Adjunctive Lanicemine (AZD6765) in Patients with Major Depressive Disorder and History of Inadequate Response to Antidepressants: A Randomized, Placebo-Controlled Study.

The objective of this study was to investigate the efficacy and safety of adjunctive lanicemine (NMDA channel blocker) in the treatment of major depressive disorder (MDD) over 12 weeks. This phase IIb, randomized, parallel-arm, double-blind, placebo-controlled study was conducted at 49 centers in four countries between December 2011 and August 2013 in 302 patients aged 18-70 years, meeting criteria for single episode or recurrent MDD and with a history of inadequate treatment response. Patients were required to be taking an allowed antidepressant for at least four weeks prior to screening. Patients were randomized equally to receive 15 double-blind intravenous infusions of adjunctive lanicemine 50 mg, lanicemine 100 mg, or saline over a 12-week course, in addition to ongoing antidepressant. The primary efficacy end point was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from baseline to week 6. Secondary efficacy outcome variables included change in MADRS score from baseline to week 12, response and remission rates, and changes in Clinical Global Impression scale, Quick Inventory of Depressive Symptomology Self-Report score, and Sheehan Disability Scale score. Of 302 randomized patients, 240 (79.5%) completed treatment. Although lanicemine was generally well tolerated, neither dose was superior to placebo in reducing depressive symptoms on the primary end point or any secondary measures. There was no significant difference between lanicemine and placebo treatment on any outcome measures related to MDD. Post hoc analyses were performed to explore the possible effects of trial design and patient characteristics in accounting for the contrasting results with a previously reported trial.

Phase I, open-label, randomized, parallel study to evaluate the pharmacokinetics, safety, and tolerability of one intramuscular injection of risperidone ISM at different dose strengths in patients with schizophrenia or schizoaffective disorder (PRISMA-1).

The aim of this study was to characterize the pharmacokinetics and to evaluate the safety of risperidone ISM in patients with schizophrenia or schizoaffective disorder after a single gluteal intramuscular injection at three different dose strengths (50, 75, and 100 mg). A total of 36 patients were randomized and blood samples were collected to measure the plasma concentrations. The pharmacokinetic of the active moiety was biphasic for all three dose groups, and the mean plasma concentration was 21.45, 24.60, and 29.68 ng/ml in the 50, 75, and 100 mg group, respectively, 24 h after dose administration; 22.81, 24.57, and 31.41 ng/ml in the 50, 75, and 100 mg group, respectively, 48 h after dose administration, and 12.26, 17.31, and 20.01 ng/ml in the 50, 75, and 100 mg group, respectively, 30 days after dose administration. Overall, 34 patients experienced at least one treatment-emergent adverse event (TEAE). Two patients experienced a serious TEAE and no deaths occurred. There were no extrapyramidal symptoms-related serious TEAEs and no significant changes in any Columbia Suicide Severity Rating Scale parameter were observed during the study. Risperidone ISM provided a sustained release of risperidone that achieved therapeutic plasma levels within the first day. Risperidone ISM was safe, well tolerated, and should be suitable for a 4-weekly administration without oral supplementation.

Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia.

OBJECTIVE: Relapse and acute exacerbation are common in schizophrenia and may impact treatment response and outcome. Evidence is conflicting in respect to superiority of long-acting injectable antipsychotic therapies versus oral antipsychotics in relapse prevention. This randomized controlled study assessed the efficacy of paliperidone palmitate versus oral antipsychotics for relapse prevention. METHOD: Eligible patients with a recent diagnosis of schizophrenia (within 1-5 years) were randomized 1:1 to paliperidone palmitate (n=376) or oral antipsychotic monotherapy (n=388) and entered a 2-week initial acute oral treatment phase. Patients who met predefined response criteria were eligible to enter the 24-month rater-blinded core treatment phase. Patients were evaluated for relapse, symptoms, functioning, quality of life, treatment satisfaction, and tolerability. RESULTS: In the core treatment phase, time to relapse was significantly longer in the paliperidone palmitate (n=352) compared with the oral antipsychotics arm (n=363): 85% of patients were relapse-free at 469 versus 249 days (P=0.019). Significantly fewer patients receiving paliperidone palmitate met the relapse criteria (52 [14.8%] versus 76 [20.9%, oral antipsychotics]; P=0.032), representing a 29.4% relative risk reduction. For paliperidone palmitate, a significantly greater improvement in Positive and Negative Syndrome Scale total score on Day 8 (P=0.021) and a trend at endpoint (P=0.075) were observed. Functioning improvements were comparable between treatment arms. No new safety signals were identified. CONCLUSION: The observed time to relapse superiority of paliperidone palmitate over oral antipsychotics provides further evidence for the value of long-acting injectable antipsychotic therapies in the treatment of schizophrenia, including during the early stages of illness.

Two randomized controlled trials of SB742457 in mild-to-moderate Alzheimer's disease.

BACKGROUND: Two previous studies of SB742457, a 5-hydroxytryptamine (5-HT6) receptor antagonist, suggested the efficacy of improvements in cognition and global outcome in Alzheimer's disease (AD). METHODS: Two randomized, placebo-controlled trials investigated SB742457 15 and 35 mg daily in subjects with mild-to-moderate AD (Mini-Mental Health State Examination [MMSE] 10-26). Study 1 (n = 576) investigated SB742457 and donepezil (5-10 mg daily) as monotherapy for 6 months. Study 2 (n = 684) investigated SB742457 in subjects who were maintained on donepezil. Coprimary endpoints at 24 weeks assessed cognition (AD Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global outcome (Study 1: Clinician Interview-Based Impression of Change Plus Caregiver Input [CIBIC+]; Study 2: Clinical Dementia Rating-Sum of Boxes [CDR-SB]). Safety was assessed throughout. RESULTS: Both studies failed to achieve formal statistical significance for their primary objectives. Study 1: SB742457 monotherapy was not statistically significantly different from placebo on any endpoint. Donepezil improved CIBIC+ but not ADAS-Cog. Study 2: SB742457 35 mg showed statistically significant differences relative to placebo for ADAS-cog (weeks 12, 24, and 48, but not week 36), ADCS-ADL (weeks 12-36, but not week 48), and CDR-SB (week 12 only). CONCLUSION: Neither study met the overall criteria for success, but as an adjunct to donepezil, SB742457 was associated with sustained improvements for up to 48 weeks in cognition and ADL, compared with donepezil alone.Clinical Trial Registration: Clinicaltrials.gov: Study 1 NCT00708552; Study 2 NCT00710684.

Lithium as add-on to quetiapine XR in adult patients with acute mania: a 6-week, multicenter, double-blind, randomized, placebo-controlled study.

Quetiapine extended release (XR) and lithium are treatments with proven efficacy in acute mania. This randomized study evaluated the efficacy and safety of lithium or placebo as add-on to quetiapine XR in adult patients with manic or mixed symptoms of bipolar I disorder. In this 6-week, double-blind study (Trial D144AC00003), adult patients with DSM-IV-TR-diagnosed bipolar I disorder (current episode manic or mixed), a Young Mania Rating Scale (YMRS) total score ≥20, and score ≥4 on two of four core YMRS items were administered quetiapine XR (400 to 800 mg/day) and randomly assigned to receive add-on lithium (600 to 1,800 mg/day) or placebo. The primary efficacy end point was change in the YMRS total score from baseline to day 43, analyzed using a mixed-model for repeated measures (MMRM) approach. Secondary efficacy and safety end points were also measured. Rating scales were administered by trained staff. Three hundred fifty-six patients treated with quetiapine XR were randomized to add-on lithium (n = 173) or placebo (n = 183). Two hundred ninety-one patients (81.7%) completed the study. At day 43, least squares mean change in YMRS total score was -22.8 for add-on lithium and -20.1 for add-on placebo, a statistically significant treatment group difference of -2.69 (p < 0.001). On secondary measures, add-on lithium was associated with significant improvements in response, remission, illness severity, and overall illness versus add-on placebo (p < 0.05). The number needed to treat was 9.1 for response and 7.9 for remission for add-on lithium compared with add-on placebo. Lithium in combination with quetiapine XR was generally well tolerated, with a similar profile to quetiapine XR in combination with placebo. The addition of lithium to quetiapine XR therapy was associated with significantly greater efficacy than placebo as add-on and was generally well tolerated in patients with acute bipolar I mania. This study was registered under Clinicaltrials.gov Identifier NCT00931723.

Effects of quetiapine and haloperidol on body mass index and glycaemic control: a long-term, randomized, controlled trial.

The topic of antipsychotic-induced weight-gain and its relationship to glucose metabolism is under-studied. We evaluated the long-term effects of a new-generation antipsychotic, quetiapine and a conventional antipsychotic, haloperidol on body mass index (BMI) and glycaemic control in patients with schizophrenia previously treated with conventional antipsychotics. Forty-five clinically stable patients with schizophrenia participated in this randomized, investigator-blinded, parallel-group comparison of flexible doses of quetiapine and haloperidol treatment over 52 wk. Primary outcome measures were change from baseline in BMI and glycosylated haemoglobin (HBA1c) levels. There were no between-group differences at any of the time-points for BMI (F = 1.90, p = 0.1) and HBA1c (F = 1.17, p = 0.3) values, and there were no significant changes in BMI from baseline for either group. HBA1c levels decreased significantly at end-point for the haloperidol group (-1.5%, p = 0.04), but not for the quetiapine group (-0.3%, p = 0.5). Although the sample was not generally obese (mean baseline BMI 25.5 +/- 6.3 kg/m2), a large proportion exhibited evidence of abnormal glycaemic control prior to randomization (mean HBA1c 6.7 +/- 1.9%), with 48% having values that were at least mildly elevated (HBA1c > 6.1%) and 19% markedly elevated (HBA1c > 7%). The number of subjects with elevated HBA1c values decreased from baseline in both the haloperidol and quetiapine treatment groups. These findings suggest that switching treatment from a conventional antipsychotic to quetiapine is not associated with weight gain or worsening of glycaemic control, even in the long term. The study also highlights the high incidence of unrecognized glucose dysregulation in patients with schizophrenia receiving conventional antipsychotic treatment.

A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia.

BACKGROUND: While the atypical antipsychotics should ultimately reduce the prevalence of tardive dyskinesia, it is likely to remain a significant clinical problem for a long time to come. No strategy has clearly emerged as the treatment of choice for tardive dyskinesia. Atypical antipsychotics have reduced propensities for producing acute extrapyramidal symptoms (EPS) and possibly tardive dyskinesia and may be effective in treating patients with established tardive dyskinesia. METHOD: This 12-month, randomized, investigator-blinded study compared the efficacy of quetiapine (N = 22) and haloperidol (N = 23) in treating patients with DSM-IV schizophrenia or schizoaffective disorder and established tardive dyskinesia. Dyskinesia was assessed using the Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia subscale scores and the Clinical Global Impression (CGI) dyskinesia scores. Other EPS, weight, serum prolactin level, and glycosylated hemoglobin level were also assessed. Subjects were enrolled in the study between April 2000 and March 2002. RESULTS: Mean endpoint doses were 400 mg/day of quetiapine and 8.5 mg/day of haloperidol. Compared with the haloperidol group, the quetiapine group showed significantly greater improvements in ESRS dyskinesia (6 and 9 months [p or= 50% symptom reduction) was greater with quetiapine than haloperidol (64% [9/14] and 37% [6/16] at 6 months; 55% [6/11] and 28% [4/14] at 12 months). Other EPS decreased significantly with quetiapine at 3 (p =.01), 6 (p =.01), and 9 (p =.002) months. Serum prolactin levels decreased with quetiapine but increased with haloperidol, differing significantly between the groups at endpoint (p =.005). No significant changes in weight or glucose metabolism were recorded in either group. CONCLUSION: Quetiapine effectively reduces the severity of tardive dyskinesia and is well tolerated in patients with established tardive dyskinesia.