Ibrahim Turkoz

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

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

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

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

A randomized, double-blind, placebo-controlled study of maintenance treatment with adjunctive risperidone long-acting therapy in patients with bipolar I disorder who relapse frequently.

OBJECTIVE No large controlled trials have evaluated adjunctive maintenance treatment with long-acting injectable antipsychotics in patients with bipolar disorder. This study assessed whether adjunctive maintenance treatment with risperidone long-acting therapy (RLAT), added to treatment-as-usual (TAU) medications for bipolar disorder, delays relapse in patients with bipolar disorder type I. METHODS This study included patients with bipolar disorder type I with > or = four mood episodes in the 12 months prior to study entry. Following a 16-week, open-label stabilization phase with RLAT plus TAU, remitted patients entered a 52-week, double-blind, placebo-controlled, relapse-prevention phase. Randomized patients continued treatment with adjunctive RLAT (25-50 mg every two weeks) plus TAU (n = 65) or switched to adjunctive placebo injection plus TAU (n = 59). The primary outcome measure was time to relapse to any mood episode. RESULTS Of 240 enrolled patients, 124 entered double-blind treatment. Time to relapse was longer in patients receiving adjunctive RLAT (p = 0.010). Relapse rates were 23.1% (n = 15) with adjunctive RLAT versus 45.8% (n = 27) with adjunctive placebo; relative relapse risk was 2.3-fold higher with adjunctive placebo (p = 0.011). Completion rates were: adjunctive RLAT, 60.0% (n = 39) and adjunctive placebo, 42.4% (n = 25; p = 0.050). Adverse event (AE)-related discontinuations were 4.6% (n = 3) and 1.7% (n = 1), respectively. Common AEs (adjunctive RLAT versus adjunctive placebo) were: tremor (24.6% versus 10.2%), insomnia (20.0% versus 18.6%), muscle rigidity (12.3% versus 5.1%), weight increased (6.2% versus 1.7%), and hypokinesia (7.7% versus 0.0%). CONCLUSIONS Adjunctive RLAT significantly delayed time to relapse in patients with bipolar disorder type I who relapse frequently. Safety and tolerability of RLAT were generally consistent with that previously observed.

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 3–12 mg/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) 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 (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.

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.

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.

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.

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.

The Impact of Insight on Functioning in Patients With Schizophrenia or Schizoaffective Disorder Receiving Risperidone Long-Acting Injectable

This post hoc analysis explored the role of insight as a mediator of functioning in a 52-week, double-blind, international trial of 323 patients with schizophrenia or schizoaffective disorder receiving risperidone long-acting injectable. Measures included the Positive and Negative Syndrome Scale (PANSS) insight item, PANSS factors, Clinical Global Impressions–Severity (CGI-S), Strauss-Carpenter Levels of Functioning (LOF), Personal and Social Performance (PSP) scale, and a cognitive test battery. Correlation/regression analyses examined associations between demographic and clinical characteristics, including insight, and functional measures. Insight scores correlated significantly with CGI-S, PANSS subscales, PSP, LOF, and several cognitive measures. Regression models demonstrated that changes in insight, changes in negative symptoms, and study duration were significantly associated with PSP and LOF total change scores. Findings identified important variables to consider for intervention to improve functioning in schizophrenia.

Long-acting injectable paliperidone palmitate versus oral paliperidone extended release: a comparative analysis from two placebo-controlled relapse prevention studies

BackgroundIncreasing availability and use of long-acting injectable antipsychotics have generated a need to compare these formulations with their oral equivalents; however, a paucity of relevant data is available.MethodsThis post hoc comparison of the long-term efficacy, safety and tolerability of maintenance treatment with paliperidone palmitate (PP) versus oral paliperidone extended release (ER) used data from two similarly designed, randomised, double-blind (DB), placebo-controlled schizophrenia relapse prevention trials. Assessments included measures of time to relapse, symptom changes/functioning and treatment-emergent adverse events (TEAEs). Time to relapse between treatment groups was evaluated using a Cox proportional hazards model. Between-group differences for continuous variables for change scores during the DB phase were assessed using analysis of co-variance models. Categorical variables were evaluated using Chi-square and Fishers exact tests. No adjustment was made for multiplicity.ResultsApproximately 45% of enrolled subjects in both trials were stabilised and randomised to the DB relapse prevention phase. Risk of relapse was higher in subjects treated with paliperidone ER than in those treated with PP [paliperidone ER/PP hazard ratio (HR), 2.52; 95% confidence interval (CI), 1.46–4.35; p < 0.001]. Similarly, risk of relapse after withdrawal of paliperidone ER treatment (placebo group of the paliperidone ER study) was higher than after withdrawal of PP (paliperidone ER placebo/PP placebo HR, 2.25; 95% CI, 1.59–3.18; p < 0.001). Stabilised schizophrenic subjects treated with PP maintained functioning demonstrated by the same proportions of subjects with mild to no difficulties in functioning at DB baseline and end point [Personal and Social Performance (PSP) scale total score >70, both approximately 58.5%; p = 1.000] compared with a 10.9% decrease for paliperidone ER (58.5% vs 47.6%, respectively; p = 0.048). The least squares mean change for Positive and Negative Syndrome Scale (PANSS) total score at DB end point in these previously stabilised subjects was 3.5 points in favour of PP (6.0 vs 2.5; p = 0.025). The rates of TEAEs and AEs of interest appeared similar.ConclusionsThis analysis supports maintenance of effect with the injectable compared with the oral formulation of paliperidone in patients with schizophrenia. The safety profile of PP was similar to that of paliperidone ER. Future studies are needed to confirm these findings.

Paliperidone extended-release for schizophrenia: effects on symptoms and functioning in acutely ill patients with negative symptoms.

BACKGROUND Most patients with schizophrenia exhibit negative symptoms, even during acute episodes. These difficult-to-treat symptoms are often associated with poor functioning and outcomes. METHODS 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 and <40% of the maximum positive factor score on the Positive and Negative Syndrome Scale [PANSS]). RESULTS 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 values <0.05). Adverse events reported in >or=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). CONCLUSIONS 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.