Risperidone 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.
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 also may be an appropriate first-line option for some patients, including those 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, current symptomatology, concurrent medical conditions, other medications and treatments, adverse effect profile, and the patient's preference for a specific drug, including route of administration. 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.
Risperidone is used orally for the treatment of schizophrenia in adults and adolescents 13-17 years of age and IM as an extended-release injection for the treatment of schizophrenia in adults. 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 risperidone for the treatment of schizophrenia in adults was established in 4 controlled studies of 4-8 weeks' duration in patients who met DSM-III-R criteria for schizophrenia and who were hospitalized for psychotic symptoms. In these and other clinical studies conducted principally in patients with schizophrenia, oral risperidone was more effective than placebo and at least as effective as conventional (e.g., haloperidol, perphenazine) and certain atypical (e.g., olanzapine) antipsychotics in the treatment of schizophrenia. Data from limited clinical studies indicate that risperidone improves both positive and negative manifestations of schizophrenia, but that such improvements may not be substantially greater than those achieved by haloperidol, a conventional antipsychotic. In these studies, improvement in manifestations of schizophrenia was based on the results of various psychiatric rating scales, including the Brief Psychiatric Rating Scale (BPRS) that assesses factors such as anergy, thought disturbances, activation, hostility/suspiciousness, and anxiety/depression; the BPRS psychosis cluster that assesses factors such as conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content in actively psychotic schizophrenic patients; the Scale for the Assessment of Negative Symptoms (SANS); the Positive and Negative Syndrome Scale (PANSS); and the Clinical Global Impression (CGI) scale.
Long-term efficacy of oral risperidone for the treatment of schizophrenia was established in a randomized, double-blind study in 365 adult outpatients who met DSM-IV criteria for schizophrenia or schizoaffective disorder. Patients were randomized to receive either flexible dosages of risperidone (2-8 mg daily) or haloperidol (5-20 mg daily) for 1-2 years and observed for relapse. Patients receiving risperidone experienced a substantially longer time to relapse than those who received haloperidol. In this study, approximately 25% of patients who received usual dosages of risperidone had relapsed by the end of the study compared with approximately 40% of those receiving usual dosages of haloperidol.
Efficacy of oral risperidone for the treatment of schizophrenia in adolescents was demonstrated in 2 short-term, double-blind clinical trials of 6-8 weeks' duration in adolescent patients 13-17 years of age who met DSM-IV criteria for schizophrenia and were experiencing an acute episode of schizophrenia at the time of enrollment. In the first study, patients were randomized to receive flexible dosages of risperidone of 1-3 mg daily or 4-6 mg daily or placebo. In the second study, patients were randomized to receive either risperidone target dosages of 0.15-0.6 mg daily or 1.5-6 mg daily. The primary efficacy measure in both studies was the change in total PANSS score from baseline. In these studies, risperidone in the target dosage groups from 1-6 mg daily was found to be more effective than placebo in substantially reducing the total PANSS score; however, dosages higher than 3 mg daily did not demonstrate additional efficacy.
Efficacy of the extended-release IM formulation of risperidone (Risperdal Consta) in the treatment of schizophrenia in adults was established, in part, based on extrapolation of efficacy data from oral risperidone. In addition, efficacy of extended-release IM risperidone was established in a multicenter, placebo-controlled study of 12 weeks' duration in adult inpatients and outpatients who met DSM-IV criteria for schizophrenia. During the 1-week run-in period of this study, other oral antipsychotic agents were discontinued and all patients received oral risperidone therapy (initially, 2 mg daily and titrated up to 4 mg daily for at least 3 days). During the 12-week, double-blind phase, patients were randomized to receive IM injections of 25, 50, or 75 mg of extended-release risperidone or placebo every 2 weeks. Patients receiving extended-release IM injections of risperidone were also given oral risperidone (2 mg daily in the 25-mg group, 4 mg in the 50-mg group, and 6 mg in the 75-mg group) for 3 weeks following the first injection to provide therapeutic plasma concentrations of the drug until the main release phase of risperidone from the IM injection site had begun; patients who received placebo injections were given placebo tablets. The primary efficacy measure in this study was the change in total PANSS score from baseline to end point. Total PANSS scores demonstrated substantially greater improvement in the patients treated with each of the 3 IM dosages of extended-release risperidone (25, 50, and 75 mg every 2 weeks) compared with patients receiving placebo. Although there were no significant differences in treatment effects between the 3 dosage groups, the effect size for the 75-mg group was numerically less than that of the 50-mg group. Subgroup analyses did not reveal any differences in treatment outcomes based on age, race, or gender.
Efficacy of extended-release IM risperidone in the treatment of schizophrenia has not been evaluated in controlled clinical trials for longer than 12 weeks; however, oral risperidone has been shown to be effective in delaying time to relapse with longer-term use. If the extended-release IM injection of risperidone is used for extended periods, the long-term risks and benefits of the drug should be reassessed periodically on an individualized basis.
Parenteral antipsychotic therapy with a long-acting IM preparation may be particularly useful in patients with schizophrenia and a history of poor compliance. In addition, long-acting antipsychotic preparations may be useful in patients with suspected GI malabsorption or variable GI absorption of the drug. The principal disadvantage of long-acting parenteral antipsychotics is the inability to terminate the drug's action when severe adverse reactions occur.
The manufacturer of extended-release IM risperidone recommends that patients should first receive oral risperidone therapy to establish tolerability of the drug before the long-acting IM preparation is used.
For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program,
Although risperidone has been studied for use in the management of psychosis and aggression in institutionalized geriatric patients with moderate to severe dementia of the Alzheimer's type (Alzheimer's disease, presenile or senile dementia), vascular dementia, or a combination of the 2 types of dementia (i.e., mixed dementia), use of the drug in geriatric patients with dementia-related psychosis is associated with an increased risk of adverse cerebrovascular events. In randomized, placebo-controlled studies in nursing home residents with dementia, oral risperidone at a dosage of approximately 1 mg daily was more effective than placebo in decreasing psychotic and behavioral symptoms (e.g., aggression, agitation) of dementia, as assessed by the Behavioral Pathology in Alzheimer's Disease scale (BEHAVE-AD) and the Cohen-Mansfield Agitation Inventory (CMAI). However, evidence from these studies showed a significantly higher incidence of adverse cerebrovascular events such as stroke and transient ischemic attacks (TIAs) associated with risperidone therapy relative to placebo. In addition, geriatric patients with dementia-related psychosis treated with atypical antipsychotic agents are at an increased risk of death compared with that among patients receiving placebo.
(See Cautions: Geriatric Precautions.)Risperidone is not approved for the treatment of dementia-related psychosis.
Risperidone is used orally as monotherapy for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults and adolescents 10-17 years of age, or in conjunction with lithium or valproate for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults. Risperidone as an extended-release injection is also used IM as monotherapy or adjunctive therapy with lithium or valproate for the maintenance treatment of bipolar I disorder in adults.
Efficacy of oral risperidone monotherapy in the treatment of acute manic and mixed episodes has been demonstrated in 2 placebo-controlled trials of 3 weeks' duration in adults who met the DSM-IV criteria for bipolar I disorder with acute manic or mixed episodes with or without psychotic features. 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). In the first 3-week, placebo-controlled trial, which was limited to patients with manic episodes, risperidone monotherapy was given at an initial dosage of 3 mg daily and subsequently in a flexible dosage ranging from 1-6 mg daily; the mean modal dosage was 4.1 mg daily. In the second 3-week, placebo-controlled trial, patients also were given an initial dosage of risperidone 3 mg daily and subsequently a flexible dosage ranging from 1-6 mg daily; the mean modal dosage was 5.6 mg daily. Risperidone was found to be superior to placebo in the reduction of the Y-MRS total score in both studies.
Efficacy of oral risperidone as monotherapy in the treatment of acute manic or mixed episodes associated with bipolar I disorder in children and adolescents 10-17 years of age was demonstrated in a 3-week, double-blind, placebo-controlled trial. The pediatric patients were randomized to receive 1 of 2 dosage ranges of risperidone or placebo. Risperidone was initiated at 0.25 mg daily and titrated to the maximum tolerated dosage within the target dosage ranges of 0.5-2.5 mg daily or 3-6 mg daily within 10 days. The principal rating instrument used for assessing manic symptoms in this trial was the Y-MRS. Both dosage ranges of risperidone were found to be substantially superior to placebo in reducing the Y-MRS total score; however, dosages exceeding 2.5 mg daily did not demonstrate greater efficacy than lower dosages of the drug (0.5-2.5 mg daily).
Efficacy of oral risperidone when used in conjunction with lithium or valproate in the treatment of acute manic or mixed episodes associated with bipolar I disorder has been demonstrated in one placebo-controlled trial of 3 weeks' duration in adults who met the DSM-IV criteria for bipolar I disorder (with or without a rapid cycling course) and who met diagnostic criteria for an acute manic or mixed episode (with or without psychotic features). In this study, inpatients and outpatients with bipolar disorder experiencing manic or mixed episodes who had not adequately responded to lithium or valproate monotherapy were randomized to receive risperidone, haloperidol, or placebo in conjunction with their original therapy. Risperidone therapy was given in an initial dosage of 2 mg daily and subsequently given in a flexible dosage ranging from 1-6 mg daily; the mean modal dosage was 3.8 mg daily. Lithium and valproate were given in conjunction with risperidone and plasma drug concentrations were maintained within therapeutic ranges of 0.6-1.4 mEq/L for lithium and 50-120 mcg/mL for valproate. Addition of risperidone to lithium or valproate was shown to be superior to continued monotherapy with lithium or valproate as assessed by reduction of Y-MRS total score.
In a second 3-week, placebo-controlled trial, inpatients and outpatients with bipolar mania receiving lithium, valproate (as divalproex), or carbamazepine therapy with inadequately controlled manic or mixed symptoms were randomized to receive oral risperidone or placebo in conjunction with their original therapy. Risperidone was given in a flexible dosage range of 1-6 mg daily, with an initial dosage of 2 mg daily; the mean modal dosage was 3.7 mg daily. Addition of risperidone to lithium, valproate, or carbamazepine therapy (with plasma drug concentrations maintained within therapeutic ranges of 0.6-1.4 mEq/L, 50-125 mcg/mL, or 4-12 mcg/mL, respectively) was not found to be superior to lithium, valproate, or carbamazepine given alone as assessed by reduction of the Y-MRS total score. A possible explanation for the failure of this trial was enzymatic induction of clearance of risperidone and its principal active metabolite, 9-hydroxyrisperidone, by carbamazepine in the subgroup of patients receiving combined therapy with these drugs, resulting in subtherapeutic plasma concentrations of risperidone and 9-hydroxyrisperidone.
Efficacy of the extended-release IM formulation of risperidone (Risperdal Consta) as monotherapy in the maintenance treatment of bipolar I disorder was established in a multicenter, placebo-controlled trial in adults who met the DSM-IV criteria for bipolar I disorder and who were either stable on their drug regimen or experiencing an acute manic or mixed episode. All patients in this study were treated with open-label extended-release IM risperidone therapy for 26 weeks. Patients received an initial risperidone dosage of 25 mg IM every 2 weeks; the dosage was increased to 37.5 or 50 mg or decreased to 12.5 mg every 2 weeks as clinically indicated; patients who maintained response at 26 weeks were randomized to double-blind treatment with either the same IM dosage of risperidone or placebo and then monitored for relapse. Time to relapse to any mood episode (the primary outcome variable) was substantially delayed in patients receiving extended-release IM risperidone therapy compared with placebo. The majority of relapses were caused by manic rather than depressive symptoms; based on patient history, patients enrolled in the study had more manic episodes than depressive episodes.
Efficacy of extended-release IM risperidone as adjunctive therapy with lithium or valproate in the maintenance treatment of bipolar I disorder was established in a multicenter, double-blind, placebo-controlled study in adults with bipolar I disorder treated with mood stabilizers (primarily lithium or valproate), antidepressants, and/or anxiolytics who had experienced at least 4 episodes of mood disorder requiring clinical intervention in the previous 12 months and at least 2 episodes in the previous 6 months. Following a 16-week, open-label treatment phase with extended-release IM risperidone (initial risperidone dosage of 25 mg every 2 weeks and increased to 37.5 or 50 mg or decreased to 12.5 mg, if necessary), patients who remained stable were randomized either to continue IM risperidone at the same dosage or to receive placebo for up to 52 weeks while continuing their usual treatment and were observed for relapse. Continuation of IM risperidone therapy in addition to mood stabilizers delayed time to relapse to any mood episode (depression, mania, hypomania, or mixed) compared with placebo; the relapses were approximately half depressive and half manic or mixed episodes in this study.
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, combined therapy with an antipsychotic and lithium or valproate is recommended as first-line therapy. For further information on the management of bipolar disorder,
The manufacturers state that clinicians who elect to use risperidone for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.
Risperidone is used orally for the management of irritability associated with autistic disorder in children and adolescents, including symptoms of aggression towards others, deliberate self-injuriousness, temper tantrums, and quickly changing moods.
Short-term efficacy of oral risperidone in children and adolescents with autistic disorder was established in 2 placebo-controlled trials of 8 weeks' duration in 156 children and adolescents (aged 5-16 years) who met the DSM-IV criteria for autistic disorder. Over 90% of the patients in these 2 trials were under 12 years of age and the majority weighed over 20 kg (weight range: 16-104.3 kg). The principal rating instruments used for assessing efficacy in these trials were the Aberrant Behavior Checklist (ABC) and the Clinical Global Impression-Change (CGI-C) scale. The primary outcome measure in both trials was the change from baseline to endpoint in the Irritability subscale of the ABC (ABC-I), which measures the emotional and behavioral symptoms of autism, including aggression toward others, deliberate self-injuriousness, temper tantrums, and rapidly changing moods. The CGI-C rating at endpoint was a co-primary outcome measure in one of the studies.
In the first 8-week, placebo-controlled trial, children and adolescents 5-16 years of age with autistic disorder received twice-daily placebo or risperidone 0.5-3.5 mg daily on a weight-adjusted basis, starting at 0.25 mg daily or 0.5 mg daily if baseline weight was less than 20 kg or 20 kg or greater, respectively; dosage was then titrated according to clinical response. Risperidone (mean modal dosage of 1.9 mg/day; equivalent to 0.06 mg/kg daily) was found to substantially improve scores on the ABC-I subscale and the CGI-C scale compared with placebo in this study.
In the second 8-week, placebo-controlled trial, children and adolescents 5-12 years of age with autistic disorder were given an initial risperidone dosage of 0.01 mg/kg daily, which was then titrated up to 0.02-0.06 mg/kg daily based on clinical response. Risperidone (mean modal dosage of 0.05 mg/kg daily; equivalent to 1.4 mg daily) substantially improved scores on the ABC-I subscale compared with placebo.
A third clinical trial conducted in children and adolescents 5-17 years of age who met DSM-IV criteria for autistic disorder and who had associated irritability and related behavioral symptoms compared 2 weight-based, fixed dosages of oral risperidone (high-dose and low-dose). Over 77% of the enrolled patients were younger than 12 years of age (mean age: 9 years) and 88% of the patients were male. In this 6-week, multicenter, double-blind study, patients were randomized to receive high-dose risperidone (1.25 mg daily for patients weighing from 20 to up to 45 kg and 1.75 mg daily for patients weighing 45 kg or more), low-dose risperidone (0.125 mg daily for those weighing from 20 to up to 45 kg and 0.175 mg daily for those weighing 45 kg or more), or placebo; the doses were administered once daily in the morning or evening (if sedation occurred). The primary outcome measure in this study was the change from baseline to end point in the ABC-I subscale. Treatment with risperidone substantially improved ABC-I scores in the high-dose risperidone group but not in the low-dose group, compared with placebo.
The efficacy of oral risperidone for long-term use (i.e., longer than 8 weeks) in children and adolescents with autistic disorder has been demonstrated in an open-label extension of the first 8-week, placebo-controlled trial in which 63 patients received risperidone for 4 or 6 months (depending on whether they received risperidone or placebo in the double-blind study). During the open-label treatment period, patients were maintained on a mean modal risperidone dosage of 1.8-2.1 mg daily (equivalent to 0.05-0.07 mg/kg daily).
Children and adolescents who maintained their positive response to risperidone (defined as at least a 25% improvement on the ABC-I subscale and a CGI-C rating of much improved or very much improved) during the 4-6 month, open-label treatment period (average duration of therapy was 140 days) were randomized to receive either risperidone or placebo during an 8-week, double-blind withdrawal trial. A substantially lower relapse rate was observed in the risperidone group compared with the placebo group during the pre-planned interim analysis of data from this trial. Based on the interim analysis results, the study was terminated since a statistically significant effect on relapse prevention was demonstrated. Relapse was defined as at least a 25% worsening on the most recent assessment of the ABC-I subscale (in relation to baseline for the randomized withdrawal phase).
The manufacturers state that clinicians who elect to use risperidone in children and adolescents with autistic disorder for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient.
Although not curative, pharmacologic agents, such as risperidone, generally are used in children and adolescents with autistic disorder to reduce behavioral disturbances associated with autism and to help facilitate the child's or adolescent's adjustment and engagement in intensive, targeted educational interventions. In clinical studies, risperidone was not found to improve certain core symptoms of autism (e.g., language deficits, impaired social relatedness). However, the drug was more effective than placebo in improving scores on subscales for sensory motor behaviors, affectual reactions, and sensory responses in a controlled study. The possible risks, including clinically important weight gain, tardive dyskinesia, withdrawal dyskinesia, and other extrapyramidal reactions associated with the drug, should be considered.
Risperidone also has been used in a limited number of adults for the treatment of autistic disorder and other pervasive developmental disorders.