriverdi Cayci Y, Keleş Uludağ S, Durupinar B. Source Ondokuz Mayis Universitesi Tip Fakültesi, Mikrobiyoloji ve Klinik Mikrobiyoloji Anabilim Dali, Samsun
  157. ^ FEMS Immunol Med Microbiol. 2003 Jan 21;35(1):11-5.Interaction of sertraline with Candida species selectively attenuates fungal virulence in vitro. Lass-Flörl C, Ledochowski M, Fuchs D, Speth C, Kacani L, Dierich MP, Fuchs A, Würzner R. Source Department of Hygiene and Social Medicine, University of Innsbruck, Fritz Pregl Str. 3, 6020 Innsbruck, Austria.
  158. ^ Takahashi, K; Miyoshi, H; Otomo, M; Osada, K; Yamaguchi, N; Nakashima, H (2010). "Suppression of dynamin GTPase activity by sertraline leads to inhibition of dynamin-dependent endocytosis". Biochemical and biophysical research communications 391 (1): 382–7. doi:10.1016/j.bbrc.2009.11.067. PMID 19913505. 
  159. ^ Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K (1999). "Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro". Drug Metab. Dispos. 27 (7): 763–6. PMID 10383917. 
  160. ^ Hamelin BA, Turgeon J, Vallée F, Bélanger PM, Paquet F, LeBel M (1996). "The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin". Clin. Pharmacol. Ther. 60 (5): 512–21. doi:10.1016/S0009-9236(96)90147-2. PMID 8941024. 
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  164. ^ Sarges R, Tretter JR, Tenen SS, Weissman A (1973). "5,8-Disubstituted 1-Aminotetralins. A Class of Compounds with a Novel Profile of Central Nervous System Activity". Journal of Medicinal Chemistry 16 (9): 1003–1011. doi:10.1021/jm00267a010. PMID 4795663. 
  165. ^ See also: Mullin R (2006). "ACS Award for Team Innovation". Chemical & Engineering News 84 (5): 45–52. doi:10.1021/cen-v084n010.p045. 
  166. ^ A short blurb on the history of sertraline, see: Couzin J (2005). "The brains behind blockbusters". Science 309 (5735): 728. doi:10.1126/science.309.5735.728. PMID 16051786. 
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  • Sertraline — Général Nom IUPAC (1S,4S) 4 (3,4 dichlorophényl) N méthyl 1,2,3,4 tétrahydronaphthalén 1 amine …   Wikipédia en Français

  • sertraline — noun Etymology: perhaps from serotonin + tetrahydro (combined with four atoms of hydrogen) + naphthalene + amine Date: 1983 an antidepressant drug C17H17NCl2 administered in the form of its hydrochloride and acting to enhance serotonin activity …   New Collegiate Dictionary

  • sertraline — ser·tra·line (sərʹtrə lēn ) n. An oral antidepressant that enhances serotonin activity by inhibiting its uptake by neurons of the central nervous system.   [serotonin + tetra + naphthalene + amine.] * * * …   Universalium

  • sertraline — noun An SSRI antidepressant, marketed as Zoloft …   Wiktionary

  • sertraline — An antidepressant which exhibits selectivity for the blockade of serotonin reuptake; similar to fluoxetine. * * * ser·tra·line sər trə .lēn n an antidepressant drug that functions as an SSRI and is administered orally in the form of its… …   Medical dictionary

  • sertraline — n. an antidepressant drug that acts by prolonging the action of the neurotransmitter serotonin (5 hydroxytryptamine) in the brain (see SSRI). It is taken by mouth for the treatment of depression and obsessive–compulsive disorder; side effects may …   The new mediacal dictionary

  • sertraline — A drug used to treat depression. It is a type of selective serotonin reuptake inhibitor (SSRI). Also called Zoloft …   English dictionary of cancer terms

  • sertraline — noun a selective serotonin reuptake inhibitor commonly prescribed as an antidepressant (trade name Zoloft) • Syn: ↑Zoloft • Usage Domain: ↑trade name (for: ↑Zoloft) • Hypernyms: ↑selective sero …   Useful english dictionary

  • sertraline hydrochloride — ser·tra·line hy·dro·chlo·ride (surґtrə lēn) a selective serotonin reuptake inhibitor, used to treat depressive, obsessive compulsive, and panic disorders; administered orally …   Medical dictionary

  • 79617-96-2 — Sertraline Sertraline Général No CAS …   Wikipédia en Français

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