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Background: Cochrane recently published a review of esketamine and other glutamate receptor modulators in depression. Aim: To address the limitations of the review, analyses of esketamine data were conducted to provide additional perspective to the reviewers’ interpretation of their findings. Methods: Response rate, remission rate, and change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score were determined using data from all esketamine phase 2/3 registration studies of treatment-resistant depression (TRD) and, separately, all esketamine phase 2/3 registration studies of major depressive disorder (MDD) and active suicidal ideation with intent. Outcomes were assessed at all timepoints (i.e., 24 h, 72 h (MDD with active suicidal intent only), and 1, 2, and 4 weeks). Enrollment criteria of the TRD studies were different than those of the studies of MDD and active suicidal ideation with intent, resulting in differences in patients’ clinical characteristics and depression severity between the cohorts. Thus, we did not compare results between these cohorts (as was done in the Cochrane review). Results/outcomes: In the combined TRD studies, a statistically significant between-group difference favored esketamine plus antidepressant over antidepressant plus placebo at 24 h (based on response, remission, and change in MADRS score), 1 week (change in MADRS score), 2 weeks (response and change in MADRS score), and 4 weeks (response, remission, and change in MADRS score). In the combined studies of MDD and active suicidal ideation with intent, the between-group difference was statistically different, favoring esketamine plus standard-of-care over placebo plus standard-of-care, at 24 h (response, remission, and change in MADRS score), 72 h and 1 week (change in MADRS score), 2 weeks (response), and 4 weeks (response, remission, and change in MADRS score). For both study types, the between-group difference in outcomes was not statistically significant at the other timepoints. Conclusions/interpretation: Esketamine improves response, remission, and depressive symptoms as early as 24 h post-first dose among patients with TRD and among patients with MDD and active suicidal ideation with intent.

Supplemental digital content is available in the text., Purpose/Background Numerous health authority approvals of esketamine nasal spray, combined with oral antidepressant, to treat depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior were based on 2 identically designed, double-blind, phase 3 studies. Methods/Procedures Across both ASPIRE studies (NCT03039192, NCT03097133), patients (N = 456) were randomized to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks plus comprehensive standard of care, including hospitalization and newly initiated or optimized antidepressant(s). In post hoc analyses of pooled data, changes from baseline at 24 hours after the first dose in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression–Severity of Suicidality–Revised, in the full cohort and in subgroups, were analyzed using analysis of covariance. Findings/Results Esketamine plus standard of care demonstrated significantly greater improvement in Montgomery-Åsberg Depression Rating Scale total score versus placebo plus standard of care at 24 hours (least square mean difference [95% confidence interval], −3.8 [−5.75 to −1.89]) and at earlier (4 hours: −3.4 [−5.05 to −1.71]) and later time points (day 25: −3.4 [−5.36 to −1.36]). The between-group difference (95% confidence interval) for change in Clinical Global Impression–Severity of Suicidality–Revised at 24 hours was −0.20 (−0.43 to 0.04) for all patients and −0.31 (−0.61 to −0.01) for those with a history of suicide attempt. Common adverse events (≥20%) during esketamine treatment were dizziness, dissociation, nausea, somnolence, and headache. Implications/Conclusions Esketamine plus comprehensive standard of care rapidly reduces depressive symptoms in patients with major depressive disorder who have acute suicidal ideation or behavior, especially in those with a history of suicide attempt, providing a new treatment option for this particularly ill and vulnerable population.

OBJECTIVE: Most assessments of suicidal ideation and behavior (SIB) are limited by reliance on a single assessor, typically a clinician or patient, with scant detail on patient-related drivers of SIB and inability to detect rapid change in SIB. Furthermore, many techniques do not include a semistructured interview, increasing rater variability. The Suicide Ideation and Behavior Assessment Tool (SIBAT) addresses these limitations. DESIGN: More than 30 experts in scale development, statistics, and clinical management of suicidal patients collaborated over a greater than four-year period to develop the SIBAT. Input for content and validity was received from patients, clinicians, and regulatory authorities in the United States (US) and Europe. Psychometric properties of the SIBAT were evaluated in validation studies. RESULTS: The SIBAT is organized into eight independent patient- or clinician-rated modules with branching logic and scoring algorithms, which necessitates computerization. Patient-reported information is first captured in Modules 1 to 5. Thereafter, an experienced clinician reviews the patient’s report, conducts a semistructured interview (Module 6), and assesses the patient’s suicide risk (Module 7) and optimal antisuicide management (Module 8). Input from cognitive interviews of diverse adult, adolescent, and clinician participants was incorporated into the final version of the SIBAT. Psychometric testing demonstrated good inter-rater reliability (intraclass coefficient range: 0.68–0.82), intra-rater reliability (weighted-kappa range: 0.64–0.76), and concurrent validity with other instruments for assessing SIB. CONCLUSION: Patient- and clinician-based assessments and the psychometric studies summarized in this report support the validity and reliability of the SIBAT for capturing critical information related to assessment of SIB in adolescents and adults at risk for suicide.

Introduction It is critical to assess who is being treated with a new marketed drug like esketamine to understand how it is used in the real‐world setting and the effects of the medication. Methods Retrospective analysis using two large U.S. health care databases that included commercially insured and Medicaid patients. Patients treated with esketamine were identified and their baseline characteristics described and compared with the baseline characteristics of patients with treatment resistant depression (TRD) and with patients undergoing transcranial magnetic stimulation (TMS). To quantify the differences, standardized mean differences were calculated. Results In the commercially insured database, 418 patients were treated with esketamine and 830,047 patients were in the TRD group. Large differences in baseline characteristics were observed. Patients in the esketamine group were more likely to have severe depression, suicidal thoughts, and prior treatments with TMS or electroconvulsive therapy than the TRD control group. Patients in the esketamine group had more comorbid psychiatric conditions (anxiety disorder, posttraumatic stress disorders, substance use disorders) and higher exposure to antipsychotics, antiepileptics, hypnotics and sedatives. In terms of general health, patients in the esketamine group had many more outpatient visits, were more likely to have chronic pain and higher Charlson comorbidity scores, a predicator of mortality. Results were similar for both the Medicaid and TMS populations. Conclusion Patients treated with esketamine have a higher burden of disease than other patients with TRD. In any real‐world comparative effectiveness or safety study these differences need to be understood and accounted for to produce valid results.

BackgroundPatients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment.MethodsThis double-blind study (ASPIRE II) randomized adults (aged 18–64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression–Severity of Suicidality–revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change.ResultsOf 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: –15.7 [11.56]) vs placebo (–12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: –3.9 [1.39], 95% CI: –6.60, –1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference –4.2, 95% CI: –6.38, –1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression–Severity of Suicidality–revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia.ConclusionThis study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent.Trial Registration: Clinical Trials.gov identifier: NCT03097133

Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine enantiomers, has been used as an anesthetic, analgesic and more recently, as an antidepressant. However, ketamine has known abuse liability (the tendency of a drug to be used in non-medical situations due to its psychoactive effects), which raises concerns for its therapeutic use. (S)-ketamine was recently approved by the United States’ FDA for treatment-resistant depression. Recent studies showed that (R)-ketamine has greater efficacy than (S)-ketamine in preclinical models of depression, but its clinical antidepressant efficacy has not been established. The behavioral effects of racemic ketamine have been studied extensively in preclinical models predictive of abuse liability in humans (self-administration and conditioned place preference [CPP]). In contrast, the behavioral effects of each enantiomer in these models are unknown. We show here that in the intravenous drug self-administration model, the gold standard procedure to assess potential abuse liability of drugs in humans, rats self-administered (S)-ketamine but not (R)-ketamine. Subanesthetic, antidepressant-like doses of (S)-ketamine, but not of (R)-ketamine, induced locomotor activity (in an opioid receptor-dependent manner), induced psychomotor sensitization, induced CPP in mice, and selectively increased metabolic activity and dopamine tone in medial prefrontal cortex (mPFC) of rats. Pharmacological screening across thousands of human proteins and at biological targets known to interact with ketamine yielded divergent binding and functional enantiomer profiles, including selective mu and kappa opioid receptor activation by (S)-ketamine in mPFC. Our results demonstrate divergence in the pharmacological, functional, and behavioral effects of ketamine enantiomers, and suggest that racemic ketamine’s abuse liability in humans is primarily due to the pharmacological effects of its (S)-enantiomer.

The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk.In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25.A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=-5.3, SE=2.10; effect size=0.61) and at ∼24 hours (least-square mean difference=-7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=-4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide.

Nicotinic agonists have been shown to improve cognition and mood, but this improvement is inconsistent and short-lived, possibly due to receptor desensitization. Positive Allosteric Modulators (PAMs) of the nicotinic alpha-7 nicotinic-acetyl-choline receptor (a7nAChR) are hypothesized to change the configuration of the nicotinic receptor and delay desensitization, potentially increasing the duration of the activation of the receptor, and improving clinical efficacy. This was a randomized controlled trial (RCT) adding JNJ-39393406 9 (a PAM of the a7nAChR) (n=35) or placebo (n=36) to treatment as usual for two weeks in 71 patients with unipolar depression. Mixed models for repeated measures analyses were performed Primary outcome measures were the Brief Assessment of Cognition in Schizophrenia (BACS) composite and the Montgomery-Asperg Depression Rating Scale (MADRS) scores. The drug was well tolerated, however mixed models for repeated measures comparing JNJ-39393406 to placebo showed no significant difference for MADRS total score (p=0.78), BACS composite score (p=0.34), or any of the secondary outcome measures. There was no significant difference in adverse events between the study groups (p=0.44). In conclusion, this study's findings do not support the hypothesis that a positive nicotinic receptor modulator can improve cognitive or depressive symptomatology in patients with unipolar depression.

The objective of this analysis was to determine if there are sex differences with esketamine for treatment-resistant depression (TRD). Post hoc analyses of three randomized, controlled studies of esketamine in patients with TRD (TRANSFORM-1, TRANSFORM-2 [18–64 years], TRANSFORM-3 [≥ 65 years]) were performed. In each 4-week study, adults with TRD were randomized to esketamine or placebo nasal spray, each with a newly initiated oral antidepressant. Change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was assessed by sex in pooled data from TRANSFORM-1/TRANSFORM-2 and separately in data from TRANSFORM-3 using a mixed-effects model for repeated measures. Use of hormonal therapy was assessed in all women, and menopausal status was assessed in women in TRANSFORM-1/TRANSFORM-2. Altogether, 702 adults (464 women) received ≥ 1 dose of intranasal study drug and antidepressant. Mean MADRS total score (SD) decreased from baseline to day 28, more so among patients treated with esketamine/antidepressant vs. antidepressant/placebo in both women and men: TRANSFORM-1/TRANSFORM-2 women—esketamine/antidepressant -20.3 (13.19) vs. antidepressant/placebo -15.8 (14.67), men—esketamine/antidepressant -18.3 (14.08) vs. antidepressant/placebo -16.0 (14.30); TRANSFORM-3 women—esketamine/antidepressant -9.9 (13.34) vs. antidepressant/placebo -6.9 (9.65), men—esketamine/antidepressant -10.3 (11.96) vs. antidepressant/placebo -5.5 (7.64). There was no significant sex effect or treatment-by-sex interaction (p > 0.35). The most common adverse events in esketamine-treated patients were nausea, dissociation, dizziness, and vertigo, each reported at a rate higher in women than men. The analyses support antidepressant efficacy and overall safety of esketamine nasal spray are similar between women and men with TRD. The TRANSFORM studies are registered at clinicaltrials.gov (identifiers: NCT02417064 (first posted 15 April 2015; last updated 4 May 2020), NCT02418585 (first posted 16 April 2015; last updated 2 June 2020), and NCT02422186 (first posted 21 April 2015; last updated 29 September 2021)).

Objective To compare esketamine to placebo, each in addition to standard-of-care treatment, for rapidly reducing major depressive disorder symptoms, including suicidal ideation. Methods This phase 3, double-blind, multicenter study (ASPIRE I), conducted between June 2017 and December 2018, enrolled 226 adults having major depressive disorder based on Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-5) criteria, active suicidal ideation with intent, and need for psychiatric hospitalization. Patients were randomized 1:1 to esketamine 84 mg or placebo nasal spray twice-weekly for 4 weeks, each with comprehensive standard-of-care treatment (initial psychiatric hospitalization and newly initiated or optimized oral antidepressant[s] therapy). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale (MADRS) total score (primary endpoint) was analyzed using analysis of covariance (ANCOVA), and change in Clinical Global Impression of Severity of Suicidality Revised version (CGI-SS-r; key secondary endpoint) score was analyzed using ANCOVA on ranks with treatment difference estimated using the Hodges-Lehmann estimate. Results Greater improvement in MADRS total score was observed with esketamine + standard-of-care versus placebo + standard-of-care at 24 hours (least-squares mean difference [SE]: -3.8 [1.39]; 95% CI, -6.56 to -1.09; 2-sided P = .006), as well as at earlier (4 hours) and later time points during 4-week double-blind treatment. The difference between groups in the severity of suicidality was not statistically significant (median of treatment difference [95% CI]: 0.0 [-1.00 to 0.00]; 2-sided P = .107). The most common adverse events among esketamine-treated patients were dizziness, dissociation, headache, nausea, and somnolence. Conclusions These findings demonstrate rapid and robust efficacy of esketamine nasal spray in reducing depressive symptoms in severely ill patients with major depressive disorder who have active suicidal ideation with intent. Trial registration ClinicalTrials.gov identifier: NCT03039192.

This study sought to: 1. determine the frequency of rehospitalization with diagnosis of suicidal ideation or suicide attempt (SI/SA) within a year and how often patients had multiple rehospitalizations; 2. identify the time period for which the risk of rehospitalization is highest; and 3. determine the characteristics of patients with multiple rehospitalizations. We conducted a retrospective cohort study of adults with depression using 4 US health claims databases. We defined hospitalization as an inpatient or emergency room visit with codes indicating a suicide attempt or suicidal thoughts using a validated algorithm. Rates of rehospitalization with SI or SA were analyzed together and separately, including multiple re-hospitalizations with SI/SA. Across all databases 121,065 patients were hospitalized with a diagnosis of SI/SA. Rates of rehospitalization within a year ranged from 7.96% to 11.24%. The risk of rehospitalization with SI/SA is highest during the first month. Nearly 50% of rehospitalizations occurred within 3 months after initial hospitalization. Patients with rehospitalization(s) had more anxiety disorders, sleep disorders and substance use disorders than patients without. Among patients with depression hospitalized for SI/SA, rehospitalization for SI/SA within a year is not uncommon. Risk of rehospitalization with a diagnosis of SI/SA is highest during the first month.

In March 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of esketamine for the treatment of resistant depression in adults. Esketamine is the S-enantiomer of ketamine, an FDA-approved anaesthetic, known to cause dissociation and, occasionally, hallucinations. While ketamine has not been approved for depression in the USA or in any other country, it has been used off-label in cases of severe depression. This commentary critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science.

The psychometric properties of the Suicide Ideation and Behavior Assessment Tool (SIBAT) were evaluated in 130 participants with varying levels of suicidality. Inter- and intra-rater reliability were assessed for clinician-rated outcomes, including the revised Clinical Global Impressions (CGI) of severity of suicidality (CGI-SS-r). Concurrent validity of patient-reported modules with Patient-reported Outcomes Measurement Information System (PROMIS) depression scale and Sheehan-Suicidality Tracking Scale Clinically Meaningful Change Measure (S-STS CMCM), and concordance between Columbia Classification Algorithm of Suicide Assessment (C-CASA) mappings for SIBAT, S-STS CMCM and Columbia-Suicide Severity Rating Scale (C-SSRS) were assessed. 52/130 participants (mean [SD] age: 38.3 [17.77] years) consented for multiple interviews (C-CASA mappings: n=52; rater-reliability: n=25/52). SIBAT demonstrated good intra-rater reliability (weighted-kappa range:0.64-0.76; CGI-SS-r, 0.75) and adequate inter-rater reliability (ICC range:0.68-0.82; CGI-SS-r, 0.81). There were strong correlations between PROMIS depression scores and SIBAT Module 5 ratings (Spearman correlations, r=0.64-0.74) and moderate correlations (r=0.29-0.72) between S-STS CMCM and SIBAT Modules 2, 3 and 5 ratings. Moderate agreement was noted between SIBAT C-CASA mappings and corresponding mappings from S-STS CMCM (weighted kappa: 0.54) and C-SSRS (weighted kappa: 0.56). Thus, the SIBAT provided valid assessment of suicidal ideation and behavior that could be reliably rated and adequately mapped to the C-CASA.

OBJECTIVE Schizoaffective 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. METHOD The 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. RESULTS 334 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. CONCLUSIONS Paliperidone 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. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01193153.

Patients with schizophrenia often suffer from comorbid hepatic disease. This multicenter, open-label, single-arm, crossover study evaluated the safety and efficacy of paliperidone extended-release (ER) in patients with schizophrenia or schizoaffective disorder and hepatic disease.The study comprised a screening period, followed by 9 weeks' open-label treatment, divided into 2 phases. Phase 1 (4 weeks) was a continuation of usual antipsychotic treatment (UAT); phase 2 (5 weeks) consisted of a 1-week cross-titration from UAT to flexibly dosed paliperidone ER (3-12 mg/d), followed by 4 weeks of paliperidone ER alone. Treatment-emergent adverse events (TEAEs), including those considered more relevant to antipsychotic treatment (prespecified adverse events [AEs]), were analyzed.Although more subjects reported TEAEs during the paliperidone ER alone period than during the UAT period, no significant differences occurred in prespecified AE rates. No new safety signals were detected, and minimal shifts in liver function test values were observed. Improvements in psychiatric symptoms and functioning were observed after 4 weeks' paliperidone ER treatment.This study suggests that paliperidone ER is well tolerated in patients with schizophrenia or schizoaffective disorder and hepatic disease. To the best of our knowledge, this is the largest prospective study to date in this population.

Supplemental digital contents are available in the text., 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.

The aim of this post-hoc analysis was to describe change in employment status over time in patients with schizophrenia.Data were from three 52-week open-label extensions of the double-blind pivotal trials of paliperidone extended-release (ER) (trial numbers NCT00650793, NCT00210769 and NCT00668837). Employment status prior to trial entry was recorded at baseline of the open-label phase and change was measured at 4-week intervals. Patients were included if they were in the open-label, intent-to-treat analysis set (i.e., received at least one dose of the study medication and had a baseline and at least one post-baseline efficacy measurement) and had valid dates in the productivity data. Employment categories included full-time, part-time, casual, sheltered work, unemployed but seeking work, unemployed and not seeking work, retired, not employed outside the home and student. Change in employment status from baseline to post-baseline (last visit) was assessed using McNemar's test.Of the 1077 patients enrolled in the open-label extensions, 1012 (94.0%) met inclusion criteria. The average age was 37.7 years (SD 10.9) and 59.1% were male. At baseline, the largest percentage of patients was unemployed and not seeking work (56.8%), followed by retired (14.9%) and unemployed but seeking work (11.7%). Five different definitions of employment were created. Employment rates increased according to all five definitions (p0.0001), ranging from a 43% increase according to the definition most similar to that used by the US Bureau of Labor Statistics to an increase of 114% when only part-time and full-time employment were considered.In this uncontrolled population of patients with schizophrenia who were treated with paliperidone ER, the percentage of patients who were employed increased over time. By using multiple measures of employment, researchers can identify the nature of the employment status change.

Background: The metabolic/biotransformation pathways of atypical antipsychotics (aripiprazole, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, and ziprasidone) have been characterized and reviewed. However, comparisons of excretory pathways remain unexplored. Objective: To analyze the excretion profile of atypical antipsychotic agents and compare the overall magnitude of metabolism (changed vs. unchanged drug) and route of excretion (feces vs. urine). Secondary objectives include providing: 1) dosing information in hepatic and renal impairment, and 2) context of the specific enzymes and pathways involved in each agents biotransformation. Methods: Published literature and each manufacturers radiolabeled drug absorption, distribution, metabolism and excretion data and U.S. prescribing information were reviewed. Results: With the exception of paliperidone, atypical antipsychotics undergo extensive metabolism (i.e.,≤50% of dose recovered unchanged). Quetiapine undergoes the greatest overall metabolism ( < 1% of the dose recovered unchanged) and paliperidone the least (59% recovered unchanged in the urine). Between-agent differences exist in the extent of cytochrome P450 (CYP450) metabolism and the specific isozymes involved. After administration of a radioactive dose, fecal elimination of unchanged drug plus metabolites ranged from 11% (paliperidone) to 71% (ziprasidone) and renal elimination ranged from 21% (ziprasidone) to 80% (paliperidone). Conclusions: Understanding the differences in the elimination profiles of atypical antipsychotics agents may permit better-informed drug and dose selection in special populations such as those with comorbid conditions (e.g. hepatitis, diabetes, end-stage renal disease) or pharmacogenetic variability; or at risk for drug-drug interactions. The use of patient tailored drug and dose-selection may result in greater treatment efficacy and a reduction in adverse events.

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.

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 + or - standard deviation MSQ score improved from 2.7 + or - 0.8 (very to somewhat dissatisfied) at baseline to 5.1 + or - 1.2 (somewhat satisfied) at endpoint (P0.001). 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 + or - 13.1; P0.001). 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.

Effective early and persistent antipsychotic treatment in recently diagnosed schizophrenia may positively impact long-term outcomes. Paliperidone extended-release (ER) was assessed in this population.Post hoc analysis of pooled data from three 6-week, double-blind (DB), placebo-controlled, and three 1-year open-label (OL) studies of paliperidone ER in schizophrenia patients. Data stratified by time since diagnosis (or =3 vs.3 years).At DB (n = 1193) and OL baselines (n = 744), 259 (21.9%) and 188 (25.3%) patients were diagnosedor =3 years. At DB end point, both populations improved with paliperidone ER versus placebo on Positive and Negative Syndrome Scale (PANSS) total, Clinical Global Impressions-Severity and Personal and Social Performance (PSP) scale scores (all P0.05). At OL end point, there were significant improvements from DB baseline in both populations on these scales (P0.0001), with greater improvement in theor =3-year population on PANSS total (P0.001) and PSP (P0.001) scores. During DB treatment, only theor =3-year population reported adverse events (AEs) inor =5% (placebo-adjusted rate) of subjects receiving paliperidone ER: akathisia, extrapyramidal disorder not otherwise specified and somnolence. During OL treatment, akathisia and somnolence occurred more frequently (or =5%) in theor =3- versus3-year population. OL study completion rates were 51.1% inor =3-year, and 48.2% in3-year subjects.Paliperidone ER significantly improved symptoms and functioning in schizophrenia patients, regardless of time since diagnosis. Recently diagnosed patients who continued treatment exhibited greater symptom reduction and functional benefit over the long term. Results also suggest that these patients may be more susceptible to certain AEs.

In daily practice, clinicians are interested in knowing when to expect treatment response after initiating a new antipsychotic medication. This analysis examined whether response onset and persistence can distinguish true drug from placebo responses. The methodology proposed by Quitkin et al (1984) was applied to data from three 6-week double-blind placebo-controlled trials in schizophrenia to examine response (> or =30% Positive and Negative Syndrome Scale total score reduction from baseline) here using the antipsychotic paliperidone extended release (3-12 mg/d) versus placebo. Response patterns were categorized by persistence (persistent: response at every time point from first response to end point for > or =2 time points; nonpersistent: other patterns) and onset (early: first response at day 4 to week 2; later: week 3 to end point). Persistent responses occurred in 39.8% of antipsychotic-treated patients and in 20.2% of subjects receiving placebo (P < 0.001). An early persistent response was achieved in 23.5% of those who received antipsychotic medication and by 14.2% of the subjects who received placebo, and a later persistent response was achieved in 16.3% and in 6.0%, respectively (P < 0.001 for both comparisons). A nonpersistent response occurred in 16.9% and in 18.1%, respectively (P = 0.631). No response occurred in 37.1% of the antipsychotic-treated patients and in 58.6% of the placebo-treated subjects over 6 weeks (P < 0.001). In conclusion, persistent response (occurring either early or later) is more likely achieved with antipsychotic medication than with placebo, and response patterns may be useful in assessing true drug response. Results suggest that persistent response requires continuing antipsychotic treatment beyond 2 weeks in some patients. These results may be useful for clinical decision making and patient education.

Most patients with schizophrenia exhibit negative symptoms, even during acute episodes. These difficult-to-treat symptoms are often associated with poor functioning and outcomes.A post-hoc analysis of pooled data from three 6-week double-blind studies included patients in an acute episode of schizophrenia who received paliperidone extended-release (ER) (3, 6, 9, or 12 mg) or placebo. Based on criteria developed by the authors, patients were stratified by the presence or absence of predominant negative symptoms at baseline (or=40% of the maximum negative factor score and40% of the maximum positive factor score on the Positive and Negative Syndrome Scale [PANSS]).Although these studies were not designed to examine patients with predominant negative symptoms, the criteria identified 23% of acutely ill patients (270/1193). The mean (SD) baseline PANSS negative symptoms factor score, 27.4 (3.3), was 49% of the maximum; the positive symptoms factor score, 23.7 (2.8), was 33% of the maximum. Completion rates with paliperidone ER (n=195) and placebo (n=75) were 64.6% and 44.0%, respectively. Greater improvements occurred with paliperidone ER vs placebo on PANSS (total, negative and other factors), Clinical Global Impressions-Severity and Personal and Social Performance scores at endpoint (all P values0.05). Adverse events reported inor=10% of patients were (paliperidone ER vs placebo): headache (14.4% vs 6.7%), insomnia (13.8% vs 21.3%) and sinus tachycardia (10.3% vs 1.3%). Paliperidone ER treatment was associated with a similar response profile in patients without predominant negative symptoms (paliperidone ER, n=647; placebo, n=276).Schizophrenia patients with predominant negative symptoms were identified in a population of acutely ill patients. Findings of this post-hoc analysis suggest that acutely ill patients with or without predominant negative symptoms respond similarly to treatment with paliperidone ER. No unexpected tolerability findings were observed.

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...

Background Psychosis has been identified in as many as 68% of patients with bipolar mania. This analysis identified psychotic symptoms in these patients. Methods Data were from two placebo-controlled, 3-week studies in patients with an acute episode of bipolar mania. Symptoms were identified by the 30-item Positive and Negative Syndrome Scale (PANSS; item ratings, 1 = absent to 7 = extremely severe), the Young Mania Rating Scale, and the Global Assessment Scale. Results Psychotic features at study entry were diagnosed in 264 (51.3%) of the 515 patients. At baseline, these patients had significantly more severe scores on the PANSS, Young Mania Rating Scale, and Global Assessment Scale than patients without psychotic features. Patients with psychotic features had mean (± SD) scores of mild (3) or greater on six PANSS items: grandiosity (4.5 ± 1.4), delusions (4.4 ± 1.4), lack of judgment/insight (4.1 ± 1.5), excitement (3.9 ± 1.3), suspiciousness/persecution (3.1 ± 1.6), and hostility (3.1 ± 1.5). Grandiosity symptoms of delusional proportions (scores ≥ 4) were noted in 205 (78%) of patients with a diagnosis of psychotic features and in 113 (45%) patients without the diagnosis. Limitations The study was not specifically designed to assess patients with psychotic features and the PANSS was developed to evaluate symptoms of schizophrenia. Conclusions These findings support prior reports indicating high rates of psychosis in patients with bipolar mania and identify the most prominent symptoms in these patients.

The effect of risperidone augmentation of citalopram for relapse prevention in older patients with antidepressant-resistant depression was evaluated.Patients with major depression agedor =55 years who had failed at least one adequate trial of an antidepressant received citalopram monotherapy (20-40 mg) for 4 to 6 weeks to confirm nonresponse (50% reduction in Hamilton Rating Scale for Depression [HAM-D] scores). Those who achieved remission (HAM-D scoreor =7 or Clinical Global Impressions severity score 1 or 2) after 4 to 6 weeks of open-label risperidone augmentation (0.25-1 mg) then entered a 24-week double-blind maintenance phase during which they received citalopram augmented with risperidone or placebo.The patients' mean age was 63.4 +/- 7.9 years; 58% were women; 61% had received two or more antidepressants during the current episode; 93 met the criterion for citalopram nonresponse and entered open-label risperidone augmentation. Of the 89 patients who completed risperidone augmentation, 63 achieved symptom resolution and entered the 6-month double-blind maintenance phase: 32 received risperidone augmentation and 31 received placebo augmentation. The median time to relapse (Kaplan-Meier estimates) was 105 days in the risperidone group and 57 days in the placebo group (Wilcoxon chi(2): 3.2, df = 1, p = 0.069). Overall, 18 of 32 (56%) from the risperidone group and 20 of 31 (65%) from the placebo group relapsed. Treatment was well tolerated.In older patients with resistant depression and poor response to standard treatments, risperidone augmentation resulted in symptom resolution in a substantial number of patients and a nonsignificant delay in time to relapse.

Ibrahim Turkoz, Cynthia A Bossie, Bryan Dirks, Carla M CanusoOrtho-McNeil Janssen Scientific Affairs, LLC, Titusville, NJ, USAAbstract: 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.Keywords: antipsychotic, paliperidone ER, path analysis, psychotropic, schizophrenia

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 with50% reduction in HAM-D-17 scores entered the risperidone augmentation phase (0.25-2.0 mg/day). Patients with HAM-D-17or =7 or CGI-Sor = 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 had50% 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 (por = 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.

This study evaluated the efficacy and safety of risperidone monotherapy in the treatment of acute bipolar mania.Patients with DSM-IV bipolar I disorder experiencing an acute manic episode (baseline Young Mania Rating Scale score/==" BORDER="0"20) were randomly assigned to 3 weeks of treatment with risperidone (flexible dose: 1-6 mg/day) or placebo. The primary efficacy measure was the mean baseline-to-endpoint change in total score on the Young Mania Rating Scale. Secondary efficacy measures included the Clinical Global Impression (CGI) severity rating and scores on the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, and Global Assessment Scale (GAS). Safety assessments consisted of monitoring adverse events, vital signs, electrocardiogram and laboratory results, and scores on the Extrapyramidal Symptom Rating Scale.Subjects (N=259) received treatment with either risperidone (N=134) or placebo (N=125). The mean modal dose of risperidone was 4.1 mg/day. Improvement in mean Young Mania Rating Scale total score (adjusted for covariates) was significantly greater in the risperidone than in the placebo group at endpoint (mean change=-10.6 [SD=9.5] versus -4.8 [SD=9.5], respectively), with significant between-group differences seen as early as 3 days after start of treatment (change with risperidone: mean=-6.8 [SD=5.8]; change with placebo: mean=-4.0 [SD=5.8]) and continuing throughout all time points. Improvements in CGI severity ratings and scores on the Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale, and GAS were also significantly greater among patients receiving risperidone than those given placebo. The most common adverse event reported among risperidone patients was somnolence. While Extrapyramidal Symptom Rating Scale scores were significantly greater in patients receiving risperidone, mean total and subscale scores were low.Risperidone monotherapy was significantly more efficacious than placebo in the treatment of acute mania and demonstrated a rapid onset of action. Risperidone was well tolerated by patients in this study.

Approximately half of patients with schizophrenia have at least one comorbid psychiatric or medical condition, worsening prognosis and contributing to the high rate of morbidity and mortality. Depression is associated with suicide, the leading cause of premature death in patients with schizophrenia; obsessive-compulsive symptoms may worsen prognosis; alcohol and substance use disorders are associated with a poor outcome; and comorbid medical conditions, including cardiac and pulmonary disease, infectious diseases, diabetes, hyperlipidemia, hypogonadism, and osteoporosis, are often underrecognized and undertreated. The new generation of antipsychotic medications has improved the potential outcome of patients with schizophrenia. Providing optimal treatment for patients and fully realizing the potential of these new agents require focused attention on detection, recognition, and treatment of comorbid psychiatric and medical conditions in patients with schizophrenia.

Some, but not all, antipsychotics elevate serum prolactin. Antipsychotic-induced hyperprolactinemia is thought to account for high rates of menstrual dysfunction and diminished estrogen levels in women with schizophrenia. However, few studies have directly assessed the relationships between prolactin, menstrual function, and ovarian hormone levels in this population. Sixteen premenopausal women with schizophrenia and schizoaffective disorder, eight treated with an antipsychotic with prolactin-elevating potential (five with typical antipsychotics and three with risperidone) and eight treated with an antipsychotic with prolactin-sparing potential (seven with olanzapine and one with clozapine), were studied for eight weeks. Data were collected on menstrual functioning and on serum prolactin, estradiol, and progesterone levels, and were compared between subjects who received an antipsychotic with prolactin-elevating potential and an antipsychotic with prolactin-sparing potential, and between subjects with hyperprolactinemia (N=6) and normoprolactinemia (N=10). Additionally, peak ovarian hormone levels were compared to normal values. While mean prolactin levels of subjects who received an antipsychotic with prolactin-elevating potential were significantly greater than those of subjects who received an antipsychotic with prolactin-sparing potential, there were no differences in rates of menstrual dysfunction or in ovarian hormone values between the two groups. Additionally, similar rates of menstrual dysfunction and ovarian hormone values were observed between the hyperprolactinemic and normoprolactinemic subjects. Moreover, irrespective of medication type or prolactin status, most subjects had peak estradiol levels below normal reference values for the periovulatory phase of the menstrual cycle. While our sample size is small, warranting the need for further investigation, the findings of this preliminary study suggest that antipsychotic-induced hyperprolactinemia, alone, may not adequately explain the observed ovarian dysfunction in women with schizophrenia.

Atypical antipsychotics have an important role in the acute and maintenance treatment of bipolar disorder. While robust evidence supports the efficacy of these agents in the treatment of mania and in the prevention of manic relapse, few atypical antipsychotics have shown efficacy in the treatment or prevention of depressive episodes. These agents pose a lower risk of extrapyramidal side effects compared to typical neuroleptics, but carry a significant liability for weight gain and other metabolic side effects such as hyperglycemia and hyperlipidemia. More comparative effectiveness studies are needed to assess the optimal treatment regimens, including the relative benefits and risks of antipsychotics versus mood stabilizers. The exploration of the molecular mechanisms of antipsychotics has helped to shed further light on the underlying neurobiology of bipolar disorder, since these compounds target systems thought to be key to the pathophysiology of bipolar disorder. In addition to modulating monoaminergic neurotransmission, atypical antipsychotics appear to share properties with mood-stabilizing agents known to alter intracellular signal transduction leading to changes in neuronal activity and gene expression. Atypical antipsychotic drugs have been shown to exhibit neuroprotective properties that are mediated by upregulation of trophic and cellular resilience factors. Building on our understanding of existing therapeutics, especially as it relates to underlying disease pathology, newer "plasticity enhancing" strategies hold promise for future treatments of bipolar disorder.

The Clinical Global Impression for Schizoaffective Disorder scale is a new rating scale adapted from the Clinical Global Impression scale for use in patients with schizoaffective disorder. The psychometric characteristics of the Clinical Global Impression for Schizoaffective Disorder are described.Content validity was assessed using an investigator questionnaire. Inter-rater reliability was determined with 12 sets of videotaped interviews rated independently by two trained individuals. Test-retest reliability was assessed using 30 randomly selected raters from clinical trials who evaluated the same videos on separate occasions two weeks apart. Convergent and divergent validity and effect size were evaluated by comparing scores between the Clinical Global Impression for Schizoaffective Disorder and the Positive and Negative Syndrome Scale, 21-item Hamilton Rating Scale for Depression, and Young Mania Rating Scale scales using pooled patient data from two clinical trials. Clinical Global Impression for Schizoaffective Disorder scores were then linked to corresponding Positive and Negative Syndrome Scale scores.Content validity was strong. Inter-rater agreement was good to excellent for most scales and subscales (intra-class correlation coefficient ≥ 0.50). Test-retest showed good reproducibility, with intraclass correlation coefficients ranging from 0.444 to 0.898. Spearman correlations between Clinical Global Impression for Schizoaffective Disorder domains and corresponding symptom scales were 0.60 or greater, and effect sizes for Clinical Global Impression for Schizoaffective Disorder overall and domain scores were similar to Positive and Negative Syndrome Scale Young Mania Rating Scale, and 21-item Hamilton Rating Scale for Depression scores. Raters anticipated that the scale might be less effective in distinguishing negative from depressive symptoms, and, in fact, the results here may reflect that clinical reality.Multiple lines of evidence support the reliability and validity of the Clinical Global Impression for Schizoaffective Disorder for studies in schizoaffective disorder.

Atypical antipsychotics have an important role in the acute and maintenance treatment of bipolar disorder. While robust evidence supports the efficacy of these agents in the treatment of mania and in the prevention of manic relapse, few atypical antipsychotics have shown efficacy in the treatment or prevention of depressive episodes. These agents pose a lower risk of extrapyramidal side effects compared to typical neuroleptics, but carry a significant liability for weight gain and other metabolic side effects such as hyperglycemia and hyperlipidemia. More comparative effectiveness studies are needed to assess the optimal treatment regimens, including the relative benefits and risks of antipsychotics versus mood stabilizers. The exploration of the molecular mechanisms of antipsychotics has helped to shed further light on the underlying neurobiology of bipolar disorder, since these compounds target systems thought to be key to the pathophysiology of bipolar disorder. In addition to modulating monoaminergic neurotransmission, atypical antipsychotics appear to share properties with mood-stabilizing agents known to alter intracellular signal transduction leading to changes in neuronal activity and gene expression. Atypical antipsychotic drugs have been shown to exhibit neuroprotective properties that are mediated by upregulation of trophic and cellular resilience factors. Building on our understanding of existing therapeutics, especially as it relates to underlying disease pathology, newer “plasticity enhancing” strategies hold promise for future treatments of bipolar disorder.

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.

Background The purpose of this analysis was to evaluate relationships between hospital admission or discharge and scores for symptom or functioning in patients with schizophrenia. Methods Data were from three 52-week open-label extensions of the double-blind pivotal trials of paliperidone extended-release (ER). Symptoms and patient function were measured every 4 weeks using the Personal and Social Performance (PSP) scale and the Positive and Negative Syndrome Scale (PANSS). The intent-to-treat analysis set was defined as open-label patients who had at least one post-baseline PSP and PANSS measurement. Time until first hospitalization was evaluated using the Cox proportional hazard model with categorical time-dependent measures for the PSP (1 to 30, 31 to 70, 71 to 100) or PANSS (< 75, ≥ 75 to < 95, ≥ 95), as well as age, gender, schizophrenia duration, and country. Similar analyses were performed for time to discharge. Results Of the 1,077 enrolled patients, 1,028 (95.5%) met study criteria; of these, 382 (37.2%) were hospitalized at open-label baseline. Compared with patients with PSP ≥ 71 group, the hazard for new hospitalization was 8.351 times greater (P = 0.0001) for patients with the poorest functioning (PSP 1 to 30) and 1.977 times greater (P = 0.0295) for patients with PSP of 31-70 compared to the ≥ 71 group. The hazard for new hospitalization was 5.457 times greater (P < 0.0001) for patients PANSS ≥ 95 and 2.316 times greater (P = 0.0027) for the ≥ 75 to < 95 group compared with the < 75 group. For patients hospitalized at baseline, the PANSS ≥ 95 patients had a discharge hazard that was 0.456 times lower than for the < 75 patients (P < 0.0001). The hazard for discharge was 0.646 times lower (P = 0.0012) for the PANSS ≥ 75 to < 95 group compared with the < 75 group. A patient's country was a significant predictor variable, with US patients being admitted and discharged faster. Conclusions Better functioning or being less symptomatic is associated with reduced risk for hospitalization and greater chance for early discharge. Treatments or programs that reduce symptoms or improve function decrease the risk of hospitalization in community patients or increase the chance of discharge for hospitalized patients.

The Medication Satisfaction Questionnaire (MSQ) is a single-item questionnaire which evaluates satisfaction with antipsychotic medication in schizophrenia patients. This study evaluated the reliability and validity for its use in research and clinical settings. Data pooled across treatment groups (control vs. Paliperidone ER) from a randomized 6-week study were used to conduct four psychometric assessments of the MSQ: (1) test-retest reliability, (2) convergent validity, (3) known-groups validity, and (4) minimally important difference (MID). This analysis included 191 randomized subjects. Test-retest reliability was evaluated for patients with no change in satisfaction from weeks 2 to 4 and weeks 4 to 6 (ICC=0.80; 0.83, respectively). Convergent validity was demonstrated through large correlations with Treatment Satisfaction Questionnaire for Medication (TSQM) global score (r=0.72-0.77), and through small correlations with variables measuring clinical symptoms and functioning (e.g., Positive and Negative Syndrome Scale (PANSS) total score [r=-0.30 to -0.17], CGI-S [r=-0.35 to -0.27], SF-36 Physical Functioning Score [r=0.18] and side effects and extrapiramidal measures (including UKU, ESRS-A, SAS). Mean MSQ scores were significantly different between those who completed and discontinued the study, and between different satisfaction groups based on TSQM, demonstrating good known-groups validity. MID estimates for the MSQ ranged from 0.47 (standard error of measurement) to 0.58 (anchor-based method). Results suggest that the MSQ has acceptable reliability and validity, making this single-item questionnaire appropriate and easy to use in clinical research and potentially in clinical practice. A 1-point change on the MSQ may be considered clinically meaningful.

This post-hoc analysis evaluated the effects of paliperidone extended-release (ER) in patients with schizophrenia and prominent affective symptoms.Pooled data from three 6-week, randomized, double-blind, placebo-controlled studies were analyzed. Subjects received fixed doses of paliperidone ER 3-12 mg/day or placebo. Prominent affective symptoms were defined as depressive (Positive and Negative Syndrome Scale [PANSS] depression item score ofor =5 [moderately severe]) and/or manic (PANSS grandiosity score ofor =4 [moderate], plus a score ofor =4 [moderate] on at least 1 PANSS item for excitement, hostility, uncooperativeness, or poor impulse control). Assessments included PANSS, Clinical Global Impressions-Severity (CGI-S), Personal and Social Performance (PSP) scale, and adverse events (AEs).Among 193 patients with prominent affective symptoms, 140 received paliperidone ER and 53 received placebo. Paliperidone ER showed significant mean (SD) improvements vs. placebo in PANSS total (-20.5 [23.8] vs. -6.3 [27.2]; p0.001, respectively) and all factor scores (p0.01). Significant mean (SD) improvements were observed in PSP (7.2 [15.8] vs. 0.4 [14.6]; p=0.004) and CGI-S (-0.9 [1.2] vs. -0.3 [1.2]; p0.001) scores. Most common AEs with paliperidone ER vs. placebo: headache (16.4% vs. 13.2%), insomnia (7.9% vs. 9.4%), akathisia (7.1% vs. 1.9%), sedation (7.1% vs. 3.8%).These studies were not designed to examine patients with prominent affective symptoms. Authors' clinical judgment was used to define prominent affective symptoms, using relevant PANSS items.Paliperidone ER was well tolerated and associated with significantly greater improvements in symptomatology, functioning, and overall clinical status vs. placebo in patients with schizophrenia and prominent affective symptoms.

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 3-12 mg/day or placebo. Patients had to have received risperidone foror =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) mg/day for paliperidone ER and 527.0 (805.3) days and 4.1 (2.5) mg/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 (P0.05) 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. AEsor =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.

What are the important gender differences seen in men and women with schizophrenia? Although schizophrenia affects men and women with equal frequency, the illness is expressed differently between the sexes. Women with schizophrenia tend to have better premorbid functioning, a later age at onset, a distinct symptom profile and better course of illness, and different structural brain abnormalities and cognitive deficits. Additionally, premenopausal women appear to have a superior response to typical antipsychotics compared to men and postmenopausal women. These gender differences are thought to arise from the interplay between hormonal and psychosocial factors. It has been hypothesized that estrogen, with effects on both neurodevelopment and neurotransmission, may play a protective role in women with schizophrenia and account for some of the gender differences observed in the disorder. Despite the potential benefit of estrogen in this population, women with schizophrenia appear to be at risk for hypoestrogenism, either as a consequence of antipsychotic-induced hyperprolactinemia or, possibly, as a manifestation of the illness itself. The mechanism and consequences of hypoestrogenism in women with schizophrenia, as well as the role for hormonal therapies in this population, require further study.