Sertraline detailed information
Sertraline hydrochloride (trade names Zoloft, 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 clinical 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.
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. Sertraline is highly effective for the treatment of panic disorder, but cognitive behavioral therapy is a better treatment for obsessive-compulsive disorder, whether by itself or in combination with sertraline. Although approved for social phobia and posttraumatic stress disorder, sertraline leads to only modest improvement in these conditions. 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, it does not cause weight gain, and its effects on cognition are mild. 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 suicidality. Due to the rarity of this side effect, statistically significant data are difficult to obtain, and suicidality continues to be a subject of controversy.

# History
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. 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 typein 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.
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. The FDA committee achieved a consensus that sertraline was safe and effective for the treatment of 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. For example, 40% of participants dropped out of the trials, significantly decreasing their validity.
Sertraline entered the Australian market in 1994 and became the most often prescribed antidepressant in 1996 (2004 data). It was measured as among the top ten drugs ranked by cost to the Australian government in 1998 and 200001, having cost $45 million and $87 million in subsidies respectively. Sertraline is less popular in the UK (2003 data) and Canada (2006 data)in both countries it was fifth, based on the number of prescriptions.
Until 2003, 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 (trade nameTemplate:Ref label Prozac), SSRIs are not suitable for the treatment of depression in patients under 18. However, sertraline can still be used in the UK for the treatment of OCD in children and adolescents. In 2005, the FDA added a black box warning concerning pediatric suicidality to all antidepressants, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidality in young adults ages 18 to 24.
The U.S. patent for Zoloft expired in 2006, and sertraline is now available in generic form.

# Indications
Sertraline has been approved for the following indications: depression, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), panic disorder  and social phobia (social anxiety disorder).

## Depression
The original pre-marketing clinical trials demonstrated only weak-to-moderate efficacy of sertraline for depression. 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. Sertraline is effective for both severe depression and dysthymia, a milder and more chronic variety of depression. In several double-blind studies, sertraline was consistently more effective than placebo for dysthymia and comparable to imipramine (Tofranil) in that respect. 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. These results also held up in a two-year follow-up of sertraline-treated and interpersonal-therapy-treated groups.  In the treatment of depression accompanied by OCD, sertraline performed significantly better than desipramine (Norpramine) on the measures of both OCD and depression. Sertraline was equivalent to imipramine for the treatment of depression with co-morbid panic disorder, but it was better tolerated. 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.

### 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) and amitriptyline (Elavil). 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. However, there were more cases of nausea and sexual dysfunction in the sertraline group. 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.
A large and thorough double-blind study compared sertralineprescribed for chronic (longer than two years) depression or depression with dysthymiato 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 and the 16-week continuation phase. 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.  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.
TCAs as a group are considered to work better than selective serotonin reuptake inhibitors for melancholic depression and in inpatients, but not necessarily for simply more severe depression. 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. 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. 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.

### Comparison with other antidepressants
Comparative clinical trials demonstrated that sertraline's efficacy in depression is similar to that of moclobemide (Aurorix), nefazodone (Serzone), escitalopram (Lexapro), bupropion (Wellbutrin), citalopram (Celexa), fluvoxamine (Luvox), paroxetine (Paxil) and mirtazapine (Remeron). 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%). 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. The greatest advantage of sertraline over fluoxetine was seen among severely depressed and melancholic patients with low anxiety. Comparative studies of sertraline and venlafaxine (Effexor) found marginal differences in favor of venlafaxine or no differences.

### 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. 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. The authors were sharply criticized by Bernard Carroll, a one-time chairman of the  FDA Psychopharmacological Drugs Advisory Committee, 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."

## Obsessive-compulsive disorder
Placebo-controlled studies have demonstrated sertraline to be efficacious for the treatment of OCD in adults and children. It was better tolerated and, based on intention to treat analysis, performed better than the gold standard of OCD treatment clomipramine. Sertraline was also marginally more efficacious than fluoxetine (Prozac). If the patient did not respond to sertraline, increasing the dose to 250400 mg, higher than the maximum recommended, did not bring any additional benefits. The patients who responded to sertraline during a short-term trial sustained their improvement when the treatment continued for a year and longer. 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. More of the subjects who stopped taking sertraline, than of those who continued, subsequently dropped out of the study, mostly, due to worsening of the OCD symptoms and side effects, possibly withdrawal syndrome. 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. CBT alone was superior to sertraline in both adults and children; however, the best results were achieved using a combination of these treatments. A review mentions that sertraline can be used for the treatment of OCD co-morbid with Tourette syndrome; however, sertraline may cause exacerbation of tics in Tourette syndrome.

## 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 (50200 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. Sertraline was equally effective for men and women and for patients with or without agoraphobia. Previous unsuccessful treatment with benzodiazepines did not diminish its efficacy. However, the response rate was lower for the patients with more severe panic. Double-blind comparative studies found sertraline to have the same effect on panic disorder as paroxetine (Paxil) or the gold standard of panic disorder treatment alprazolam (Xanax). 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. 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. 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.

## Social phobia
Sertraline has been successfully used for the treatment of social phobia. 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. The response was higher among the patients with later onset, especially adult onset, of the disorder. 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. 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. 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.

## 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 5060% of cases treated with sertraline vs. 2030% 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. 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. 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. Taking sertraline only during the luteal phase, that is, the 1214 days before menses, was shown to work as well as continuous treatment. 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. The most recent (2006) trial findings indicate that continuous treatment with sub-therapeutic doses of sertraline (25 mg vs. usual 50100 mg) may both afford the highest effectiveness and minimize the side effects.

## 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, 5360% of the patients treated with sertraline were much or very much improved vs. 3238% for placebo. 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. 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. Longer-term treatment has been advocated in such cases.
Three-way (placebosertralinethird antidepressant) comparison trials of sertraline for PTSD found it to be better than placebo and equivalent to venlafaxine (Effexor) or citalopram (Celexa), and in a two-way comparison it had the same efficacy as nefazodone (Serzone). Sertraline was not effective for veterans with combat-related PTSD.

## 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, the other showed only marginal improvement of anxiety, and insignificant improvement of quality of life. Small double-blind studies of sertraline for eating disorders, such as binge eating disorder, night eating syndrome and bulimia nervosa indicated its effectiveness.
Although sertraline can be used for the treatment of premature ejaculation a comparative study found it to be inferior to another SSRI, paroxetine. A general disadvantage of SSRIs is that they require continuous daily treatment to delay ejaculation significantly. For the occasional "on-demand", a few hours before coitus, treatment, clomipramine gave better results than paroxetine in one study, while in another study both sertraline and clomipramine were indistinguishable from the pausesqueeze technique and inferior to paroxetine. 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, with on-demand sertraline, paroxetine or clomipramine, and with the pausesqueeze technique.
A small study suggested that sertraline may help some children and adolescents with refractory syncope. Subsequent case reports indicated that sertraline may itself cause syncope in adolescents and that sertraline treatment of syncope may make it more frequent.

# Adverse effects
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.
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). Those that most often resulted in interruption of the treatment were nausea (3%), diarrhea (2%) and insomnia (2%). Sertraline appears to be associated with microscopic colitis, a rare condition of unknown etiology.
Akathisiathat is, "inner tension, restlessness, and the inability to stay still"caused by sertraline was observed in 16% of patients in a case series. This and other reports 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. 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".
Over more than six months of sertraline therapy for depression, patients showed an insignificant weight increase of 0.1%. Similarly, a 30-month-long treatment with sertraline for OCD resulted in a mean weight gain of 1.5% (1 kg). 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, 36% 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.
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. 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 year as compared to healthy controls. 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.

## Birth defects and effects on breast-fed infants
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. 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). 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. 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.

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

## Suicidality
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 suicidality in the 1824 age group.
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 suicidality with a marginal statistical significance by 37% or 50% 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". The more complete data submitted later by the sertraline manufacturer Pfizer indicated increased suicidality. 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.

## 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. During the 58-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.  In a double-blind study of remitted panic disorder patients, abrupt discontinuation of sertraline treatment resulted in insomnia and dizziness (both 1617% vs. 4% for continuing treatment), although headache, depression and malaise did not increase significantly. 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.

# Mechanism of action
Sertraline is primarily a serotonin reuptake inhibitor (SRI). Therapeutic doses of sertraline (50200 mg/day) taken by patients for four weeks resulted in 8090% 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. Sertraline is also a dopamine reuptake inhibitor, with 1% of its SRI potency, and a sigma-1 receptor agonist with 5% of its SRI potency. Sertraline weakly blocks 1-adrenoreceptors with 110% of its SRI potency.

# Pharmacokinetics
Sertraline is absorbed slowly when taken by mouth, achieving its maximal concentration in the plasma 46 hours after ingestion. In the blood, it is 98.5% bound to plasma proteins. Its half-life in the body is 1345 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. 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. No differences in sertraline pharmacokinetics were observed between people with high and low activity of CYP2D6; however, poor CYP2C19 metabolizers had a 1.5-times-higher level of sertraline than normal metabolizers. 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. Sertraline can be deaminated in vitro by monoamine oxidases; however, this metabolic pathway has never been studied in vivo. The major metabolite of sertraline, desmethylsertraline, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible.

# Interactions
Sertraline is a moderate inhibitor of CYP2D6 and CYP2B6 in vitro. Accordingly, in human trials it caused increased blood levels of CYP2D6 substrates such as metoprolol (Lopressor, Toprol XL), dextromethorphan (Robitussin cough suppressant), desipramine (Norpramin), imipramine (Tofranil) and nortriptyline (Pamelor), as well as the CYP3A4/CYP2D6 substrate haloperidol (Haldol). 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. 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. Sertraline had a slight inhibitory effect on the metabolism of diazepam (Valium), tolbutamide (Orinase) and warfarin (Coumadin), which are CYP2C9 or CYP2C19 substrates; this effect was not considered to be clinically relevant. As expected from in vitro data, sertraline did not alter the human metabolism of the CYP3A4 substrates erythromycin, alprazolam (Xanax), carbamazepine (Tegretol), clonazepam (Klonopin), and terfenadine (Seldane); neither did it affect metabolism of the CYP1A2 substrate clozapine (Clozaril). Sertraline had no effect on the actions of digoxin (Lanoxin) and atenolol (Tenormin), which are not metabolized in the liver. Case reports suggest that taking sertraline with phenytoin (Dilantin) or zolpidem (Ambien) may induce sertraline metabolism and decrease its efficacy, and taking sertraline with lamotrigine (Lamictal) may increase the blood level of lamotrigine via an unknown mechanism. Clinical reports indicate that interaction between sertraline and the MAOIs isocarboxazid (Marplan) and tranylcypromine (Parnate) 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.

# Controversy
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". However, the FDA reacted promptly with a warning letter when a Zoloft advertisement omitted information about the risk of suicidality.
In the case of Regina vs Hawkins, an Australian criminal case from the state of New South Wales, Zoloft was described as an important factor in David Hawkins's killing in 1999 (through strangling) of his wife. Hawkins had been depressed, was prescribed 50 mg of Zoloft a day and on his first day of treatment took 250 mg. He claimed that on the night of the murder he could not sleep and was agitated, and that he had hallucinations during the attack on his wife. Several experts agreed that "Zoloft can cause agitation and a certain amount of disinhibition so that some individuals engage in aggressive or dangerous behaviours without due regard for the consequences and in a manner that is out of character for them" and that the prisoner's behavior was consistent with agitated depression further exacerbated by akathisia and toxic delirium that developed as a result of Zoloft overdose.  The court concluded that "it can be seen that the medical evidence strongly supports a conclusion that, but for the effects of the 250 milligrams of Zoloft he had taken, it is wholly unlikely that the prisoner would have committed the crime to which he has pleaded guilty. Furthermore, it is common ground that his having done such an act is quite foreign to his former life history, his personality and psychological make up. It was also wholly inconsistent with his love for his marriage partner of nearly fifty years."
In 2004, a Los Angeles nurse sued Pfizer as a private attorney general "on behalf of all California residents who have been misled about Zoloft", claiming the company covered up side effects. In 2005, the Los Angeles Superior Court dismissed the case and ordered the plaintiff to pay Pfizer's cost of the suit.

# Notes