A multicenter, single-arm, open-label interventional study of adherence to brexpiprazole during switching from previous antipsychotic drugs in patients with schizophrenia or schizoaffective disorder.

The rate of medication persistence was examined in patients with schizophrenia or schizoaffective disorder during switching from previously administered antipsychotics to brexpiprazole, a new dopamine D2 receptor partial agonist. A multicenter, single-arm, open-label 24-week interventional study was conducted, consisting of two 12-week consecutive periods: an initial switch (by plateau cross-titration) with the subsequent period, followed by a second maintenance period. Prior antipsychotics were olanzapine or risperidone/paliperidone. The primary and secondary outcome measures were medication persistence rates after the first 12 weeks and changes from baseline in the Specific Levels of Functioning Scale (SLOF), Subjective Well-being under Neuroleptic drug treatment Short form (SWNS), and Positive and Negative Syndrome Scale (PANSS) scores, respectively. In total, 79 patients were administered brexpiprazole and the medication persistence rate at 12 weeks was 78.5%, which was significantly higher than the predefined threshold of 65%. Regarding the prior medication, the persistence rate at 12 weeks was 84.6% for olanzapine and 72.5% for risperidone/paliperidone. Significant improvements from baseline were observed in the SLOF, SWNS, and PANSS scores. There were no adverse events of concern. Thus, brexpiprazole appeared to be a suitable antipsychotic on switching from olanzapine, risperidone, or paliperidone.

Treatment Discontinuation Among Patients with Schizophrenia Treated with Brexpiprazole and Other Oral Atypical Antipsychotics in Japan: A Retrospective Observational Study.

INTRODUCTION: Treatment continuation is essential for relapse prevention in patients with schizophrenia. The aim of this exploratory study was to compare the time to treatment discontinuation between patients with schizophrenia prescribed brexpiprazole (BRX group) and those prescribed other atypical antipsychotics (OAA group) in clinical settings in Japan using health insurance claims data. METHODS: De-identified data of working individuals with schizophrenia aged < 75 years and their dependents were assessed from April 2017 to May 2020 using a nationwide claims database. Cox proportional hazards models, adjusted for baseline patient variables, were used to compare the time to treatment discontinuation (primary outcome) for 180 days between BRX and OAA groups and to estimate the hazard ratio (HR) with 95% confidence interval (CI). The cumulative treatment continuation rates at 180 days were also estimated. Sensitivity and subgroup analyses were conducted for the primary outcome. RESULTS: The analysis included 978 and 4898 patients in the BRX and OAA groups, respectively. Patients in the BRX group were significantly less likely to discontinue treatment than those in the OAA group (HR 0.86, 95% CI 0.78-0.95; p = 0.0024). The cumulative treatment continuation rates were higher in the BRX group (45.9%, 95% CI 42.5-49.2]) than in the OAA group (39.5%, 95% CI 38.1-41.0; log-rank test, p < 0.0001). Based on patients matched by propensity score, the BRX group was significantly less likely to discontinue treatment than the OAA group (log-rank test, p = 0.0466). Similar results were obtained in sensitivity and subgroup analyses. CONCLUSION: This real-world study showed that patients in the BRX group were less likely to discontinue treatments than those in the OAA group. These findings suggest that BRX may contribute to treatment continuation among patients with schizophrenia. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Clinical Trials Registry: UMIN000044682.

Real-World Treatment Patterns and Adherence to Oral Medication Among Patients with Bipolar Disorders: A Retrospective, Observational Study Using a Healthcare Claims Database.

PURPOSE: This study aimed to describe real-world treatment patterns and medication adherence among patients with bipolar disorder (BD) in Japan. PATIENTS AND METHODS: Adult patients with a BD diagnosis were identified between July 2013 and February 2018, using an employment-based health insurance claims database from the JMDC Inc. Treatment patterns of target drugs (mood stabilizers, antipsychotics) and adherence (measured by the proportion of days covered [PDC]) were assessed during the first- through third-year follow-up. Adherence was also assessed for patient subgroups. RESULTS: The analyzed population included 13,788 patients with BD. They were mostly prescribed sodium valproate, lithium, or aripiprazole (range: 21.1-27.4%) across 3 years of follow-up, whereas lamotrigine was prescribed to 11.2-12.8% of patients. Benzodiazepines (70-87%) and antidepressants (52-71%) were commonly prescribed during all three follow-up periods. The mean PDC among all patients with BD was 0.51 during the first and increased to 0.61 during the third year. The mean PDC was 0.42 (first year) in patients aged <30 years and 0.49 in those aged 30-40 years. The PDC was 0.44-0.61 (depending on the drug class) in those who were prescribed a single-class target drug and 0.68-0.83 in those prescribed two drug classes concomitantly. CONCLUSION: This study documented generally low medication adherence among patients with BD, and those at young age. These patients may require more attention.

Safety of switching to brexpiprazole in Japanese patients with schizophrenia: A post-hoc analysis of a long-term open-label study.

OBJECTIVES: To determine the long-term safety of switching to brexpiprazole from aripiprazole or non-aripiprazole dopamine antagonists. METHODS: Post-hoc analysis of 56-week study of Japanese outpatients with schizophrenia switched to brexpiprazole 2 mg/day over 4-week switching period with further titration (1-4 mg/day) allowed during the 52-week, open-label period. Major assessment items: total/low-density lipoprotein (LDL)-/high-density lipoprotein (HDL)-cholesterol, triglycerides, blood glucose, body weight and prolactin. Secondary evaluations were related to efficacy, treatment emergent adverse events (TEAEs), extrapyramidal symptoms, and corrected QT interval (QTc). RESULTS: 84/186 (45.2%) patients (aripiprazole, 32.9%; non-aripiprazole, 54.8%) discontinued treatment over 56 weeks mainly because of consent withdrawal/adverse events. From baseline to Week 56, both groups showed minimal mean changes in total/LDL-/HDL-cholesterol, triglycerides, and glucose levels and a slight increase in mean (SD) body weight (aripiprazole, 1.1 [4.4] kg; non-aripiprazole, 0.4 [4.6] kg). Mean prolactin levels increased slightly in the aripiprazole group, but decreased in the non-aripiprazole group. Symptom severity scores decreased similarly in both groups. TEAEs occurred in 161/186 (86.6%) patients (aripiprazole, 84.1% [serious, 9.8%]; non-aripiprazole, 88.5% [serious, 14.4%]). Few changes occurred in extrapyramidal symptom scales or QTc interval. CONCLUSIONS: Switching to brexpiprazole is associated with a low long-term risk for metabolic abnormalities (including weight gain), hyperprolactinemia, extrapyramidal symptoms and QTc changes and minimal changes in psychiatric symptoms.

Brexpiprazole for the Treatment of Schizophrenia in Adults: An Overview of Its Clinical Efficacy and Safety and a Psychiatrist's Perspective.

While the prognosis of patients with schizophrenia has dramatically improved after the advent of chlorpromazine, the antipsychotics currently available are so numerous that it has become a challenge for psychiatrists to choose from among these drugs for each patient presenting for care. In addition, while numerous studies show that an effective antipsychotic should be continued indefinitely to prevent relapses or worsening, many patients appear to have difficulty remaining on any drug thus initiated. Brexpiprazole, a dopamine D2 receptor partial agonist, appears to provide a unique profile that has much to offer in this light. Specifically, this novel drug is potentially better suited for long-term use, with decreased risk of extrapyramidal side effects, hyperprolactinemia, weight gain, psychosis, insomnia, akathisia, nausea/vomiting or restlessness, thus potentially facilitating patients' reintegration into society. Indeed, brexpiprazole has been shown in randomized, double-blind, placebo-controlled trials to have proven efficacy not only in improving the symptoms of schizophrenia but in preventing relapses. It is also suggested in both short- and long-term studies that brexpiprazole offers a favorable safety and tolerability profile. This review also includes a proposed treatment algorithm incorporating brexpiprazole, based on the clinical trial results available, as well as on the authors' clinical experience, where brexpiprazole may be best used as a drug of first choice for the treatment of schizophrenia. Thus, overall, brexpiprazole appears to play a more significant role in the treatment of schizophrenia than other antipsychotics.

Long-Term Efficacy and Safety of Brexpiprazole in Elderly Japanese Patients with Schizophrenia: A Subgroup Analysis of an Open-Label Study.

PURPOSE: This study was performed to assess the long-term efficacy, safety, and tolerability of brexpiprazole in elderly Japanese patients with schizophrenia. METHODS: This is a post hoc analysis of a previous open-label study conducted over 56 weeks which consisted of two consecutive phases: a 4-week switching period and a 52-week open-label period. Mean change in the Positive and Negative Syndrome Scale (PANSS) total score, response rates, number and incidence of treatment-emergent adverse events (TEAEs), and other safety parameters were analyzed using descriptive statistics based on age group (elderly, ≥65 and non-elderly, <65). RESULTS: This post hoc analysis included 208 de novo patients of which 33 were elderly. The continuation rate in elderly patients was 54.5%, and the mean daily dose and treatment duration of brexpiprazole in elderly patients at week 56 were similar to those of non-elderly patients. The mean change in the PANSS total score from the baseline to week 56 was -13.8 in elderly patients and this improvement was maintained throughout the open-label phase. This outcome was comparable to that of the non-elderly patients (-9.0). The incidence rate of TEAEs was 97.0% in elderly patients and 82.3% in non-elderly patients. Most of the TEAEs were either mild (75.8%) or moderate (18.2%) in severity in the elderly patients and the incidence of TEAEs leading to discontinuation was lower in elderly (9.1%) than in non-elderly patients (13.1%). The most commonly observed adverse events in elderly patients were nasopharyngitis (30.3%) and worsening of schizophrenia (27.3%). The safety profiles in both groups were similar. CONCLUSION: Brexpiprazole was shown to be safe and effective in the treatment of elderly Japanese patients with schizophrenia.

Treatment Persistence Between Long-Acting Injectable Versus Orally Administered Aripiprazole Among Patients with Schizophrenia in a Real-World Clinical Setting in Japan.

INTRODUCTION: Persistence with antipsychotic treatment is critical in managing patients with schizophrenia. To evaluate whether aripiprazole long-acting injection (aripiprazole once-monthly, AOM) can contribute to longer treatment persistence compared with daily orally administered aripiprazole (OA) in real-world clinical settings in Japan, treatment persistence in patients with schizophrenia was compared between patients treated with AOM and those with OA, using a claims database compiled by JMDC Inc., Tokyo, Japan. METHODS: Data of patients with schizophrenia who newly initiated AOM or OA treatment between May 2015 and November 2017 were analyzed. The Cox proportional hazard model was used to estimate the hazard ratio (HR) for treatment discontinuation of AOM vs. OA treatment, adjusted for age, sex, chlorpromazine-equivalent dose of antipsychotics, and the number of psychiatric hospitalizations. RESULTS: The analysis included 198 patients in the AOM group and 1240 patients in the OA group (mean age 38.4 ± 11.9 years and 39.3 ± 12.4 years, respectively). The AOM group was significantly less likely to discontinue treatment than the OA group (adjusted HR 0.54, 95% confidence interval [CI] 0.43-0.68). When using the tolerable patients extracted from the OA group (i.e., patients with at least two OA prescriptions; n = 983) vs. the whole AOM group, AOM users were again significantly less likely to discontinue treatment (adjusted HR 0.67, 95% CI 0.53-0.86). CONCLUSION: AOM was associated with longer treatment persistence than OA in the antipsychotic treatment of patients with schizophrenia in real-world clinical settings in Japan, suggesting that the use of AOM may contribute to longer antipsychotic treatment.

Attenuated stress-induced catecholamine release in mice lacking the vasopressin V1b receptor.

Vasopressin V(1b) receptor is specifically expressed in the pituitary and mediates adrenocorticotropin release, thereby regulating stress responses via its corticotropin releasing factor-like action. In the present study we examined catecholamine release in response to two types of stress in mice lacking the V(1b) receptor gene (V(1b)R(-/-) mice) vs. wild-type mice. There were no significant differences in the basal plasma levels of catecholamines between the two genotypes. In response to stress induced by forced swimming, norepinephrine (NE), but not epinephrine (E) or dopamine (DA), was increased in wild-type mice, whereas the increases in NE and DA were not observed in V(1b)R(-/-) mice. In wild-type mice, E, but not NE or DA, was increased in response to social isolation stress, whereas the increase in E was not observed in V(1b)R(-/-) mice. These results suggest that the V(1b) receptor regulates stress-induced catecholamine release. Because it has been suggested that arginine-vasopressin (AVP) is related to the development of depression, we also evaluated immobility time in the forced swimming test, and we found no significant change in V(1b)R(-/-) mice. Taken together, these findings suggest that, in addition to the previously elucidated effect on the hypothalamic-pituitary-adrenal axis, vasopressin activity via V(1b) receptors regulates stress-induced catecholamine release.

Mechanism of action of aripiprazole predicts clinical efficacy and a favourable side-effect profile.

The antipsychotic efficacy of aripiprazole is not generally associated with extrapyramidal symptoms, cardiovascular effects, sedation or elevations in serum prolactin that characterize typical or atypical antipsychotics. The aim of this study was to clarify the mechanism of action of aripiprazole that underlies its favourable clinical profiles. The preclinical efficacy and side-effect profiles of aripiprazole were evaluated using several pharmaco-behavioural test systems in mice and rats, both in vivo and ex vivo, and compared with those of other conventional and atypical antipsychotics. Each of the antipsychotics induced catalepsy and inhibited apomorphine-induced stereotypy. The catalepsy liability ratios for these drugs were 6.5 for aripiprazole, 4.7 for both olanzapine and risperidone. The ptosis liability ratios for aripiprazole, olanzapine and risperidone were 14, 7.2 and 3.3, respectively. Aripiprazole slightly increased DOPA accumulation in the forebrain of reserpinised mice, reduced 5-HTP accumulation at the highest dose and exhibited a weaker inhibition of 5-methoxy-N,N-dimethyl-tryptamine-induced head twitches. Aripiprazole did not inhibit physostigmine- or norepinephrine-induced lethality in rats. In conclusion, aripiprazole shows a favourable preclinical efficacy and side-effect profile compared to a typical antipsychotics. This profile may result from its high affinity partial agonist activity at D2 and 5-HT1A receptors and its antagonism of 5-HT2A receptors.

Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone.

Catalepsy and changes in striatal and limbic dopamine metabolism were investigated in mice after oral administration of aripiprazole, haloperidol, and risperidone. Catalepsy duration decreased with chronic (21 day) aripiprazole compared with acute (single dose) treatment across a wide dose range, whereas catalepsy duration persisted with chronic haloperidol treatment. At the time of maximal catalepsy, acute aripiprazole did not alter neostriatal dopamine metabolite/dopamine ratios or homovanillic acid (HVA) levels, and produced small increases in dihydroxyphenylacetic acid (DOPAC). Effects were similar in the olfactory tubercle. Dopamine metabolism was essentially unchanged in both regions after chronic aripiprazole. Acute treatments with haloperidol or risperidone elevated DOPAC, HVA, and metabolite/dopamine ratios in both brain areas and these remained elevated with chronic treatment. The subtle effects of aripiprazole on striatal and limbic dopamine metabolism, and the decrease in catalepsy with chronic administration, illustrate fundamental differences in dopamine neurochemical actions and behavioral sequelae of aripiprazole compared to haloperidol or risperidone.

Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethanesulfonate).

Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits.