Ramy Mahmoud

Effects of Risperidone Augmentation in Patients with Treatment-Resistant Depression: Results of Open-Label Treatment Followed by Double-Blind Continuation

Approximately one-third of persons with depression do not respond to antidepressant monotherapy. Studies suggest that atypical antipsychotic augmentation may benefit these patients. We investigated the longer-term efficacy of risperidone augmentation of serotonin-selective reuptake inhibitor treatment for resistant depression. In 57 in- and outpatient centers in three countries, we conducted a three-phase study with 4–6 weeks of open-label citalopram monotherapy, 4–6 weeks of open-label risperidone augmentation, and a 24-week double-blind, placebo-controlled discontinuation phase. A total of 489 patients with major depressive disorder and 1–3 documented treatment failures entered the citalopram monotherapy phase (20–60 mg/day). Patients with <50% reduction in HAM-D-17 scores entered the risperidone augmentation phase (0.25–2.0 mg/day). Patients with HAM-D-17⩽7 or CGI-S⩽2 were randomized to risperidone or placebo augmentation. The primary outcome was time to relapse during the double-blind phase. During citalopram monotherapy, 434 patients had <50% HAM-D-17 reduction; 299 (68.9%) were fully nonresponsive (<25% reduction) and 135 were partially nonresponsive (25–49% reduction). Of the 386 nonresponders who entered the augmentation phase, 243 remitted and 241 entered the double-blind phase. Median time to relapse was 102 days with risperidone augmentation and 85 days with placebo (NS); relapse rates were 53.3 and 54.6%, respectively. In a post hoc analysis of patients fully nonresponsive to citalopram monotherapy, median time to relapse was 97 days with risperidone augmentation and 56 with placebo (p=0.05); relapse rates were 56.1 and 64.1%, respectively (p⩽0.05). Open-label risperidone augmentation substantially enhanced response in treatment-resistant patients, but the longer-term benefits of augmentation were not demonstrated in this study.

Risperidone for Treatment-Refractory Major Depressive Disorder: A Randomized Trial

Context Does augmentation with an atypical antipsychotic improve symptoms in patients with major depression that is suboptimally responsive to antidepressant monotherapy? Contribution This double-blind randomized trial found that 6 weeks of treatment with risperidone improved symptoms more than placebo in 274 adults with major depression that was suboptimally responsive to antidepressant monotherapy. Risperidone, compared with placebo, resulted in more remissions (25% vs. 11%), as well as more cases of somnolence (5% vs. 2%) and dry mouth (5% vs. 1%). Caution The trial duration was short, and 19% of risperidone recipients did not complete treatment. Implication Risperidone augmentation may improve symptoms in some patients with suboptimal response to antidepressant monotherapy. The Editors Major depressive disorder is the leading cause of disability worldwide (1), affecting nearly 121 million people. It is associated with increased overall mortality (2, 3); premature cardiovascular-related death (4, 5); and morbidity, including disability, lost productivity, and decreased wages, compared with individuals without depression (6). Selective serotonin reuptake inhibitors (SSRIs) and serotoninnorepinephrine reuptake inhibitors are generally considered first-line treatments for depression. Despite a sufficient dose and duration of antidepressant treatment, symptoms do not resolve in 30% to 40% of patients with major depressive disorder (710). Remission, defined as the virtual absence of depressive symptoms, is important because it is associated with improved patient prognosis and functioning relative to response (generally defined as 50% reduction in symptoms) (11, 12). In an effort to improve the therapeutic efficacy of antidepressant monotherapy, several pharmacologic strategies to modulate different or additional neurotransmitters (1315) are commonly used, despite a paucity of evidence from randomized clinical trials. These strategies include switching monotherapy within (10, 1618) or between antidepressant classes (10, 1921), combination regimens consisting of 2 antidepressants (2226), and augmentation of antidepressants with nonstandard treatmentsfor example, thyroid hormone (27); S-adenosyl-l-methionine (28); lithium (29); cyclooxygenase-2 inhibitors (30); or an atypical antipsychotic (3133), such as risperidone. Findings of several open-label studies (3135) suggest that atypical antipsychotic augmentation provides benefit in major depressive disorder that is suboptimally responsive to antidepressant monotherapy. Risperidone, whose activity includes blockade of certain serotonin and dopamine receptors, is considered an atypical antipsychotic. It is approved in the United States for treatment of bipolar mania and schizophrenia and in other countries for additional uses. The efficacy of risperidone has also been studied for various psychoses and behavioral disorders, including treatment-resistant depression and anxiety spectrum disorders (34, 3639). We hypothesized that low-dose risperidone augmentation would reduce symptoms of major depressive disorder, enhance clinical response and remission rates, and reduce disability and improve quality of life compared with continued antidepressant monotherapy. Preliminary data suggest that persons with a confirmed suboptimal response to previous treatment may respond to risperidone augmentation within 4 to 6 weeks (38). We therefore conducted a large, multicenter, double-blind, placebo-controlled trial to assess the clinical efficacy of risperidone augmentation from the clinician and patient perspectives and to evaluate tolerability in patients with major depressive disorder who continue to experience symptoms despite an adequate trial of standard antidepressants. Methods Design Consenting persons entered a 4-week prospective open-label run-in period during which they received their current antidepressant monotherapy at the dosages recommended in product labeling, so that we could confirm an insufficient response to standard monotherapy. The run-in period was followed by a 6-week double-blind treatment phase; during this phase, patients who continued to experience depressive symptoms, defined as a Clinical Global ImpressionSeverity of illness (CGI-S) score of 4 or greater and a Carroll Depression Scale (40) score of 20 or greater, were randomly assigned to receive risperidone augmentation therapy or placebo. A 4-week follow-up phase of open-label risperidone augmentation therapy was available to participants who completed at least 4 weeks of double-blind treatment (results not shown). Setting and Participants Outpatients 18 to 65 years of age who had received antidepressant monotherapy for at least 4 weeks and met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (41), criteria for unremitting major depressive disorder (single or recurrent episodes) and a CGI-S score of 4 or more (42) at the start of both the open-label and double-blind phases were eligible. The CGI-S is scored on a scale of increasing intensity from 1 to 7, with 4 representing moderate illness. We recruited participants by using various methods, including media advertisements, and enrolled persons from 75 public and private primary care (n= 41) and psychiatric (n= 34) centers in the United States between 19 October 2004 and 17 November 2005. Ethical approval was obtained from the institutional review board of each site, and written informed consent was obtained from all patients. Exclusion criteria were pregnancy; serious suicidal risk or serious medical or neurologic illness; active substance or alcohol use disorders; or current treatment with a tricyclic antidepressant, monoamine oxidase inhibitor, mood stabilizer, antiepileptic, or a centrally acting agent for attention deficit disorder/attention deficit hyperactivity disorder or narcolepsy. Randomization and Interventions Patients who were eligible for randomization continued their standard antidepressant regimen and dosage and were assigned to receive risperidone or placebo. Tablets were identical in appearance. The investigators, study staff, and patients were blinded to the treatment assignment. The randomization code was centrally generated and administered by a telephone interactive voice response system, was stratified by antidepressant class (SSRI or non-SSRI) and center, and occurred in random permuted blocks. An independent statistician provided the randomization codes. The dosing schedule was 0.25 mg for the first 3 days, 0.5 mg on days 4 to 15, and 1.0 mg on days 16 to 28. On day 29, patients with insufficient treatment response in the opinion of the investigator could continue augmentation at the current dosage, have the dosage increased to 2 mg/d, or discontinue double-blind treatment. Concomitant medications were allowed as necessary for medical conditions. Sedative agents (zolpidem, 2.5 to 10 mg/d, or zaleplon, 5 to 20 mg/d, as needed) were allowed for insomnia. During double-blind treatment, benztropine mesylate was permitted as needed for potential treatment-emergent motor effects. Measurements and Outcomes At each visit (end of the open-label phase and weeks 1, 2, 4, and 6), trained personnel administered the grid version of the 17-item Hamilton Rating Scale for Depression (HRSD-17) (43, 44) and the CGI-S (42), both clinician-rated instruments. Scores on the HRSD-17 range from 0 to 52; higher scores indicate more severe depression. Patients also independently rated their response by using the telephone interactive voice response system at baseline and weekly thereafter. Other patient-reported outcomes were scores on 3 validated instruments: the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) (45), the Patient Global Improvement Scale (7-point rating from 1 [very much improved] to 7 [very much worse]), and the Sheehan Disability Scale (SDS). Change in HRSD-17 total score from baseline to study end was the a priori primary efficacy measure. Response (50% reduction in HRSD-17 total score from baseline) and remission (HRSD-17 total score 7) were assessed at each time point. Secondary measures were changes in the CGI-S, Q-LES-Q, SDS, and Patient Global Improvement Scale scores. Follow-up Patients underwent physical examination, including assessment of vital signs, at regular intervals. Research staff maintained records of trial medication and assessed treatment compliance by matching doses taken with the number of treatment days. To assess adverse effects, patients were interviewed at each study visit with open-ended questions about potential adverse events; spontaneous reports were also taken into account. All adverse events were recorded, and the investigator assessed each event for severity and relationship to the study drug (probable, possible, not related). Statistical Analysis A sample of 116 patients per group was anticipated to have 90% power to detect an arbitrary difference in change in mean HRSD-17 total score of 3.0 units, assuming a common SD of 7.0 using a 2-group t test and a 2-sided significance level of 0.05. We also assumed that approximately 30% of the participants would not complete double-blind treatment and planned for 332 persons to undergo randomization. We further assumed that during the open-label run-in phase, 30% of participants would discontinue the study and 20% would respond to standard antidepressant treatment and therefore be ineligible for randomization; thus, we sought 592 persons for the open-label run-in phase. All analyses were performed by using SAS, version 8.2 (SAS Institute, Cary, North Carolina), and statistical analysis personnel were blinded to patient group assignment. Baseline patient characteristics were summarized by using descriptive statistics. Efficacy and safety analyses were based on the intention-to-treat population (that is, all persons who underwent randomization and received at least 1 dose of medication in the double-blind phase). Obser

The nasal approach to delivering treatment for brain diseases: an anatomic, physiologic, and delivery technology overview

The intricate pathophysiology of brain disorders, difficult access to the brain, and the complexity and high risks and costs of drug development represent major hurdles for improving therapies. Nose-to-brain drug transport offers an attractive alternative or addition to formulation-only strategies attempting to enhance drug penetration into the CNS. Although still a matter of controversy, many studies in animals claim direct nose-to-brain transport along the olfactory and trigeminal nerves, circumventing the traditional barriers to CNS entry. Some clinical trials in man also suggest nose-to-brain drug delivery, although definitive proof in man is lacking. This review focuses on new nasal delivery technologies designed to overcome inherent anatomical and physiological challenges and facilitate more efficient and targeted drug delivery for CNS disorders.

Risperidone treatment in elderly patients with dementia: relative risk of cerebrovascular events versus other antipsychotics

BACKGROUND The possibility that low-dose antipsychotic treatment is associated with increased risk of cerebrovascular events (CVEs) in elderly patients with dementia has been raised. The objective was to determine whether risperidone is associated with an increased risk of CVEs relative to other commonly considered alternative treatments. METHODS An analysis of Medicaid data from 1999 to 2002, representing approximately 8 million enrollees from multiple states, was conducted. The primary outcome was the incidence of acute inpatient admission for a CVE within 3 months following initiation of treatment with atypical antipsychotics (risperidone, olanzapine, quetiapine, or ziprasidone), haloperidol, or benzo-diazepines. RESULTS Descriptive analyses found similar rates of incident CVEs across evaluated agents. Multivariate analyses found no differences in comparisons of risperidone with olanzapine or quetiapine. Risperidone and other antipsychotics as a group were also not associated with a higher odds ratio (OR) of incident CVE than either haloperidol or benzodiazepines. With risperidone as the reference group: olanzapine, OR = 1.05, 95% CI 0.63-1.73; quetiapine, OR = 0.66, 95% CI 0.23-1.87; haloperidol, OR = 1.91, 95% CI 1.02-3.60; benzodiazepines, OR = 1.97, 95% CI 1.30-2.98. With benzodiazepines as the reference group, the OR of incident CVE for all antipsychotics as a class was 0.49, 95%CI 0.35-0.69. CONCLUSIONS This study found no significant difference in the incidence of CVEs between patients taking risperidone and those taking other atypical antipsychotics. Risperidone and all atypical antipsychotics were not associated with higher risk than two common treatment alternatives (haloperidol and benzodiazepines). These findings do not support the conclusion that risperidone is associated with a higher risk of CVE than other available treatment alternatives. The data also suggest that patient characteristics other than antipsychotic use are more significant predictors of CVEs. Given the relatively low rates of incident CVEs, a larger sample of patients with groups closely balanced on a wide spectrum of potential risk factors could provide a more precise assessment of risk.

A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization

OBJECTIVE This study compared the effects of atypical antipsychotics (risperidone or quetiapine) with placebo and with each other in recently exacerbated patients with schizophrenia requiring hospitalization. METHODS This international, randomized, double-blind study included a 2-week monotherapy phase followed by a 4-week additive therapy phase. Recently exacerbated patients with schizophrenia or schizoaffective disorder (DSM-IV) were randomized (2:2:1) to risperidone (n = 153), quetiapine (n = 156), or placebo (n = 73). Target doses were 4 or 6 mg/day of risperidone and 400 or 600 mg/day of quetiapine by day 5, with the ability to increase to 600 or 800 mg/day of quetiapine on day 8. The main outcome measures were the total Positive and Negative Syndrome Scale (PANSS) and need for additional psychotropic medications. RESULTS Monotherapy Phase: The combined atypical antipsychotic group (n = 308) reached borderline superiority to placebo (n = 71) at the 2-week endpoint on mean change in total PANSS score (-24.1 +/- 1.2 and -20.2 +/- 2.0, respectively; p = 0.067). The change in the atypical group was driven by the improvement with risperidone (-27.7 +/- 1.5 vs. -20.2 +/- 2.0 with placebo, p < 0.01; and vs. -20.5 +/- 1.5 with quetiapine, p < 0.01); the improvement with quetiapine was similar to placebo, p = 0.879. Results were similar on other efficacy endpoints. Additive Therapy Phase: Additional psychotropics were prescribed to fewer (p < 0.01) risperidone (36%) than quetiapine (53%) or placebo patients (59%). The overall discontinuation rate was 18%, 26%, and 38%, respectively. Risperidone, compared with placebo, was associated with more parkinsonism, akathisia, plasma prolactin changes, and weight gain; while quetiapine was associated with more somnolence, sedation, dizziness, constipation, tachycardia, thyroid dysregulation, and weight gain. CONCLUSION While the combined atypical antipsychotic group did not experience greater improvements than the placebo group, risperidone, but not quetiapine, was significantly superior in all measured domains to placebo in the management of recently exacerbated hospitalized patients with schizophrenia or schizoaffective disorder, with no unexpected tolerability findings.

Differences in health values among patients, family members, and providers for outcomes in schizophrenia.

Objective.The objectives of this study were to determine whether there are important differences in how patients, family members, and health care providers (HCPs) value health outcomes in schizophrenia and to assess the degree to which such differences, if they exist, could adversely affect clinical and policy decision making. Methods.Participants viewed videotaped depictions of simulated patients with mild and moderate symptoms of schizophrenia, with and without a common adverse drug effect (pseudoparkinsonism), and then provided standard gamble and visual analog scale ratings of desirability of these states. Subjects.A convenience sample of unrelated patients (n = 148), family members of patients (n = 91), and HCPs (nurses, psychologists, doctors of pharmacy, and doctors of medicine; n = 99) was drawn from geographically and clinically diverse environments. Results.Patients’ and family members’ utilities for health states averaged 0.1 to 0.15 units higher than those of HCPs (P <0.002 for differences between groups, ANOVA for multiple observations). The disutility of adverse drug effects was less for health professionals than patients and family members (P = 0.008). Health professionals tended to prefer states with mild symptoms with extrapyramidal side effects to states with moderate symptoms. Patients and family members found these states equally preferable (P <0.007 for differences between groups). Conclusions.There are systematic differences in values for health outcomes between patients and HCPs with regard to states with adverse effects of antipsychotic drugs. Family members of patients in general had values that were more similar to those of patients than were those of health professionals. The results emphasize the importance of participation by patients (or family member proxies) in clinical decision making and guideline development.

Randomized, Double-Blind, Placebo-Controlled Study of Paliperidone Extended-Release and Quetiapine in Inpatients With Recently Exacerbated Schizophrenia

OBJECTIVE The authors compared paliperidone extended-release and quetiapine in patients with recently exacerbated schizophrenia requiring hospitalization. METHOD In a 6-week double-blind study, inpatients with a recent exacerbation of schizophrenia were randomly assigned to treatment with paliperidone extended-release, quetiapine, or placebo. A 2-week monotherapy phase was followed by a 4-week additive-therapy phase. Target doses were at the upper end of recommended ranges: paliperidone extended-release, 9 or 12 mg/day, and quetiapine, 600 or 800 mg/day. The primary endpoint was the difference in mean total change score on the Positive and Negative Syndrome Scale (PANSS) between paliperidone extended-release and quetiapine at the 2-week monotherapy phase endpoint. RESULTS Six-week completion rates were 77.5% (124/160) with paliperidone extended-release, 66.7% (106/159) quetiapine, and 63.8% (51/80) placebo. Improvement in mean PANSS total change score was greater with paliperidone extended-release than with quetiapine from day 5 (-11.4 versus -8.2) through the monotherapy phase endpoint (-23.4 versus -17.1). Only paliperidone extended-release showed significantly greater PANSS improvement compared with placebo at 2 weeks. At the 6-week study endpoint, there was a significantly greater improvement with paliperidone extended-release compared with quetiapine despite similar use of additive therapy (predominantly other antipsychotics). Common adverse events with paliperidone extended-release, quetiapine, and placebo, respectively, were tremor (13.9%, 5.0%, 7.5%), somnolence (8.9%, 11.9%, 1.3%), insomnia (10.1%, 9.4%, 11.3%), and headache (12.0%, 7.5%, 13.8%). Six-week adverse event-related discontinuation rates were 6.3%, 10.1%, and 6.3%, respectively, in the paliperidone extended-release, quetiapine, and placebo groups. CONCLUSIONS Compared with quetiapine, paliperidone extended-release improved symptoms earlier and to a greater degree in patients with recently exacerbated schizophrenia requiring hospitalization, with no unexpected tolerability findings.

The heterogeneity of schizophrenia in disease states

PREVIOUS PRESENTATION Some of the contents of this paper have been previously presented at the 16th Annual Meeting of the International Society for Technology Assessment in Health Care June 20, 2000 in the Hague, Netherlands and at the 21st Annual Meeting of the Society for Medical Decision Making as a poster on October 3, 1999 in Reno, NV. BACKGROUND Studies of schizophrenia treatment often oversimplify the array of health outcomes among patients. Our objective was to derive a set of disease states for schizophrenia using the Positive and Negative Symptom Assessment Scale (PANSS) that captured the heterogeneity of symptom responses. METHODS Using data from a 1-year clinical trial that collected PANSS scores and costs on schizophrenic patients (N=663), we conducted a k-means cluster analyses on PANSS scores for items in five factor domains. Results of the cluster analysis were compared with a conceptual framework of disease states developed by an expert panel. Final disease states were defined by combining our conceptual framework with the empirical results. We tested its utility by examining the influence of disease state on treatment costs and prognosis. RESULTS Analyses led to an eight-state framework with varying levels of positive, negative, and cognitive impairment. The extent of hostile/aggressive symptoms and mood disorders correlated with severity of disease states. Direct treatment costs for schizophrenia vary significantly across disease states (F=27.47, df=7, p<0.0001), and disease state at baseline was among the most important predictors of treatment outcomes. CONCLUSION The disease states we describe offer a useful paradigm for understanding the links between symptom profiles and outcomes.

Differential effects of antipsychotic agents on the risk of development of type 2 diabetes mellitus in patients with mood disorders

BACKGROUND Atypical antipsychotics are being used increasingly in the management of mood disorders. OBJECTIVE The objective of this study was to investigate the association between exposure to antipsychotic therapy and newly reported type 2 diabetes mellitus in patients with mood disorders. METHODS Claims data for the period January 1996 through December 1997 were analyzed for patients with mood disorders in 2 large US health plans. Logistic regression models were used to determine the odds of reporting diabetes in patients exposed to risperidone, olanzapine, or high- or low-potency conventional antipsychotics compared with untreated patients, taking into account duration of treatment and dosage. Some of the covariates used in the models were concurrent use of antipsychotics, use of other psychotropic drugs, age, sex, and length of observation. RESULTS Based on the claims data, 849 patients were exposed to risperidone, 656 to olanzapine, 785 to high-potency conventional antipsychotics, and 302 to low-potency conventional antipsychotics; 2644 patients were untreated. The odds of newly reported type 2 diabetes in patients who received risperidone were not significantly different from those in untreated patients (12-month odds ratio [OR] = 1.024; 95% CI, 0.351-3.015). The odds in patients treated with high-potency conventional antipsychotics also did not differ significantly from those of untreated patients (12-month OR = 1.945; 95% CI, 0.794-4.786). Unlike patients who received risperidone or high-potency conventional antipsychotics, patients who received olanzapine (12-month OR = 4.289; 95% CI, 2.102-8.827) and low-potency conventional antipsychotics (12-month OR = 4.972; 95% CI, 1.967-12.612) had significantly higher odds for the development of type 2 diabetes compared with untreated patients. CONCLUSIONS These findings suggest that some antipsychotics may increase the risk for the development of type 2 diabetes in patients with mood disorders and that the effect may vary by drug. In contrast to olanzapine and low-potency conventional antipsychotics, risperidone and high-potency conventional antipsychotics were not associated with an increased risk for development of type 2 diabetes in this patient population.

Risperidone versus Conventional Antipsychotics for Schizophrenia and Schizoaffective Disorder : Symptoms, Quality of Life and Resource Use under Customary Clinical Care.

AbstractObjective: To prospectively compare risperidone with conventional anti-psychotic agents among schizophrenia patients treated under usual practice conditions. Design: One-year, multicentre, open-label, randomised trial carried out in 21 centres in 17 states of the US. Patients: 684 patients were followed from 1995 to 1997, and must have experienced a symptom relapse at study start. Interventions: Patients were randomly assigned to risperidone therapy or their physician’s ‘best choice’ of any one of the 13 conventional antipsychotic medications approved in the US. Main outcome measures and results: Outcomes measured were changes in psychiatric symptoms, side effects, satisfaction with drug therapy, quality of life (including health-related quality of life [HRQOL]) and resource utilisation. A subgroup analysis of the non-switchers was also conducted. Irrespective of treatment group, treatment switching and days with no drug therapy were observed. Compared with patients on conventional antipsychotics, those in the risperidone group achieved statistically superior scores on the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) [PANSS total score improved from 83.32 to 61.80 vs 81.42 to 66.99 in the risperidone and conventional groups, respectively), Barnes Akathisia Scale (scores improved from 0.89 to 0.55 vs 0.87 to 0.81 in the risperidone and conventional groups, respectively), and 36-Item Short Form Health Survey (SF-36) scale (scores improved from 32.83 to 39.92 vs 32.55 to 37.22 in the risperidone and conventional groups, respectively) during the 1-year treatment period. A significantly higher percentage of risperidone-treated patients had a 60% improvement in PANSS scores at 12 months (20.9% of patients compared with 10.7% in the risperidone and conventional groups, respectively). There was no statistically significant difference in resource utilisation between the two groups. Among non-switchers, patients in the risperidone group had lower total costs and more clinical benefits. Conclusions: Conditions of usual practice resulted in a high degree of non-treatment, treatment changing and multi-antipsychotic drug therapy. Patients in the risperidone group had better clinical outcomes (e.g. reduced psychiatric symptoms and side effects) and improved HRQOL. There were no significant differences in healthcare utilisation between the two study groups.