Carla M. Canuso

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

OBJECTIVEnThe authors compared paliperidone extended-release and quetiapine in patients with recently exacerbated schizophrenia requiring hospitalization.nnnMETHODnIn 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.nnnRESULTSnSix-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.nnnCONCLUSIONSnCompared 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.

Polydipsia and water intoxication in a long-term psychiatric hospital

This cross-sectional survey attempts to establish the prevalence of polydipsia and water intoxication at a state hospital (N = 360) using staff diagnosis, specific gravity of the urine (SPGU), weight changes, and chart review. There were 150 [42%, 95% confidence interval (CI) 37-47%] patients diagnosed as polydipsic by the staff or by SPGU. At least 93 (26%, CI 21-30%) had primary polydipsia not explained by other causes. Chart review identified 17 (5%, CI 3-7%) patients with a history of water intoxication. Using a case-control study design, schizophrenia, extended duration of hospitalization, and heavy smoking were associated with primary polydipsia in a logistic regression analysis (respective odds ratios were 1.6, 1.8, and 3.6). All patients with a history of water intoxication were Caucasian (versus 83% in those without a history) and had significantly more extended hospitalizations (94 vs. 49%). Future case-control studies should combine longitudinal identification of true cases and controls and exhaustive collections of clinical information in a standardized way.

Paliperidone extended-release tablets in schizophrenia patients previously treated with risperidone.

To assess the effect of paliperidone extended-release (ER) tablets in patients with acute symptoms who had previously received risperidone. Data for this post-hoc analysis were pooled from three 6-week, double-blind, placebo-controlled trials in patients treated with paliperidone ER 3–12u2009mg/day or placebo. Patients had to have received risperidone for ≥4 weeks within 2 weeks of study entry. Assessments were done using the Positive and Negative Syndrome Scale, Clinical Global Impressions–Severity scale, Personal and Social Performance scale, the Simpson–Angus Scale , and adverse event (AE) reports. Altogether, 198 patients (paliperidone ER, n=142; placebo, n=56) met the established criteria. Mean (SD) duration of prior risperidone treatment and dose were 418.8 (572.8) days and 4.4 (2.5)u2009mg/day for paliperidone ER and 527.0 (805.3) days and 4.1 (2.5)u2009mg/day for placebo. Study completion rates were 61.3% for paliperidone ER versus 42.9% for placebo. At endpoint, paliperidone ER showed significant improvement versus placebo (P<0.05) in Positive and Negative Syndrome Scale, Clinical Global Impressions–Severity, and Personal and Social Performance scores. Mean baseline Simpson–Angus Scale scores were low, with no significant changes at endpoint in either group. AEs ≥10% with paliperidone ER versus placebo were headache (16.2 vs. 16.1%), insomnia (14.1 vs. 16.1%), and agitation (8.5 vs. 10.7%). AE-related discontinuations were 2.1% with paliperidone ER and 5.4% with placebo. In patients who had received risperidone previously but remained sufficiently symptomatic for enrollment, paliperidone ER was significantly more effective than placebo in reducing symptoms and producing functional gains.

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

OBJECTIVEnThis study was designed to assess efficacy and safety of paliperidone extended-release (ER) in patients with schizoaffective disorder.nnnMETHODnA 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.nnnRESULTSnA 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.nnnCONCLUSIONSnHigher-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.nnnTRIAL REGISTRATIONnclincaltrials.gov Identifier: NCT00397033.

Paliperidone palmitate once-monthly reduces risk of relapse of psychotic, depressive, and manic symptoms and maintains functioning in a double-blind, randomized study of schizoaffective disorder.

OBJECTIVEnSchizoaffective disorder is a complex illness for which optimal treatment is not well established. Results of the first controlled, relapse-prevention study of paliperidone palmitate once-monthly injectable (paliperidone monthly) in schizoaffective disorder are presented.nnnMETHODnThe study was conducted between September 20, 2010, and October 22, 2013. Patients with schizoaffective disorder (confirmed by the Structured Clinical Interview for DSM-IV Axis I Disorders) experiencing acute exacerbation of psychotic and depressive/manic symptoms were stabilized with paliperidone monthly as monotherapy or as adjunctive therapy to mood stabilizers or antidepressants and randomly assigned (1:1) to paliperidone monthly or placebo in a 15-month, double-blind, relapse-prevention phase. Randomization was stratified by administration as monotherapy or adjunctive therapy and by study center. The primary endpoint was time to relapse.nnnRESULTSn334 patients were evaluated. Paliperidone monthly significantly delayed time to relapse for psychotic, depressive, and manic symptoms compared with placebo (P < .001, log-rank test). Relapse risk was 2.49 times greater for placebo (hazard ratio = 2.49; 95% CI, 1.55 to 3.99; P < .001, Cox proportional hazards model). Overall relapse rates were 33.5% for placebo and 15.2% for paliperidone monthly. For monotherapy, relapse risk was 3.38 times greater with placebo (P = .002), and for adjunctive treatment it was 2.03 times greater with placebo (P = .021). Paliperidone monthly was superior to placebo in maintaining functioning as measured by the Personal and Social Performance scale (P = .014, mixed-model repeated-measures analysis). The most common adverse events (placebo, paliperidone monthly) were increased weight (4.7%, 8.5%), insomnia (7.1%, 4.9%), schizoaffective disorder (5.9%, 3.0%), headache (3.5%, 5.5%), and nasopharyngitis (3.5%, 5.5%). Incidence of any extrapyramidal-related adverse event was 7.1% for placebo and 8.5% for paliperidone monthly.nnnCONCLUSIONSnPaliperidone monthly as monotherapy or adjunctive therapy significantly delayed psychotic, depressive, and/or manic relapses; reduced their risk; and better maintained functioning in patients with schizoaffective disorder. Results support the value of maintenance treatment with paliperidone monthly in schizoaffective disorder.nnnTRIAL REGISTRATIONnClinicalTrials.gov identifier: NCT01193153.

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.

Medication satisfaction in schizophrenia: a blinded-initiation study of paliperidone extended release in patients suboptimally responsive to risperidone.

Patient-reported outcomes, including treatment satisfaction, are now recognized as important and valid measures in assessment of therapeutic interventions. This randomized, 6-week, prospective, blinded-initiation study evaluated medication satisfaction as a primary outcome measure in a schizophrenia trial. Participants with suboptimal response to oral risperidone were randomized to paliperidone extended release (ER) immediate or delayed (week 2) initiation. Primary endpoint was change in Medication Satisfaction Questionnaire (MSQ; ratings from 1=extremely dissatisfied to 7=extremely satisfied) score at endpoint (last observation carried forward) for the overall population (all randomized participants). In total, 201 participants were randomized to immediate (n=100) or delayed (n=101) initiation of paliperidone ER. In the overall population, the mean±standard deviation MSQ score improved from 2.7±0.8 (very to somewhat dissatisfied) at baseline to 5.1±1.2 (somewhat satisfied) at endpoint (P<0.001). On the basis of dichotomized analysis of the MSQ scale (score 1–4=dissatisfied, 5–7=satisfied), 82.7% of participants were satisfied with their medication at endpoint. At the 2-week time point, significantly more participants in the immediate initiation group reported satisfaction (67.7%) compared with those in the delayed initiation group (45.3%) (P=0.002), who were still receiving risperidone at this time. Positive And Negative Syndrome Scale total scores also improved from baseline to endpoint (−12.9±13.1; P<0.001). Most common adverse events were insomnia (9.1%), constipation (7.6%), headache (7.6%) and somnolence (6.6%). Participants with schizophrenia who were suboptimally responsive to risperidone reported improved medication satisfaction after initiation of paliperidone ER.

Direct and indirect effects of paliperidone extended-release tablets on negative symptoms of schizophrenia.

Direct and indirect effects of the new psychotropic paliperidone extended-release (paliperidone ER) tablets on negative symptom improvement in schizophrenia were investigated using path analysis. A post hoc analysis of pooled data from three 6-week, double-blind, placebo-controlled studies of paliperidone ER in patients experiencing acute exacerbation was conducted. Regression analysis explored relationships between baseline/study characteristics and negative symptoms. Change in Positive and Negative Syndrome Scale (PANSS) negative factor score at endpoint was the dependent variable; explanatory variables included demographic and clinical characteristics. Path analysis determined direct and indirect effects of treatment on negative symptom change. Indirect mediators of negative symptom change in the model included changes in positive symptoms, anxiety/depression symptoms and movement disorders. Path analysis indicated that up to 33% of negative symptom improvement was a direct treatment effect. Indirect effects on negative symptoms were mediated through changes in positive symptoms (51%) and anxiety/depression symptoms (18%), whereas changes in movement disorders had a 2.1% inverse effect. Path analysis indicated that paliperidone ER has a direct effect on negative symptoms. Negative symptom improvement also was indirectly mediated via changes in positive and depressive symptoms.

Paliperidone Palmitate Once-monthly Injectable Treatment for Acute Exacerbations of Schizoaffective Disorder

Abstract The optimal treatment for schizoaffective disorder (SCA) is not well established. In this initial 6-month open-label treatment period of a large, multiphase, relapse-prevention study, the efficacy and safety of paliperidone palmitate once-monthly (PP1M) injectable were evaluated in subjects with symptomatic SCA. Subjects with acute exacerbation of SCA (ie, with psychotic and either depressive and/or manic symptoms) were enrolled and treated with PP1M either as monotherapy or in combination with antidepressants or mood stabilizers (combination therapy group). After flexible-dose treatment with PP1M for 13 weeks, stabilized subjects continued into a 12-week fixed-dose PP1M treatment period. A total of 667 subjects were enrolled; 320 received monotherapy and 347 received PP1M as combination therapy; 334 subjects completed the entire 25-week treatment. Statistically significant and clinically meaningful improvements from baseline were observed for all efficacy measures in psychosis (per Positive and Negative Syndrome Scale), mood symptoms (per Young Mania Rating Scale and Hamilton Depression Rating Scale—21 items), and functioning (per Personal and Social Performance Scale) from week 1 to all time points during the 25-week treatment period (P < 0.001). Similar improvements in efficacy measures were observed between subjects receiving monotherapy or combination therapy. Efficacy benefits persisted throughout the 25-week period. The most common adverse events were akathisia (11.1%), injection-site pain (10.6%), and insomnia (10.0%). Paliperidone palmitate once-monthly administered as monotherapy or in combination with mood stabilizers or antidepressants in patients with an acute exacerbation of SCA provided rapid, broad, and persistent reduction in psychotic, depressive, and manic symptoms, as well as improved functioning.

Erratum: Effects of risperidone augmentation in patients with treatment-resistant depression: Results of open-label treatment followed by double-blind continuation (Neuropsychopharmacology (2006) 31, 2505-2513) DOI: 10.1038/sj.npp.1301113

Correction to: Neuropsychopharmacology (2006) 31, 2505–2513. doi:10.1038/sj.npp.1301113 Dr Nemeroff consults to, serves on the Speakers’ Bureau and/or Board of Directors, has been a grant recipient, and/or owned equity in one or more of the following: Abbott Laboratories, Acadia Pharmaceuticals, AFSP, APIRE, AstraZeneca, BMC-JR LLC, Bristol-Myers Squibb, CeNeRx, Corcept, Cypress Biosciences, Cyberonics, Eli Lilly, Entrepreneurs Fund, Forest Laboratories, George West Mental Health Foundation, GlaxoSmithKline, i3 DLN, Janssen Pharmaceutica, Lundbeck, NARSAD, Neuronetics, NIMH, NFMH, NovaDel Pharma, Otsuka, Pfizer Inc., Quintiles, Reevax, UCB Pharma, Wyeth.