Major Depressive Disorder
Sertraline is used in the treatment of major depressive disorder. A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks). According to DSM-IV criteria, a major depressive episode includes at least 5 of the following 9 symptoms (with at least one of the symptoms being either depressed mood or loss of interest or pleasure): depressed mood most of the day as indicated by subjective report (e.g., feels sad or empty) or observation made by others; markedly diminished interest or pleasure in all, or almost all, activities most of the day; significant weight loss (when not dieting) or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite; insomnia or hypersomnia; psychomotor agitation or retardation (observable by others, not merely subjective feelings of restlessness or being slowed down); fatigue or loss of energy; feelings of worthlessness or excessive or inappropriate guilt (not merely self-reproach or guilt about being sick); diminished ability to think or concentrate or indecisiveness (either by subjective account or as observed by others); and recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or specific plan for committing suicide.
Treatment of major depressive disorder generally consists of an acute phase (to induce remission), a continuation phase (to preserve remission), and a maintenance phase (to prevent recurrence). Various interventions (e.g., psychotherapy, antidepressant drug therapy, electroconvulsive therapy [ECT]) are used alone or in combination to treat major depressive episodes. Treatment should be individualized and the most appropriate strategy for a particular patient is determined by clinical factors such as severity of depression (e.g., mild, moderate, severe), presence or absence of certain psychiatric features (e.g., suicide risk, catatonia, psychotic or atypical features, alcohol or substance abuse or dependence, panic or other anxiety disorder, cognitive dysfunction, dysthymia, personality disorder, seasonal affective disorder), and concurrent illness (e.g., asthma, cardiac disease, dementia, seizure disorder, glaucoma, hypertension). Demographic and psychosocial factors as well as patient preference also are used to determine the most effective treatment strategy.
While use of psychotherapy alone may be considered as an initial treatment strategy for patients with mild to moderate major depressive disorder (based on patient preference and presence of clinical features such as psychosocial stressors), combined use of antidepressant drug therapy and psychotherapy may be useful for initial treatment of patients with moderate to severe major depressive disorder with psychosocial issues, interpersonal problems, or a comorbid axis II disorder. In addition, combined use of antidepressant drug therapy and psychotherapy may be beneficial in patients who have a history of poor compliance or only partial response to adequate trials of either antidepressant drug therapy or psychotherapy alone.
Antidepressant drug therapy can be used alone for initial treatment of patients with mild major depressive disorder (if preferred by the patient) and usually is indicated alone or in combination with psychotherapy for initial treatment of patients with moderate to severe major depressive disorder (unless ECT is planned). ECT is not generally used for initial treatment of uncomplicated major depression, but is recommended as first-line treatment for severe major depressive disorder when it is coupled with psychotic features, catatonic stupor, severe suicidality, food refusal leading to nutritional compromise, or other situations when a rapid antidepressant response is required. ECT also is recommended for patients who have previously shown a positive response or a preference for this treatment modality and can be considered for patients with moderate or severe depression who have not responded to or cannot receive antidepressant drug therapy. In certain situations involving depressed patients unresponsive to adequate trials of several individual antidepressant agents, adjunctive therapy with another agent (e.g., buspirone, lithium) or concomitant use of a second antidepressant agent (e.g., bupropion) has been used; however, such combination therapy is associated with an increased risk of adverse reactions, may require dosage adjustments, and (if not contraindicated) should be undertaken only after careful consideration of the relative risks and benefits.
(See Drug Interactions: Serotonergic Drugs, Drug Interactions: Tricyclic and Other Antidepressants, and Drug Interactions: Lithium.)
The efficacy of sertraline for the acute treatment of major depression has been established by 2 placebo-controlled studies in adult outpatients who met DSM-III criteria for major depression. In the first study of 8 weeks' duration, sertraline was administered with flexible dosing in a range of 50-200 mg daily; the mean daily dosage for patients completing the study was 145 mg daily. In the second study of 6 weeks' duration, sertraline was administered in fixed doses of 50, 100, and 200 mg daily. Overall, these 2 studies demonstrated that sertraline was superior to placebo in improving scores on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement Scales. However, the second study was not readily interpretable regarding whether there was a dose-response relationship for the drug's efficacy.
In a third study, depressed outpatients who had responded by the end of an initial 8-week open treatment phase to sertraline 50-200 mg daily were randomized to continue sertraline in the same dosage range or placebo for 44 weeks in a double-blind manner. The mean daily dosage of sertraline in those who completed this long-term study was 70 mg daily, and the relapse rate in the sertraline-treated patients was substantially lower than in those who received placebo.
An analysis of these 3 controlled studies for possible gender-related effects on treatment outcome did not suggest any difference in efficacy based on the gender of the patient.
While the optimum duration of sertraline therapy has not been established, many experts state that acute depressive episodes require several months or longer of sustained antidepressant therapy. In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression). The efficacy of sertraline in maintaining an antidepressant response for up to 1 year without increased toxicity has been demonstrated in a controlled setting. The manufacturers state that the usefulness of the drug in patients receiving prolonged therapy should be reevaluated periodically.
(See Dosage and Administration: Dosage.)
The manufacturers state that the drug's antidepressant efficacy in hospital settings has not been adequately studied to date.
As with certain other antidepressants, the possibility that sertraline may precipitate hypomanic or manic attacks in patients with bipolar or other major affective disorder should be considered. Sertraline is not approved for use in treating bipolar depression in adults.
Considerations in Choosing an Antidepressant
A variety of antidepressant drugs is available for the treatment of major depressive disorder, including selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs; e.g., desvenlafaxine, duloxetine, venlafaxine), tricyclic antidepressants (e.g., amitriptyline, amoxapine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trimipramine), monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine), and other antidepressants (e.g., bupropion, maprotiline, nefazodone, trazodone, vilazodone). Most clinical studies have shown that the antidepressant effect of usual dosages of sertraline in patients with depression is greater than that of placebo and comparable to that of usual dosages of tricyclic antidepressants (e.g., amitriptyline), other SSRIs (e.g., fluoxetine), and other antidepressants (e.g., nefazodone). In geriatric patients with major depression, sertraline appears to be as effective as amitriptyline. The onset of action of sertraline appears to be comparable to that of tricyclic antidepressants.
In general, response rates in patients with major depression are similar for currently available antidepressants, and the choice of antidepressant agent for a given patient depends principally on other factors such as potential adverse effects, safety or tolerability of these adverse effects in the individual patient, psychiatric and medical history, patient or family history of response to specific therapies, patient preference, quantity and quality of available clinical data, cost, and relative acute overdose safety. No single antidepressant can be recommended as optimal for all patients because of substantial heterogeneity in individual responses and in the nature, likelihood, and severity of adverse effects. In addition, patients vary in the degree to which certain adverse effects and other inconveniences of drug therapy (e.g., cost, dietary restrictions) affect their preferences.
In the large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) effectiveness trial, patients with major depressive disorder who did not respond to or could not tolerate therapy with one SSRI (citalopram) were randomized to switch to extended-release (''sustained-release'') bupropion, sertraline, or extended-release venlafaxine as a second step of treatment (level 2). Remission rates as assessed by the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Quick Inventory of Depressive Symptomatology--Self Report (QIDS-SR-16) were approximately 21 and 26% for extended-release bupropion, 18 and 27% for sertraline, and 25 and 25% for extended-release venlafaxine therapy, respectively; response rates as assessed by the QIDS-SR-16 were 26, 27, and 28% for extended-release bupropion, sertraline, and extended-release venlafaxine therapy, respectively. These results suggest that after unsuccessful initial treatment of depressed patients with an SSRI, approximately 25% of patients will achieve remission after therapy is switched to another antidepressant and that either another SSRI (e.g., sertraline) or an agent from another class (e.g., bupropion, venlafaxine) may be reasonable alternative antidepressants in patients not responding to initial SSRI therapy.
Patient Tolerance Considerations
Because of differences in the adverse effect profile between SSRIs and tricyclic antidepressants, particularly less frequent anticholinergic effects, cardiovascular effects, and weight gain with SSRIs, these drugs may be preferred in patients in whom such effects are not tolerated or are of potential concern. The decreased incidence of anticholinergic effects associated with sertraline and other SSRIs compared with tricyclic antidepressants is a potential advantage, since such effects may result in discontinuance of the drug early during therapy in unusually sensitive patients. In addition, some anticholinergic effects may become troublesome during long-term tricyclic antidepressant therapy (e.g., persistent dry mouth may result in tooth decay). Although SSRIs share the same overall tolerability profile, certain patients may tolerate one drug in this class better than another. In an open study, most patients who had discontinued fluoxetine therapy because of adverse effects subsequently tolerated sertraline therapy. Antidepressants other than SSRIs may be preferred in patients in whom certain adverse GI effects (e.g., nausea, anorexia), nervous system effects (e.g., anxiety, nervousness, insomnia), and/or weight loss are not tolerated or are of concern, since such effects appear to occur more frequently with this class of drugs.
The clinical presentation of depression in children and adolescents can differ from that in adults and generally varies with the age and developmental stages of the child. Younger children may exhibit behavioral problems such as social withdrawal, aggressive behavior, apathy, sleep disruption, and weight loss; adolescents may present with somatic complaints, self esteem problems, rebelliousness, poor performance in school, or a pattern of engaging in risky or aggressive behavior.
Only limited data are available to date from controlled clinical studies evaluating various antidepressant agents in children and adolescents, and many of these studies have methodologic limitations (e.g., nonrandomized or uncontrolled, small sample size, short duration, nonspecific inclusion criteria). However, there is some evidence that the response to antidepressants in pediatric patients may differ from that seen in adults, and caution should be used in extrapolating data from adult studies when making treatment decisions for pediatric patients. Results of several studies evaluating tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) in preadolescent and adolescent patients with major depression indicate a lack of overall efficacy in this age group. Based on the lack of efficacy data regarding use of tricyclic antidepressants and MAO inhibitors in pediatric patients and because of the potential for life-threatening adverse effects associated with the use of these drugs, many experts consider selective serotonin-reuptake inhibitors, including sertraline, the drugs of choice when antidepressant therapy is indicated for the treatment of major depressive disorder in children and adolescents. However, the US Food and Drug Administration (FDA) states that, while efficacy of fluoxetine has been established in pediatric patients, efficacy of other newer antidepressants (i.e., sertraline, citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, mirtazapine, nefazodone, paroxetine, venlafaxine) was not conclusively established in clinical trials in pediatric patients with major depressive disorder. In addition, FDA now warns that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders.
(See Cautions: Pediatric Precautions.)FDA currently states that anyone considering using an antidepressant in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need. (See Cautions: Precautions and Contraindications.)
The response to antidepressants in depressed geriatric patients without dementia is similar to that reported in younger adults, but depression in geriatric patients often is not recognized and is not treated. In geriatric patients with major depressive disorder, selective serotonin-reuptake inhibitors (SSRIs) appear to be as effective as tricyclic antidepressants (e.g., amitriptyline) but generally are associated with fewer overall adverse effects than these other agents. Geriatric patients appear to be especially sensitive to anticholinergic (e.g., dry mouth, constipation, vision disturbance), cardiovascular, orthostatic hypotensive, and sedative effects of tricyclic antidepressants. The low incidence of anticholinergic effects associated with sertraline and other SSRIs compared with tricyclic antidepressants also is a potential advantage in geriatric patients, since such effects (e.g., constipation, dry mouth, confusion, memory impairment) may be particularly troublesome in these patients. However, SSRI therapy may be associated with other troublesome adverse effects (e.g., nausea and vomiting, agitation and akathisia, parkinsonian adverse effects, sexual dysfunction, weight loss, hyponatremia). Some clinicians state that SSRIs such as sertraline may be preferred for treating depression in geriatric patients in whom the orthostatic hypotension associated with many antidepressants (e.g., tricyclics) potentially may result in injuries (such as severe falls). However, despite the fewer cardiovascular and anticholinergic effects associated with SSRIs, these drugs did not show any advantage over tricyclic antidepressants with regard to hip fracture in a case-control study. In addition, there was little difference in the rates of falls between nursing home residents receiving SSRIs and those receiving tricyclic antidepressants in a retrospective study. Therefore, all geriatric individuals receiving either type of antidepressant should be considered at increased risk of falls and appropriate measures should be taken. In addition, clinicians prescribing SSRIs in geriatric patients should be aware of the many possible drug interactions associated with these drugs, including those involving metabolism of the drugs through the cytochrome P-450 system.
(See Drug Interactions.)
Patients with dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia) often present with depressive symptoms, such as depressed mood, appetite loss, insomnia, fatigue, irritability, and agitation. Most experts recommend that patients with dementia of the Alzheimer's type who present with clinically important and persistent depressive symptoms be considered as candidates for pharmacotherapy even if they fail to meet the criteria for a major depressive syndrome. The goals of such therapy are to improve mood, functional status (e.g., cognition), and quality of life. Treatment of depression also may reduce other neuropsychiatric symptoms associated with depression in patients with dementia, including aggression, anxiety, apathy, and psychosis. Although patients may present with depressed mood alone, the possibility of more extensive depressive symptomatology should be considered. Therefore, patients should be evaluated and monitored carefully for indices of major depression, suicidal ideation, and neurovegetative signs since safety measures (e.g., hospitalization for suicidality) and more vigorous and aggressive therapy (e.g., relatively high dosages, multiple drug trials) may be needed in some patients.
Although placebo-controlled trials of antidepressants in depressed patients with concurrent dementia have shown mixed results, the available evidence and experience with the use of antidepressants in patients with dementia of the Alzheimer's type and associated depressive manifestations indicate that depressive symptoms (including depressed mood alone and with neurovegetative changes) in such patients are responsive to antidepressant therapy. In some patients, cognitive deficits may partially or fully resolve during antidepressant therapy, but the extent of response will be limited to the degree of cognitive impairment that is directly related to depression. SSRIs such as sertraline, citalopram, escitalopram, fluoxetine, or paroxetine are generally considered as first-line agents in the treatment of depressed patients with dementia since they are better tolerated than some other antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors). Some possible alternative agents to SSRIs include bupropion, mirtazapine, and venlafaxine. Some geriatric patients with dementia and depression may be unable to tolerate the antidepressant dosages needed to achieve full remission. When a rapid antidepressant response is not critical, some experts therefore recommend a very gradual dosage increase to increase the likelihood that a therapeutic dosage of the SSRI or other antidepressant will be reached and tolerated. In a randomized, placebo-controlled study in a limited number of patients with major depression and Alzheimer's disease, sertraline was found to be superior to placebo; depression reduction in this study was accompanied by lessened behavior disturbance and improved activities of daily living but not improved cognition.
The relatively low incidence of adverse cardiovascular effects, including orthostatic hypotension and conduction disturbances, associated with sertraline and most other SSRIs may be advantageous in patients in whom the cardiovascular effects associated with tricyclic antidepressants may be hazardous. Patients with a recent history of myocardial infarction or unstable cardiovascular disease were excluded from premarketing clinical studies with sertraline. However, the cardiovascular safety of sertraline (50-200 mg daily for 24 weeks; mean dosage of 89 mg daily) was evaluated in a postmarketing, double-blind, placebo-controlled study in adult outpatients with major depressive disorder and a recent history of myocardial infarction or unstable angina pectoris requiring hospitalization but who were otherwise free of life-threatening medical conditions. When therapy was initiated during the acute phase of recovery (within 30 days after a myocardial infarction or hospitalization for unstable angina), sertraline therapy did not differ from placebo on the following cardiovascular end points at week 16: left ventricular ejection fraction and total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, chronic heart failure, myocardial infarction, tachycardia, bradycardia, blood pressure changes). Although not statistically significant, approximately 20% fewer major cardiovascular events involving death or requiring hospitalization (e.g., for myocardial infarction, chronic heart failure, stroke, angina) occurred in the sertraline-treated patients compared with those receiving placebo.
(See Cautions: Cardiovascular Effectsand also see Cautions: Precautions and Contraindications.)
Because sertraline and other SSRIs are generally less sedating than some other antidepressants (e.g., tricyclics), some clinicians state that these drugs may be preferable in patients who do not require the sedative effects associated with many antidepressant agents; however, an antidepressant with more prominent sedative effects (e.g., trazodone) may be preferable in certain patients (e.g., those with insomnia).
Suicidal Risk Considerations
Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidal thinking and behavior (suicidality) in certain patients during the early phases of treatment. FDA states that antidepressants increased the risk of suicidality in short-term studies in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.
(See Cautions: Pediatric Precautions.)An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older. It currently is unknown whether the suicidality risk extends to longer-term antidepressant use (i.e., beyond several months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with major depressive disorder that antidepressants can delay the recurrence of depression. Because the risk of suicidality in depressed patients may persist until substantial remission of depression occurs, appropriate monitoring and close observation of all patients who are receiving antidepressant therapy is recommended. (See Cautions: Precautions and Contraindications.)
Sertraline has been effective in patients with moderate to severe depression.
In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) level 2 trial, patients with major depressive disorder who did not respond to or could not tolerate therapy with citalopram (another SSRI) were randomized to receive either extended-release (''sustained-release'') bupropion or buspirone therapy in addition to citalopram. Although both extended-release bupropion and buspirone were found to produce similar remission rates, extended-release bupropion produced a greater reduction in the number and severity of symptoms and a lower rate of drug discontinuance than buspirone in this large-scale, effectiveness trial. These results suggest that augmentation of SSRI therapy with extended-release bupropion may be useful in some patients with refractory depression.
Sertraline has been effective in patients with depression and concurrent human immunodeficiency virus (HIV) infection and depression with anxiety.
In a double-blind, placebo-controlled study, both sertraline and imipramine were found to be more effective than placebo in reducing the depressive symptoms and improving psychosocial functioning in patients with dysthymia without concurrent major depression; moreover, fewer patients treated with sertraline than those treated with imipramine or placebo discontinued therapy because of adverse effects. The results of several other studies, both controlled and uncontrolled, also suggest that sertraline may be effective in patients with dysthymia. Because dysthymia is a chronic condition and requires prolonged antidepressant therapy, the good tolerability demonstrated in clinical studies to date may be advantageous. Sertraline also has been used in the treatment of anger attacks associated with atypical depression and dysthymia in a limited number of patients.
Sertraline is used in the treatment of obsessive-compulsive disorder when the obsessions or compulsions cause marked distress, are time consuming (take longer than 1 hour daily), or interfere substantially with the patient's normal routine, occupational or academic functioning, or usual social activities or relationships. Obsessions are recurrent and persistent ideas, thoughts, impulses, or images that, at some time during the disturbance, are experienced as intrusive and inappropriate (i.e., ''ego dystonic'') and that cause marked anxiety or distress but that are not simply excessive worries about real-life problems. Compulsions are repetitive, intentional behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) performed in response to an obsession or according to rules that must be applied rigidly (e.g., in a stereotyped fashion). Although the behaviors or acts are aimed at preventing or reducing distress or preventing some dreaded event or situation, they either are not connected in a realistic manner with what they are designed to neutralize or prevent or are clearly excessive. At some time during the course of the disturbance, the patient, if an adult, recognizes that the obsessions or compulsions are excessive or unreasonable; children may not make such a recognition.
The efficacy of sertraline for the management of obsessive-compulsive disorder has been established in several multicenter, placebo-controlled studies, including one study of 8 weeks' duration and 2 studies of 12 weeks' duration in adults and one study of 12 weeks' duration in children and adolescents 6-17 years of age. Patients in these studies had moderate to severe obsessive-compulsive disorder with mean baseline total scores on the Yale-Brown Obsessive-Compulsive Scale (YBOCS) of 23-25 in adults and 22 in children and adolescents (measured in the Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]). In the 8-week study with flexible dosing, adult patients received sertraline in dosages ranging from 50-200 mg daily; the mean dosage for those completing the study was 186 mg daily. Total scores on the YBOCS decreased by an average of approximately 4 points in sertraline-treated patients and 2 points in patients receiving placebo; this difference was statistically significant.
In a fixed-dose study of 12 weeks' duration involving sertraline dosages of 50, 100, and 200 mg daily, adult patients receiving 50 and 200 mg of the drug daily experienced substantially greater reductions in the YBOCS total score than those receiving placebo (approximately 6 to approximately 3 points, respectively). In a 12-week study with flexible dosing in the range of 50-200 mg daily, the mean sertraline dosage in adult patients completing the study was 185 mg daily. YBOCS total scores in the sertraline-treated patients were reduced by a mean of approximately 7 points, which was better than the mean reduction of approximately 4 points reported in the placebo-treated patients.
In a 12-week study with flexible dosing, sertraline therapy was initiated at dosages of 25 or 50 mg daily in children 6-12 years of age or adolescents 13-17 years of age, respectively. Subsequent dosage was titrated according to individual tolerance over the first 4 weeks to a maximum dosage of 200 mg daily; the mean dosage for those completing the study was 178 mg daily. The drug produced substantially greater reductions in scores in the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), the National Institute of Mental Health Global Obsessive-Compulsive Scale (NIMH-OC), and the Clinical Global Impressions (CGI) Improvement Scale; total scores on the CY-BOCS decreased by an average of approximately 7 units in sertraline-treated patients and 3 units in patients receiving placebo. An analysis of these controlled studies for possible age- and gender-related effects on treatment outcome did not suggest any difference in efficacy based on either the age or gender of the patient.
In addition, in an uncontrolled 6-week study with flexible dosing (50-200 mg daily) in children or adolescents 6-17 years of age with obsessive-compulsive disorder or major depression, those with a diagnosis of obsessive-compulsive disorder had mean baseline total scores on the CY-BOCS, NIMH-OC, and CGI of about 24.9, 10.2, and 5.2, respectively. Sertraline produced substantial reductions in all 3 of the scales; total scores on CY-BOCS, NIMH-OC, and CGI decreased to 12.9, 6.7, and 3.4, respectively. In another uncontrolled, 6-week study employing a sertraline dosage that was escalated from 25 to 200 mg daily over 3 weeks, the drug combined with behavioral therapy was effective in a limited number of adolescents 13-17 years of age with obsessive-compulsive disorder refractory to other therapies; total scores on the CY-BOCS at the end of the study decreased by 11 points (from 25.4 to 14.4).
Results from comparative studies to date suggest sertraline and other selective serotonin-reuptake inhibitors (SSRIs; e.g., fluoxetine, fluvoxamine, paroxetine) are as effective or somewhat less effective than clomipramine and more effective than tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline) in the management of obsessive-compulsive disorder. In a pooled analysis of separate short-term (10-13 weeks) studies comparing clomipramine, fluoxetine, fluvoxamine, or sertraline with placebo, clomipramine was calculated as being more effective (as determined by measures on the YBOC scale) than SSRIs, although all drugs were superior to placebo. Like clomipramine, SSRIs reduce but do not completely eliminate obsessions and compulsions.
Many clinicians consider an SSRI (e.g., sertraline, fluoxetine, fluvoxamine, paroxetine) or clomipramine to be the drugs of choice for the pharmacologic treatment of obsessive-compulsive disorder. The decision whether to initiate therapy with an SSRI or clomipramine often is made based on the adverse effect profile of these drugs. For example, some clinicians prefer clomipramine in patients who may not tolerate the adverse effect profile of SSRIs (nausea, headache, overstimulation, sleep disturbances) while SSRIs may be useful alternatives in patients unable to tolerate the adverse effects (anticholinergic effects, cardiovascular effects, sedation) associated with clomipramine therapy. Consideration of individual patient characteristics (age, concurrent medical conditions), pharmacokinetics of the drug, potential drug interactions, and cost of therapy may also influence clinicians when selecting between SSRIs and clomipramine as first-line therapy in patients with obsessive-compulsive disorder. Although not clearly established, it has been suggested that the mechanism of action of sertraline and other potent serotonin-reuptake inhibitors (e.g., clomipramine, fluoxetine, fluvoxamine, paroxetine) used in the management of obsessive-compulsive disorder may be related to their serotonergic activity.
Sertraline is used in the treatment of panic disorder with or without agoraphobia. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a clinically important change in behavior related to the attacks.
According to DSM-IV, panic disorder is characterized by recurrent unexpected panic attacks, which consist of a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: palpitations, pounding heart, or accelerated heart rate; sweating; trembling or shaking; sensations of shortness of breath or smothering; feeling of choking; chest pain or discomfort; nausea or abdominal distress; feeling dizzy, unsteady, lightheaded, or faint; derealization (feelings of unreality) or depersonalization (being detached from oneself); fear of losing control; fear of dying; paresthesias (numbness or tingling sensations); and chills or hot flushes.
The efficacy of sertraline for the management of panic disorder has been established by 3 double-blind, placebo-controlled studies in adult outpatients who met DSM-III-R criteria for panic disorder with or without agoraphobia. The first 2 studies were of 10 weeks' duration and used a flexible dosing schedule. Sertraline therapy was initiated in a dosage of 25 mg daily for the first week and then dosage was escalated to 50-200 mg daily depending on clinical response and tolerability. The mean sertraline dosages for completers were 131 and 144 mg daily for the first 2 studies. Overall, these 2 studies demonstrated that sertraline was superior to placebo in decreasing the frequency of panic attacks and in improving scores on the Clinical Global Impression Severity of Illness and Global Improvement Scales. The difference between sertraline and placebo in reduction in the number of full panic attacks per week compared with baseline was approximately 2 in both studies.
The third study was a fixed-dose study of 12 weeks' duration. Sertraline was given in dosages of 50, 100, and 200 mg daily. The patients receiving sertraline demonstrated a substantially greater reduction in panic attack frequency than patients receiving placebo. However, the results of this study were not readily interpretable regarding a dose-response relationship for efficacy in this condition.
An analysis of these 3 controlled studies for possible age-, race-, or gender-related effects on treatment outcome did not suggest any difference in efficacy based on these patient characteristics.
Panic disorder can be treated with cognitive and behavioral psychotherapy and/or pharmacologic therapy. There are several classes of drugs that appear to be effective in the pharmacologic management of panic disorder, including tricyclic antidepressants, MAO inhibitors (e.g., phenelzine), selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, paroxetine, sertraline), and benzodiazepines (e.g., alprazolam, clonazepam). When choosing among the available drugs, clinicians should consider their acceptance and tolerability by patients; their ability to reduce or eliminate panic attacks, reduce clinically important anxiety and disability secondary to phobic avoidance, and ameliorate other common comorbid conditions (such as depression); and their ability to prevent relapse during long-term therapy. Because of their better tolerability when compared with other agents (such as the tricyclic antidepressants and benzodiazepines), the lack of physical dependence problems commonly associated with benzodiazepines, and efficacy in panic disorder with comorbid conditions (e.g., depression, other anxiety disorders such as obsessive-compulsive disorder, alcoholism), many clinicians prefer SSRIs as first-line therapy in the management of panic disorder. If SSRI therapy is ineffective or not tolerated, use of a tricyclic antidepressant or a benzodiazepine is recommended.
Sertraline has improved chronic idiopathic urticaria associated with panic disorder in at least one patient, but further study is needed to determine whether serotonin is involved in the pathogenesis of urticaria and whether SSRIs are effective in this condition.
Posttraumatic Stress Disorder
Sertraline is used in the treatment of posttraumatic stress disorder (PTSD). PTSD is an anxiety disorder that involves the development of certain characteristic symptoms following personal exposure to an extreme traumatic stressor. According to DSM-IV, PTSD requires exposure to a traumatic event(s) that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and the response to the event must involve intense fear, helplessness, or horror (in children the response may be expressed by disorganized or agitated behavior). PTSD is characterized by persistent symptoms of reexperiencing the trauma (e.g., intrusive distressing recollections of the event; recurrent distressing dreams of the event; acting or feeling as if the event were recurring including illusions, hallucinations, or flashbacks; intense distress at exposure to internal or external cues that symbolize or resemble an aspect of the event; physiologic reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the event), persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (e.g., efforts to avoid thoughts, feelings, or conversations related to the event; efforts to avoid activities, places, or people that arouse recollections of the event; inability to recall an important aspect of the event; markedly diminished interest or participation in significant activities; feeling of detachment or estrangement from others; restricted emotions and/or range of affect not present before the event; sense of a foreshortened future), and persistent symptoms of increased arousal (e.g., difficulty sleeping; irritability/outbursts of anger; difficulty concentrating; hypervigilance; exaggerated startle response). According to DSM-IV, a PTSD diagnosis requires the presence of 1 or more symptoms of reexperiencing, 3 or more symptoms of avoidance, and 2 or more symptoms of increased arousal, all of which must be present for at least one month and cause clinically important distress or impairment in social, occupational, or other important areas of functioning. PTSD, like other anxiety disorders, rarely occurs alone, and patients with PTSD often present with comorbid disorders (e.g., major depressive disorder, substance abuse disorders, panic disorder, generalized anxiety disorders, obsessive-compulsive disorder, social phobia); it is unknown whether these comorbid disorders precede or follow the onset of PTSD.
Psychotherapy alone or in combination with pharmacotherapy generally is considered the treatment of choice for PTSD. Pharmacologic therapy may be indicated in addition to psychotherapy for initial treatment of PTSD in patients who have comorbid disorders (e.g., major depressive disorder, bipolar disorder, other anxiety disorders) and also may be indicated in those who do not respond to initial treatment with psychotherapy alone. If pharmacotherapy is indicated in patients with PTSD, selective serotonin-reuptake inhibitors (SSRIs; e.g., sertraline, fluoxetine, paroxetine) usually are considered the drugs of choice (except in patients with bipolar disorder who require treatment with mood stabilizing agents).
The efficacy of sertraline for the management of PTSD has been established in 2 placebo-controlled studies of 12 weeks' duration in adult outpatients (76% women) who met DSM-III-R criteria for chronic PTSD (duration of symptoms 3 months or longer). The mean duration of PTSD for these patients was approximately 12 years and 44% of patients had secondary depressive disorders. Sertraline therapy was initiated at a dosage of 25 mg daily for the first week and then dosage was escalated (using a flexible dosage schedule) to 50-200 mg daily based on clinical response and tolerability. The mean sertraline dosage for patients who completed studies 1 and 2 was 146 mg and 151 mg daily, respectively. Overall, these 2 studies showed that sertraline was superior to placebo in improving scores on the Clinician-Administered PTSD Scale Part 2 total severity scale (a measure of the intensity and frequency of all 3 PTSD diagnostic symptom clusters [reexperiencing/intrusion, avoidance/numbing, and hyperarousal]), Impact of Event Scale (a patient rated measurement of the intrusion and avoidance symptoms), and the Clinical Global Impressions Severity of Illness and Global Improvement Scales.
However, in 2 additional placebo-controlled studies of similar design and duration, the difference in response to treatment on key assessment scales between patients receiving sertraline and those receiving placebo was not statistically significant. In one study of mostly female patients who met the DSM-III-R criteria for PTSD related to sexual/physical trauma, those receiving placebo experienced substantially greater improvement on the Impact of Event Scale than those receiving sertraline therapy. Although this study enrolled a higher proportion of patients with comorbid anxiety disorders and a higher proportion of patients receiving placebo with a successful response to previous psychotropic therapies than the studies demonstrating efficacy of the drug, it is unknown whether these factors alone account for the high placebo response in the study.
Efficacy of sertraline for the management of PTSD related to war or combat was evaluated in a study involving primarily white men in a VA medical center outpatient setting (mean duration of PTSD approximately 18 years). At the end of this study, patients receiving sertraline did not differ from those receiving placebo on any of the key efficacy assessment scales (e.g., Clinician-Administered PTSD scale, Davidson Self-Rating Trauma scale, Impact of Event Scale). In addition, the mean change from baseline for both treatment groups in this study was of a lesser magnitude than those of patients receiving placebo in the other reported studies. The lack of response to sertraline treatment in these combat veterans is consistent with controlled studies evaluating other selective serotonin-reuptake inhibitors (e.g., fluoxetine, brofaromine [not commercially available in the US]) in Vietnam veterans with PTSD. Some experts suggest that patients with combat- or war-related PTSD may be less responsive to treatment than patients with PTSD related to other traumatic events (e.g., sexual assault, accidents, natural disasters) because of some factor inherent in combat- or war-related trauma. However, other experts suggest that the poor treatment response in studies evaluating use in veterans may be the result of sampling error since veterans receiving treatment at VA hospitals may constitute a self-selected group of patients with chronic PTSD who have multiple impairments (comorbid disorders, substance abuse) that make them less responsive to treatment.
Since PTSD is a more common disorder in women than men, the majority (76%) of patients in reported studies were women. A retrospective analysis of pooled data has shown a substantial difference between sertraline and placebo on key efficacy assessment scales (e.g., Clinician-Administered PTSD scale, Impact of Event Scale, Clinical Global Impressions Severity of Illness Scale) in women (regardless of a baseline diagnosis of comorbid depression), but essentially no effect in the limited number of men studied. The clinical importance of this apparent gender effect is unknown; however, only limited data are available to date regarding use of SSRIs in men who have PTSD related to noncombat-related trauma (e.g., sexual assault, accidents, natural disasters). There are insufficient data to date to determine whether race or age has any effect on the efficacy of sertraline in the management of PTSD.
For additional information on the use of SSRIs in the treatment of PTSD, .
Premenstrual Dysphoric Disorder
Sertraline is used in the treatment of premenstrual dysphoric disorder (previously late luteal phase dysphoric disorder). DSM-IV criteria for premenstrual dysphoric disorder (PMDD) require that in most menstrual cycles of the previous year at least 5 of the following 11 symptoms must have been present for most of the time during the last week of the luteal phase (with at least one of the symptoms being one of the first 4 listed): marked depressed mood, feelings of hopelessness, or self-deprecating thoughts; marked anxiety, tension, feelings of being ''keyed up'' or on ''edge''; marked affective lability (e.g., feeling suddenly sad or tearful or increased sensitivity to rejection); persistent and marked anger or irritability or increased interpersonal conflicts; decreased interest in usual activities (e.g., work, school, friends, hobbies); a subjective sense of difficulty in concentrating; lethargy, easy fatigability, or marked lack of energy; marked change in appetite, overeating, or specific food cravings; hypersomnia or insomnia; a subjective sense of being overwhelmed or out of control; and other physical symptoms, such as breast tenderness or swelling, headaches, joint or muscle pain, or a sensation of ''bloating'' or weight gain. Such symptoms should begin to remit within a few days of the onset of menses (follicular phase) and are always absent in the week following menses. The presence of this cyclical pattern of symptoms must be confirmed by at least 2 consecutive months of prospective daily symptom ratings. PMDD should be distinguished from the more common premenstrual syndrome (PMS) by prospective daily ratings and the strict criteria listed above.
The efficacy of sertraline for the management of PMDD has been established in 2 randomized, placebo-controlled studies over 3 menstrual cycles in adult women who met DSM-III-R or DSM-IV criteria for PMDD. In these studies, flexible dosages (range: 50-150 mg daily) of sertraline administered continuously throughout the menstrual cycle or during the luteal phase only (i.e., for 2 weeks prior to the onset of menses) were shown to be substantially more effective than placebo in improving scores from baseline on the Daily Record of Severity of Problems (DRSP), the Clinical Global Impression of Severity of Illness (CGI-S) and Improvement (CGI-I), and/or the Hamilton Depression Rating Scales (HAMD-17). The mean dosage of sertraline in patients completing these trials was 102 or 74 mg daily for those receiving continuous or luteal-phase dosing of the drug, respectively.
When given in a flexible dosage of 50-150 mg daily in a separate double-blind, placebo-controlled study, sertraline was substantially better than placebo in improving symptoms (depressive symptoms, physical symptoms, anger/irritability) and functional impairment associated with this disorder. The beneficial effect of the drug was apparent by the first treatment cycle. In an open study comparing sertraline and desipramine in the treatment of premenstrual dysphoric disorder, sertraline and possibly desipramine were found to be effective; however, sertraline was better tolerated than desipramine. Additional controlled studies are needed to determine whether the efficacy of the drug is sustained during longer-term, maintenance therapy in women with this condition. In addition, efficacy of sertraline used in conjunction with oral contraceptives for the treatment of PMDD has not been determined since patients receiving oral contraceptives were excluded from most clinical studies to date.
Sertraline is used in the treatment of social phobia (social anxiety disorder). According to DSM-IV, social phobia is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. Exposure to the feared situation almost invariably provokes anxiety, which may approach the intensity of a panic attack. The feared situations are avoided or endured with intense anxiety or distress. The avoidance, fear, or anxious anticipation of encountering the social or performance situation interferes significantly with the person's daily routine, occupational or academic functioning, or social activities or relationships, or there is marked distress about having the phobias. Lesser degrees of performance anxiety or shyness generally do not require psychotherapy or pharmacologic treatment.
The efficacy of sertraline in the treatment of social phobia has been established in 2 multicenter, placebo-controlled studies in adult outpatients who met DSM-IV criteria for social phobia. In one study of 12 weeks' duration, 47% of patients receiving flexible dosages of sertraline (50-200 mg daily; mean dosage of 144 mg daily) were characterized as responders (defined as a score of 1 or 2 on the Clinical Global Impressions [CGI] Global Improvement Scale) compared with 26% of those receiving placebo (intent-to-treat analysis). Sertraline also was found to be superior to placebo on the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered measure of fear, anxiety, and avoidance of social and performance situation, and on most secondary efficacy measures, including the Duke Brief Social Phobia Scale (BSPS) total score, fear and avoidance subscales of BSPS, and fear/anxiety and avoidance subscales of LSAS. These results were similar to those seen in a flexible-dose study of 20 weeks' duration, in which a score of 1 (''very much improved'') or 2 (''much improved'') on the CGI Global Improvement Scale was attained by the end of the treatment period by 53 or 29% of patients receiving sertraline (50-200 mg daily; mean dosage of 147 mg daily) or placebo, respectively (intent-to-treat analysis). Sixty-five patients in this study subsequently were enrolled in a separate controlled study, including 50 patients who had responded to sertraline in the initial study and then were randomized to receive either continued treatment with sertraline or placebo in the subsequent study and 15 patients who had responded to placebo in the initial study and continued to receive placebo in the subsequent study. Based on an intent-to-treat analysis, 4% of patients who continued treatment with sertraline, 36% of patients randomized to receive placebo, and 27% of those who continued treatment with placebo relapsed (defined as an increase of 2 or more points from baseline in the CGI Severity of Illness score or discontinuance of the study drug because of lack of efficacy) at the end of the 24-week treatment period. Similar to results of pivotal, short-term clinical studies, sertraline also was shown to be substantially more effective than placebo on the CGI Severity of Illness Scale, Marks Fear Questionnaire (MFQ) Social Phobia subscale, and BSPS total score.
Subgroup analysis of short-term, controlled studies in adult outpatients with social anxiety disorder did not reveal any evidence of gender-related differences in treatment outcome. There was insufficient information to determine the effect of race or age on treatment outcome. Safety and efficacy of sertraline for the treatment of social phobia in children or adolescents have not been established to date.
Like some other serotonin-reuptake inhibitors, sertraline has been used with some success in the treatment of premature ejaculation. In a placebo-controlled study, sertraline produced substantial improvements compared with placebo in time to ejaculation, number of successful attempts at intercourse, and incidence of ejaculation during foreplay, as well as overall clinical judgment of improvement. In addition, the drug was well tolerated in most patients. A trial with drug therapy may be particularly useful in patients who fail or refuse behavioral or psychotherapeutic treatment or when partners are unwilling to cooperate with such therapy.
Sertraline has been used in a limited number of patients with various types of headache with variable results; however, its use in this condition may be limited by frequent adverse effects.