Paroxetine is commercially available in the US as paroxetine hydrochloride (e.g., Paxil, Paxil CR) and as paroxetine mesylate (i.e., Pexeva). The US Food and Drug Administration (FDA) considers paroxetine mesylate (Pexeva) conventional tablets to be a pharmaceutical alternative (as described in section 505[b] of the Federal Food, Drug, and Cosmetic Act) and not a pharmaceutical (generic) equivalent to paroxetine hydrochloride conventional tablets (e.g., Paxil), since both contain the same active moiety (paroxetine) but have different salts. The clinical studies that established efficacy of paroxetine in various conditions have been conducted with paroxetine hydrochloride. Because paroxetine hydrochloride and paroxetine mesylate contain the same active moiety (paroxetine), clinical efficacy is expected to be similar between the 2 different salts.
Paroxetine hydrochloride conventional tablets and oral suspension are used in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder with or without agoraphobia, social phobia (social anxiety disorder), generalized anxiety disorder, and posttraumatic stress disorder. Paroxetine hydrochloride extended-release tablets are used in the treatment of major depressive disorder, panic disorder with or without agoraphobia, social phobia, and premenstrual dysphoric disorder (PMDD). Paroxetine mesylate conventional tablets are used in the treatment of major depressive disorder, obsessive-compulsive disorder, and panic disorder with or without agoraphobia. In addition, paroxetine has been used in the treatment of premature ejaculation, diabetic neuropathy, chronic headache, and depression associated with bipolar disorder.
Major Depressive Disorder
Paroxetine 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, see Drug Interactions: Tricyclic and Other Antidepressants, and see Drug Interactions: Lithium.)
The efficacy of paroxetine for the management of major depression has been established by placebo-controlled studies of 6 weeks' duration in adult outpatients from 18-73 years of age who met DSM-III criteria for major depressive disorder. In these studies, paroxetine hydrochloride was found to be more effective than placebo in improving scores by at least 2 on the Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression and Severity of Illness Scale. Paroxetine hydrochloride also was more effective than placebo in improving HDRS subfactor scores, including the depressed mood item, sleep disturbance factor, and the anxiety factor.
The efficacy of paroxetine hydrochloride extended-release tablets for the management of depression has been established in 2 flexible-dosage, controlled studies of 12-weeks' duration in adults 18-88 years of age who met DSM-IV criteria for major depressive disorder. In these studies, paroxetine was more effective than placebo in improving scores on the HDRS, the Hamilton depressed mood item, and the Clinical Global Impression-Severity of Illness Scale.
In a study of depressed outpatients who had responded by the end of an initial 8-week open treatment phase to paroxetine (mean dosage: approximately 30 mg daily; HDRS total score of less than 8) and were randomized to continue paroxetine or receive placebo for 1 year, the relapse rate in the paroxetine-treated patients (15%) was substantially lower than that in those who received placebo (39%). An analysis of these data for possible gender-related effects on treatment outcome did not suggest any difference in efficacy based on the gender of the patient. In controlled studies of depressed patients who had responded to a 6-week course of paroxetine or imipramine and were randomized to receive either the same antidepressant or placebo for up to 1 year, both paroxetine and imipramine were more effective than placebo in maintaining euthymia; however, paroxetine was better tolerated than imipramine during long-term therapy. While the optimum duration of paroxetine 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). In placebo-controlled studies, paroxetine has been shown to be effective for the long-term (e.g., up to 1 year) management of depression. In addition, the drug has been used in some patients for longer periods (e.g., up to 4 years) without apparent loss of clinical effect or increased toxicity. However, when paroxetine is used for extended periods, the need for continued therapy should be reassessed periodically.
(See Dosage and Administration: Dosage.)
The efficacy of paroxetine as an antidepressant in hospital settings has not been studied adequately to date; however, the drug has been shown to be effective in hospitalized patients with severe depression in at least one controlled study.
As with other antidepressants, the possibility that paroxetine may precipitate hypomanic or manic attacks in patients with bipolar or other major affective disorder should be considered. Paroxetine is not approved for use in treating bipolar depression.
Considerations in Choosing Antidepressants
A variety of antidepressant drugs are 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 paroxetine in patients with depression is greater than that of placebo and comparable to that of usual dosages of tricyclic antidepressants (e.g., amitriptyline, imipramine, doxepin), other SSRIs (e.g., fluoxetine, fluvoxamine, sertraline), and other antidepressants (e.g., nefazodone). The onset of antidepressant action of paroxetine appears to be comparable to that of tricyclic antidepressants and other SSRIs, although there is some evidence that the onset of action may occur slightly earlier with paroxetine than with imipramine and fluoxetine.
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/or 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 paroxetine 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. 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 paroxetine and other drugs in this class.
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.
Data from controlled clinical studies evaluating various antidepressant agents in children and adolescents are less extensive than with adults, 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 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., paroxetine, citalopram, desvenlafaxine, duloxetine, escitalopram, fluvoxamine, mirtazapine, nefazodone, sertraline, venlafaxine) was not conclusively established in clinical trials in pediatric patients with major depressive disorder. In addition, FDA 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, SSRIs appear to be as effective as tricyclic antidepressants but may cause 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 paroxetine and other SSRIs compared with tricyclic antidepressants 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, and hyponatremia). Some clinicians state that SSRIs including paroxetine 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 suicidal ideation) 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 citalopram, escitalopram, fluoxetine, paroxetine, or sertraline are generally considered as first-line agents in the treatment of depressed patients with dementia since they usually 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 controlled study comparing paroxetine and imipramine in patients with coexisting depression and dementia, both drugs were found to be effective; however, paroxetine was better tolerated (fewer anticholinergic and serious adverse effects).
The relatively low incidence of adverse cardiovascular effects, including orthostatic hypotension and conduction disturbances, associated with paroxetine and most other SSRIs may be advantageous in patients in whom the cardiovascular effects associated with tricyclic antidepressants may be hazardous. In a controlled trial comparing paroxetine and nortriptyline in patients with stable ischemic disease, both antidepressants were found to be effective in treating depression and neither drug substantially affected blood pressure or conduction intervals; however, paroxetine did not produce sustained effects on heart rate or rhythm or heart rate variability whereas nortriptyline increased heart rate and reduced heart rate variability. Most clinical studies of paroxetine for the management of depression did not include individuals with cardiovascular disease (e.g., those with a recent history of myocardial infarction or unstable cardiovascular disease), and further experience in such patients is necessary to confirm the relative lack of cardiotoxicity reported with the drug to date.
(See Cautions: Cardiovascular Effectsand see Cautions: Precautions and Contraindications.)
Because paroxetine and other SSRIs generally are 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 or in patients who are prone to accidents; 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 is currently 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 patients of all ages who are receiving antidepressant therapy are recommended. ( See Suicidality under Cautions: Nervous System Effects, and see Cautions: Precautions and Contraindications.)
Paroxetine has been effective in patients with moderate to severe depression, endogenous depression, reactive depression (including traumatic grief), depression associated with human immunodeficiency virus (HIV) infection, and depression associated with anxiety and/or agitation.
Paroxetine is used in the treatment of obsessive-compulsive disorder when 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 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 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 recognition.
The efficacy of paroxetine hydrochloride for the management of obsessive-compulsive disorder in adults has been established by 2 multicenter, placebo-controlled studies of 12 weeks' duration. In these clinical studies, paroxetine was more effective than placebo in reducing the severity of obsessive-compulsive manifestations in adult outpatients with moderate to severe obsessive-compulsive disorder (Yale-Brown Obsessive-Compulsive Scale [YBOCS] baseline values of 23-26). In a fixed-dose study of 12 weeks' duration involving paroxetine dosages of 20, 40, or 60 mg daily, patients receiving 40 or 60 mg of the drug daily experienced substantially greater reductions in the YBOCS total score (approximately 6 and 7 points, respectively) than those receiving paroxetine 20 mg daily (approximately 4 points) or placebo (approximately 3 points). The effective dosage of paroxetine was 40 or 60 mg daily. In a 12-week study with flexible dosing of paroxetine (20-60 mg daily) or clomipramine (25-250 mg daily) compared with placebo, paroxetine-treated patients exhibited a mean reduction of approximately 7 points on the YBOCS total score, which was substantially greater than the mean reduction of approximately 4 points in patients receiving placebo. No age- or gender-related differences in outcome were noted in either of these studies.
The efficacy of paroxetine for long-term use (i.e., longer than 12 weeks) has been demonstrated in a 6-month relapse prevention trial, which was an extension of the fixed-dose study of 12 weeks' duration in patients who had responded to paroxetine. Patients who received paroxetine relapsed substantially less frequently than those receiving placebo in a double-blind placebo-controlled study. The manufacturers and many experts state that obsessive-compulsive disorder is chronic and requires several months or longer of sustained therapy. Therefore, it is reasonable to continue therapy in responding patients. If paroxetine is used for extended periods, dosage should be adjusted so that patients are maintained on the lowest effective dosage, and the need for continued therapy with the drug should be reassessed periodically.
Results from comparative studies to date suggest that paroxetine and other SSRIs (e.g., fluoxetine, fluvoxamine, sertraline) are as effective as or somewhat less effective than clomipramine 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., paroxetine, fluoxetine, fluvoxamine, sertraline) 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.
In children with obsessive-compulsive disorder, cognitive behavioral therapy and/or serotonin-reuptake inhibitors (such as clomipramine and SSRIs) may be beneficial. Controlled studies evaluating paroxetine in this setting currently are lacking and it remains to be established whether one serotonin-reuptake inhibitor is more effective than another. Pending further data, some experts state that the choice of an agent may depend on their adverse effect profile, potential for adverse drug interactions, and the presence of comorbid conditions. Although clomipramine has been more extensively studied to date than SSRIs, it has the most prominent anticholinergic effects, requires electrocardiographic (ECG) monitoring, and is the most toxic following acute overdosage. SSRIs do not require ECG monitoring; however, they are associated with headache, nausea, insomnia, and agitation. If a decision is made to initiate SSRI therapy in a child with obsessive-compulsive disorder, some experts recommend starting with a low initial dosage and then gradually increasing the dosage as tolerated. If there is no clinical response after 10-12 weeks, consideration should be given to switching to another SSRI or clomipramine.
(See Cautions: Pediatric Precautions.)
Although combined clomipramine and SSRI therapy has been effective in a limited number of children and adolescents with obsessive-compulsive disorder, very close monitoring of the ECG, blood clomipramine concentrations, and vital signs is necessary because of the risks of potentially dangerous drug interactions (including serotonin syndrome) and adverse effects with such combinations.
(See Drug Interactions: Serotonergic Drugs.)As in adults, the optimal duration of pharmacologic therapy in children with obsessive-compulsive disorder remains unclear. Although periodic trials of gradual withdrawal from drug therapy are advisable, some children appear to require long-term maintenance therapy to prevent relapse.
Paroxetine 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 paroxetine hydrochloride for the management of panic disorder with or without agoraphobia has been established by multicenter, double-blind, placebo-controlled studies in adult outpatients who met DSM-IIIR criteria for panic disorder with or without agoraphobia. In a fixed-dose study of 10 weeks' duration in which paroxetine was given in dosages of 10, 20, and 40 mg daily, a substantially greater reduction in panic attack frequency from placebo was noted only in the patients receiving paroxetine 40 mg daily; at the end of the study, 76% of patients receiving paroxetine 40 mg daily were free of panic attacks compared with 44% of those receiving placebo. In 2 studies of 12 weeks' duration employing a flexible dosing schedule, greater improvement was reported in patients receiving paroxetine 10-60 mg daily than in those receiving placebo. In one study, 51% of the paroxetine recipients compared with 32% of the placebo recipients were free of panic attacks at the end of the study, and in the other study which was conducted in patients receiving standardized cognitive behavioral therapy, 33% of patients receiving paroxetine 10-60 mg daily had a reduction in panic attack frequency to 0 or 1 panic attacks during the study period compared with 14% of those receiving placebo. The mean paroxetine dosage for those completing these 2 flexible-dose studies was approximately 40 mg daily.
In these studies, paroxetine was found to be substantially more effective than placebo in the treatment of panic disorder in at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness Scale. The results of the studies conducted to date demonstrate that paroxetine reduces global anxiety, depressive symptoms, phobic avoidance, and improves overall impairment associated with panic disorder.
The efficacy of paroxetine hydrochloride extended-release tablets for the management of panic disorder with or without agoraphobia has been established in multicenter, placebo-controlled, flexible-dosage studies in patients with panic disorder with or without agoraphobia. In 2 studies, paroxetine extended-release tablets were more effective than placebo, but a third study failed to show any benefit compared with placebo.
The efficacy of paroxetine for long-term use (i.e., longer than 12 weeks) has been demonstrated in controlled studies. In a 3-month relapse prevention trial which was an extension of the 10-week, fixed-dose study, patients who were responders to paroxetine were randomized to receive either paroxetine (10, 20, or 40 mg daily) or placebo. The patients receiving long-term therapy with paroxetine relapsed substantially less frequently than those receiving placebo. In another controlled study, patients receiving paroxetine therapy for 1 year demonstrated not only long-term efficacy but also continued improvement. The manufacturers and some clinicians state that panic disorder is a chronic condition; therefore, it is reasonable to continue therapy in responding patients. Dosage adjustment may be necessary to maintain the patient on the lowest effective dosage, and patients should be reassessed periodically to determine the need for continued therapy.
Subgroup analysis in controlled studies for possible age- or gender-related effects on treatment outcome did not suggest any difference in efficacy based on either the age or sex of the patient.
The results of controlled studies suggest that paroxetine is as effective as and better tolerated than clomipramine in the treatment of panic disorder. In addition, paroxetine was found to have a more rapid onset of action than clomipramine in reducing the number of panic attacks in one study.
Unlike imipramine which reduces heart rate variability in patients with panic disorder (a condition associated with decreased heart rate variability and consequently an increased risk of serious cardiovascular problems including sudden cardiac death), paroxetine has been shown to normalize heart rate variability in a limited number of patients with panic disorder. The clinical importance of these findings with regard to potentially decreasing cardiovascular mortality in patients with panic disorder remains to be determined.
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 (e.g., imipramine, clomipramine), monoamine oxidase (MAO) inhibitors (e.g., phenelzine), selective serotonin-reuptake inhibitors (SSRIs; e.g., citalopram, fluoxetine, sertraline, paroxetine), 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 is not tolerated, use of a tricyclic antidepressant or a benzodiazepine is recommended.
Paroxetine hydrochloride 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 paroxetine hydrochloride in the treatment of social phobia has been established in 3 multicenter, placebo-controlled studies in adult outpatients who met DSM-IV criteria for social phobia. In 2 studies of 12 weeks' duration in which paroxetine was given in dosages ranging from 20-50 mg daily, significant improvement in the Clinical Global Impressions (CGI) Improvement score and Liebowitz Social Anxiety Scale (LSAS) were noted. In these studies, 69 or 77% of paroxetine-treated patients were CGI Improvement responders compared with 29 or 42% of placebo-treated patients. In the third study, paroxetine was given in fixed dosages of 20, 40, or 60 mg daily for 12 weeks. There was significant improvement in the CGI Improvement responder criterion and LSAS Total Score in patients receiving 20 mg daily compared with placebo. Although there were trends in superiority noted in those receiving 40 or 60 mg daily compared with placebo, the results did not reach statistical significance and there was no indication that dosages exceeding 20 mg daily provide any additional benefit.
Subgroup analysis of these controlled studies in adult outpatients with social anxiety disorder did not reveal any evidence of age- or gender-related differences in treatment outcome. Safety and efficacy of paroxetine for the treatment of social phobia in children or adolescents have not been established to date.
Paroxetine hydrochloride is used in the management of generalized anxiety disorder. According to DSM-IV-TR, generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (e.g., work or school performance). Patients with generalized anxiety disorder find it difficult to control the worry. The anxiety and worry are accompanied by at least 3 of the following somatic symptoms in adults and at least 1 of these symptoms in children: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance (e.g., difficulty falling or staying asleep, restless unsatisfying sleep). These symptoms cause clinically important distress or impairment in social, occupational, or other important areas of functioning and are not caused by direct physiologic effects of substances (e.g., medications, drugs of abuse, toxin exposure) or by a general medical condition (e.g., hyperthyroidism). Although patients with generalized anxiety disorder may have another underlying mental disorder (axis I disorder), the focus of the anxiety and worry is unrelated to the latter disorder and does not occur only during the course of a mood, psychotic, or pervasive developmental disorder.
Selective serotonin-reuptake inhibitors (SSRIs) are among several classes of antidepressants recommended by some clinicians as first-line treatment for generalized anxiety disorder because of their safety, tolerability (e.g., lack of physical dependence problems commonly associated with benzodiazepines), and proven efficacy in the treatment of depression and other anxiety disorders (e.g., obsessive-compulsive disorder, panic disorder) that frequently present as comorbid conditions in patients with generalized anxiety disorder. Because an estimated 80% of patients with generalized anxiety disorder will have a comorbid mood disorder (e.g., depression) during their lifetime, an SSRI or a drug that predominantly inhibits serotonin and norepinephrine reuptake (e.g., venlafaxine) is preferred by some clinicians for treatment of patients with long-standing generalized anxiety disorder and in those with several comorbid mood or anxiety disorders. However, the efficacy of antidepressants, including paroxetine, in the management of generalized anxiety disorder in patients with comorbid conditions such as depression has yet to be established, since such patients have been excluded from study entry, and therefore further research is needed.
Efficacy of paroxetine hydrochloride for the management of generalized anxiety disorder has been established in 2 randomized, multicenter, placebo-controlled studies of 8 weeks' duration in adult outpatients who met DSM-IV criteria for generalized anxiety disorder. One study employed fixed paroxetine dosages, and the other employed a flexible dosing schedule. In the flexible-dose study, approximately 62% of patients receiving paroxetine (20-50 mg daily; mean dosage of 26.8 mg daily) had a score of 1 (''very much improved'') or 2 (''much improved'') on the Clinical Global Impressions (CGI) Global Improvement scale, and approximately 36% of these patients had complete or nearly complete resolution of anxiety (defined as a Hamilton Rating Scale for Anxiety [HAM-A] total score of 7 or less), compared with approximately 47 and 23%, respectively, of patients receiving placebo. These results were similar to those seen in the fixed-dose study, in which a score of 1 or 2 on the CGI Global Improvement scale was attained by 62, 68, or 46%, respectively, and a HAM-A total score of 10 or less was attained by 49, 52, or 33%, respectively, of patients receiving paroxetine 20 or 40 mg daily or placebo. However, in a third study, reductions in HAM-A total score attained by patients receiving flexible dosages of paroxetine (20-50 mg daily; mean dosage of 23.8 mg daily) were not substantially different than those attained by patients receiving placebo. Subgroup analysis of these controlled studies in adult outpatients with generalized anxiety disorder did not reveal any evidence of gender- or race-related differences in treatment outcome.
Systematic evaluation of continuing paroxetine for periods of up to 6 months in patients with generalized anxiety disorder who had responded while taking paroxetine during an 8-week acute treatment phase has demonstrated a benefit of such maintenance therapy. In a double-blind, 24-week relapse prevention trial that was an extension of a single-blind, 8-week acute treatment study, patients who had responded to paroxetine 20-50 mg daily were randomized to receive either paroxetine at the same dosage or placebo. Relapse during the double-blind phase was defined as an increase of 2 or more points on the CGI-Severity of Illness scale to a score of 4 or higher or drug discontinuance due to lack of efficacy. The paroxetine-treated patients experienced a significantly lower relapse rate over the 24-week period compared with those receiving placebo. In addition, 73% of patients receiving a total of 32 weeks of paroxetine therapy achieved remission (defined as a HAM-A total score of 7 or less) compared with about 34% of those who received 8 weeks of therapy and then received 24 weeks of placebo. Because generalized anxiety disorder is a chronic condition, it is reasonable to continue therapy in responding patients. Dosage adjustment may be necessary to maintain patients receiving long-term paroxetine therapy on the lowest effective dosage, and patients should be reassessed periodically to determine the need for continued therapy.
Results of a comparative study indicate that the anxiolytic effects of paroxetine are comparable to those of imipramine, a tricyclic antidepressant, and slightly superior to those of 2'-chlordesmethyldiazepam, a benzodiazepine (not commercially available in the US). In this study, during the first 2 weeks of therapy, 2'-chlordesmethyldiazepam displayed greater anxiolytic efficacy, as measured by HAM-A score, than paroxetine or imipramine; however, following 8 weeks of therapy, a 50% or greater decrease in HAM-A score was attained by 68, 72, or 55% of patients receiving paroxetine, imipramine, or 2'-chlordesmethyldiazepam, respectively. Antidepressants such as paroxetine appear to affect predominantly psychic symptoms, whereas benzodiazepines such as 2'-chlordesmethyldiazepam appear to affect predominately somatic symptoms associated with generalized anxiety disorder.
Posttraumatic Stress Disorder
Paroxetine hydrochloride 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 1 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., fluoxetine, paroxetine, sertraline) usually are considered the drugs of choice (except in patients with bipolar disorder who require treatment with mood-stabilizing agents).
Efficacy of paroxetine hydrochloride in the treatment of PTSD has been established in 2 multicenter, placebo-controlled studies of 12 weeks' duration in adult outpatients (66-68% women) with a primary diagnosis (DSM-IV) of PTSD following physical or sexual assault (48-54%), witnessing injury or death (17-19%), serious accident or injury (6-13%), or exposure to combat (5-8%). The mean duration of PTSD for these patients was approximately 13 years and 41 or 40% of patients had secondary depressive disorders or non-PTSD anxiety disorders, respectively. In these studies, patients receiving fixed (20 or 40 mg daily) or flexible (20-50 mg daily; mean: 27.6 mg daily) dosages of paroxetine had substantially greater changes from baseline on the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score, a multi-item instrument that measures 3 aspects of PTSD with the following symptom clusters: reexperiencing/intrusion, avoidance/numbing, and hyperarousal, and were more likely to have a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression-Global Improvement Scale (CGI-I) compared with those receiving placebo. Treatment response in the fixed-dose study appeared to be unaffected by patient's gender, type of trauma, duration of PTSD, or severity of baseline PTSD or comorbid conditions. A third study, also a flexible-dose study comparing paroxetine (20-50 mg daily) with placebo, demonstrated paroxetine to be substantially superior to placebo as assessed by improvement from baseline for CAPS-2 total score, but not by proportion of responders on the CGI-I.
Use of paroxetine in the treatment of chronic PTSD did not appear to produce a complete remission in a substantial proportion of patients receiving the drug in clinical studies. Therefore, some clinicians suggest combined use of psychotherapy with pharmacotherapy in order to optimize treatment outcome; however, further studies are needed.
Premenstrual Dysphoric Disorder
Like some other selective serotonin-reuptake inhibitors (SSRIs; e.g., fluoxetine, sertraline), paroxetine is used in the treatment of premenstrual dysphoric disorder (previously late luteal phase dysphoric disorder). In women suffering from severe premenstrual dysphoric disorder treated daily for 3 menstrual cycles with paroxetine, maprotiline, or placebo, paroxetine was found to be superior to maprotiline or placebo in improving symptoms associated with this disorder. In women with severe premenstrual dysphoric disorder receiving paroxetine 5-30 mg daily for 10 consecutive menstrual cycles, paroxetine also markedly reduced symptoms (premenstrual irritability, depressed mood, increase in appetite, anxiety/tension). The improvement in symptoms continued throughout the entire treatment period; sedation, dry mouth, and nausea occurred commonly but declined during therapy whereas adverse sexual effects (reduced libido, anorgasmia) persisted. 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. For further information on use of SSRIs in the treatment of premenstrual dysphoric disorder, see
Like some other SSRIs, paroxetine has been used with some success in the treatment of premature ejaculation. In a placebo-controlled study in men with premature ejaculation, paroxetine (20 mg daily for the first week followed by 40 mg daily for 5 additional weeks) produced substantially greater clinical improvement (increased intravaginal ejaculation latency time, increased number of thrusts before ejaculation) than placebo. Nearly all the patients in this study reported some improvement in ejaculatory latency during the first week of paroxetine therapy. In an open study, paroxetine 20 mg daily improved premature ejaculation within about 14 days with all patients studied reporting a longer interval before ejaculation. When dosages of 20 or 40 mg daily were compared in patients with primary premature ejaculation, 20 mg daily was found to be sufficient; further study is needed to determine whether higher dosages may further increase ejaculation latency. In a study comparing paroxetine 20 mg daily for 6 months with paroxetine 20 mg daily for 14 days followed by 10 mg daily for a total of 6 months, both regimens were found to be similarly effective in improving premature ejaculation and were well tolerated. There is some evidence that paroxetine may be more effective than other SSRIs in terms of increasing intravaginal ejaculation latency time.
Additional studies have investigated the use of paroxetine on an ''as needed'' basis for the treatment of premature ejaculation. In one study, men with premature ejaculation (mean age: 39.5 years; mean pretreatment ejaculatory latency time: 0.3 minutes) were randomized to receive 20 mg of paroxetine or placebo 3-4 hours before planned intercourse; at 4 weeks, the mean ejaculatory latency time was 3.2-3.5 minutes in those receiving the drug compared with 0.45-0.6 minutes in those receiving placebo. However, mean ejaculatory latency time was even longer in another group of men (mean age: 40.5 years; mean pretreatment ejaculatory latency time: 0.5 minutes) who received an initial regimen of paroxetine 10 mg daily for 3 weeks and then received paroxetine 20 mg on an as needed basis for 4 weeks.
Further controlled studies are necessary to confirm these findings, to determine the optimal dosage regimen, and to evaluate the long-term efficacy of paroxetine in patients with this condition. Some clinicians advise that a trial with drug therapy may be particularly useful in patients with premature ejaculation who fail or refuse behavioral or psychotherapeutic treatment or when partners are unwilling to cooperate with such therapy.
Tricyclic antidepressants generally have been considered a mainstay of therapy for the treatment of diabetic neuropathy. However, because of potentially improved patient tolerability, therapy with selective serotonin-reuptake inhibitors (SSRIs) or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs; e.g., duloxetine, venlafaxine) has been attempted as an alternative. In a controlled study, paroxetine (40 mg daily) was effective in a limited number of patients in substantially reducing the symptoms associated with diabetic neuropathy and was somewhat less effective but better tolerated than imipramine. Because patients who did not respond as well to paroxetine as to imipramine had lower plasma paroxetine concentrations, it was suggested that dosage adjustment based on plasma concentration monitoring potentially may be useful in the management of this condition. When compared with earlier results obtained with imipramine in the management of diabetic neuropathy, SSRIs such as citalopram, fluoxetine, paroxetine, and sertraline generally appear to be less effective but better tolerated overall. Additional study and experience are needed to elucidate the relative roles of SSRIs versus tricyclic antidepressants, SNRIs, anticonvulsants (e.g., pregabalin, gabapentin), and other forms of treatment in the management of this condition.
Paroxetine has been used in a limited number of patients with chronic headache with some success. In an open study, patients with chronic daily headache unresponsive to previous therapy were treated with paroxetine 10-50 mg daily for 3-9 months; most of the patients showed reductions in the number of headache days per month. Fatigue, insomnia, and urogenital disturbances were the most common adverse effects reported in this study. In a double-blind, crossover study in nondepressed patients with chronic tension-type headache comparing paroxetine (20-30 mg daily) and sulpiride (a dopamine antagonist; not commercially available in the US), both drugs improved headache although sulpiride appeared to provide greater relief. Additional controlled studies are needed to confirm these preliminary findings.
Paroxetine has been used for the short-term management of acute depressive episodes in patients with bipolar disorder. While antidepressants such as selective serotonin-reuptake inhibitors (SSRIs) have shown good efficacy in the treatment of unipolar depression, the drugs generally have been studied as adjuncts to mood stabilizing agents such as lithium or valproate in the management of bipolar disorder; antidepressant monotherapy is not recommended, given the risk of precipitating a switch into mania. The American Psychiatric Association (APA) currently recommends that paroxetine be reserved for patients who had an inadequate therapeutic response to optimal therapy with first-line agents (i.e., lithium, lamotrigine) or who do not tolerate these drugs. If paroxetine was effective for the management of an acute depressive episode, including during the continuation phase, then maintenance therapy with the drug should be considered to prevent recurrence of major depressive episodes.