Pimavanserin for Parkinson's Disease psychosis: Effects stratified by baseline cognition and use of cognitive-enhancing medications.

BACKGROUND: PD psychosis is often associated with cognitive impairment, including dementia, and involves dopaminergic, serotonergic, and cholinergic mechanisms. OBJECTIVE: To evaluate the differential effect of the antipsychotic pimavanserin, a selective serotonin 2A receptor inverse agonist, in PD psychosis patients with versus without cognitive impairment and in those receiving versus not receiving cognitive-enhancing medications. METHODS: Data from the pivotal randomized clinical trial of pimavanserin for PD psychosis were stratified by (1) screening MMSE score as cognitively impaired (21-24) versus unimpaired (≥25) and (2) concomitant use versus nonuse of cognitive-enhancing medications. The primary outcome measure was change in the PD-adapted Scale for the Assessment of Positive Symptoms. RESULTS: Mean (pimavanserin vs. placebo) change from baseline was larger in the cognitively impaired (n = 50; -6.62 vs. -0.91; P = 0.002) versus the cognitively unimpaired (n = 135; -5.50 vs. -3.23; p = 0.046) group. The comparable change was -6.04 versus -2.18 (P = 0.012) and -5.66 versus -3.15 (P = 0.041) in patients treated (n = 69) and not treated (n = 116) with concomitant cognitive-enhancing medication. Pimavanserin was similarly tolerated across all cognitive groups with no additional safety concerns identified. Overall adverse event rates were comparable across the concomitant cognitive-enhancing medication groups; however, rates of serious adverse events and discontinuations attributed to adverse events were increased in patients taking cholinesterase inhibitors. CONCLUSIONS: The antipsychotic effect of pimavanserin is robust in PD patients with cognitive impairment and may be enhanced by concomitant cognitive-enhancing medication use. Future prospective studies are needed to confirm these preliminary findings. © 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Respondent and item level patterns of response of aripiprazole in the acute treatment of pediatric bipolar I disorder.

BACKGROUND: Few studies have evaluated the value of a parent- and subject-rated scale in detecting symptom change in response to pharmacologic treatment. METHODS: This was a post-hoc analysis of data from a 4-week, randomized, double-blind, placebo-controlled study to evaluate which informants detect response to treatment with aripiprazole in pediatric subjects experiencing a mixed or manic episode associated with bipolar I disorder. Efficacy assessments included clinician-rated scales and the parent- and subject-rated 10-item General Behavior Inventory Mania (GBI-M10) and Depression (GBI-D10) scales. Cohen's d quantified effect sizes for total scale scores and individual line items. RESULTS: Parent-GBI-M10 total, clinician-rated Young Mania Rating Scale (YMRS) total, and Clinical Global Impression-Bipolar Disorder (CGI-BP) Mania scores produced similar effect sizes, suggesting that the parent-GBI-M10 is sensitive to treatment-related improvements in manic symptoms. Aripiprazole improved a broad spectrum of parent-rated mania symptoms; six parent-GBI-M10 line item effect sizes were moderate (>0.5) in at least one of the two aripiprazole treatment arms (10 or 30 mg/day). Subject-completed GBI-M10 line item effect sizes were consistently smaller, indicating that the subjects' experience of treatment effects were less pronounced. LIMITATIONS: Study inclusion/exclusion criteria may limit generalizability of these findings. CONCLUSIONS: Parent ratings of mania severity were in agreement with clinician ratings, indicating that parent-rated assessments can be valuable in detecting symptom change over the course of treatment. These data support the use of the parent-GBI-M10 as an outcome measure in research and clinical settings.

Safety and tolerability of aripiprazole in the treatment of irritability associated with autistic disorder in pediatric subjects (6-17 years old):results from a pooled analysis of 2 studies.

BACKGROUND: With increasing use of atypical antipsychotics among pediatric patients, detailed information about safety and tolerability is crucial. METHOD: Data were pooled from two 8-week, randomized, double-blind, multicenter, parallel-group trials comparing aripiprazole versus placebo in subjects aged 6 to 17 years with irritability associated with DSM-IV-TR-diagnosed autistic disorder: one flexibly dosed (aripiprazole 2-15 mg/d; target of 5, 10, or 15 mg/d), the other fixed-dose (aripiprazole 5, 10, or 15 mg/d). The first was conducted from June 2006-April 2008, and the second, from June 2006-June 2008. Adverse events were characterized with respect to incidence, duration, severity, timing of peak incidence of onset, and dose-response relationship. Extrapyramidal symptoms, drooling, and metabolic parameters were evaluated. RESULTS: Three hundred thirteen subjects comprised the safety sample (aripiprazole 212, placebo 101). Discontinuations due to adverse events with aripiprazole versus placebo were, overall, 10.4% versus 6.9%; subjects 6-12 years: 10.8% versus 5.1%; and subjects 13-17 years: 8.9% versus 13.6%. Common adverse events with aripiprazole versus placebo included sedation (20.8% vs 4.0%), fatigue (16.5% vs 2.0%), vomiting (13.7% vs 6.9%), increased appetite (12.7% vs 6.9%), somnolence (10.4% vs 4.0%), and tremor (9.9% vs 0.0%). Most adverse events were mild or moderate and occurred early. Only fatigue showed a dose-response relationship (P < .05). Mean body weight change (last observation carried forward, 1.6 vs 0.4 kg) was higher with aripiprazole than placebo (P < .001). There were no between-treatment differences in metabolic changes. The extrapyramidal symptom-related adverse event incidence with aripiprazole versus placebo was, overall, 20.8% vs 9.9%; the incidence of akathisia-related events was 3.3% vs 8.9%. CONCLUSIONS: Aripiprazole was generally safe and well tolerated in subjects (6-17 years) with irritability associated with autistic disorder in these 8-week studies; clinicians should be aware of this clinical profile and strategies to manage adverse events if they occur. TRIAL REGISTRATION: clinicaltrials.gov Identifiers NCT00332241 and NCT00337571.

Efficacy and safety of adjunctive aripiprazole in major depressive disorder in older patients: a pooled subpopulation analysis.

OBJECTIVES: To evaluate the efficacy and safety of adjunctive aripiprazole compared with standard antidepressant therapy (ADT) for older patients with major depressive disorder (MDD) who demonstrated an incomplete response to standard antidepressant monotherapy. METHODS: Data from three similar 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled for this post hoc analysis. Two age groups were defined: younger patients (aged 18-49 years) and older patients (aged 50-67 years). The older patient group was further divided into three subgroups: 50-55, 56-60, and 61-67 years. The efficacy endpoint was the mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score from end of the prospective phase (Week 8) to endpoint (Week 14, last observation carried forward (LOCF)). Remission was defined as MADRS total score ≤10 at endpoint. RESULTS: Four hundred and nine older patients (placebo, n = 198; aripiprazole, n = 211) and 679 younger patients (placebo, n = 341; aripiprazole, n = 338) were included in this analysis. Older patients receiving aripiprazole demonstrated significantly greater improvement in MADRS total score versus placebo at Week 14 (-10.0 vs. -6.4; p < 0.001; LOCF), similar to the improvement seen in younger patients. Remission rates were significantly higher with aripiprazole versus placebo in older (32.5% vs. 17.1%; p < 0.001) and younger (26.9% vs. 16.4%; p < 0.001) patients. Akathisia was the most common adverse event in both the older (17.1%) and younger (26.0%) patient groups. CONCLUSIONS: Adjunctive aripiprazole was effective in improving depressive symptoms in older patients, 50-67 years, with MDD who have had an inadequate response to standard antidepressant medication.

Wisconsin Card Sorting Test performance in schizophrenia: the role of working memory.

Schizophrenia typically results in reduced performance on the Wisconsin Card Sorting Test (WCST). In the current study, we used a variety of approaches to examine the role of working memory (WM) in this deficit. One approach was to examine patterns of perseverative and non-perseverative errors. A second approach involved the comparison of the standard WCST to a modified version that used visual cues to reduce demands on WM. A third approach was to quantify the impact of WM demands on performance on a trial by trial basis. Consistent with theories of WM, the schizophrenia group showed increases in both perseverative and non-perseverative errors and differences between individuals with schizophrenia and controls were largest when WM demands were high. The visual cues helped the schizophrenia group overcome the high WM demands of the test, although they did not reduce the impairment in terms of standard scoring procedures. All impairments disappeared, however, after controlling for group differences on a measure of the speed of encoding information in WM. The pattern of results supports the conclusion that WM impairment contributes to poor performance on the WCST in individuals with schizophrenia, with additional evidence that this impairment results from generalized slowing of information processing.

Striatal volume changes in the rat following long-term administration of typical and atypical antipsychotic drugs.

Striatal enlargement has been consistently reported in schizophrenics receiving chronic neuroleptic treatment although the results following atypical antipsychotic treatment have been equivocal. In order to disentangle patient illness from a possible drug effect on brain structure, young adult rats were administered either haloperidol, risperidone, clozapine, olanzapine, or vehicle daily for four or eight months via drinking water. Significant increases in caudate-putamen volumes were seen in animals receiving either haloperidol or clozapine when compared with control animals following eight months of drug administration. Conversely, olanzapine-treated animals showed significant decreases in caudate-putamen volumes when compared with control animals after eight months of drug. Thus, converging evidence indicates that the neuroplastic response of the striatum following neuroleptic exposure causes volumetric increases, whereas atypical antipsychotics affect the basal ganglia differentially. The current data suggests that such differential responses may be due to both the pharmacological properties and the relative doses of the atypical agents.