Sertraline hydrochloride (brand names
Zoloft and
Lustral) is an
antidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
of the
selective serotonin reuptake inhibitor Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
(SSRI) class. It was introduced to the market by
PfizerPfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as
obsessive–compulsiveObsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
,
panicPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
, and
social anxiety disorderSocial anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...
s 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 antidepressantTricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s, 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
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac) for some subtypes of depression. 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. Although approved for
social phobiaSocial anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...
and posttraumatic stress disorder, sertraline leads to only modest improvement in these conditions. Sertraline also alleviates the symptoms of
premenstrual dysphoric disorderPremenstrual dysphoric disorder is a severe form of premenstrual syndrome, afflicting 3% to 8% of women. It is a diagnosis associated primarily with the luteal phase of the menstrual cycle...
and can be used in sub-therapeutic doses or intermittently for its treatment.
Sertraline shares the common side effects and
contraindicationIn medicine, a contraindication is a condition or factor that serves as a reason to withhold a certain medical treatment.Some contraindications are absolute, meaning that there are no reasonable circumstances for undertaking a course of action...
s of other SSRIs, with high rates of nausea, diarrhea, insomnia, and sexual side effects; however, has relatively mild effects on both
cognitionIn science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
and
vigilanceIn modern psychology, vigilance, also termed sustained attention, is defined as the ability to maintain attention and alertness over prolonged periods of time. The study of vigilance has expanded since the 1940s mainly due to the increased interaction of people with machines for applications...
. The unique effect of sertraline on
dopaminergicDopaminergic means related to the neurotransmitter dopamine. For example, certain proteins such as the dopamine transporter , vesicular monoamine transporter 2 , and dopamine receptors can be classified as dopaminergic, and neurons which synthesize or contain dopamine and synapses with dopamine...
neurotransmissionNeurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
may be related to these favorable effects on cognition and vigilance. 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 defectA congenital anomaly is a condition which is present at the time of birth which varies from the standard presentation....
s. 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 significantIn statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
data are difficult to obtain, and suicidal behavior continues to be a subject of controversy.
Medical uses
Sertraline is used for a number of conditions including: major depression,
obsessive-compulsive disorderObsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
(OCD), posttraumatic stress disorder (PTSD),
premenstrual dysphoric disorderPremenstrual dysphoric disorder is a severe form of premenstrual syndrome, afflicting 3% to 8% of women. It is a diagnosis associated primarily with the luteal phase of the menstrual cycle...
(PMDD),
panic disorderPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
and social phobia (
social anxiety disorderSocial anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...
). It has also been used for
premature ejaculationPremature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....
and vascular headaches but evidence of the effectiveness in treating those conditions is less robust.
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
placeboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
for dysthymia and comparable to
imipramineImipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
(Tofranil) in that respect. Sertraline also improved the depression of dysthymic patients to a greater degree than group cognitive behavioral therapy or
interpersonal psychotherapyInterpersonal Psychotherapy is a time-limited psychotherapy that focuses on the interpersonal context and on building interpersonal skills. IPT is based on the belief that interpersonal factors may contribute heavily to psychological problems. It is commonly distinguished from other forms of...
, 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
OCDObsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
, sertraline performed
significantlyIn statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
better than
desipramineDesipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
(Norpramine) on the measures of both OCD and depression. Sertraline was equivalent to imipramine for the treatment of depression with co-morbid
panic disorderPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
, but it was better tolerated. Sertraline treatment of depressed patients with co-morbid
personality disorderPersonality disorders, formerly referred to as character disorders, are a class of personality types and behaviors. Personality disorders are noted on Axis II of the Diagnostic and Statistical Manual of Mental Disorders or DSM-IV-TR of the American Psychiatric Association.Personality disorders are...
s 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 antidepressantTricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s (TCAs); however, it is better tolerated and results in a better
quality of lifeThe term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
. Similar improvement of depression scores was seen in studies comparing sertraline with
clomipramineClomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
(Anafranil) and
amitriptylineAmitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
(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
placeboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
), particularly dry mouth, somnolence, constipation and increased appetite. However, there were more cases of nausea and
sexual dysfunctionSexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
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 sertraline—prescribed for chronic (longer than two years) depression or depression with
dysthymia—to the "gold standard" of depression treatment, the TCA
imipramineImipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
(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 functioningAn interpersonal relationship is an association between two or more people that may range from fleeting to enduring. This association may be based on limerence, love, solidarity, regular business interactions, or some other type of social commitment. Interpersonal relationships are formed in the...
.
TCAs as a group are considered to work better than
selective serotonin reuptake inhibitor Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s for
melancholic depressionMelancholic depression, or 'depression with melancholic features' is a subtype of major depression characterized by major depressive disorder with the following specific features: anhedonia , severe weight loss, psychomotor agitation or retardation, insomnia with early morning awakenings, guilt...
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-labelAn open-label trial or open trial is a type of clinical trial in which both the researchers and participants know which treatment is being administered....
study of general practice patients, funded by
PfizerPfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
, 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
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.
ReboxetineReboxetine is a drug marketed as an antidepressant for use in the treatment of clinical depression, panic disorder and ADD/ADHD, developed by Pharmacia . Its mesylate salt is sold under tradenames including Edronax, Norebox, Prolift, Solvex, Davedax or Vestra...
was significantly worse.
Comparative clinical trials demonstrated that sertraline's efficacy in depression is similar to that of
moclobemideMoclobemide is a monoamine oxidase inhibitor drug primarily used to treat depression and social anxiety. Although clinical trials with the medicine began in 1977, it is not approved for use in the United States...
(Aurorix),
nefazodoneNefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
(Serzone),
escitalopramEscitalopram is an antidepressant of the selective serotonin reuptake inhibitor class. It is approved by the U.S...
(Lexapro),
bupropionBupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
(Wellbutrin),
citalopramCitalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa),
fluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
(Luvox),
paroxetineParoxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil) and
mirtazapineMirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
(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-analysisIn statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
by the independent
Cochrane CollaborationThe Cochrane Collaboration is a group of over 28,000 volunteers in more than 100 countries who review the effects of health care interventions tested in biomedical randomized controlled trials. A few more recent reviews have also studied the results of non-randomized, observational studies...
indicated that sertraline is more effective for the treatment of depression than
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(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
melancholicMelancholic depression, or 'depression with melancholic features' is a subtype of major depression characterized by major depressive disorder with the following specific features: anhedonia , severe weight loss, psychomotor agitation or retardation, insomnia with early morning awakenings, guilt...
patients with low anxiety. Comparative studies of sertraline and
venlafaxineVenlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(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
placeboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
and comparable to another SSRI fluoxetine, and TCAs amitriptyline,
nortriptylineNortriptyline is a second-generation tricyclic antidepressant marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis...
(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 significantIn statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
(that is, unlikely to occur by chance), but clinically very modest improvement in depression and no improvement in
quality of lifeThe term quality of life is used to evaluate the general well-being of individuals and societies. The term is used in a wide range of contexts, including the fields of international development, healthcare, and politics. Quality of life should not be confused with the concept of standard of...
. 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 analysisIn epidemiology, an intention to treat analysis is an analysis based on the initial treatment intent, not on the treatment eventually administered. ITT analysis is intended to avoid various misleading artifacts that can arise in intervention research...
, performed better than the gold standard of OCD treatment
clomipramineClomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
. Sertraline was also marginally more efficacious than
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac). It is generally accepted that the sertraline dosages necessary for the effective treatment of OCD are higher than the usual dosage for depression. 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. 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.
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. 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.
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. A review mentions that sertraline can be used for the treatment of OCD co-morbid with
Tourette syndromeTourette syndrome is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical tics and at least one vocal tic; these tics characteristically wax and wane...
; 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
placeboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
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. Sertraline was equally effective for men and women and for patients with or without
agoraphobiaAgoraphobia is an anxiety disorder defined as a morbid fear of having a panic attack or panic-like symptoms in a situation from which it is perceived to be difficult to escape. These situations can include, but are not limited to, wide-open spaces, crowds, or uncontrolled social conditions...
. Previous unsuccessful treatment with
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s 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
paroxetineParoxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(Paxil) or the gold standard of panic disorder treatment
alprazolamAlprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
(Xanax). While imprecise, comparison of the results of trials of sertraline with separate trials of other anti-panic agents (
clomipramineClomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
(Anafranil),
imipramineImipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
(Tofranil),
clonazepamClonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
(Klonopin), alprazolam,
fluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
(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 (
social anxiety disorderSocial anxiety disorder , also known as social phobia, is an anxiety disorder characterized by intense fear in social situations causing considerable distress and impaired ability to function in at least some parts of daily life...
). 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
PMDDPremenstrual dysphoric disorder is a severe form of premenstrual syndrome, afflicting 3% to 8% of women. It is a diagnosis associated primarily with the luteal phase of the menstrual cycle...
, 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. Despite the well-known sexual side effects of sertraline, significantly higher improvement of
sexual functionSexual function is a model developed at the Karolinska Institute in Stockholm, Sweden, defining different aspects of the assessment of sexual dysfunction comprises the following components....
ing was achieved by the sertraline group as compared to the placebo group. A three-way comparison of sertraline,
norepinephrine reuptake inhibitorA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
tricyclic antidepressantTricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
desipramineDesipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
, and placebo demonstrated the superiority of sertraline, while desipramine fared no better than placebo. Taking sertraline only during the
luteal phaseThe luteal phase is the latter phase of the menstrual cycle or the estrous cycle . It begins with the formation of the corpus luteum and ends in either pregnancy or luteolysis...
, that is, the 12–14 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 50–100 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, 53–60% of the patients treated with sertraline were much or very much improved vs. 32–38% 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 (placebo–sertraline–third antidepressant) comparison trials of sertraline for PTSD found it to be better than placebo and equivalent to
venlafaxineVenlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
(Effexor) or
citalopramCitalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa), and in a two-way comparison it had the same efficacy as
nefazodoneNefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
(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 disorderEating disorders refer to a group of conditions defined by abnormal eating habits that may involve either insufficient or excessive food intake to the detriment of an individual's physical and mental health. Bulimia nervosa, anorexia nervosa, and binge eating disorder are the most common specific...
s, such as
binge eating disorderBinge eating disorder is the most common eating disorder in the United States affecting 3.5% of females and 2% of males and is prevalent in up to 30% of those seeking weight loss treatment...
,
night eating syndromeNight eating syndrome, or NES, is an emerging eating disorder diagnosis, which primarily characterizes an ongoing, persistent pattern of late-night binge eating....
and
bulimia nervosaBulimia nervosa is an eating disorder characterized by binge eating and purging or consuming a large amount of food in a short amount of time, followed by an attempt to rid oneself of the food consumed, usually by purging and/or by laxative, diuretics or excessive exercise. Bulimia nervosa is...
indicated its effectiveness.
Although sertraline can be used for the treatment of
premature ejaculationPremature ejaculation is a condition in which a man ejaculates earlier than he or his partner would like him to. Premature ejaculation is also known as rapid ejaculation, rapid climax, premature climax, or early ejaculation....
a comparative study found it to be inferior to another SSRI,
paroxetineParoxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
. 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,
clomipramineClomipramine is a tricyclic antidepressant . It was developed in the 1960s by the Swiss drug manufacturer Geigy and has been in clinical use worldwide ever since.- Indications :...
gave better results than paroxetine in one study, while in another study both sertraline and clomipramine were indistinguishable from the pause–squeeze technique and inferior to paroxetine. The most recent research, conducted in 2007, suggests that on-demand treatment with
sildenafilSildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
(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 pause–squeeze technique.
A small study suggested that sertraline may help some children and adolescents with refractory
syncopeA vasovagal episode or vasovagal response or vasovagal attack is a malaise mediated by the vagus nerve. When it leads to syncope or "fainting", it is called a vasovagal syncope, which is the most common type of fainting.There are a number of different syncope syndromes which all fall under the...
. 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 inhibitorMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
s or the
antipsychoticAn antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
pimozidePimozide is an antipsychotic drug of the diphenylbutylpiperidine class. It was discovered at Janssen Pharmaceutica in 1963. It has a high potency compared to chlorpromazine . On a weight basis it is even more potent than haloperidol. It also has special neurologic indications for Tourette syndrome...
(Orap). Sertraline concentrate contains alcohol, and is therefore contraindicated with
disulfiramDisulfiram is a drug discovered in the 1920s and used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals...
(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
placeboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
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),
somnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(13% vs. 7% for placebo), dizziness (12% vs. 7% for placebo), tremor (8% vs. 2% for placebo) and decreased
libidoLibido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
(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 colitisMicroscopic colitis refers to two medical conditions which cause diarrhea: collagenous colitis and lymphocytic colitis. Both conditions are characterised by the following triad of clinicopathological features:# Chronic watery diarrhoea;# Normal colonoscopy;...
, a rare condition of unknown
etiologyEtiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
.
AkathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
—that is, "inner tension, restlessness, and the inability to stay still"—caused by sertraline was observed in 16% of patients in a
case seriesA case series is a medical research descriptive study that tracks patients with a known exposure given similar treatment or examines their medical records for exposure and outcome. It can be retrospective or prospective and usually involves a smaller number of patients than more powerful...
. 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
anxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
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 significanceIn statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
, the weight gain was lower for
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac) (1%) but higher for
citalopramCitalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
(Celexa),
fluvoxamineFluvoxamine is an antidepressant which functions as a selective serotonin reuptake inhibitor . Fluvoxamine was first approved by the U.S. Food and Drug Administration in 1993 for the treatment of obsessive compulsive disorder . Fluvoxamine CR is approved to treat social anxiety disorder...
(Luvox) and
paroxetineParoxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
(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.
Over a two-week treatment of healthy volunteers, sertraline slightly improved verbal
fluencyFluency is the property of a person or of a system that delivers information quickly and with expertise.-Speech:...
but did not affect word learning,
short-term memoryShort-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...
,
vigilanceAlertness is the state of paying close and continuous attention, being watchful and prompt to meet danger or emergency, or being quick to perceive and act. It is related to psychology as well as to physiology...
,
flicker fusion timeThe flicker fusion threshold is a concept in the psychophysics of vision. It is defined as the frequency at which an intermittent light stimulus appears to be completely steady to the observer...
, choice reaction time,
memory spanIn psychology and neuroscience, memory span is the longest list of items that a person can repeat back in correct order immediately after presentation on 50% of all trials. Items may include words, numbers, or letters. The task is known as digit span when numbers are used. Memory span is a common...
, or
psychomotor coordinationthumb|right|Motor coordination is shown in this animated sequence by [[Eadweard Muybridge]] of himself throwing a diskMotor coordination is the combination of body movements created with the kinematic and kinetic parameters that result in intended actions. Such movements usually smoothly and...
. 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. 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.
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.
In pregnancy and lactation
The studies comparing the levels of sertraline and its principal
metaboliteMetabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...
,
desmethylsertralineDesmethylsertraline is an active metabolite of the antidepressant drug sertraline. Like sertraline, desmethylsertraline functions as a selective serotonin reuptake inhibitor , and is responsible for some of its parent's therapeutic benefits....
, 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:
omphaloceleAn omphalocele is a type of abdominal wall defect in which the intestines, liver, and occasionally other organs remain outside of the abdomen in a sac because of a defect in the development of the muscles of the abdominal wall.-Presentation:The sac, which is formed from an outpouching of...
(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. 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 plasmaBlood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
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
serotoninSerotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
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
nefazodoneNefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
(Serzone) and
bupropionBupropion is an atypical antidepressant and smoking cessation aid. The drug is a non-tricyclic antidepressant and differs from most commonly prescribed antidepressants such as SSRIs, as its primary pharmacological action is thought to be norepinephrine-dopamine reuptake inhibition...
(Wellbutrin) 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 dysfunctionAnorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
(vs. 9% for placebo) on sertraline was observed in a mixed group in another study.
Sexual arousalSexual arousal, or sexual excitement, is the arousal of sexual desire, during or in anticipation of sexual activity. Things that precipitate human sexual arousal are called erotic stimuli, or colloquially known as turn-ons. There are many potential stimuli, both physical or mental, which can cause...
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.
Genital anesthesia, 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. This is known as
Post SSRI Sexual DysfunctionPost-SSRI sexual dysfunction is a name given to a reported iatrogenic sexual dysfunction caused by the previous use of selective serotonin reuptake inhibitor antidepressants. While apparently uncommon, it can last for months, years, or sometimes indefinitely after the discontinuation of SSRIs. ...
.
Suicide
The FDA requires all antidepressants, including sertraline, to carry a
black box warningIn the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
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.
Suicidal ideationSuicidal ideation is a common medical term for thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself. Although most people who undergo suicidal ideation do not commit suicide, some go on to make suicide attempts...
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% 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 suicidal behavior. Similarly, the analysis conducted by the UK
MHRAThe Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
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 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. 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. 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
paroxetineParoxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
treatment still suffered from it.
Interactions
Sertraline is a moderate
inhibitorAn enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...
of
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
and
CYP2B6Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...
in vitro. Accordingly, in human trials it caused increased blood levels of CYP2D6
substratesIn biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
such as
metoprololMetoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
,
dextromethorphanDextromethorphan is an antitussive drug. It is one of the active ingredients in many over-the-counter cold and cough medicines, such as Robitussin, NyQuil, Dimetapp, Vicks, Coricidin, Delsym, and others, including generic labels. Dextromethorphan has also found other uses in medicine, ranging...
,
desipramineDesipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
,
imipramineImipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
and
nortriptylineNortriptyline is a second-generation tricyclic antidepressant marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis...
, as well as the
CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
/
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
substrate
haloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
. 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
methadoneMethadone is a synthetic opioid, used medically as an analgesic and a maintenance anti-addictive for use in patients with opioid dependency. It was developed in Germany in 1937...
caused a 40% increase in blood levels of the latter, which is primarily metabolized by CYP2B6. Sertraline is often used in combination with
stimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
medication for the treatment of co-morbid depression and/or anxiety in ADHD Studies have shown there was an increase in the concentration of
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
in the brain in rats pretreated with 5 mg/kg sertraline. Sertraline has been shown to augment the locomotor stimulatory effect of
amphetamineAmphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...
by decreasing the metabolism of amphetamine, perhaps via actions on cytochrome P450 isozymes.
Sertraline had a slight inhibitory effect on the metabolism of
diazepamDiazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
,
tolbutamideTolbutamide is a first generation potassium channel blocker, sulfonylurea oral hypoglycemic drug sold under the brand name Orinase. This drug may be used in the management of type II diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by the pancreas...
and
warfarinWarfarin is an anticoagulant. It is most likely to be the drug popularly referred to as a "blood thinner," yet this is a misnomer, since it does not affect the thickness or viscosity of blood...
, which are
CYP2C9Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
or
CYP2C19Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
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
erythromycinErythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
,
alprazolamAlprazolam is a short-acting anxiolytic of the benzodiazepine class of psychoactive drugs. Alprazolam, like other benzodiazepines, binds to specific sites on the GABAA gamma-amino-butyric acid receptor...
,
carbamazepineCarbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
,
clonazepamClonazepamis a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe...
, and
terfenadineTerfenadine is an antihistamine formerly used for the treatment of allergic conditions. It was brought to market by Hoechst Marion Roussel and marketed under various brand names including Seldane in the United States, Triludan in the United Kingdom, and Teldane in Australia...
; neither did it affect metabolism of the
CYP1A2Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
substrate
clozapineClozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
.
Sertraline had no effect on the actions of
digoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
and
atenolol, which are not metabolized in the liver.
Case reportIn medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrence....
s suggest that taking sertraline with
phenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
or
zolpidemZolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...
may induce sertraline metabolism and decrease its efficacy, and that taking sertraline with
lamotrigineLamotrigine, marketed in the US and most of Europe as Lamictal by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used as an adjunct in treating depression, though this is considered off-label usage...
may increase the blood level of lamotrigine, possibly by inhibition of glucuronidation.
Clinical reports indicate that interaction between sertraline and the
MAOIsMonoamine oxidase inhibitors are a class of antidepressant drugs prescribed for the treatment of depression. They are particularly effective in treating atypical depression....
isocarboxazidIsocarboxazid is an irreversible and nonselective monoamine oxidase inhibitor of the hydrazine chemical class used as an antidepressant and anxiolytic...
and
tranylcypromineTranylcypromine is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor —it is a non-selective and irreversible inhibitor of the enzyme monoamine oxidase...
may cause
serotonin syndromeSerotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
. In a placebo-controlled study in which sertraline was co-administered with
lithiumLithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...
, 35% of the subjects experienced tremors, while none of those taking placebo did.
Mechanism of action
Sertraline is primarily a serotonin reuptake inhibitor (SRI), with a binding affinity (K
i) of 3.3 nM. Therapeutic doses of sertraline (50–200 mg/day) taken by patients for four weeks resulted in 80–90% inhibition of
serotonin transporterThe serotonin transporter is a monoamine transporter protein.This protein is an integral membrane protein that transports the neurotransmitter serotonin from synaptic spaces into presynaptic neurons. This transport of serotonin by the SERT protein terminates the action of serotonin and recycles it...
(SERT) in
striatumThe striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
as measured by
positron emission tomographyPositron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
. A daily 9 mg dose was sufficient to inhibit 50% of SERT.
Sertraline is also a
dopamine reuptake inhibitorA dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
, with a K
i=315 nM, a
σ1 receptorThe sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum that modulates calcium signaling through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene....
agonistAn agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
with 5% of its SRI potency, and an
α1-adrenoreceptor antagonistAlpha-1 blockers constitute a variety of drugs which block α1-adrenergic receptors in arteries and smooth muscles.-Pharmacology:...
with 1–10% of its SRI potency. However, though confirming sertraline's high affinity for
σ1 receptorsThe sigma-1 receptor is a chaperone protein at the endoplasmatic reticulum that modulates calcium signaling through the IP3 receptor. In humans, the sigma-1 receptor is encoded by the SIGMAR1 gene....
, different studies suggest that the drug actually behaves as an
antagonistAn antagonist is a character, group of characters, or institution, that represents the opposition against which the protagonist must contend...
at those.
Sertraline has shown antibacterial activity mainly against gram-positive bacteria. Sertraline demonstrated anti-fungal activity against Candida species in vivo.
Sertraline also inhibits dynamin 1 dependent
endocytosisEndocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
.
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 proteinsA drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ...
. 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. According to
in vitroIn vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
studies, sertraline is metabolized by multiple cytochrome 450 isoforms:
CYP2D6Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
,
CYP2C9Cytochrome P450 2C9 is a protein that in humans is encoded by the CYP2C9 gene.- Function :CYP2C9 is an important cytochrome P450 enzyme with a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes...
,
CYP2B6Cytochrome P450 2B6 is an enzyme that in humans is encoded by the CYP2B6 gene. CYP2B6 is a member of the Cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances.- Function :...
,
CYP2C19Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
and
CYP3A4Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. 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
metabolismMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
of sertraline would be minor. These conclusions have not been verified in human studies. Sertraline can be
deaminatedDeamination is the removal of an amine group from a molecule. Enzymes which catalyse this reaction are called deaminases.In the human body, deamination takes place primarily in the liver, however glutamate is also deaminated in the kidneys. Deamination is the process by which amino acids are...
in vitro by
monoamine oxidaseL-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
s; however, this
metabolic pathwayIn biochemistry, metabolic pathways are series of chemical reactions occurring within a cell. In each pathway, a principal chemical is modified by a series of chemical reactions. Enzymes catalyze these reactions, and often require dietary minerals, vitamins, and other cofactors in order to function...
has never been studied
in vivo. The major metabolite of sertraline,
desmethylsertralineDesmethylsertraline is an active metabolite of the antidepressant drug sertraline. Like sertraline, desmethylsertraline functions as a selective serotonin reuptake inhibitor , and is responsible for some of its parent's therapeutic benefits....
, is about 50 times weaker as a serotonin transporter inhibitor than sertraline and its clinical effect is negligible.
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.
History
The history of sertraline dates back to the early 1970s, when
PfizerPfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
chemist Reinhard Sarges invented a novel series of psychoactive compounds based on the structures of neuroleptics
chlorprothixeneChlorprothixene is a typical antipsychotic drug of the thioxanthene class and was the first of the series to be synthesized...
and
thiothixeneThiothixene is a typical antipsychotic drug of the thioxanthene class used in the treatment of psychoses like schizophrenia. It was introduced on July 24, 1967 by Pfizer.-Chemistry:*Bloom, B. M.; Muren, J. F.; 1967, See also:...
. Further work on these compounds led to
tametralineTametraline is the parent of a series of chemical compounds investigated at Pfizer that eventually led to the development of sertraline .Sertraline has been called "3,4-dichloro tametraline"...
, a
norepinephrineA norepinephrine reuptake inhibitor or adrenergic reuptake inhibitor , is a type of drug which acts as a reuptake inhibitor for the neurotransmitters norepinephrine and epinephrine by blocking the action of the norepinephrine transporter...
and weaker
dopamine reuptake inhibitorA dopamine reuptake inhibitor is a type of drug that acts as a reuptake inhibitor for the neurotransmitter dopamine by blocking the action of the dopamine transporter...
. Development of tametraline was soon stopped because of undesired
stimulantStimulants are psychoactive drugs which induce temporary improvements in either mental or physical function or both. Examples of these kinds of effects may include enhanced alertness, wakefulness, and locomotion, among others...
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 reuptakeA serotonin–norepinephrine–dopamine reuptake inhibitor , or triple reuptake inhibitor , is a drug that acts simultaneously as a reuptake inhibitor for the monoamine neurotransmitters, serotonin , norepinephrine and dopamine , by blocking the action of the serotonin transporter , norepinephrine...
inhibitors, but to the surprise of the scientists, one representative of the generally inactive cis-analogs was a serotonin reuptake inhibitor. Welch then prepared
stereoisomersStereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms , but that differ only in the three-dimensional orientations of their atoms in space. This contrasts with structural isomers, which share the same molecular formula, but the bond connections...
of this compound, which were tested
in vivoIn vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...
by animal
behavioral scientistThe term behavioural sciences encompasses all the disciplines that explore the activities of and interactions among organisms in the natural world. It involves the systematic analysis and investigation of human and animal behaviour through controlled and naturalistic observation, and disciplined...
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.
Sertraline was approved by the U.S.
Food and Drug AdministrationThe Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) in 1991 based on the recommendation of the Psychopharmacological Drugs Advisory Committee; it had already become available in
the United KingdomThe United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
the previous year. 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
placeboA placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
and criticized poor design of the trials by Pfizer. For example, 40% of participants dropped out of the trials, significantly decreasing their
validityIn logic, argument is valid if and only if its conclusion is entailed by its premises, a formula is valid if and only if it is true under every interpretation, and an argument form is valid if and only if every argument of that logical form is valid....
.
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 2000–01, 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 (among drugs marketed for the treatment of MDD, or antidepressants), based on the number of prescriptions.
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 disorderObsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
(OCD). In 2003, the UK
Medicines and Healthcare products Regulatory AgencyThe Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
issued a guidance that, apart from
fluoxetineFluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(Prozac),
SSRIs Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
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 warningIn the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
concerning pediatric suicidal behavior to all
antidepressantAn antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
s, including sertraline. In 2007, labeling was again changed to add a warning regarding suicidal behavior in young adults ages 18 to 24.
The U.S. patent for Zoloft expired in 2006, and sertraline is now available in
genericA generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
form.
In 1999, Zoloft came under great public scrutiny after it was discovered that
Eric HarrisEric David Harris and Dylan Bennet Klebold were American high school seniors who committed the Columbine High School massacre. They killed 13 people—including teacher Dave Sanders—and injured 24 others, three of whom were injured as they escaped the attack...
, one of the two shooters involved in the
Columbine High School massacreThe Columbine High School massacre occurred on Tuesday, April 20, 1999, at Columbine High School in Columbine, an unincorporated area of Jefferson County, Colorado, United States, near Denver and Littleton. Two senior students, Eric Harris and Dylan Klebold, embarked on a massacre, killing 12...
, had been taking the drug before switching to Luvox. Many immediately pointed fingers at sertraline and fluvoxamine.
Controversy
The brand-name form of sertraline, Zoloft, was
advertised to consumersDirect-to-consumer advertising usually refers to the marketing of pharmaceutical products but can apply in other areas as well. This form of advertising is directed toward patients, rather than healthcare professionals. The Food and Drug Administration holds responsibility of regulating DTC...
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 MedicinePLoS Medicine is a peer-reviewed medical journal covering the full spectrum of the medical sciences. It began operation on October 19, 2004. It was the second journal of the Public Library of Science , a non-profit open-access publisher. All content in PLoS Medicine is published under the Creative...
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 LetterThe United States Food and Drug Adminstration defines a Warning Letter as "...a correspondence that notifies regulated industry about violations that FDA has documented during its inspections or investigations...
when a Zoloft advertisement omitted information about the risk of suicidal behavior.
External links