Long-term safety and tolerability of iloperidone: results from a 25-week, open-label extension trial.

INTRODUCTION/OBJECTIVE: Long-term use of the atypical antipsychotic iloperidone has not been investigated at doses above 16 mg/d. This article describes safety and tolerability results from the 25-week open-label extension of a 4-week placebo- and ziprasidone-controlled clinical trial of iloperidone. METHODS: Patients received a dose of 24 mg/d (given as 12 mg twice daily; mean dose = 21.6 mg) that could be reduced to 12 mg/d (given once daily at bedtime) any time after day 35 at the investigator's discretion. RESULTS: A total of 72/173 patients (41.6%) completed the open-label extension. Treatment-emergent adverse events (TEAEs), most mild to moderate in severity, included headache (13.9%), weight increase (9.2%), dizziness (6.9%), nausea (6.4%), sedation (6.4%), and insomnia (5.2%). The only notable dose-related TEAEs were increased weight and headache. Levels of serum glucose, lipids, and prolactin were essentially unchanged or decreased during treatment. In general, akathisia and extrapyramidal symptoms (EPS) improved or were unchanged during treatment. There was no signal of worsening of efficacy based on changes from baseline in the Positive and Negative Syndrome Scale-Total. DISCUSSION/CONCLUSION: This study further supports the long-term safety and tolerability of iloperidone for the treatment of schizophrenia, including iloperidone's favorable effect on metabolic laboratory parameters and low propensity to cause akathisia or EPS.

THE DEPRESSION INVENTORY DEVELOPMENT SCALE: Assessment of Psychometric Properties Using Classical and Modern Measurement Theory in a CAN-BIND Trial.

Objective: The goal of the Depression Inventory Development (DID) project is to develop a comprehensive and psychometrically sound rating scale for major depressive disorder (MDD) that reflects current diagnostic criteria and conceptualizations of depression. We report here the evaluation of the current DID item bank using Classical Test Theory (CTT), Item Response Theory (IRT) and Rasch Measurement Theory (RMT). Methods: The present study was part of a larger multisite, open-label study conducted by the Canadian Biomarker Integration Network in Depression (ClinicalTrials.gov: NCT01655706). Trained raters administered the 32 DID items at each of two visits (MDD: baseline, n=211 and Week 8, n=177; healthy participants: baseline, n=112 and Week 8, n=104). The DID's "grid" structure operationalizes intensity and frequency of each item, with clear symptom definitions and a structured interview guide, with the current iteration assessing symptoms related to anhedonia, cognition, fatigue, general malaise, motivation, anxiety, negative thinking, pain, and appetite. Participants were also administered the Montgomery- Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) that allowed DID items to be evaluated against existing "benchmark" items. CTT was used to assess data quality/reliability (i.e., missing data, skewness, scoring frequency, internal consistency), IRT to assess individual item performance by modelling an item's ability to discriminate levels of depressive severity (as assessed by the MADRS), and RMT to assess how the items perform together as a scale to capture a range of depressive severity (item targeting). These analyses together provided empirical evidence to base decisions on which DID items to remove, modify, or advance. Results: Of the 32 DID items evaluated, eight items were identified by CTT as problematic, displaying low variability in the range of responses, floor effects, and/or skewness; and four items were identified by IRT to show poor discriminative properties that would limit their clinical utility. Five additional items were deemed to be redundant. The remaining 15 DID items all fit the Rasch model, with person and item difficulty estimates indicating satisfactory item targeting, with lower precision in participants with mild levels of depression. These 15 DID items also showed good internal consistency (alpha=0.95 and inter-item correlations ranging from r=0.49 to r=0.84) and all items were sensitive to change following antidepressant treatment (baseline vs. Week 8). RMT revealed problematic item targeting for the MADRS and QIDSSR, including an absence of MADRS items targeting participants with mild/moderate depression and an absence of QIDS-SR items targeting participants with mild or severe depression. Conclusion: The present study applied CTT, IRT, and RMT to assess the measurement properties of the DID items and identify those that should be advanced, modified, or removed. Of the 32 items evaluated, 15 items showed good measurement properties. These items (along with previously evaluated items) will provide the basis for validation of a penultimate DID scale assessing anhedonia, cognitive slowing, concentration, executive function, recent memory, drive, emotional fatigue, guilt, self-esteem, hopelessness, tension, rumination, irritability, reduced appetite, insomnia, sadness, worry, suicidality, and depressed mood. The strategies adopted by the DID process provide a framework for rating scale development and validation.

Multiple pain complaints in patients with major depressive disorder.

OBJECTIVE: To characterize the co-existence of multiple pain-related complaints in patients enrolled in a series of pharmaceutical company drug trials for the treatment of Major Depressive Disorder (MDD). METHOD: Pooled 'blinded' data from 2191 patients enrolled in randomized, multicenter, double-blind placebo-controlled studies for the treatment of MDD were analyzed. Painful symptoms were assessed using the seven pain symptoms subset of the Somatic Symptoms Inventory: 'Headache,' 'Pain in lower back,' 'Neck pain,' 'Pain in joints,' 'Soreness in muscles,' 'Pain in heart or chest,' and 'Pain or cramps in abdomen.' The 17-item Hamilton Depression Rating Scale (HAMD) was used to assess severity of depression. RESULTS: Of those meeting the study entry criteria (total HAMD score >or=15), 25% reported no pain complaints and 18% reported 1 pain compliant; the majority (57%) of patients reported the co-existence of multiple pain-related complaints, with 14%, 12%, 11%, 11%, 7%, and 3% of patients reporting 2, 3, 4, 5, 6 and 7 different pain symptoms, respectively. The number of pain-related symptoms experienced was moderately related to severity of depression (r = 0.35), with the most common pain symptom combinations being among headaches, lower back pain, neck pain, pain in joints, and soreness in muscles. CONCLUSIONS: This study supports pain as a component feature of MDD. The number of comorbid pain-related complaints, which generally increased as a function of depressive severity, should be considered in the diagnosis of depression, planning of treatment strategies, and measurement of treatment outcome.

Prevalence and association of somatic symptoms in patients with Major Depressive Disorder.

BACKGROUND: Painful and non-painful somatic symptoms are often reported in patients with depressive disorder. The proper identification of depression-relevant somatic symptoms is important for the accurate diagnosis of depression, development of treatment strategies and measurement of outcome. The objective of this study was to characterize the relationship between somatic symptoms and depression in patients diagnosed with Major Depressive Disorder (MDD), using data from randomized drug trials carried out by a pharmaceutical company. METHODS: Pooled 'blinded' data from 2191 patients enrolled in randomized, multicenter, double-blind placebo-controlled studies for the treatment of MDD were analyzed. Somatic symptoms were assessed using the Somatic Symptoms Inventory (SSI) and the Hamilton Depression Rating Scale (HAMD) was used to assess symptoms of depression. RESULTS: The most common somatic symptom reported by patients with MDD was 'feeling fatigued, weak, or tired all over', with 78% of patients reporting 'moderate' levels or above. This was followed by 'feeling that not in as good physical health as most of your friends' (59%), 'not feeling well most of the time in the past few years' (54%), and 'feeling weak in parts of body' (45%). 'Headache' was the most common pain-related symptom with 43% reporting 'moderate' or above. Pearson's product-moment correlations revealed that somatic symptoms generally increased as a function of overall depressive (r=0.43), with 'feeling fatigued, weak, or tired all over' (r=0.50), 'feeling that not in as good physical health as most of your friends' (r=0.42), 'feeling weak in parts of body' (r=0.41), 'heavy feeling in arms and legs' (r=0.34), 'not feeling well most of the time in the past few years' (r=0.32), and 'headache' (r=0.31) showing the strongest correlation with overall HAMD scores. Non-parametric item response analyses showed that many somatic symptoms demonstrate good relationship between item response and the overall severity of depression. In particular, 'feeling fatigued, weak, or tired all over' exhibited good discriminative properties across the full range of severity for depression. LIMITATIONS: The analysis utilized data from a 'restricted' patient population in drug trials sponsored by a pharmaceutical company. CONCLUSIONS: These results demonstrate a high prevalence and association of somatic symptoms in patients with MDD, including feelings of fatigue, physical malaise and pain-related symptoms, which could be potentially useful in the assessment of depression and in the evaluation of treatment strategies.

Symptoms of anxiety in depression: assessment of item performance of the Hamilton Anxiety Rating Scale in patients with depression.

BACKGROUND: Although diagnostically dissociable, anxiety is strongly co-morbid with depression. To examine further the clinical symptoms of anxiety in major depressive disorder (MDD), a non-parametric item response analysis on "blinded" data from four pharmaceutical company clinical trials was performed on the Hamilton Anxiety Rating Scale (HAMA) across levels of depressive severity. METHODS: The severity of depressive symptoms was assessed using the 17-item Hamilton Depression Rating Scale (HAMD). HAMA and HAMD measures were supplied for each patient on each of two post-screen visits (n=1,668 observations). Option characteristic curves were generated for all 14 HAMA items to determine the probability of scoring a particular option on the HAMA in relation to the total HAMD score. Additional analyses were conducted using Pearson's product-moment correlations. RESULTS: Results showed that anxiety-related symptomatology generally increased as a function of overall depressive severity, though there were clear differences between individual anxiety symptoms in their relationship with depressive severity. In particular, anxious mood, tension, insomnia, difficulties in concentration and memory, and depressed mood were found to discriminate over the full range of HAMD scores, increasing continuously with increases in depressive severity. By contrast, many somatic-related symptoms, including muscular, sensory, cardiovascular, respiratory, gastro-intestinal, and genito-urinary were manifested primarily at higher levels of depression and did not discriminate well at lower HAMD scores. CONCLUSIONS: These results demonstrate anxiety as a core feature of depression, and the relationship between anxiety-related symptoms and depression should be considered in the assessment of depression and evaluation of treatment strategies and outcome.

Carbamazepine and valproate for the treatment of bipolar disorder: a review of the literature.

There are an increasing number of pharmacologic therapies for bipolar disorder. Two of these agents, the anticonvulsants carbamazepine (CBZ) and valproate (VPA), were first developed over 30 years ago for the treatment of epilepsy, and subsequent studies demonstrated that they are also effective in the treatment of acute mania and suggest efficacy as maintenance therapy in bipolar disorder. Because VPA and CBZ have been in use for many years, the psychiatric community is familiar with the adverse event profiles of these agents. A review of the clinical data evaluating VPA and CBZ monotherapy for the treatment of acute mania suggests that VPA and CBZ are similarly effective in acute mania. However, when their respective adverse event profiles are considered, VPA may be more tolerable than CBZ for short-term use, while CBZ may be better suited for long-term therapy. Controlled and direct comparative studies, both short and long term, are needed to further clarify the differences between VPA and CBZ.

An open-label extension trial of risperidone monotherapy in the treatment of bipolar I disorder.

The primary objective of this 9-week open-label extension trial was to assess the effects of risperidone monotherapy in patients with acute bipolar I disorder who completed treatment in two preceding 3-week double-blind trials. Patients with DSM-IV bipolar I disorder, experiencing an acute manic episode, received a flexible dose of risperidone (1-6 mg/day) or placebo in two independent double-blind, randomized, 3-week monotherapy trials. Completers who required ongoing treatment were eligible to enter this open-label 9-week extension trial during which all patients received risperidone. The primary efficacy measure was the mean change in the Young Mania Rating Scale (YMRS) total score. Secondary efficacy measures included the Clinical Global Impressions-Severity Scale, Montgomery-Asberg Depression Rating Scale, Positive and Negative Syndrome Scale and Global Assessment Scale. Safety assessments included adverse event reports, laboratory tests, and the Extrapyramidal Symptom Rating Scale (ESRS). Of the 283 patients who entered the extension study, 160 had previously received risperidone (RIS/RIS) in the acute treatment trial and 123 had received placebo (PLA/RIS). This study was completed by 71% of these patients. The mean+/-SE modal dose of risperidone was 4.6+/-1.5 mg/day. Patients in both the RIS/RIS and PLA/RIS groups improved significantly at the endpoint of the 9-week open-label study compared to their open-label baseline scores (-5.2+/-0.69, P<0.001 and -9.12+/-1.44, P<0.001, respectively) on the YMRS. Furthermore, changes from double-blind baseline to open-label endpoint were -29.4+/-1.0 in the RIS/RIS group and -23.9+/-1.4 in the PLA/RIS group. Significant improvements from both double-blind and open-label baseline were seen at week 1 of the open-label trial (P<0.001) and at each subsequent timepoint. A similar pattern was observed on the secondary measures of efficacy. Most frequent adverse events were extrapyramidal disorder (18%) and somnolence (12%). Most adverse events were mild or moderate in severity. The mean score for the Parkinsonism subscale of the ESRS was 1.1 at open-label baseline, and decreased by 0.1 at endpoint. Mean increase in body weight from open-label baseline was 0.6 kg in patients treated with placebo in the preceding double-blind trial and 1.2 kg in patients previously treated with risperidone. Risperidone treatment was well tolerated and resulted in further improvement during the 9-week extension, beyond the 3 weeks of acute treatment. Patients switched from placebo to risperidone improved markedly. Risperidone treatment did not induce depression.

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

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

The Depression Inventory Development Workgroup: A Collaborative, Empirically Driven Initiative to Develop a New Assessment Tool for Major Depressive Disorder.

The Depression Inventory Development project is an initiative of the International Society for CNS Drug Development whose goal is to develop a comprehensive and psychometrically sound measurement tool to be utilized as a primary endpoint in clinical trials for major depressive disorder. Using an iterative process between field testing and psychometric analysis and drawing upon expertise of international researchers in depression, the Depression Inventory Development team has established an empirically driven and collaborative protocol for the creation of items to assess symptoms in major depressive disorder. Depression-relevant symptom clusters were identified based on expert clinical and patient input. In addition, as an aid for symptom identification and item construction, the psychometric properties of existing clinical scales (assessing depression and related indications) were evaluated using blinded datasets from pharmaceutical antidepressant drug trials. A series of field tests in patients with major depressive disorder provided the team with data to inform the iterative process of scale development. We report here an overview of the Depression Inventory Development initiative, including results of the third iteration of items assessing symptoms related to anhedonia, cognition, fatigue, general malaise, motivation, anxiety, negative thinking, pain and appetite. The strategies adopted from the Depression Inventory Development program, as an empirically driven and collaborative process for scale development, have provided the foundation to develop and validate measurement tools in other therapeutic areas as well.

Extended-release carbamazepine capsules as monotherapy for acute mania in bipolar disorder: a multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although carbamazepine has long been used for the treatment of acute mania, only recently was its efficacy confirmed in a large, multicenter, parallel-group, placebo-controlled, randomized trial. In the present study, we further evaluated the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ) in patients with bipolar I disorder experiencing manic or mixed episodes. METHOD: Hospitalized bipolar I disorder (DSM-IV criteria) patients (N = 239) with manic or mixed episodes were randomly assigned on a double-blind basis to receive ERC-CBZ or placebo for 3 weeks, following a single-blind placebo lead-in. Treatment with ERC-CBZ was initiated at 200 mg twice daily, and investigators were encouraged to increase doses, as necessary and tolerated, by 200 mg/day up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression. The study was conducted from July 23, 2002, to April 1, 2003. RESULTS: 144 patients (60.3%) completed the study, with a significant number of placebo patients discontinuing due to lack of efficacy (p < .001). Extended-release carbamazepine treatment was associated with significant improvements in mean YMRS total and CGI total scores, using last-observation-carried-forward analyses, beginning at day 7 (p < .05). Adverse events occurring more frequently in the ERC-CBZ-treated group included dizziness (39.3%), somnolence (30.3%), and nausea (23.8%) [corrected] Patients taking ERC-CBZ experienced a significant increase in total cholesterol, composed of increases in both high-density and low-density lipoproteins. CONCLUSION: Extended-release carbamazepine monotherapy had significantly greater efficacy compared with placebo in the treatment of acute mania in this large, randomized, double-blind, placebo-controlled trial.

A multicenter, randomized, double-blind, placebo-controlled trial of extended-release carbamazepine capsules as monotherapy for bipolar disorder patients with manic or mixed episodes.

BACKGROUND: Carbamazepine has been used to treat mania for over 2 decades. Most evaluations of carbamazepine have had important limitations, such as absence of a parallel placebo group, small sample size, or the confounding influence of concomitant treatment. All studies have used conventional, immediate-release carbamazepine formulations. We assessed the efficacy and safety of monotherapy with beaded, extended-release carbamazepine capsules (ERC-CBZ; SPD417) in bipolar disorder patients with manic or mixed episodes. METHOD: Following a single-blind placebo lead-in, DSM-IV-defined bipolar disorder patients with manic or mixed episodes were randomly assigned to receive ERC-CBZ (N = 101) or placebo (N = 103) for 3 weeks. Patients were hospitalized through the first 7 days of the double-blind period. ERC-CBZ was initiated at 400 mg/day and increased, as necessary and tolerated, up to 1600 mg/day. Efficacy was assessed weekly with the Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression (HAM-D). Data were gathered from December 1999 to June 2001. RESULTS: Ninety-six (47.1%) of 204 patients completed the study. The mean +/- SD final ERC-CBZ dose was 756.44 +/- 413.38 mg/day with a mean plasma drug level of 8.9 microg/mL. Starting at week 2, ERC-CBZ was associated with significantly greater improvements in YMRS (p =.032) using last-observation-carried-forward analyses. At end point, the responder rate (patients with at least a 50% decrease in YMRS score) also favored ERC-CBZ (41.5% vs. 22.4%; p =.0074). In a post hoc analysis of mixed patients, HAM-D score was significantly improved in patients remaining on ERC-CBZ treatment on day 21 (p =.01). Adverse events occurring more frequently in the ERC-CBZ group than in the placebo group included dizziness, nausea, and somnolence. CONCLUSION: We found ERC-CBZ to be effective in the first large, randomized, double-blind, placebo-controlled parallel trial of carbamazepine monotherapy in acute mania. This trial provides important additional evidence supporting the use of carbamazepine in acute mania.

A 6-month, multicenter, open-label evaluation of beaded, extended-release carbamazepine capsule monotherapy in bipolar disorder patients with manic or mixed episodes.

BACKGROUND: Carbamazepine is frequently used for treating bipolar disorder, but few large trials have assessed its efficacy in preventing relapse. We evaluated open-label monotherapy with beaded extended-release carbamazepine capsules (ERC-CBZ; SPD417) as continuation and short-term maintenance therapy in bipolar disorder patients with manic and mixed episodes. METHOD: A 6-month, open-label study enrolled 92 patients with DSM-IV bipolar disorder (most recent episode: 67% [N = 62] mixed, 33% [N = 30] manic) who had participated in 2 previous 3-week, double-blind, placebo-controlled studies. Subjects received beaded ERC-CBZ (200-1600 mg/day), titrated at investigators' discretion to a final mean dose of 938 mg/day and serum carbamazepine concentration of 6.6 microg/mL. The primary efficacy measure was time to relapse, and secondary efficacy measures included Young Mania Rating Scale (YMRS), Clinical Global Impressions scale (CGI), and Hamilton Rating Scale for Depression (HAM-D) scores. Data were gathered from January 2000 to January 2002. RESULTS: Of 77 patients analyzed in the intent-to-treat population, 11 (14.3%) relapsed. Fifty-three patients (68.8%) discontinued early, including 18 (23.4%) due to adverse events. Observed mean time to relapse was 61.1 days, while estimated mean time to relapse based on the Kaplan-Meier model was 141.8 days. Improvements on the YMRS, CGI, and HAM-D from the beginning of prior double-blind treatment were maintained. The most common adverse events were headache, dizziness, and rash. No significant weight gain was noted. CONCLUSION: We noted a low relapse rate with beaded ERC-CBZ in this 6-month trial. Adverse events were generally mild to moderate and were typical of those associated with carbamazepine. Controlled studies are warranted to further explore the efficacy of beaded ERC-CBZ in preventing relapse in bipolar disorder.

Open-label study of the effect of combination quetiapine/lithium therapy on lithium pharmacokinetics and tolerability.

OBJECTIVE: The aim of this study was to assess the effect of oral quetiapine on the steady-state pharmacokinetics of lithium. METHODS: This was an open-label trial in patients with schizophrenia, schizoaffective disorder, or bipolar disorder who had demonstrated tolerability to combination lithium/ antipsychotic therapy. Patients received lithium for at least 1 week before screening and throughout the 18-day trial. Quetiapine was coadministered in fixed, stepwise, increasing doses of 25 to 250 mg TID on days 4 through 11, and maintained at 250 mg TID on days 12 through 14. Blood samples were drawn to monitor plasma concentrations of lithium and quetiapine. Psychiatric assessments included the Brief Psychiatric Rating Scale, the Clinical Global Impression severity of illness item, and the modified Scale for the Assessment of Negative Symptoms. Neurologic function was assessed using the Simpson-Angus Scale and the Abnormal Involuntary Movement Scale. Other assessments included clinical laboratory testing, electrocardiography, physical examinations, and monitoring for spontaneously reported adverse events. RESULTS: Nine men and 1 woman (mean [SE] age, 32.8 [1.9] years; mean [SE] body weight, 87.6 [3.3] kg) entered and completed the 18-day trial. Eight patients had bipolar disorder, 1 had paranoid schizophrenia, and 1 had schizoaffective disorder. Morning trough concentrations of lithium in serum (days 2, 6, 8, 10, 12, 14, and 17), as well as quetiapine and 2 of its metabolites in plasma (days 12, 13, and 14), did not appear to vary noticeably. Small increases were observed in the mean values of the area under the 12-hour serum lithium concentration-time curve and the maximum and minimum observed serum lithium concentrations when quetiapine was added to the lithium regimen. However, the increases were not considered clinically relevant by the investigators and were not statistically significant. A total of 91 adverse events were reported, 67 (73.6%) of which were not attributed to trial treatment. The most commonly reported adverse events during coadministration of lithium and quetiapine were somnolence (90.0% [9/10]), asthenia (70.0% [7/10]), dry mouth (30.0% [3/10]), nausea (30.0% [3/10]), vomiting (30.0% [3/10]), dizziness (30.0% [3/10]), tremor (30.0% [3/10]), and insomnia (20.0% [2/10]). There were no serious adverse events. CONCLUSIONS: Measures of lithium and quetiapine concentrations did not vary significantly during combination therapy. Coadministered lithium and quetiapine were well tolerated in the patients studied.

Efficacy and safety of lurasidone 80 mg/day and 160 mg/day in the treatment of schizophrenia: a randomized, double-blind, placebo- and active-controlled trial.

OBJECTIVE: This study was designed to evaluate the short-term efficacy and safety of once-daily lurasidone (80 mg/day and 160 mg/day) in the treatment of an acute exacerbation of schizophrenia. METHODS: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of fixed-dose, double-blind treatment with lurasidone 80 mg (n=125), lurasidone 160 mg (n=121), quetiapine XR 600 mg (QXR-600 mg; n=119; active control included to test for assay sensitivity), or placebo (n=121), all dosed once daily in the evening. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from Baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score (the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (the key secondary efficacy measure). RESULTS: Treatment with both doses of lurasidone or with QXR-600 mg was associated with significantly greater improvement at Week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. The endpoint responder rate (≥ 20% improvement in PANSS total score) was higher in subjects treated with lurasidone 80 mg (65%; p<0.001), lurasidone 160 mg (79%; p<0.001), and QXR-600 mg (79%; p<0.001) compared with placebo (41%). The proportion of patients experiencing ≥ 7% weight gain was 4% for each lurasidone group, 15% for the QXR-600 mg group, and 3% for the placebo group. Endpoint changes in levels of cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol were comparable for both lurasidone groups and placebo, while the QXR-600 mg group showed a significant median increase compared with the placebo group in levels of cholesterol (p<0.001), LDL cholesterol (p<0.01), and triglycerides (p<0.05). CONCLUSIONS: Lurasidone 80 mg and 160 mg doses administered once-daily in the evening, were safe and effective treatments for subjects with acute schizophrenia, with increased response rates observed at the higher dose. Dose-related adverse effects were limited, and both doses were generally well-tolerated.

Lurasidone in the treatment of schizophrenia: a randomized, double-blind, placebo- and olanzapine-controlled study.

OBJECTIVE: The study was designed to evaluate the short-term efficacy and safety of lurasidone in the treatment of acute schizophrenia. METHOD: Participants, who were recently admitted inpatients with schizophrenia with an acute exacerbation of psychotic symptoms, were randomly assigned to 6 weeks of double-blind treatment with 40 mg of lurasidone, 120 mg of lurasidone, 15 mg of olanzapine (included to test for assay sensitivity), or placebo, dosed once daily. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score (as the primary efficacy measure) and Clinical Global Impressions severity (CGI-S) score (as the key secondary efficacy measure). RESULTS: Treatment with both doses of lurasidone or with olanzapine was associated with significantly greater improvement at week 6 on PANSS total score, PANSS positive and negative subscale scores, and CGI-S score compared with placebo. There was no statistically significant difference in mean PANSS total or CGI-S change scores for the lurasidone groups compared with the olanzapine group. With responders defined as those with an improvement of at least 20% on the PANSS, endpoint responder rates were significant compared with placebo for olanzapine only. The incidence of akathisia was higher with 120 mg of lurasidone (22.9%) than with 40 mg of lurasidone (11.8%), olanzapine (7.4%), or placebo (0.9%). The proportion of patients experiencing ≥ 7% weight gain was 5.9% for the lurasidone groups combined, 34.4% for the olanzapine group, and 7.0% for the placebo group. CONCLUSIONS: Lurasidone was an effective treatment for patients with acute schizophrenia. Safety assessments indicated a higher frequency of adverse events associated with 120 mg/day of lurasidone compared with 40 mg/day.

Average Out-of-Pocket Expenses Across Different Drug Categories and Commercial Third-Party Payers.

In this Trend Watch, we look at retail pharmacy prescriptions for branded and generic attention deficit hyperactivity disorder treatments, atypical antipsychotics, selective serotonin reuptake inhibitors, and serotonin and norepinephrine reuptake inhibitors and analyze the average out-of-pocket costs incurred by patients who are covered by commercial third-party prescription plans (i.e., as opposed to patients covered by Medicaid or patients with no prescription coverage). Overall, patient out-of-pocket costs in commercial third-party plans are lower for generic prescriptions than they are for brand prescriptions by at least $19.02. Comparisons across the drug classes reveal that the average co-pay for brands and generics, as well as the difference between brand and generic out-of-pocket costs, differ by drug category.

Generic penetration in the retail antidepressant market.

In this article, we explore the accelerated penetration of generic antidepressants in the United States market following the availability of generic citalopram and sertraline. Analysis suggests that overall, generic penetration into the antidepressant market has grown from approximately 41 percent in January 2004 to over 73 percent in January 2010. Similar trends are uncovered when branded and generic prescriptions are analyzed by specialty.

An analysis of the psychiatric pipeline.

In this article, we explore the current state of the psychiatry drug development pipeline. Analysis suggests that overall, the psychiatry pipeline is heavily skewed toward a few major indications and tends to have more programs in early development (Phase I and II) than later stages (Phase III). A review of development sponsors shows a fairly even split of programs between Top 50 Pharmaceutical companies and small to mid-sized biopharmaceutical companies.

A review of new atypical antipsychotic launches in the United States.

In this article we investigate the post-launch retail prescription trends of asenapine (Saphris(®), Merck and Co.) and iloperidone (Fanapt(®), Vanda Pharmaceuticals Inc./Novartis), two new atypical antipsychotics to launch in the United States market in October 2009 and January 2010, respectively. In the first 12 months following the asenapine launch, and in the nine months since the iloperidone launch, asenapine and iloperidone have secured 0.22 and 0.10 percent of the total prescription market; however, both products nearly double those respective shares when total prescriptions are isolated to new patient prescriptions (0.44% for asenapine and 0.17% for iloperidone). Since launch, asenapine has shown stronger signs of growth, largely attributed to its approval in multiple indications as compared to iloperidone's single indication.