Colette Kosik-Gonzalez

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

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.

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.

A randomized, double-blind, placebo-controlled study of 2 dose ranges of paliperidone extended-release in the treatment of subjects with schizoaffective disorder.

OBJECTIVE This study was designed to assess efficacy and safety of paliperidone extended-release (ER) in patients with schizoaffective disorder. METHOD A randomized, 6-week, double-blind, placebo-controlled study was conducted. Subjects with a Structured Clinical Interview for DSM-IV diagnosis of schizoaffective disorder, Positive and Negative Syndrome Scale (PANSS) total score >or= 60, score >or= 4 on >or= 2 PANSS items (hostility, excitement, tension, uncooperativeness, poor impulse control), and Young Mania Rating Scale and/or Hamilton Depression Rating Scale, 21-item version scores >or= 16 were eligible. Subjects received higher-dose (12 mg/d) or lower-dose (6 mg/d) paliperidone ER. Dose adjustments by 3-mg increments were allowed until day 15. The study was conducted from October 2006 through February 2008. RESULTS A total of 316 subjects were randomly assigned to paliperidone ER lower dose (n = 109), higher dose (n = 100), or placebo (n = 107). Mean +/- SD modal dose in lower- and higher-dose groups: 5.7 +/- 0.9 and 11.6 +/- 1.0 mg/d, respectively. Mean +/- SE PANSS total score (primary outcome) improved significantly with higher-dose paliperidone ER versus placebo (-32.4 +/- 2.1 versus -24.1 +/- 2.1; P = .003). Change with lower-dose paliperidone ER (-27.7 +/- 2.1) was not significantly different from placebo (P = .187). No new safety issues were identified; common adverse events were headache (placebo: 16.8%; paliperidone ER: lower dose, 13.9%, higher dose, 13.3%) and tremor (3.7%, 12.0%, 11.2%, respectively). Mean prolactin and weight changes were greater with active treatment than placebo. CONCLUSIONS Higher-dose paliperidone ER was effective and well tolerated in patients with acute schizoaffective disorder. These findings and those from a companion study constitute the first registration program for antipsychotic treatment in schizoaffective disorder. TRIAL REGISTRATION clincaltrials.gov Identifier: NCT00397033.

Reduction in psychotic symptoms as a predictor of patient satisfaction with antipsychotic medication in schizophrenia: Data from a randomized double-blind trial

BackgroundPatient satisfaction with antipsychotic treatment is important. Limited evidence suggests that satisfaction is associated with symptom improvement and compliance. Predictors of patient satisfaction with antipsychotic medication were examined in a study of patients with a recent exacerbation of schizophrenia.MethodsData are from a randomized, double-blind trial comparing risperidone (n = 152), quetiapine (n = 156), and placebo (n = 73). Medication Satisfaction Questionnaire (MSQ) was completed after 14 days of treatment and after 6 weeks at last study visit.ResultsMedication satisfaction at both time points was significantly associated in multiple regression analysis with improvement on 3 Positive and Negative Syndrome Scale (PANSS) factor scores (positive symptoms p < .01; uncontrolled hostility/excitement, p < .0005; anxiety/depression, p < .04) and treatment with risperidone (p < .03); at day 14, significant association was also found with older age (p = .01). At both time points, predictor variables explained over 30% of the variance in medication satisfaction. Change in Hamilton Depression Scale, prolactin levels, sex, and reported adverse events of extrapyramidal symptoms, sedation, and movement disorders were not significant predictors of satisfaction. Lower level of medication satisfaction at day 14 was associated with earlier discontinuation in the trial at week 6 end point. A focused principal components analysis of PANSS factors and MSQ suggested that medication satisfaction relates to 3 groups of factors in descending order of magnitude: lower levels of (a) uncontrolled hostility/excitement, (b) positive symptoms, and (c) negative symptoms, disorganized thoughts, and anxiety/depression.ConclusionResults give further support that treatment satisfaction is positively associated with symptom improvement, particularly psychotic symptoms, and suggest that satisfaction may also be related to compliance, as those who were more satisfied remained in the trial for a longer period of time.Trial registration numberTrial registration number NCT00061802

Paliperidone extended-release in schizoaffective disorder: a randomized, controlled study comparing a flexible dose with placebo in patients treated with and without antidepressants and/or mood stabilizers.

This 6-week, double-blind, placebo-controlled study evaluated paliperidone extended-release (ER) as both monotherapy and adjunctive therapy to mood stabilizers and/or antidepressants (MS/ADs) for schizoaffective disorder. Included subjects had a schizoaffective disorder diagnosis; a Positive and Negative Syndrome Scale (PANSS) total score of 60 or higher; a score of 4 or higher on 2 or more of the PANSS items for hostility, excitement, tension, uncooperativeness, or poor impulse control; and prominent mood symptoms (≥16 on the Young Mania Rating Scale and/or the 21-item Hamilton Rating Scale for Depression). Subjects were randomized to 6 mg/d paliperidone ER or placebo with flexible dosing (3-12 mg/d) until day 15. Randomization was stratified by use of MS/AD and study site. The primary analysis outcome was change in PANSS total score at week 6 last observation carried forward end point. A total of 311 subjects received paliperidone ER (n = 216) or placebo (n = 95); 52.0% received MS/AD. The mean (SD) modal dose of paliperidone ER was 8.6 (2.5) mg/d. Greater improvement was observed with paliperidone ER than placebo on mean (SE) PANSS total scores: −20.0 (1.3) and −10.8 (1.9), respectively. Subjects with prominent manic or depressive symptoms showed greater improvement with paliperidone ER versus placebo: mean (SE) Young Mania Rating Scale (−10.6 [0.9] vs −5.7 [1.2], respectively) and 21-item Hamilton Rating Scale for Depression (−10.2 [0.7] vs −6.2 [1.1], respectively). The most common adverse events with paliperidone ER were headache, akathisia, dizziness, insomnia, and dyspepsia. Paliperidone ER improved psychotic and affective symptoms both as monotherapy and as an adjunct to MS/AD. No new safety findings were observed in this population.

Incidence and costs of polypharmacy: data from a randomized, double-blind, placebo-controlled study of risperidone and quetiapine in patients with schizophrenia or schizoaffective disorder.

ABSTRACT Objective: The use of adjunctive psychotropics and the costs of polypharmacy in patients randomized to receive risperidone or quetiapine were compared in a placebo-controlled double-blind study conducted in India, Romania, and the United States. Methods: The efficacy and safety of risperidone, quetiapine, and placebo were compared in a 14-day monotherapy phase in patients experiencing an acute exacerbation of symptoms of schizophrenia or schizoaffective disorder. This was followed by a 28-day, additive-therapy phase during which addition of antipsychotics or other psychotropic medications was permitted. Risperidone was received by 153 patients in the monotherapy phase and 133 in the additive therapy phase, quetiapine by 156 and 122, respectively, and placebo by 73 and 53. Rates of polypharmacy were examined using the Cochran–Mantel–Haenszel, Kaplan–Meier, and Cox regression methods. Costs of polypharmacy were analyzed by nonparametric Wilcoxon 2-sample tests. Results: Primary study results have been reported elsewhere (Potkin et al., Schizophr Res 2006;85:254-65). Mean (±SD) doses at the additive-therapy baseline were 4.7 ± 0.9 mg/day of risperidone and 579.0 ± 128.9 mg/day of quetiapine. Additional psychotropics were received by 36% of the risperidone group, 58% of the quetiapine group ( p < 0.01), and by 58% of the placebo group. Antipsychotics accounted for > 95% of the added psychotropics, the most common being olanzapine and haloperidol. The relative risk (quetiapine vs. risperidone) for antipsychotic polypharmacy was 1.90 ( p = 0.001; 95% CI 1.29, 2.80). The mean projected cost of additional antipsychotics per randomized patient during the additive-therapy phase was

Psychometric evaluation of the Readiness for Discharge Questionnaire

57.03 in the risperidone group and

EXHANCE-12: 1-year study of the exhalation delivery system with fluticasone (EDS-FLU) in chronic rhinosinusitis: EDS-FLU in chronic rhinosinusitis

101.64 in the quetiapine group ( p < 0.01). Conclusions: The results confirm earlier reports of higher rates of polypharmacy with quetiapine than with risperidone. The findings also reveal substantial between-treatment differences in costs associated with polypharmacy. Limitations of the study include that the study was of short duration and that a high proportion of patients were recruited from countries other than the United States.

NAVIGATE II: Randomized, double-blind trial of the exhalation delivery system with fluticasone for nasal polyposis

OBJECTIVE The Readiness for Discharge Questionnaire (RDQ) was developed as an easy to use tool for assessing readiness for discharge, independent of socio-economic factors, for inpatients with schizophrenia. The psychometric properties of the RDQ are described. METHODS The RDQ consists of 6 items assessing suicidality/homicidality, control of aggression/impulsivity, activities of daily living, medication-taking, delusions/hallucinations interfering with functioning and global status. A final yes/no question assesses readiness for discharge. Data derived from 3 studies (500 patients in 3 countries) were used in analyzing inter-rater and test-retest reliability, content and construct validity, and sensitivity to change. RESULTS The inter-rater reliability was high for all items of the RDQ (reliability coefficients >0.9) and moderate to high for the readiness for discharge status (Session I: 84% agreement, kappa 0.39, polychoric correlation r=0.81; Session II: 89% agreement, kappa 0.63, polychoric correlation r=0.81. Test-retest reliability was also high for all items of the RDQ (reliability coefficients >0.9) and the readiness for discharge status (kappa=0.743; tetrachoric correlation r=0.819). Overall, 84% of the raters agreed (mean score=5.0 of possible 6.0) that the RDQ was useful in assessing a patients readiness for discharge from the hospital. Evidence of good construct validity included significant correlations with PANSS total and factor scores, and a significant relationship with actual discharge. Significantly more patients with symptom improvement were judged ready for discharge (compared to those without symptom improvement), indicating that the RDQ was sensitive to change over time. CONCLUSIONS The RDQ has favorable reliability and validity properties, and is an easy to use instrument in research studies for assessing readiness for discharge of inpatients with schizophrenia. Additional work in naturalistic settings is required to further validate the instrument for routine clinical use.