Aripiprazole is used orally for the symptomatic management of psychotic disorders (e.g., schizophrenia). Aripiprazole also is used orally for the treatment of manic and mixed episodes associated with bipolar I disorder, as an adjunct to antidepressants for the acute treatment of major depressive disorder, for the acute treatment of irritability associated with autistic disorder, and for the treatment of Tourette's syndrome (Gilles de la Tourette's syndrome). Short-acting (immediate-release) aripiprazole injection (Abilify) is used IM for the management of acute agitation in patients with bipolar disorder or schizophrenia. Extended-release IM preparations of aripiprazole (Abilify Maintena) and aripiprazole lauroxil (Aristada) are used for the treatment of schizophrenia.
Aripiprazole is used orally and parenterally for the symptomatic management of psychotic disorders (e.g., schizophrenia). Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.
Aripiprazole is used orally for the acute and maintenance treatment of schizophrenia. In addition, extended-release formulations of aripiprazole (Abilify Maintena) and aripiprazole lauroxil (Aristada) are used IM for the treatment of schizophrenia. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.
Short-term efficacy of oral aripiprazole monotherapy in the acute treatment of schizophrenia in adults was evaluated in 5 placebo-controlled studies of 4 and 6 weeks' duration principally in acutely relapsed, hospitalized patients who predominantly met DSM-III/IV criteria for schizophrenia. Four of the 5 studies were able to distinguish aripiprazole from placebo, but the smallest study did not. In the 4 positive studies, assessment of improvement in manifestations of schizophrenia was based on results of psychiatric rating scales, including the Positive and Negative Syndrome Scale (PANSS), the PANSS positive subscale, the PANSS negative subscale, and the Clinical Global Impressions (CGI) scale. Aripiprazole generally was found to be superior to placebo in improving both positive and negative manifestations in acute exacerbations of schizophrenia in these 4 studies. Efficacy of 10-, 15-, 20-, and 30-mg daily dosages of aripiprazole was established in 2 studies for each dosage; however, there was no evidence that higher dosages offered any therapeutic advantage over lower dosages in these studies. Active controls (haloperidol or risperidone) were used in addition to placebo controls in 3 of these studies, but study design did not allow for comparison between aripiprazole and the active controls. An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.
In a longer-term study, adult inpatients or outpatients who met DSM-IV criteria for schizophrenia and who were, by history, symptomatically stable on other antipsychotic agents for at least 3 months were discontinued from those other agents and randomized to receive either oral aripiprazole 15 mg daily or placebo for up to 26 weeks of observation for relapse in the double-blind phase. Relapse was based on results of the CGI-Improvement and PANSS psychiatric rating scales. Patients receiving aripiprazole experienced a significantly longer time to relapse over the subsequent 26 weeks compared with those receiving placebo. In addition, pooled data from 2 double-blind, multicenter studies in acutely ill patients with schizophrenia in whom therapy with aripiprazole or haloperidol was continued for 52 weeks demonstrated a substantially higher rate of symptomatic remission across 52 weeks in the aripiprazole-treated patients compared with the haloperidol-treated patients; improved tolerability with aripiprazole may have contributed to the higher overall remission rates observed in this pooled analysis.
Short-term efficacy of oral aripiprazole in the acute treatment of schizophrenia in adolescents 13-17 years of age was evaluated in a double-blind, placebo-controlled trial of 6 weeks' duration in 302 outpatients who met DSM-IV criteria for schizophrenia and had a PANSS total score of 70 or more at baseline. Patients were randomized to receive a fixed dosage of aripiprazole 10 mg daily or 30 mg daily or to receive placebo. Both dosages of aripiprazole were found to be superior to placebo in reducing the PANSS total score, which was the primary efficacy measure; the 10-mg daily dosage also demonstrated superiority over placebo on the PANSS negative subscale score at the study end point. However, the 30-mg daily dosage failed to demonstrate superiority over the 10-mg daily dosage. The drug was generally well tolerated.
Short-term efficacy of the extended-release IM formulation of aripiprazole (Abilify Maintena) in the treatment of schizophrenia in adults was established in a multicenter, double-blind, placebo-controlled study of 12 weeks' duration in acutely relapsed inpatients who met DSM-IV-TR criteria for schizophrenia and who were experiencing an acute psychotic episode. Patients in this study were randomized to receive IM injections of extended-release aripiprazole (400 mg) or placebo every 4 weeks. Patients receiving extended-release IM aripiprazole were also given oral aripiprazole (10-20 mg daily) for 14 days beginning on the day of the first injection to provide therapeutic plasma concentrations, which may take longer to achieve in some patients; patients who received placebo injections were given placebo tablets for the first 14 days. The IM dosage of extended-release aripiprazole could be adjusted down to 300 mg and increased back to 400 mg on a one-time basis. The primary efficacy measure in this study was the change in PANSS total score from baseline to end point (week 10). Patients treated with extended-release IM aripiprazole injection demonstrated substantially greater improvement in mean PANSS total scores compared with those receiving placebo.
In a longer-term maintenance study, adults who met DSM-IV-TR criteria for schizophrenia and who were receiving at least one antipsychotic agent were treated with open-label oral aripiprazole for 4-6 weeks followed by extended-release aripiprazole (Abilify Maintena) 400 mg IM once every 4 weeks with oral aripiprazole continued for the first 2 weeks after the initial injection. The IM extended-release aripiprazole dosage could be adjusted down to 300 mg based on tolerability and increased back to 400 mg on a one-time basis. Patients who remained stable on the extended-release IM injection for at least 12 weeks were then randomized either to continue receiving extended-release IM aripiprazole at the same dosage or to receive placebo injection IM every 4 weeks for up to 52 weeks and observed for relapse in the double-blind withdrawal phase. The primary efficacy measure was the time from randomization to relapse, and patients who received extended-release IM aripiprazole had a substantially longer time to relapse than those who received placebo.
Efficacy of extended-release aripiprazole lauroxil IM injection (Aristada) in the treatment of schizophrenia was established, in part, based on extrapolation of efficacy data from clinical trials with oral aripiprazole. In addition, efficacy was established in a multicenter, double-blind, placebo-controlled, fixed-dose study of 12 weeks' duration in adults who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute exacerbation or relapse. Patients were randomized to receive extended-release aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo by IM injection every 4 weeks. After establishing tolerability to oral aripiprazole, patients concomitantly received oral aripiprazole 15 mg daily (if randomized to aripiprazole) or placebo for the first 3 weeks. The primary efficacy measure in this study was the change in PANSS total score from baseline to end point (week 12). At the study end point, both dosages of extended-release aripiprazole lauroxil injection resulted in substantially greater improvement in the PANSS total score compared with placebo. Substantial improvements in the PANSS total score were evident as early as day 8 with extended-release aripiprazole lauroxil therapy and continued through the end of the treatment period. The secondary efficacy end point was the Clinical Global Impression-Improvement (CGI-I) score on day 85. Both groups of patients receiving extended-release aripiprazole lauroxil therapy demonstrated substantially better CGI-I scores compared with the placebo group. An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, race, or body weight.
Although the efficacy of oral aripiprazole as maintenance therapy in pediatric patients with schizophrenia has not been systematically evaluated, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
If aripiprazole is used for extended periods as maintenance therapy for schizophrenia, the need for continued therapy should be reassessed periodically. (
See Dosage and Administration: Dosageand see also Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions.)
The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial. The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients. Conventional antipsychotic agents may be considered first-line therapy in patients who have been treated successfully in the past with or who prefer conventional agents. The choice of an antipsychotic agent should be individualized, considering past response to therapy, adverse effect profile (including the patient's experience of subjective effects such as dysphoria), and the patient's preference for a specific drug, including route of administration.
Aripiprazole is used orally as monotherapy or as an adjunct to either lithium or valproate for the acute treatment of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. According to DSM-IV criteria, manic episodes are distinct periods lasting 1 week or longer (or less than 1 week if hospitalization is required) of abnormally and persistently elevated, expansive, or irritable mood accompanied by at least 3 (or 4 if the mood is only irritability) of the following 7 symptoms: grandiosity, reduced need for sleep, pressure of speech, flight of ideas, distractability, increased goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation, and engaging in high-risk behavior (e.g., unrestrained buying sprees, sexual indiscretions, foolish business investments).
Efficacy of aripiprazole monotherapy in the treatment of acute manic and mixed episodes has been demonstrated in 4 short-term (i.e., 3 weeks' duration), placebo-controlled trials in hospitalized adults who met DSM-IV criteria for bipolar I disorder with manic or mixed episodes. These studies included patients with or without psychotic features and 2 of the studies also included patients with or without a rapid cycling course. The principal rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). The main secondary rating instrument used in these trials was the Clinical Global Impression-Bipolar (CGI-BP) scale. In these trials, aripiprazole 15-30 mg once daily (with an initial dosage of 15 mg daily in 2 studies and an initial dosage of 30 mg daily in the other 2 studies) was found to be superior to placebo in the reduction of the Y-MRS total score and the CGI-BP Severity of Illness score (mania). In the 2 studies with an initial aripiprazole dosage of 15 mg daily, 48 and 44% of patients were receiving 15 mg daily at the study end point; in the 2 studies with an initial dosage of 30 mg daily, 86 and 85% of patients were receiving 30 mg daily at end point.
Aripiprazole is used as monotherapy for the acute treatment of manic and mixed episodes associated with bipolar I disorder with or without psychotic features in pediatric patients 10-17 years of age. Efficacy of aripiprazole in the acute treatment of manic and mixed episodes has been demonstrated in a double-blind, placebo-controlled study of 4 weeks' duration in pediatric outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed episodes (with or without psychotic features) and who had Y-MRS scores of 20 or greater at baseline. Patients in this study received aripiprazole 10 mg daily, aripiprazole 30 mg daily, or placebo. Aripiprazole was initiated at a dosage of 2 mg daily, then titrated to 5 mg daily after 2 days, and to the target dosage of 10 mg daily in 5 days or 30 mg daily in 13 days. Both dosages of aripiprazole were found to be superior to placebo in the reduction of the Y-MRS total score from baseline to week 4.
Efficacy of aripiprazole as an adjunct to lithium or valproate in the treatment of acute manic and mixed episodes has been demonstrated in a placebo-controlled study of 6 weeks' duration in adult outpatients who met DSM-IV criteria for bipolar I disorder manic or mixed type (with or without psychotic features). Patients initially received open-label lithium (dosage producing a serum lithium concentration of 0.6-1 mEq/L) or valproate (dosage producing a serum valproic acid concentration of 50-125 mcg/mL) monotherapy for 2 weeks during the lead-in phase. At the end of 2 weeks, patients demonstrating an inadequate response to lithium or valproate were randomized to receive either aripiprazole (15 mg daily or increased to 30 mg daily as early as day 7) or placebo as adjunctive therapy with open-label lithium or valproate during the 6-week, placebo-controlled phase. Patients who received adjunctive aripiprazole with lithium or valproate demonstrated greater reductions in the Y-MRS total score and the CGI-BP Severity of Illness score (mania) compared with patients who received adjunctive placebo with lithium or valproate.
The use of aripiprazole as an adjunct to lithium or valproate in the acute treatment of manic or mixed episodes associated with bipolar I disorder has not been evaluated in the pediatric population. However, the manufacturer states that such efficacy can be extrapolated from adult data in addition to comparisons of aripiprazole pharmacokinetic parameters in adult and pediatric patients.
For the initial management of less severe manic or mixed episodes in patients with bipolar disorder, current APA recommendations state that monotherapy with lithium, valproate (e.g., valproate sodium, valproic acid, divalproex), or an antipsychotic such as olanzapine may be adequate. For more severe manic or mixed episodes, combination therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy.
Aripiprazole has been used as monotherapy and adjunctive therapy in the maintenance treatment of bipolar I disorder. However, efficacy results from controlled, long-term studies conducted to date have not been compelling, particularly with regard to delaying time to relapse to depressive episodes compared with placebo, and maintenance treatment of bipolar disorder is no longer included as a labeled indication in the prescribing information for oral aripiprazole in the US.
Efficacy of oral aripiprazole as monotherapy for the maintenance treatment of bipolar I disorder was evaluated in a 26-week, double-blind, placebo-controlled trial in patients with a recent manic or mixed episode who had been stabilized on open-label aripiprazole monotherapy (15-30 mg daily); patients who maintained clinical response with the drug for at least 6 weeks were randomized to either continue aripiprazole at the same dosage or be switched to placebo and monitored for manic or depressive relapse. In this study, time to relapse to any mood episode, particularly manic episode, was substantially longer and there were fewer manic relapses among patients receiving aripiprazole than in those receiving placebo. There were no differences between aripiprazole and placebo in time to relapse to depressive or mixed episodes or in the number of depressive episodes. A 74-week extension of the study also found that time to relapse to any mood episode, particularly manic episode, was substantially longer with aripiprazole than placebo at 100 weeks of treatment; however, the design and interpretation of these study findings suggesting aripiprazole's efficacy in the maintenance therapy of bipolar disorder have been criticized (i.e., insufficient duration to demonstrate prophylactic efficacy, use of an ''enriched'' patient sample consisting of aripiprazole responders, abrupt discontinuance of aripiprazole in patients randomized to placebo, and low study completion rate). Time to relapse to depressive episode was not substantially different between treatment groups during the 74-week extension phase.
Aripiprazole as adjunctive maintenance therapy in adults with bipolar I disorder was evaluated in a double-blind, placebo-controlled trial in patients with a recent manic or mixed episode. Patients in this study had received lithium or valproate therapy for at least 2 weeks, and those with an inadequate response to the mood stabilizer also received adjunctive aripiprazole therapy (10-30 mg daily) and were maintained on the combined regimen for at least 12 weeks. Patients who maintained clinical response with aripiprazole and a mood stabilizer during this period were randomized to either continue aripiprazole or be switched to placebo (combined with lithium or valproate therapy) and monitored for manic, mixed, or depressive relapse for a maximum of 52 weeks. Patients receiving adjunctive aripiprazole therapy with lithium or valproate experienced a significant delay in time to relapse to any mood episode compared with those receiving placebo plus lithium or valproate, particularly for relapse to manic episode; no difference between the treatment groups was observed for time to relapse to depressive episode.
Major Depressive Disorder
Aripiprazole is used orally as an adjunct to antidepressants for the acute treatment of major depressive disorder. The adjunctive efficacy of aripiprazole has been demonstrated in 2 short-term, double-blind, placebo-controlled trials of 6 weeks' duration in adults who met DSM-IV criteria for major depressive disorder and who had an inadequate response to previous antidepressant therapy (1-3 courses) in the current episode and who had also demonstrated an inadequate response during a prospective treatment period to 8 weeks of antidepressant therapy with extended-release paroxetine, extended-release venlafaxine, fluoxetine, escitalopram, or sertraline. The primary instrument used for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale used to assess the degree of depressive symptomatology. The principal secondary instrument was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning (work/school, social life, and family life), with each item scored from 0 (not at all) to 10 (extreme). In both of these trials, aripiprazole was found to be superior to placebo in reducing mean MADRS total scores; aripiprazole was also superior to placebo in reducing the mean SDS score in one study. Patients in both trials initially received an aripiprazole dosage of 5 mg daily; subsequent dosage adjustments, based on efficacy and tolerability, could be made in 5-mg increments 1 week apart. Allowable aripiprazole dosages were 2, 5, 10, and 15 mg daily; patients who were not receiving the potent cytochrome P-450 (CYP) isoenzyme 2D6 inhibitors fluoxetine and paroxetine could also receive 20 mg daily.
An analysis of population subgroups did not reveal evidence of differential response based on age, choice of prospective antidepressant, or race. With regard to gender, a smaller mean reduction in the MADRS total score was observed in males than in females.
Irritability Associated with Autistic Disorder
Aripiprazole is used orally for the acute treatment of irritability associated with autistic disorder. Efficacy of aripiprazole was established in 2 double-blind, placebo-controlled trials of 8 weeks' duration in pediatric patients 6-17 years of age who met DSM-IV criteria for autistic disorder and demonstrated behaviors such as aggression towards others, self-injurious behavior, quickly changing moods, or a combination of these behaviors. Over 75% of the enrolled patients were under 13 years of age. The primary instruments used for assessing clinical efficacy were the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Improvement (CGI-I) scale. The primary outcome measure in both trials was the change from baseline to end point in the irritability subscale of the ABC (ABC-I). In one of the trials, 98 children and adolescents with autistic disorder received flexible daily dosages of aripiprazole ranging from 2-15 mg daily, starting at 2 mg daily with increases allowed up to 15 mg daily based on clinical response, or placebo. In this trial, aripiprazole improved scores on both the ABC-I subscale and on the CGI-I scale compared with placebo. The mean daily dosage of aripiprazole at the end of the 8-week treatment period was approximately 9 mg daily. In the other trial, 218 children and adolescents with autistic disorder received one of 3 fixed dosages of aripiprazole (5, 10, or 15 mg daily) or placebo. Aripiprazole therapy was started at 2 mg daily and was increased to 5 mg daily after 1 week. After the second week, the dosage was increased to 10 mg daily for patients in the 10- and 15-mg daily dosage arms; after the third week, the dosage was increased to 15 mg daily in the 15-mg daily treatment arm. Patients receiving all 3 aripiprazole dosages in this study demonstrated improved ABC-I subscale and CGI-I scores compared with placebo.
Aripiprazole is used orally for the treatment of Tourette's syndrome (Gilles de la Tourette's syndrome). Efficacy of aripiprazole was established in 2 controlled trials (one 8-week and one 10-week) in pediatric patients who met DSM-IV criteria for Tourette's disorder and who had a total tic score (TTS) of at least 20-22 on the Yale Global Tic Severity Scale (YGTSS). The YGTSS is a fully validated scale that measures current tic severity. The primary outcome measure in both trials was the change from baseline to end point in the TTS on the YGTSS (YGTSS TTS). Over 65% of the enrolled patients were under 13 years of age.
In the 8-week, placebo-controlled, fixed-dose trial, 133 patients 7-17 years of age were randomized to receive high-dose aripiprazole (target daily dosage of 10 mg for patients weighing less than 50 kg and 20 mg for those weighing 50 kg or more), low-dose aripiprazole (target daily dosage of 5 mg for those weighing less than 50 kg and 10 mg for those weighing 50 kg or more), or placebo. Aripiprazole was initiated at 2 mg daily and increased to 5 mg after 2 days with subsequent increases of 5 mg on day 7 and weekly thereafter when the target dosage was 10 mg daily or higher. Patients receiving aripiprazole in both the high-dose and low-dose groups demonstrated substantially improved scores on the YGTSS TTS compared with patients receiving placebo.
In the 10-week, placebo-controlled, flexible-dose study, which was conducted in Korea, 61 patients 6-18 years of age with Tourette's syndrome were randomized to receive flexible daily dosages of aripiprazole, starting at 2 mg daily with increases allowed up to 20 mg daily based on clinical response, or placebo. The aripiprazole-treated patients in this study demonstrated substantially improved scores on the YGTSS TTS compared with patients receiving placebo. The mean daily dosage of aripiprazole at the end of the 10-week treatment period was approximately 6.5 mg daily.
Agitation Associated with Schizophrenia or Bipolar Mania
Aripiprazole is used IM for the acute management of agitation associated with schizophrenia or bipolar disorder, manic or mixed, in patients for whom treatment with aripiprazole is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).
The efficacy of IM aripiprazole for the management of acute agitation was established in 3 short-term (i.e., single-day), placebo-controlled trials in hospitalized, agitated patients with either schizophrenia or bipolar I disorder (manic or mixed episodes, with or without psychotic features). Each of the 3 trials used a single active comparator treatment of either haloperidol injection (for the schizophrenia studies) or lorazepam (for the bipolar mania study). Patients enrolled in the studies needed to be judged by the investigators as clinically agitated and appropriate candidates for IM therapy. In addition, the patients needed to exhibit a level of agitation that met or exceeded a threshold score of 15 on the 5 items constituting the Positive and Negative Syndrome Scale (PANSS) Excited Component (i.e., poor impulse control, tension, hostility, uncooperativeness, and excitement items) with at least 2 individual item scores of 4 (''moderate'') or greater using a 1-7 scoring system, where scores of 1 or 7 indicate absent or extreme agitation, respectively. The primary measure used for assessing efficacy in managing agitation in these trials was the change from baseline in the PANSS Excited Component at 2 hours postinjection. A key secondary measure was the Clinical Global Impression-Improvement (CGI-I) scale. Patients could receive up to 3 injections of IM aripiprazole; however, patients could not receive the second injection until after the initial 2-hour period when the primary efficacy measure was assessed.
In the first placebo-controlled trial, IM aripiprazole was given in fixed single doses of 1, 5.25, 9.75, or 15 mg in agitated hospitalized patients presenting predominantly with schizophrenia. All IM aripiprazole doses, with the exception of the 1-mg dose, were found to be superior to placebo in reducing the PANSS Excited Component score and on the CGI-I scale at 2 hours following injection in this study. In the second placebo-controlled trial in agitated hospitalized patients predominantly with schizophrenia, one fixed IM dose of aripiprazole 9.75 mg was evaluated and found to be superior to placebo on the PANSS Excited Component and on the CGI-I scale at 2 hours following injection. In the third placebo-controlled trial in agitated hospitalized patients with bipolar I disorder (manic or mixed), 2 fixed aripiprazole injection doses of 9.75 mg and 15 mg were evaluated; both doses were found to be superior to placebo in reducing the PANSS Excited Component score at 2 hours postinjection. 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.