Aripiprazole Group Research Articles

Effects of Atypical Antipsychotics on Neuroactive Vitamins in Patients With Schizophrenia.

In schizophrenia, neuroactive vitamins A/D/E play vital neuroprotective roles in its pathophysiological processes. During medical treatment, atypical antipsychotics, including aripiprazole, amisulpride, olanzapine, and paliperidone, were widely used at present. However, their impact on vitamin metabolism in vivo remained unclear. In this study, we conducted a case-control research to investigate the impacts of antipsychotics on vitamin metabolism. Schizophrenic patients (n = 163), who were divided into 5 groups (aripiprazole group, amisulpride group, olanzapine group, paliperidone group, nonmedication group) according to their different medication patterns, and healthy controls (n = 75) were involved. The concentrations of vitamin A/D/E and antipsychotics were measured using liquid chromatography-tandem mass spectrometry methods. Compared with healthy controls, significantly lower vitamin D and E concentrations were found in the nonmedication group after covariance analysis adjusting for age, sex, albumin, bilirubin, triglyceride, and cholesterol. We found that aripiprazole could affect vitamin D concentrations in vivo, and a positive correlation between aripiprazole concentrations and vitamin D concentrations (r = 0.319, P = 0.025) was observed in aripiprazole group. Such result revealed the very first observation for the influence of atypical antipsychotics medication toward vitamin status in vivo. Our study showed that low concentrations of vitamin D and E in vivo could be associated with schizophrenia, suggesting that hypovitaminosis may lead to a vulnerability to schizophrenia. More importantly, aripiprazole may potentially benefit the patients through improving their vitamin D status in vivo.

T206. ANTIPSYCHOTIC EFFECTIVENESS FOCUSING ON INSIGHT

BackgroundImpaired insight is common among patients with schizophrenia, and a major obstacle for treatment adherence and improvement. Previous studies have investigated the effect of antipsychotics on insight, but findings are indecisive due to small or homogeneous samples, non-randomized design or short follow- up.The aim of this study was to investigate if there were differential effects on insight among different antipsychotic medications, and whether the effect was directly related to improvement in insight or indirectly through reduction of psychosis symptoms.MethodsData was derived from the Bergen-Stavanger-Innsbruck-Trondheim study (BestIntro). This is a randomized, rater-blinded, naturalistic study with a head- to head comparison of three antipsychotic medications: amisulpride, aripiprazole and olanzapine. Inclusion criteria were adults with a F20-F29 ICD-10 diagnosis being actively psychotic defined as a score of ≥4 on items P1, P3, P5, P6, or G9 on the Positive And Negative Syndrome Scale (PANSS). Insight was measured by PANSS item G12. We used a modified version of PANSS to assess psychosis symptoms (PANSS total score minus item G12, mPANSS). Level and change in insight and psychosis symptoms were estimated in latent growth curve models. The pattern of change indicated a piecewise model with the initial phase from baseline to week six and the long-term phase from week six to one year. The study drugs were used as predictors.ResultsA total of 144 participants were included, 35% female and 61% had previously used antipsychotic medication. Mean insight score at baseline was 3.36. Preliminary findings show differential effects on insight among the three medications, where aripiprazole was the least effective drug. The effect on insight was related to improvement in psychosis symptoms for all study drugs. In addition, we found a direct effect on insight in the long-term phase for amisulpride and olanzapine. In the same phase, the aripiprazole group showed a slight increase in impaired insight.DiscussionThis is the first randomized study with a heterogeneous sample to find an effect of antipsychotics on insight that exceeds the contribution of reduction of psychosis symptoms. Although we have not investigated the association between increased insight and medication adherence, our results imply that patients with impaired insight will benefit from antipsychotic treatment. More specifically, treatment with amisulpride or olanzapine may be more helpful in improving insight over time.

A comparative study of effectiveness, safety and cost effectiveness of olanzapine, risperidone and aripiprazole therapy in schizophrenia

Background: Schizophrenia is the most common psychotic disorder and responsible for approximately half of long-term psychiatric hospitalizations. Antipsychotic medications reduce the psychotic symptoms and prevent relapses. The choice of drug for treatment of schizophrenia depends on many issues, including effectiveness, cost, side-effect burden, availability, and tolerability. Many studies have compared antipsychotic drugs with one another, but no broad consensus has been reached. Our study compares the clinical effectiveness, safety and cost effectiveness of atypical antipsychotics in our setting.Methods: This was an observational, prospective study in which schizophrenia patients receiving either olanzapine, risperidone or aripiprazole were enrolled. Patients were followed up for 3 months. Evaluation of effectiveness was done by analysing mean reduction in PANSS score. Analysis of ADRs was done using WHO causality scale and Hartwig and Siegel severity scale. Cost analysis was done by comparing all three groups in term of cost range of antipsychotic drugs per improvement in PANSS score during the study period.Results: In the present study, the average dose of antipsychotic drugs received by a patient per day was 8.83±2.98 mg in olanzapine group, 4.76±1.12 mg in risperidone group and 20.43±8.5 mg in aripiprazole group. Mean reduction in PANSS score from baseline to 12 weeks was 23.79% in olanzapine group, 25.41% in risperidone group and 24.65% in aripiprazole group. Conclusions: All the groups were equally effective in reduction in PANSS score while risperidone was the most cost effective.

Safety and Tolerability of Antipsychotic Drugs in Pediatric Patients: Data From a 1-Year Naturalistic Study.

Background: Antipsychotic drugs (APs) are increasingly used to treat a variety of psychiatric disorders in children and adolescents. However, their safety and tolerability profiles, when used in a developmental age context, show different characteristics from the ones observed in adult patients. Treatment with APs in pediatric patients is often long-term. However, the tolerability data regarding these patients mostly derive from short-term studies.Methods: Starting from April 2017, for a 1-year period, patients between 4 and 18 years of age followed by five units of developmental age neuropsychiatry, who initiated a treatment with at least an AP (ATC class N05A) were included into the study. Patient-related data have been collected at baseline and regularly thereafter, as allowed by the clinical routine. Changes to continuous variables over time have been analyzed using a linear mixed model in subsamples of our population treated with risperidone or aripiprazole.Results: During the observation period, 158 patients were initially enrolled, but only 116 completed 12 months of therapy with an AP. Risperidone was the most used AP (n = 52) followed by aripiprazole (n = 44) and olanzapine (n = 7). For both the aripiprazole and risperidone groups, the mean body mass index (BMI) (P < 0.001 for both groups) and heart rate (P = 0.026 for aripiprazole group and P < 0.001 for the risperidone one) values significantly increased over time. The mean prolactin concentration value significantly increased over time only in the risperidone group (P = 0.04). Eighty-six patients experienced at least one adverse drug reaction (ADR), accounting for a total of 238 specific reactions, with the most frequent being weight gain (n = 34), increased serum prolactin levels (n = 21), hyperphagia (n = 20), and hypercholesterolemia (n = 14). Among these, only 24 ADRs were classifiable as serious.Conclusions: The results of this study confirm that risperidone and aripiprazole are relatively well-tolerated therapeutic options for the treatment of a variety of psychiatric disorders in pediatric patients. However, in findings such as statistically significant increments of BMI and heart rate mean values, the variations over time in prolactin levels observed with risperidone and the differences between the two drugs remark the necessity of systematic monitoring.

Aripiprazole for prevention of delirium in the neurosurgical intensive care unit: a double-blind, randomized, placebo-controlled study.

Delirium is reported in over 50% of critically ill ICU patients, and is associated with increased mortality and long-term cognitive consequences. Prevention and early management of delirium are essential components of ICU care. However, pharmacological interventions have not been effective in delirium prevention. This study investigated the effect of aripiprazole in the prevention of delirium in a neurosurgical intensive care unit. In this prospective, randomized placebo-controlled small clinical trial, 53 patients, 18 to 80 years old, were randomized to receive enteric aripiprazole (15mg) or placebo for up to 7days. Delirium, detected by the Confusion Assessment Method-ICU, ICU events, laboratory studies, aripiprazole safety, time to delirium onset, delirium-free days, delirium prevalence during follow-up and ICU length of stay were recorded. Forty patients with similar baseline characteristics, including age, sex, neurosurgery types and APACHE II scores, completed the study. Delirium incidence and the mean days to its onset were 20% vs. 55% (p = 0.022) and 2.17 ± 0.41 vs. 2.09 ± 0.30 (p = 0.076) in the aripiprazole and placebo groups, respectively. The mean number of delirium-free days were: 5.6 (95%CI, 4.6-6.5) and 4.3 (95%CI, 3.2-5.4), in aripiprazole and placebo groups, respectively (p = 0.111). The prevalence of delirium during the follow-up was significantly lower in the aripiprazole group (p = 0.018). Serious aripiprazole adverse reactions were not observed. Aripiprazole can reduce the incidence of delirium in the neurosurgical ICU. Studies with larger sample size in diverse ICU settings and longer follow-up are needed to confirm our findings.

Dopamine D2 Receptor Occupancy Estimated From Plasma Concentrations of Four Different Antipsychotics and the Subjective Experience of Physical and Mental Well-Being in Schizophrenia: Results From the Randomized NeSSy Trial.

Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). An innovative double randomization process was used for allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this association could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. Our results suggest that high plasma levels and consequently high occupancy at D2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful.

Randomized controlled clinical trial comparing the efficacy and tolerability of aripiprazole and sodium valproate in the treatment of Tourette syndrome

ObjectiveThis study compared the efficacy and tolerability of sodium valproate and aripiprazole in the treatment of Tourette syndrome (TS).Method24 children and adolescents with a diagnosis of TS from the Jiamusi Central Hospital between January 2014 and August 2017 were randomly divided into sodium valproate group and aripiprazole group according to the order of clinic visits and treated for 10 days. Tic severity was rated using the Yale Global Tic Severity Scale (YGTSS) and the Clinical Global Impressions Scale for tics (CGI-Tics) and the adverse reactions were valued using the Treatment Emergent Symptom Scale (TESS) at baseline and at each follow-up visit.ResultsThe TTS score in the YGTSS scale decreased over time in both groups while the aripiprazole group was significantly higher on the 5th day (p < 0.05) and 10th day (p < 0.05) than the sodium valproate group. There was no significant difference in TESS score between the two groups.ConclusionsThe study indicates that the patients treated with sodium valproate injection have a faster onset time than the patients treated with oral aripiprazole in controlling tics.

Aripiprazole Versus Lithium in Management of Acute Mania: a Randomized Clinical Trial

This study aimed to compare aripiprazole with lithium for the effectiveness of treating Iranian male patients with acute mania. A total of 30 male in-patients with bipolar I disorder who presented with relapse or new emergence of an episode of acute mania were equally randomised to receive 4 weeks of aripiprazole (5 mg uncoated tablets) or lithium carbonate (300 mg uncoated tablets) according to standard practice guidelines and titration protocols. The Manic State Rating Scale (MSRS) was used to determine the severity of manic symptoms at baseline (week 0) and up to week 4. The Bech-Rafaelsen Mania Scale (BRMS), Schedule for Assessment of Insight (SAI), and Clinical Global Impressions-Global Improvement scale (CGI-G) were used to determine the severity of manic symptoms, insight, and overall illness severity, respectively. All outcome measures were recorded by a single experienced psychiatrist. The frequency and intensity of manic symptoms (MSRS score) in both groups decreased significantly from baseline to week 4. In the aripiprazole and lithium groups, the intensity of manic symptoms decreased by ≥25% in 5 and 7 patients and by >50% in 1 and 5 patients, respectively. Between-group analysis showed that lithium was more effective at weeks 3 and 4 in decreasing the frequency and intensity of manic symptoms. The lithium group achieved greater improvement in symptoms than the aripiprazole group in terms of BRMS score, SAI score, and CGI-G. Lithium is more effective than aripiprazole in improving manic symptoms.

Assessment of Long Term Metabolic Effects of Atypical Antipsychotics in Schizophrenia Patients

Abstract Background and aims. Patients with schizophrenia have a shorter life expectancy than normal population partially due to the metabolic side effects of antipsychotic treatment. The aim of this study is to evaluate the long-term evolution of the metabolic syndrome in chronic schizophrenia patients on fixed second generation antipsychotics (SGA). Material and method. The components of metabolic syndrome were evaluated repeatedly in a minimum 6 months and maximum 2 years follow-up period. The presence of metabolic syndrome (MetS) and metabolic risk scores (cMetS) according to National Cholesterol Education Program Adult Treatment Panel III were calculated and compared in time. In the prevalence, incidence and normalization logistic regression studies included all the known risk factors together with the follow-up period. Finally, all these rates were compared depending on the type of SGA. Results. Only cMetS, waist circumference and diastolic blood pressure presented significant increase in the follow-up period which was in average 385.5 days. The prevalence of MetS at base-line was 39.4%, which increased to 48.5% after the follow-up period. The calculated incidence of 30% was associated with a 23.1% rate of normalization. Logistic regression studies revealed as independent risk factors the age and base-line cMetS/weight for incidence and for normalization. In the aripiprazole group the normalization rate exceeded the incidence rate (33.3% vs 20%). Conclusions. The results emphasize the highly dynamic character of the metabolic syndrome even in chronic schizophrenia patients with fixed SGA regimen. The normalization of MetS is a possibility that should not ignored. The age and weight continue to remain independent risk factors, thus close monitoring in elderly and strict weight control plan are necessary. Aripiprazole showed better safety profile, but more extensive studies are required for definitive conclusions.

Long-term Effects of Aripiprazole Treatment during Adolescence on Cognitive Function and Dopamine D2 Receptor Expression in Neurodevelopmentally Normal Rats.

ObjectiveThis study aimed to investigate the long-term effects of aripiprazole treatment during adolescence on behavior, cognitive function, and dopamine D2 receptor (D2R) expression in adult rats.MethodsAdolescent male Sprague-Dawley rats were injected intraperitoneally with aripiprazole, risperidone, or vehicle control for 3 weeks (postnatal day 36–56). After a 2-week washout period, locomotion, anxiety, and spatial working memory were evaluated in adulthood (postnatal day 71–84), using an open field test, elevated plus maze, and Y-maze, respectively. In addition, we assessed D2R levels in the dorsolateral and medial prefrontal cortex (PFC), dorsal and ventral striatum, and hippocampus using western blot analysis.ResultsSpontaneous alternation performance (SAP) in the Y-maze, a measure of spatial working memory, differed significantly among the 3 groups (F = 3.89, p = 0.033). A post-hoc test confirmed that SAP in the aripiprazole group was significantly higher than that in the risperidone group (post-hoc test p = 0.013). D2R levels in the medial PFC (F = 8.72, p = 0.001) and hippocampus (F = 13.54, p < 0.001) were different among the 3 groups. D2R levels in the medial PFC and hippocampus were significantly lower in the aripiprazole-treated rats than that in the risperidone-treated rats (post-hoc test p = 0.025 and p < 0.001, respectively) and controls (post-hoc test p < 0.001, all).ConclusionThis study showed that aripiprazole treatment in adolescence could influence cognitive function and dopaminergic neurotransmission into early adulthood.

Preventative effects of aripiprazole and quetiapine on seizure and lethality in a mice cocaine toxicity model: an experimental study.

ObjectiveTo assess the effectiveness of pre-treatment with aripiprazole and quetiapine to prevent acute cocaine toxicity in a mouse model of cocaine toxicity.MethodsThis experimental study included three groups (n = 25 per group) of mice that were intraperitoneally injected with normal saline solution, 10 mg/kg quetiapine or 10 mg/kg aripiprazole 15 min before 105 mg/kg cocaine hydrochloride. When the cocaine administration was completed, researchers blinded to the study groups observed the mice in terms of seizures and death for a further 30 min.ResultsIn the cocaine + quetiapine group, the mean ± SE time to the first seizure was 10.80 ± 2.27 min and seizure activity was detected in 18 mice (72%) by the end of the 30 min. In the cocaine + aripiprazole group, the mean ± SE time to the first seizure was 18.10 ± 1.94 min and seizure activity was detected in 15 mice (60%) by the end of the 30 min. When compared with the control group, there was a significant difference between the cocaine + quetiapine and cocaine + aripiprazole groups in terms of seizure activity. Survival time was increased in the cocaine + aripiprazole group compared with the control and cocaine + quetiapine groups.ConclusionQuetiapine and aripiprazole pre-treatment reduced seizure activity and delayed the onset of seizures compared with the control group.

Pharmacotherapy of Autism Spectrum Disorder: Results from the Randomized BAART Clinical Trial.

The objective of this trial, Biomarkers in Autism of Aripiprazole and Risperidone Treatment (BAART), was to provide support and guidance for an evidence-based approach for the selection and monitoring of initial pharmacotherapy in patients with autism by assessing predictors of efficacy, tolerability, and safety. This randomized double-blind parallel-group study was conducted in three academic medical centers and a single private pediatric practice. Eighty children or adolescents (aged 6-17yrs) with autistic disorder were enrolled, and 61 patients were randomized to the study drug. Of those patients, 51 completed the 10-week trial, and 31 completed an optional 12-week blinded extension phase. All patients were treated with 2weeks of placebo before random assignment to receive aripiprazole (31 patients) or risperidone (30 patients) for 10weeks. Sixteen placebo responders (20%) were excluded from further analysis. Drug dosing followed U.S. Food and Drug Administration (FDA) labeling, and weekly dosage adjustments were allowed until week 4; patients were then maintained on a fixed dose for 6 additional weeks. Safety, physical, and psychological assessments were recorded weekly or every 2 weeks. No significant differences in severity of illness between the aripiprazole and risperidone groups were noted at baseline. All patients significantly improved on the Aberrant Behavior Checklist-Irritability subscale after 1 week and continued for the remaining 9weeks and the extension phase. Improvement was greatest in the risperidone group at every assessment period and was statistically significantly better than that in the aripiprazole group at weeks 3 and 6 (p<0.05). No dose-limiting adverse events occurred during the dose-titration period. Mean weight gain in the aripiprazole group was significantly less than that in the risperidone group at week 4 (0.62 vs 1.38kg, p=0.033) and week 10 (1.61 vs 3.31kg, p<0.001), but the difference became nonsignificant for the 31 patients completing the 3-month extension phase (4.36 vs 5.55kg, p=0.26). Pharmacotherapy of patients with autism spectrum disorder resulted in behavioral improvement within 1 week and lasted at least 22weeks. Weight gain occurred to a greater degree with risperidone than aripiprazole initially, but the differences became nonsignificant by the end of the trial. Our trial supports previous results of drug efficacy and safety in patients with autism spectrum disorder from other trials and extends the evidence-based support for choosing an FDA-approved drug for initial pharmacotherapy for autism spectrum disorder.

Low- and high-dose aripiprazole augmentation and plasma levels of homovanillic acid in major depressive disorder: A randomized, open-label study.

This randomized controlled study evaluated the efficacy of low-dose (LD) and high-dose (HD) aripiprazole augmentation in major depressive disorder. Additionally, we examined the relationship between clinical response and changes in plasma homovanillic acid (pHVA) levels during aripiprazole augmentation. Thirty-one patients with inadequate response to antidepressants were randomized to receive adjunctive treatment with LD (3mg/day, n=17) or HD (up to 12mg/day, n=14) aripiprazole for 6weeks. We evaluated the Montgomery-Åsberg Depression Rating Scale (MADRS) and measured pHVA at baseline, Week 2, and end point. Both LD and HD aripiprazole significantly decreased MADRS score after 6weeks, and the response rate was higher in HD aripiprazole group at end point. HD aripiprazole significantly decreased MADRS score at Week 2 compared with LD aripiprazole (p=.015). There was a significant difference in changes in pHVA between responders and nonresponders, showing pHVA decreased significantly in responders at Week 2 (p=.044). Increasing aripiprazole from the early period appeared useful for immediate response, although caution is needed when increasing the dose >6mg/day. pHVA may be a possible indicator of the response to aripiprazole augmentation. Caution is needed in interpreting these findings because of the small sample size.

Effects of combined escitalopram and aripiprazole in rats: role of the 5-HT1a receptor.

Pre-clinical and clinical studies have suggested that the antidepressant efficacy of escitalopram (ESC) can be augmented by co-administration of aripiprazole (ARI). To establish if the effects of ESC + ARI can be altered by modulating the 5-HT1a receptor. Sprague-Dawley male rats received ESC + ARI (10 and 2mg/kg/day, respectively, via osmotic or by cumulative injections), as well as the 5-HT1a antagonist WAY-100635 (WAY; 0.01-1mg/kg) and the 5-HT1a agonist 8-OH-DPAT (DPAT; 0.3-1mg/kg) prior to testing in locomotion chambers and in the forced swim test (FST). Expression of the 5-HT1a receptor mRNA in the dorsal raphe nucleus, hippocampus, septum, and entorhinal cortex was also assessed. WAY generally synergized, while DPAT antagonized, the effect of ESC + ARI on motor activity. All groups showed significantly lower 5-HT1a mRNA in the dorsal raphe nucleus. In the hippocampus, ESC + ARI and WAY + ESC + ARI groups displayed equivalent elevations of 5-HT1a mRNA, but this was not observed in groups that received DPAT + ESC + ARI. Finally, the addition of ARI to ESC augmented the effect that ESC alone had on reducing immobility in the FST. Importantly, WAY antagonized this effect, while DPAT had no consequences. Taken together, these results in rats indicate that the 5-HT1a receptor is involved in the behavioral and brain region-specific mRNA effects of ESC + ARI.

Analyse coût-efficacité de l’aripiprazole injectable à libération prolongée (AILP) comparé au palmitate de palipéridone (PP) dans le traitement de la schizophrénie en France

ObjectiveThe aim of the study was to estimate the cost-effectiveness ratio of aripiprazole once-monthly compared to once-monthly injectable paliperidone palmitate in the treatment of schizophrenia in France on the basis of results and data from the QUALIFY study. MethodsConsumed resources data measured with a dedicated questionnaire and results on the quality of life scales from the QUALIFY study were combined with French standard unit costs of each collected consumed resources during QUALIFY to estimate the cost-effectiveness ratios of the two products. Multivariate sensitivity analyses were performed to test the combined impact of the different assumptions. ResultsFindings of the study showed greater efficacy on the quality of life (QLS) and psychiatric evaluation scales (CGI-S and CGI-I) observed in QUALIFY of aripiprazole compared with paliperidone palmitate. Findings also suggest a trend (P=0.0733) in the reduction of total costs linked to a statistical decrease (P<0,0001) in drug costs in the aripiprazole group. These findings are reinforced by the probabilistic sensitivity analyses. ConclusionAripiprazole appeared to be more cost-effective than paliperidone palmitate in the French context. Limits of this study are mainly related with the duration of the clinical trial and to assumptions on the transposability of measured consumed resources in the international clinical trial to the French healthcare system.

Results of Discontinuation Rate, Remission Rate, and Improvement in Social Functioning Associated with Atypical Antipsychotic Medications in Patients with Schizophrenia: 52-Week Evaluation of JUMPs, a Randomised, Open-Label, Naturalistic Study in Japan

Background: The Japan Useful Medication Program for Schizophrenia (JUMPs) is the first large-scale, long-term (2 years) naturalistic study to assess effectiveness and safety of aripiprazole, blonanserin, and paliperidone in patients with schizophrenia. Here, we present the 52-week results. Methods: This open-label, three-arm, multicentre, randomised, parallel-group study was conducted at 75 sites in Japan. Outpatients with schizophrenia, age ≥20 years, requiring antipsychotic treatment or switching were randomised (1:1:1) to receive oral aripiprazole, blonanserin, or paliperidone as monotherapy during a 4-week titration period (start of monotherapy). The primary endpoint was treatment discontinuation rate over 52 weeks using Kaplan-Meier analysis. Secondary outcomes included social functioning score (Personal and Social Performance Scale [PSP]; Euro QOL-5 dimensions) and safety over 52 weeks. Findings: A total of 251 patients were randomised (July 2012 to December 2013) to receive aripiprazole (n=82), blonanserin (n=85), and paliperidone (n=84). The mean (SD) age was 46·5 (13·3) years and disease duration was 17·1 (12·3) years; 53% were men. Discontinuation rate over 52 weeks (68·3%, 68·2%, and 65·5%) did not differ significantly in aripiprazole, blonanserin, and paliperidone groups, respectively (log-rank test, p=0·9771). The median (95% confidence interval; interquartile range: quartile (Q)1-Q3) time to treatment discontinuation was 144·5 (91·0‒210·0; 51-not applicable), 144·0 (81·0‒238·0; 56-417), and 129·5 (84·0‒252·0; 54.5-not applicable) days in the aripiprazole, blonanserin, and paliperidone groups, respectively. In comparison to eligibility assessments, significant improvements (all p<0·05) in PSP scores were observed at start of monotherapy, week 26, and week 52 in the overall cohort and blonanserin group and at week 26 in the aripiprazole group. The adverse event profile favoured blonanserin. Interpretation: The treatment discontinuation rate of aripiprazole, blonanserin, and paliperidone was similar in patients with chronic schizophrenia in Japan. Clinical Trial Number: (UMIN Clinical Trials Registry 000007942) Funding Statement: Funding provided by The Waksman Foundation of Japan Inc. Declaration of Interests: J. Ishigooka reports grant from The Waksman Foundation of Japan Inc. for the work under consideration for publication, personal fees from Dainippon Sumitomo, Eisai, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Shionogi, and Takeda, outside the submitted work. K. Nakagome reports grant from The Waksman Foundation of Japan Inc. during the conduct of this study and from Meiji Seika Pharma, Otsuka pharmaceutical, Sumitomo Dainippon pharma, Mochida pharmaceutical, Janssen pharmaceutical K.K., Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim (BI), Astellas pharma, Asahi Kasei pharma and Shionogi and personal fees from Meiji Seika Pharma, MSD K.K., Otsuka pharmaceutical, Kyowa Hakko Kirin, Sumitomo Dainippon pharma, Takeda pharmaceutical, Eli Lilly Japan, K.K., Pfizer Japan, Nippon BI, Toyama Chemical, Mochida pharmaceutical, Janssen pharmaceutical, Page 16 of 30 Yoshitomiyakuhin corporation, Taisho Toyama Pharma, and Kowa, outside the submitted work. T. Ohmori reports personal fees from Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Meiji, Mochida, MSD, Novartis, Otsuka, Pfizer, Takeda, Mitsubishi Tanabe, and Yoshitomi, and grants from Astellas, Dainippon Sumitomo, Eisai, Meiji, Otsuka, and Pfizer. N. Iwata reports personal fees from Dainippon Sumitomo, Eli Lilly, Janssen, Otsuka, Meiji, and Pfizer and grant from Otsuka, outside of submitted work. K. Inada reports personal fees from Dainippon Sumitomo, Eisai, Eli Lilly, Janssen, MeijiSeika Pharma, Mochida, MSD, Novartis, Otsuka, Shionogi, Tanabe-Mitsubishi, and Yoshitomi and grant from MSD, outside the submitted work. J. Iga reports personal fees from Dainippon Sumitomo, Eli Lilly, Janssen, Meiji-Seika Pharma, Mochida, MSD, Mylan, Novartis, and Otsuka, outside the submitted work. T. Kishi reports personal fees from Daiichi Sankyo, Dainippon Sumitomo, Eisai, Janssen, Otsuka, Meiji, MSD, Tanabe-Mitsubishi, and Yoshitomi, outside the submitted work and grants from the Health and Labor Sciences and Fujita Health University School of Medicine for the work under consideration for publication. H. Tabuse reports personal fees from Dainippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Otsuka, Meiji, Pfizer, Tanabe-Mitsubishi, and Yoshitomi, outside the submitted work. Hiroshi Terada reports personal fees from Eli Lilly Japan K.K., Janssen pharmaceuticals K.K., Otsuka, Meiji, Dainippon Sumitomo, Tanabe-Mitsubishi, and Yoshitomiyakuhin, outside the submitted work. Y. Tsutsumi reports personal fees from Otsuka and Janssen, outside the submitted work. Y. Kanda reports personal fees from Eli Lilly Japan K.K. and Janssen pharmaceutical K.K. during the conduct of the study and from Eli Lilly Japan K.K. outside the submitted work. K. Sekiyama reports personal fees from Otsuka, outside the submitted work. K. Fujita, Y. Kikuchi, T. Shichijo, S. Koretsune, Haruko Terada, T. Kishimoto, and K. Ohi have no conflicts of interest. Ethics Approval Statement: The study was approved by the appropriate institutional review boards and was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation Tripartite Guidelines for Good Clinical Practice, and the Ethics Guidelines for Clinical Research (Ministry of Health, Labour and Welfare, 2008 revision). Written informed consent was obtained from all patients.

Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.

Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes. Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored. Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain. Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Effects of ABCB1 gene polymorphisms on autonomic nervous system activity during atypical antipsychotic treatment in schizophrenia

BackgroundThere are interindividual differences in the adverse effects of atypical antipsychotics, which include autonomic nervous system (ANS) dysfunction. Accordingly, to clarify the interindividual differences in the adverse effects of specific atypical antipsychotics in schizophrenia, we investigated the association between ANS dysfunction and ATP-binding cassette transport sub-family B member 1 (ABCB1) gene polymorphisms in patients with schizophrenia.MethodsIn total, 233 Japanese patients with schizophrenia participated in this study. All of the participants received an atypical antipsychotic as monotherapy: 89 participants received risperidone, 69 olanzapine, 48 aripiprazole, and 27 quetiapine. ANS activity was assessed by means of a power spectral analysis of heart rate variability. Four single nucleotide polymorphisms (SNPs) in ABCB1 (rs1045642, rs1128503, rs2032582, and rs2235048) were genotyped using the TaqMan method.ResultsFor aripiprazole, sympathetic and total autonomic nervous activities were significantly lower in the rs1045642 T allele carrier–rs2235048 C allele carrier group than in the rs1045642 non-T allele carrier–rs2235048 non-C allele carrier group. In addition, in the aripiprazole group, the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582) was associated with decreased ANS activity. However, there were no significant associations between ANS activity and ABCB1 gene polymorphisms in the risperidone, olanzapine, and quetiapine groups. Multiple regression analysis revealed that sympathetic and total nervous activities were significantly associated with the ABCB1 rs1045642–rs2235048 genotype and the T-C-T-A haplotype (rs1045642-rs2235048-rs1128503-rs2032582).ConclusionWe suggest that ABCB1 genetic polymorphisms affect aripiprazole-related ANS dysfunction but do not affect risperidone-, olanzapine-, or quetiapine-related ANS dysfunction.

High-density lipoprotein-cholesterol and antipsychotic medication in overweight inpatients with schizophrenia: post-hoc analysis of a Japanese nationwide survey

BackgroundPatients with schizophrenia have an increased prevalence of metabolic disturbances compared with the general population. However, the mechanisms underlying the metabolic side effects of antipsychotics are unknown. The aim of the present study was to compare the levels of high-density lipoprotein (HDL)-cholesterol in Japanese schizophrenia patients medicated with olanzapine, risperidone, or aripiprazole monotherapy.MethodsThis study was a post-hoc analysis of a nationwide survey, which included 433 Japanese outpatients with schizophrenia and 674 inpatients. A brief questionnaire was compiled that covered demographic data, systolic blood pressure, diastolic blood pressure, and HDL-cholesterol after reviewing the relevant literature and guidelines. To compare demographic and clinical characteristics, analysis of variance was performed for continuous variables and the chi-square test was performed for categorical variables. For comparisons of HDL-cholesterol levels among the three antipsychotic groups, analysis of covariance was carried out with age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference as confounding variables after stratification by body mass index (BMI) for each outpatient group and inpatient group.ResultsThe mean age was 57.9 ± 14.0 years and the mean BMI was 23.4 ± 4.5 kg/m2. HDL-cholesterol levels when stratified by BMI differed significantly (p = 0.019) between the three antipsychotic groups after age, diastolic blood pressure, chlorpromazine-equivalent dosage, and waist circumference in inpatients. A significant difference in HDL-cholesterol levels was only found in the overweight inpatient group, and no significant differences in HDL-cholesterol levels were found among the three antipsychotics for outpatients of all BMI stratifications or inpatients that were underweight or of normal weight. For post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group (p = 0.023).ConclusionsThis study reveals a difference in HDL-cholesterol levels in overweight Japanese inpatients with schizophrenia resulting from the use of different antipsychotics. In the post-hoc analysis of HDL-cholesterol levels in overweight inpatients, HDL-cholesterol was significantly lower in the olanzapine group than in the aripiprazole group. Further studies incorporating more detailed evaluations, including diet and physical activity, are needed to clarify the differences in HDL-cholesterol according to antipsychotic use.

Aripiprazole as an adjuvant treatment for obsessive and compulsive symptoms in manic phase of bipolar disorder: A randomized, double-blind, placebo-controlled clinical trial

Background and objectiveOur Objective is to study the effects of aripiprazole as an adjuvant treatment for obsessive and compulsive (OC) symptoms in patients with bipolar disorder (BD) type I, manic phase. Patients and methodsIn this 8-week, double-blind, placebo-controlled randomized clinical trial, 56 patients with BD who had OC symptoms were randomly allocated to receive aripiprazole or placebo plus their routine medication regimen (lithium + clonazepam). Yale Brown obsessive compulsive behavior scale (YBOCS) was administered to evaluate the outcomes. Adverse effects were also registered. ResultsOf 56 BD patients with OC symptoms which were randomly allocated in two groups of aripiprazole (n = 29) and placebo group (n = 27), 46 patients (23 in aripiprazole group and 23 in placebo group) completed the trial. Throughout the trial, the mean score of YBOCS in the aripiprazole group decreased from 21 ± 4.81 to 9.6 ± 2.2 (P < 0.001) and in the placebo group dropped from 20.46 ± 4.8 to 17.32 ± 3.7 (P < 0.001). At the end of the study, 21 (91.30%) patients in the aripiprazole group and 1 (4.34%) patient in the placebo group had >34% decline in YBOCS score (P < 0.01). No serious adverse effects were reported in any groups. ConclusionsThe results of our study revealed that aripiprazole can be used as an effective adjuvant agent for treatment of obsessive and compulsive symptoms in manic patients.