Search

Background: Second-generation antipsychotics (SGAs) are commonly used to treat schizophrenia (SCZ), but SGAs may differ in the severity of side effects. Long-term studies are lacking, and previous observational studies have limitations, such as failure to account for confounding factors and short follow-up durations., Aims: To compare the long-term anthropometric and metabolic side effects of seven SGAs in a Chinese population, using a within-subject approach to reduce the risk of confounding., Method: We collected longitudinal data of SGA prescriptions, concomitant medications, fasting blood glucose (BG), lipid profiles, and BMI in a cohort of 767 patients with SCZ, with follow-up lasting up to 18.7 years (median ∼6.2 years). A total of 192,152 prescription records were retrieved, with 27,723 metabolic measures analysed. Linear mixed models were used to estimate the effects of SGA on BG, lipid profiles and BMI. Besides studying the effects of SGA medications (as binary predictors), we also investigated the effects of SGA dosage on metabolic profiles., Results: Considering SGA medications as binary predictors, clozapine and olanzapine were associated with the most substantial worsening of lipid profiles and BMI. A significant increase in BG was observed with clozapine only. Amisulpride, paliperidone and quetiapine were associated with worsened lipid profiles and increased BMI. Conversely, aripiprazole was associated with significant improvement in lipid profiles but a small increase in BMI. When SGA dosage was considered, the model showed consistent results overall. At the minimum effective dose, clozapine was associated with the most severe metabolic side effects, followed by olanzapine. Risperidone and aripiprazole showed the least metabolic side effects, with aripiprazole being significantly associated with lower lipids., Conclusions: This study clarified the long-term and dose-dependent effects of different SGAs on anthropometric and metabolic parameters in Chinese SCZ patients. Our findings may inform clinicians and SCZ patients of SGA choices., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Schizophrenia is a serious mental disorder, and monitoring remission is a widely used measure of effectiveness of the treatment provided. It is very important to identify possible factors correlating with remission. In our substudy of BeSt InTro, a randomized controlled trial of three antipsychotic drugs, 126 patients with ICD-10 diagnoses F20-29 (F23 excluded) were randomized to one of the second-generation antipsychotic drugs amisulpride, aripiprazole or olanzapine. Remission rate was calculated at seven assessment points, with and without using the time criterion of six months included in the consensus remission criteria. Because of drop-out (n = 77), we had data for 49 patients at one-year follow-up. These data were used to calculate the one-year remission rate to 55 % (27/49), without taking into consideration the 6-month time criterion. When we applied the consensus remission criteria with the 6-month time criterion included, the one-year remission rate was calculated for 59 patients: 29 % (17/59). Antipsychotic drug naivety and low negative symptom load at baseline correlated highly with belonging to the remission group. Use of amisulpride was more probable to lead to remission than that of aripiprazole, but it was not more probable than the use of olanzapine (in per-protocol analyses). Negative symptoms showed the largest resistance to treatment. The lack of remission for the majority of the participants in this closely monitored antipsychotic drug trial is alarming and could act as a reminder that novel treatment principles are needed, especially targeted towards the negative symptoms in schizophrenia., Competing Interests: Declaration of competing interest The authors have declared that there are no conflicts of interest in relation to this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The incidence of major depressive disorder (MDD) after heart transplantation is high; however, there are no reports on treatment options when antidepressant therapy fails to improve the condition. We herein report on the case of a woman with MDD after heart transplantation who partially improved with antidepressant treatment but continued to have a loss of appetite. Augmentation treatment with aripiprazole improved her appetite, and her MDD went into remission. When antidepressant treatment is not sufficiently effective for MDD after heart transplantation, augmentation treatment with antipsychotics, such as aripiprazole, should be considered., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Antipsychotic polypharmacy is commonly used in clinical settings, with a growing trend in using long-acting injections to mitigate many side effects of polypharmacy. A previous study demonstrated that long-acting aripiprazole once-monthly (AOM) injection increased treatment adherence, restored functionality, and improved symptoms. However, there is insufficient evidence to demonstrate the therapeutic effects of AOM in polypharmacy practice. This observational study aimed to investigate the real-world clinical benefits and effectiveness of AOM by assessing changes in drug dosage, the number of drugs, clinical functioning, psychotic symptoms, and the duration of drug efficacy. Study participants were recruited from eight study sites, with the baseline visit marking the initiation of drug treatment. Clinical and demographic data were collected from medical records at screening, baseline, and months 1, 3, 6, 9, and 12. Over 12 months, we analyzed changes in drug dosage, the number of drugs, and scores of the Positive and Negative Syndrome Scale-6 (PANSS-6), Global Assessment of Functioning (GAF), and Clinical Global Impression-Severity (CGIS). Data from 139 participants were analyzed. Total 12-month antipsychotic doses calculated in chlorpromazine equivalents (CPE) were reduced by 32.6%. A comparison of total monthly antipsychotic doses in CPE between the first and last months showed a 24.6% reduction in the dose. Additionally, the quantity of benzodiazepine tablets/capsules, total benzodiazepine doses calculated in lorazepam equivalents, and quantity of tablets/capsules of mood stabilizers, anticholinergics, and beta blockers were significantly reduced. GAF scores increased by 14.1% over 12 months, and PANSS-6 total scores reduced by 17.3% over 12 months, with significant differences observed from month 1 and baseline, respectively. The scores steadily improved until month 9 compared to those of the previous months, continuing to improve through month 12. The CGI-S score reduced by 14.3% over 12 months, showing a significant decrease from month 1 and a steady improvement until month 6, maintaining this improvement until month 12. In conclusion, this study demonstrated the early effectiveness of AOM in treating Korean patients with schizophrenia on polypharmacy. AOM improved function and clinical symptoms in patients with schizophrenia from treatment onset and caused a decrease in the quantity and dosage of drugs taken by the patients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This report presents challenging psychopharmacotherapy management of a psychotic disorder in a patient with a delicate pharmacogenetic profile and drug-drug interactions. A 31-year old woman diagnosed with schizophrenia in 2017 was referred by her psychiatrist to a clinical pharmacologist for interpretation of a pharmacogenetic test and advice regarding optimal psychopharmacotherapy. In spite of adherence to aripiprazole, olanzapine, risperidone, and levomepromazine, and rational anxiolytic therapy, she still experienced anxiety, anhedonia, loss of appetite, sleeping problems, and auditory hallucinations with commands to harm herself. Due to a lack of alternative therapeutic steps, low aripiprazole serum concentrations, and a lack of explanation for pharmacotherapy unresponsiveness, pharmacogenetic testing was performed. The patient was defined as CYP2D6 *1/*1, CYP1A2 *1F/*1F, CYP3A4 *1/*1B, CYP3A5 *1/*3, and having increased activity of the enzymes UGT1A4 and UGT2B7, intermediate activity of ABCB1 transporter, and low activity of COMT. Carbamazepine was discontinued, aripiprazole was increased to a maximum of 30 mg/day orally with long-acting injection (400 mg monthly), and olanzapine was increased to a daily dose of 35 mg orally. These changes led to an optimal therapeutic drug concentration and improved clinical status. At the last follow-up, the patient was without severe auditory hallucinations, became more engaged in daily life, had more interaction with others, had found a job, and even had started an emotional relationship. In psychiatry, pharmacogenetic testing is an important tool for guiding pharmacological therapy, particularly in patients with an unsatisfactory clinical response and a lack of alternative therapeutic steps for pharmacotherapy unresponsiveness.

Delirium is a disorder of consciousness and it is caused by acute brain disfunction in the course of, e.g., severe somatic condition, intoxication or withdrawal syndrome. Delirium management is based on the treatment of the state that caused disturbance in central nervous system. Severe delirium syndromes such as agitation, disorganized behavior or hallucinations require additional pharmacological treatment with antypsychotics. Aripiprazole is used in treatment of schizophrenia, bipolar disorder and Tourette syndrome, but also off-label in delirium. A systematic review of databases was carried out and results were limited to case reports, clinical trials and randomized controlled trials. There is evidence that there is no difference in effectiveness of aripiprazole compared to haloperidol and other atypical neuroleptics. Aripirazole could be a better option in particular groups of patients due to its safer cardiological and metabolic profile as well as better tolerance of treatment. However, data from clinical findings are still insufficient to recommend a routine use of aripiprazole in the treatment of delirium. Therefore, further investigations are necessary to work out new strategy of managing delirium syndrome.

Objective: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic, has 2 initiation options: 1-day (AL NanoCrystal Dispersion [AL NCD ] injection plus 30 mg oral aripiprazole on day 1 only) and 21-day (15 mg oral aripiprazole for 21 days). This post hoc analysis assessed the safety and tolerability of both initiation approaches., Methods: We analyzed data from the first 4 weeks of 2 AL studies, one using the 1-day initiation regimen (conducted between November 2017 and March 2019) and the other using the 21-day initiation regimen (conducted between December 2011 and March 2014). Outcomes of interest during the matched 4-week period included the likelihood of adverse events (AEs), including those associated with discontinuation, rated as serious, or of special interest (injection site reactions [ISRs] and akathisia)., Results: The 1-day (n = 99) and 21-day (n = 415) initiation regimens had comparable rates of AEs (57.6% and 52.0%, respectively; most were mild), serious AEs (2.0% and 1.4%), and AEs leading to discontinuation (4.0% and 3.1%). The incidence of ISRs was 11.1% after the AL NCD injection (day 1) in the 1-day initiation regimen. ISR rates for the AL starting doses were 9.2% for the 1-day regimen (AL 1064 mg on day 8) and 3.9% for the 21-day regimen (AL 441 mg/882 mg on day 1). Rates of akathisia were 9.1% and 11.1% for the 1-day and 21-day regimens, respectively. One patient discontinued because of an ISR in the 21-day study, and 2 patients in the 21-day study discontinued because of akathisia. Mean changes from baseline in week 4 Positive and Negative Syndrome Scale total scores were -17.4 (1-day) and -19.5 (21-day)., Conclusions: Four-week safety and tolerability were similar following the initiation of AL with either the 1-day or 21-day regimen, supporting the utility of both initiation regimens. Engaging patients in discussions regarding options for initiating AL may help facilitate shared decision-making and personalization of treatment for patients with schizophrenia., Trial Registration: ClinicalTrials.gov identifiers: NCT03345979 and NCT01469039., (© Copyright 2024 Physicians Postgraduate Press, Inc.)

Rationale: The efficacy and safety of antidepressant augmentation therapy with aripiprazole (AATA) has been established; however, the ongoing effects of continuing aripiprazole after remission remain unclear because no studies have examined this issue., Objectives: We aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA., Methods: This 24-week, multicenter, placebo-controlled, double-blind, randomized trial evaluated recurrence risk in patients with MDD who achieved remission with AATA. Differences in MDD recurrence, as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, between the two groups were compared using survival analysis. The differences in depressive symptom severity and social functioning between the two groups were compared using a mixed model with repeated measures. Extrapyramidal symptoms and akathisia were also assessed., Results: Twenty-three participants were randomized and treated. Two patients in each group experienced recurrence during the study. Kaplan-Meier analysis with Log-rank comparison showed no difference in recurrence between groups (p = 0.642). No significant difference in interactions between group and period was observed in the 17-item Hamilton depression rating scale (p = 0.492) or the Social and Occupational Functioning Assessment Scale (p = 0.638). No patients developed extrapyramidal symptoms or akathisia., Conclusions: Definitive conclusions could not be drawn owing to the small sample size. This study represents a starting point for investigating the safety of aripiprazole discontinuation on recurrence in patients with MDD who have achieved remission with AATA. Future studies with appropriate sample sizes calculated based on this study are needed., (© 2024. The Author(s).)

Objective: Weight gain, blood lipids and/or glucose dysregulation can follow aripiprazole treatment onset. Whether aripiprazole dosage is associated with an increase in these metabolic parameters remains uncertain. The present study investigates aripiprazole dose associations with weight change, blood glucose, lipids, and blood pressure., Methods: 422 patients taking aripiprazole for a minimum of three weeks to one year were selected from PsyMetab and PsyClin cohorts. Associations between aripiprazole dose and metabolic outcomes were examined using linear mixed-effect models., Results: Aripiprazole dose was associated with weight change when considering its interaction with treatment duration (interaction term: -0.10, p < 0.001). This interaction resulted in greater weight gain for high versus low doses at the beginning of the treatment, this result being overturned at approximately five months, with greater weight increase for low versus high doses thereafter. LDL and HDL cholesterol levels were associated with aripiprazole dose over five months independently of treatment duration, with an average of 0.06 and 0.02 mmol/l increase for each 5 mg increment, respectively (p = 0.033 and p = 0.016, respectively). Furthermore, mean dose increases were associated with greater odds (+30 % per 5 mg increase) of clinically relevant weight gain (i.e., ≥7 %) over one year (p = 0.025)., Conclusion: Aripiprazole dose was associated with one-year weight changes when considering its interaction with treatment duration. Increasing its dose could lead to metabolic worsening over the first five months of treatment, during which minimum effective doses should be particularly preferred., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest in relation to the content of this work. Disclosure CBE received honoraria for conferences from Forum pour la formation médicale, Idorsia, Janssen-Cilag, Lundbeck, Otsuka, Sandoz, Servier, Sunovion, Takeda, Vifor-Pharma, and Zeller in the past 3 years., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Both biphasic dissolution and simultaneous dissolution-permeation (D-P) systems have great potential to improve the in vitro-in vivo correlation compared to simple dissolution assays, but the assay conditions, and the evaluation methods still need to be refined in order to effectively use these apparatuses in drug development. Therefore, this comprehensive study aimed to compare the predictive accuracy of small-volume (16-20 mL) D-P system and small-volume (40-80 mL) biphasic dissolution apparatus in bioequivalence prediction of five aripiprazole (ARP) containing marketed drug products. Assay conditions, specifically dose dependence were studied to overcome the limitations of both small-scale systems. In case of biphasic dissolution the in vivo maximum plasma concentration (C max ) prediction greatly improved with the dose reduction of ARP, while in case of the D-P setup the use of whole tablet gave just as accurate prediction as the scaled dose. With the dose reduction strategy both equipment was able to reach 100 % accuracy in bioequivalence prediction for C max ratio. In case of the in vivo area under the curve (AUC) prediction the predictive accuracy for the AUC ratio was not dependent on the dose, and both apparatus had a 100 % accuracy predicting bioequivalence based on AUC results. This paper presents for the first time that not only selected parameters of flux assays (like permeability, initial flux, AUC value) were used as an input parameter of a mechanistic model (gastrointestinal unified theory) to predict absorption rate but the whole in vitro flux profile was used. All fraction absorbed values estimated by Predictor Software fell within the ±15 % acceptance range during the comparison with the in vivo data., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Antipsychotic polypharmacy (APP) has become prevalent over the years, but several concerns have been raised over APP. Accumulating evidence suggests that aripiprazole long-acting injectable (LAI) may reduce the rate of APP, but the association remains speculative. This retrospective observational study included 127 patients with psychosis and observed them for 1.8 ± 1.3 years, up to 4 years. Prescription data of antipsychotics (APs), mood stabilisers, benzodiazepines, and anti-extrapyramidal side effect medications were obtained at baseline and the last observation. Daily chlorpromazine equivalent (CPZ) dose of APs decreased from 124.40 ± 235.35 mg to 77.95 ± 210.36 mg ( P = 0.027). The daily dose of anticholinergics and beta-blockers also significantly decreased after introducing aripiprazole LAI. Among the patients having APP, the number of concurrent APs along with daily CPZ dose of APs decreased after initiation of aripiprazole LAI from 1.28 ± 0.62 to 0.85 ± 0.73 ( P < 0.001) and 298.33 ± 308.70 mg to 155.43 ± 280.53 mg ( P = 0.004), respectively. Treatment with aripiprazole LAI for up to 4 years in patients with psychosis was associated with a reduced number of prescribed APs in patients having an APP and a reduced dose of APs and concurrent psychotropic medications., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The augmentative antidepressant effects of dopamine partial agonists (aripiprazole, brexpiprazole, and cariprazine) for treatment-resistant depression have been compared in a previous network meta-analysis. However, the comparative efficacy of the dose-responses of these drugs remains unclear. Therefore, we aimed to estimate the dose-response relationships and compare the effects of each dopamine partial agonist doses., Methods: We conducted a systematic review of the Cochrane Library, PubMed, CINHAL, and ClinicalTrials.gov databases until January 1, 2023. Double-blind, randomized, placebo-controlled trials evaluating aripiprazole, brexpiprazole, and cariprazine for treatment-resistant depression were included. A random-effect dose-response model-based network meta-analysis was conducted. This study was registered in PROSPERO (CRD42023393035)., Results: The maximum effective doses were 5.5 mg for aripiprazole, 1.6 mg for brexpiprazole, and 1.5 mg for cariprazine, respectively. Although all doses of the 3 drugs were significantly more effective than placebo, aripiprazole ranging from 5.5 to 12.5 mg was significantly more effective than brexpiprazole 0.5 mg and cariprazine ranging from 0.5 to 1 mg. Moreover, aripiprazole ranging from 7.5 to 12.5 mg was significantly more effective than all doses of cariprazine. In addition, brexpiprazole ranging from 1 to 3 mg was significantly more effective than cariprazine 0.5 mg and brexpiprazole ranging from 1.6 to 2.5 mg was significantly superior to cariprazine 1 mg. There were no doses at which brexpiprazole overcame aripiprazole, and cariprazine overcame aripiprazole or brexpiprazole., Conclusions: Aripiprazole, brexpiprazole, and cariprazine may be effective in treatment-resistant depression in that order, with the maximum effective doses at 5.5 mg, 1.6 mg, and 1.5 mg, respectively., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Delirium is a neuropsychiatric condition that commonly occurs in medical settings, especially among older individuals. Despite the lack of strong evidence in the literature, haloperidol is considered the first-line pharmacological intervention. Unfortunately, its adverse effects can be severe, and psychiatrists are considering the use of alternative drugs targeting dopamine and serotonin domains (atypical antipsychotics). Among them, aripiprazole is considered to have one of the safest pharmacological profiles., Aims: The purpose of this study is to examine the studies on aripiprazole as a pharmacological treatment of delirium present in today's literature., Methods: We carried out systematic research of MedLine, PubMed, Cochrane, Embase, and ScienceDirect examining articles written between January 2002 and September 2023, including experimental studies published in peer-reviewed journals., Results: The 6 final included studies examined a total of 130 patients, showing a delirium resolution in a 7-day span of 73.8% of patients treated with aripiprazole., Conclusions: Considering the limited data currently available, we can assert that aripiprazole is at least as efficient as haloperidol, the true point is that it has a far better tolerability and safety profile. Nonetheless, further studies are necessary to provide more compelling data, together with a more precise indication regarding minimum efficient dose, as the main limitations of our review are the very small sample size, the small percentage of subjects with preexisting dementia, and the fact that most studies used scales with low specificity for the examined condition., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Treatment-resistant schizophrenia (TRS) is a challenging condition to treat for the correctional psychiatrist. Guidelines from the American Psychiatric Association indicate that the first-line pharmacotherapy for TRS is the use of the atypical antipsychotic clozapine. The use of clozapine is unique in that it requires patient adherence with weekly blood draws as a prophylactic measure against agranulocytosis and leukopenia. In the correctional setting, patients with severe and persistent schizophrenia are frequently nonadherent due to lack of insight and anemic access to health care resources, specifically as these pertain to clozapine. Therefore, an alternative treatment option would be a welcome solution for this demographic. Our literature review demonstrates a limited number of studies documenting the successful use of clozapine alternatives or combination antipsychotic therapy for treatment of TRS. In this article, we present a putative case where we believe that a combination regimen of paliperidone palmitate, oral aripiprazole, and escitalopram led to a notable mitigation of both positive and negative symptoms of psychosis in the case of an incarcerated patient with TRS, as well as an improvement in functional stability, which was conducive to housing in a less restrictive setting. A brief review of the published literature follows the report.

Objectives: Aripiprazole is a second-generation atypical antipsychotic with worldwide clinical approval. Nevertheless, its perioperative antinociceptive application has not been studied. As a result, the purpose of this study was to investigate the analgesic effects of perioperative aripiprazole on reducing postoperative pain, as well as the possible adverse effects., Patients and Methods: This randomized controlled study enrolled 80 female patients scheduled for laparoscopic hysterectomy who were assigned randomly into 2 equal groups in 1:1; aripiprazole group (n = 40), patients received an aripiprazole 30 mg tablet orally 3 hours before surgery and placebo group (n = 40), patients received a placebo tablet 3 hours before surgery. The 24-hour morphine consumption postoperatively was the primary outcome, and the time to the first analgesic request, sedation scores, and the incidence of perioperative adverse events were the secondary outcomes., Results: The mean 24-hour morphine consumption was significantly lower with aripiprazole (2.5 ± 0.5 mg) than with placebo (23.7 ± 1.6 mg; mean ± SE -21.2 ± 0.3, 95% CI: -21.7 to -20.6, P < 0.001). In addition, the mean time to the first analgesic request was significantly longer with aripiprazole (212.2 ± 14.7 min) than with placebo (27.0 ± 2.0 min; mean ± SE 185.2 ± 2.3, 95% CI: 180.5 to 189.8, P < 0.001). Furthermore, the aripiprazole group reported higher sedation scores ( P < 0.001). Bradycardia and hypotension were reported more frequently among patients in the aripiprazole group ( P < 0.05)., Conclusion: Aripiprazole was effective in reducing pain after laparoscopic hysterectomy. Although self-limited, side effects should be taken into consideration when using the medication perioperatively., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899 aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval., (© 2024 Otsuka Pharmaceutical Development & Commercialization, Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Sleep problems are common and related to a worse quality of life in patients with schizophrenia. Almost all patients with schizophrenia use antipsychotic medications, which usually increase sleep. Still, the differences in subjective sleep outcomes between different antipsychotic medications are not entirely clear., Methods: This study assessed 5466 patients with schizophrenia and is part of the nationwide Finnish SUPER study. We examined how the five most common antipsychotic medications (clozapine, olanzapine, quetiapine, aripiprazole, and risperidone) associate with questionnaire-based sleep problems in logistic regression analyses, including head-to-head analyses between different antipsychotic medications. The sleep problems were difficulties initiating sleep, early morning awakenings, fatigue, poor sleep quality, short (≤6 h) and long sleep duration (≥10 h)., Results: The average number of antipsychotic medications was 1.59 per patient. Clozapine was associated with long sleep duration (49.0 % of clozapine users vs 30.2 % of other patients, OR = 2.05, 95 % CI 1.83-2.30, p < .001). Olanzapine and risperidone were in head-to-head analyses associated with less sleep problems than patients using aripiprazole, quetiapine, or no antipsychotic medication. Aripiprazole and quetiapine were associated with more insomnia symptoms and poorer sleep quality. Patients without antipsychotic medications (N = 159) had poorer sleep quality than patients with antipsychotic use, and short sleep duration was common (21.5 % of patients not using antipsychotics vs 7.8 % of patients using antipsychotics, OR = 2.97, 95 % CI 1.98-4.44, p < .001)., Conclusions: Prevalence of sleep problems is markedly related to the antipsychotic medication the patient uses. These findings underline the importance of considering and assessing sleep problems when treating schizophrenia patients with antipsychotics., Competing Interests: Declaration of competing interest Regarding conflicts of interest, Markku Lähteenvuo is an owner and board member of Genomi Solutions Ltd. and Nursie Health Ltd. and has received honoraria from Sunovion, Orion Pharma, Janssen-Cilag, Otsuka Pharma, Lundbeck, and Medscape, travel funds from Sunovion, and research grants from the Finnish Medical Foundation, the Emil Aaltonen Foundation, and the Finnish Cultural Foundation. Jari Tiihonen has participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution; has received personal fees from the Finnish Medicines Agency (Fimea), European Medicines Agency (EMA), Eli Lilly, Janssen-Cilag, Lundbeck, and Otsuka; is a member of the advisory board for Lundbeck; and has received grants from the Stanley Foundation and the Sigrid Jusélius Foundation. None of the other authors report any financial relationships with commercial interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Treatment with long-acting injection (LAI) antipsychotics, such as paliperidone palmitate, has improved the quality of life in terms of symptoms and prevention of relapses in patients with schizophrenia. Although there are plenty of evidences about the efficacy and safety of paliperidone palmitate 3-monthly injection (PP3M) in adults with schizophrenia, literature appears lacking about the use of LAIs during pregnancy. We hereby describe the clinical case of a pregnant woman affected by schizophrenia (DSM-5-TR), taking pharmacological treatment of PP3M. Considering the inadequate evidence regarding the use of PP3M in pregnancy in agreement with the patient, we switched PP3M to an oral therapy with aripiprazole. The switch to oral aripiprazole allowed the patient to improve her sense of autonomy and strengthen the therapeutic relationship. To our knowledge, this is the first case report monitoring an entire pregnancy of a women affected by schizophrenia in treatment with PP3M injection and oral aripiprazole. No obstetrical or fetal complications were reported. As the research in this field is very demanding, it would be precipitous to derive final conclusions from the current case report, but we hope to build a growing number of data that would allow us to make more appropriate and safe therapeutic choices in such a vulnerable phase as the peripartum.

It has been previously reported that among patients with schizophrenia that long-acting injectable (LAI) antipsychotic formulations can delay time to relapse longer when compared to their oral equivalents when patients discontinue therapy. Unanswered is whether this same pattern would be observed for patients with bipolar disorder receiving maintenance treatment. A systematic review was undertaken to identify relevant studies of LAI antipsychotics in maintenance treatment of bipolar disorder, employing a placebo-controlled randomized withdrawal design, and where equivalent studies using the corresponding oral formulation were also available. We found five studies [one aripiprazole monohydrate once monthly (AOM) study, one oral aripiprazole (OARI) study, two 2 weeks risperidone-LAI (RIS-LAI) studies, and one oral paliperidone (OPAL) study]. Numerically lower recurrence rates at 2, 4, 6, 8, 12, 16, 20, and 26 weeks were observed when AOM was discontinued when compared with discontinuation from OARI. Numerically lower recurrence rates at 2, 4, 6, 8, and 16 weeks were observed when RIS-LAI was discontinued when compared with discontinuation from OPAL. These results can be interpreted as a substantial delay in time to recurrence with a LAI antipsychotics formulation compared to the oral equivalent when medication is discontinued in patients with mania who had been stabilized on LAI antipsychotics or corresponding oral antipsychotics., Competing Interests: Declaration of competing interest All authors have no conflicts of interest to declare concerning this study. They also declare any potential competing interests that have arisen in the last 3 years. Dr. Kishi has received speaker's honoraria from Eisai, Janssen, Meiji, MSD, Otsuka, Sumitomo, Takeda, Tanabe-Mitsubishi, and Viatris and research grants from Eisai, Grant-in-Aid for Scientific Research (C) (19K08082 and 23K06998), Japan Agency for Medical Research and Development (JP22dk0307107 and JP22wm0525024), and the Japanese Ministry of Health, Labour and Welfare (21GC1018). Dr. Citrome serves as consultant to AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, Biogen, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, Clinilabs, COMPASS, Delpor, Eisai, Enteris BioPharma, HLS Therapeutics, Idorsia, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Luye, Lyndra, MapLight, Marvin, Medavante-ProPhase, Merck, Mitsubishi-Tanabe Pharma, Neumora, Neurocrine, Neurelis, Noema, Novartis, Noven, Otsuka, Ovid, Praxis, Recordati, Relmada, Reviva, Sage, Sumitomo/Sunovion, Supernus, Teva, University of Arizona, Vanda, Wells Fargo, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Axsome, BioXcel, Eisai, Idorsia, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Recordati, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies; owns stocks (small number of shares of common stock): Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased > 10 years ago, stock options: Reviva; and receives royalties/publishing income from Taylor & Francis (Editor-in-Chief, Current Medical Research and Opinion, 2022-date), Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics). Dr. Sakuma has received speaker's honoraria from Daiichisankyo, Eisai, Janssen, Kyowa, Meiji, Otsuka, Sumitomo, and Takeda and has received a Fujita Health University School of Medicine Research Grant for Early-Career Scientists, Grant-in-Aid for Young Scientists (B)(19K17099), Grant-in-Aid for Scientific Research (C)(23K06998), and Japan Agency for Medical Research and Development (JP22dk0307107 and JP23dk0307122). Dr. Iwata has received speaker's honoraria from Eisai, Janssen, Meiji, Otsuka, Sumitomo, Takeda, Tanabe-Mitsubishi, and Viatris and research grants from Daiichi Sankyo, Eisai, Meiji, Otsuka, Sumitomo, Takeda, Tanabe-Mitsubishi, Grant-in-Aid for Scientific Research (B)(22H03003), and Japan Agency for Medical Research and Development (JP22wm0425008)., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Non-adherence to medication significantly affects bipolar disorder outcomes. Long-Acting Injectable antipsychotics show promise by ensuring adherence and averting relapses., Areas Covered: This narrative review sought to evaluate the efficacy of second-generation injectable antipsychotics in bipolar disorder through searches in Embase, MEDLINE, and PsycInfo for randomized controlled trials and mirror-image studies.Risperidone and aripiprazole Long-Acting Injectables demonstrated effectiveness in preventing mood recurrences compared to placebos in adults with bipolar disorder. They showed superiority in preventing mania/hypomania relapses over placebos but did not appear to significantly outperform active oral controls. Notably, active controls seem to be more effective in preventing depression relapses than Long-Acting Injectables. Mirror-Image studies point toward the reduction of hospitalization rates following LAI initiation., Expert Opinion: The available evidence points thus toward the efficacy of LAIs, especially in managing manic episodes and reducing hospitalizations, The current evidence does not however immediately support prioritizing LAIs over oral medications in bipolar disorder treatment. More high-quality studies, especially comparing LAIs directly with active controls, are crucial to gain a comprehensive understanding of their efficacy. These findings highlight the need for further research to guide clinicians in optimizing treatment strategies for bipolar disorder.

Background: Aripiprazole augmentation is proven effective for antidepressant-refractory depression, but its licensed dose range is wide and optimal dosage remains unclear., Aims: To find the optimal dosage of aripiprazole augmentation., Method: Multiple electronic databases were searched (from inception to 16 February 2021) to identify all assessor-masked randomised controlled trials evaluating aripiprazole augmentation therapy in adults (≥18 years old, both genders) with major depressive disorder showing inadequate response to at least one antidepressant treatment. A random-effects, one-stage dose-effect meta-analysis with restricted cubic splines was conducted. Outcomes were efficacy (treatment response: ≥50% reduction in depression severity), tolerability (drop-out due to adverse effects) and acceptability (drop-out for any reason) after 8 weeks of treatment (range 4-12 weeks)., Results: Ten studies met the inclusion criteria. All were individually randomised, placebo-controlled, multi-centre, parallel studies including 2625 participants in total. The maximum target dose-efficacy curve showed an increase up to doses between 2 mg (odds ratio OR = 1.46, 95% CI 1.15-1.85) and 5 mg (OR = 1.93, 95% CI 1.33-2.81), and then a non-increasing trend through the higher licensed doses up to 20 mg (OR = 1.90, 95% CI 1.52-2.37). Tolerability showed a similar trend with greater uncertainty. Acceptability showed no significant difference through the examined dose range. Certainty of evidence was low to moderate., Conclusions: Low-dose aripiprazole as augmentation treatment might achieve the optimal balance between efficacy, tolerability and acceptability in the acute treatment of antidepressant-refractory depression. However, the small number of included studies and the overall moderate to high risk of bias seriously compromise the reliability of the results. Further research is required to investigate the benefits of low versus high dose.

Background: Although long-acting injectable antipsychotics (LAI-APs) have been considered as a monotherapeutic option in the maintenance treatment of schizophrenia, it has been recently reported that the combination therapy of LAI-APs and oral antipsychotics (OAPs) is common., Methods: We conducted a retrospective chart review to examine the situation of the combination therapy of LAI second-generation antipsychotics (LAI-SGAs) and OAPs, and a questionnaire survey to investigate prescribers' attitudes toward the combination therapy. We included patients who received any LAI-SGAs for 1 month or longer and classified them into monotherapy and combination therapy groups. We collected information on age, sex, primary psychiatric diagnosis, and concomitant psychotropic medications., Results: Of the 132 patients, 39 (29.5%) received the combination therapy of LAI-SGAs and OAPs. Long-acting injectable risperidone was significantly associated with receiving the combination therapy compared with LAI aripiprazole. Olanzapine was the most common OAP in combination with LAI-SGAs. Only 8 patients (20.5%) concurrently received the same type of OAPs as LAI-SGAs. More than 60% of the patients received OAP polypharmacy before the initiation of LAI-SGAs. The psychiatrists in charge prescribed LAI-SGAs mainly because of a concern about adherence, and OAPs mainly because of insufficient dose of LAI-SGAs, to patients in the combination therapy group. They estimated that adherence to OAPs in two thirds of the patients in the combination therapy group was 80% or higher., Conclusions: The present study showed that the combination therapy of LAI-SGAs and OAPs is often conducted in real-world clinical practice. Considering the reason for the introduction of LAI-APs, clinicians should carefully monitor patients' adherence to OAPs concurrently used with LAI-APs., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia., Methods: In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5-p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90-92 rats were evaluated in the behavioral and biochemical tests., Results: BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests., Conclusion: The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram., (© 2021. The Author(s).)

Purpose/background: Frontal and temporal cerebral blood flow (CBF) changes are the most common impairments of CBF described in patients with schizophrenia. Those impairments have also been associated with cognitive deficits, a hallmark of schizophrenia. In light of that fact, treatment interventions should target cognitive deficits to prevent chronic disability. However, specific therapies targeting cognitive symptoms are very few and far between. One of the treatment possibilities is aripiprazole, because several studies reported its potential procognitive effects. The objective of this study was to investigate whether use of aripiprazole in its long-acting injectable formulation (ALAI), during a 3-month treatment, has beneficial effects on CBF and cognitive functioning in patients with first episode of schizophrenia., Methods/procedures: Single-photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime was performed at 2 time points. Cognitive functions were assessed with a standardized test for cognitive functions, 5-KOG test, whereas severity of clinical symptoms was assessed with the Positive and Negative Syndrome Scale, both at the same 2 time points as single-photon emission computed tomography. Three-month treatment with ALAI was associated with improvement of several cognition indices and improvements of right-sided frontal and temporal CBF, as well as of clinical symptoms., Findings/results: Multivariate tests were used to test for the effects of ALAI treatment on cognitive functions, clinical presentation, and brain perfusion in a 3-month period. Multivariate model revealed statistical significance (F = 11.958, P < 0.001). Of 10 separate 5-KOG parameters, 3-month treatment with ALAI significantly influenced 4: undelayed recall, delayed recall, attention, and working memory-digit span forward. Finally, 3-month ALAI treatment significantly improved regional CBF in 2 of 4 investigated areas, both on the right side of the brain (frontally and temporally)., Implications/conclusions: Results of this research showed that treatment with ALAI in patients with first episode of schizophrenia is associated with improved right-sided frontal and temporal CBF, as well as with improved symptoms, including cognition indices. Although we cannot confirm it directly, it is possible that improved frontotemporal CBF led to the improvement in cognition indices., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose/background: The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs)., Methods/procedures: Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed., Findings/results: One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms., Implications/conclusions: Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

In the current study, a composite in-situ gel formulation containing aripiprazole (APZ) loaded transfersomes (TFS) was developed for the intranasal brain targeting of APZ. APZ loaded TFS were prepared by applying the film hydration method and optimized using an irregular factorial design. The prepared formulations were optimized based on different parameters including particle size, polydispersity index (PdI), zeta potential, encapsulation efficiency (EE) and release efficiency (RE). The optimized APZ-TFS were distributed in an ion-triggered deacetylated gellan gum solution (APZ-TFS-Gel) and evaluated in terms of pH, gelling time, rheological properties and in-vitro release study. The therapeutic efficacy of the best APZ-TFS-Gel was then tested in the mice model of schizophrenia induced by ketamine by evaluating various behavioral parameters. The optimized formulation showed the particle size of 72.12 ± 0.72 nm, the PdI of 0.19 ± 0.07, the zeta potential of -55.56 ± 1.9 mV, the EE of 97.06 ± 0.10%, and the RE of 70.84 ± 1.54%. The in-vivo results showed that compared with the other treatment groups, there was a considerable increase in swimming and climbing time and a decrease in locomotors activity and immobility time in the group receiving APZ-TFS-Gel. Thus, APZ-TFS-Gel was found to have desirable characteristics for therapeutic improvement.

Background: Continuous antipsychotic therapy is recommended as part of long-term maintenance treatment of schizophrenia, and gaps in antipsychotic treatment have been associated with increased risks of relapse and rehospitalization. Because the use of long-acting injectable (LAI) antipsychotics may reduce the likelihood of undetected medication gaps, initiating an LAI medication may affect resource utilization and costs. The LAI aripiprazole lauroxil (AL) was approved in the United States (US) in 2015 for the treatment of schizophrenia in adults., Objective: The objective of this retrospective observational cohort study was to examine treatment patterns, resource utilization, and costs following initiation of AL for the treatment of schizophrenia in adults., Methods: A retrospective analysis of Medicaid claims data identified a cohort of patients (N = 485) starting AL shortly after Food and Drug Administration approval in October 2015. Treatment patterns, resource utilization, and costs were compared 6 months before and after treatment initiation. Subgroup analyses were conducted based on the type of antipsychotic (LAI, oral, or none) received before initiation of AL., Results: Over 6 months of follow-up, patients received an average of 4.6 injections out of a maximum of six (77%). After initiating AL, all-cause inpatient admissions decreased by 22.4%; other significant reductions were observed in mental health-related admissions and emergency room (ER) visits. All-cause inpatient costs decreased by an average of US$2836 per patient (p < 0.05) in the 6-month post-AL period, whereas outpatient pharmacy costs increased by US$4121 (p < 0.05), resulting in no significant difference in overall costs between the pre- and post-AL periods. The subgroup of patients who had been prescribed an oral antipsychotic before starting AL had significant reductions in proportion of patients with inpatient and ER visits and costs, but also reported a significant increase in pharmacy costs., Conclusions: AL was associated with a significant reduction in inpatient costs and an increase in outpatient pharmacy costs, resulting in no changes in total healthcare costs over 6 months. The adherence rate and reductions in inpatient use may indicate the potential for greater clinical stability among patients initiated on AL compared with their previous treatment., (© 2021. The Author(s).)

To assess the bioequivalence of 2 formulations of aripiprazole orally disintegrating tablets and to monitor their safety and tolerability in Chinese subjects, a single-site, open-label, randomized, 2-preparation, single-dose, 2-period crossover design was conducted. All 60 subjects were randomly divided into the fasting group and the fed group. Blood samples were collected at scheduled times after a single oral dose of orodispersible tablets containing 10 mg of aripiprazole. In the fasting state, the geometric mean ratios (90% confidence intervals [CIs]) of the test/reference formulation were 92.22%-100.20% for the area under the concentration-time curve (AUC) from time zero to the last measured concentration (AUC 0-t ), 91.73%-100.14% for the AUC from administration to infinite time (AUC 0-∞ ), and 98.52%-112.52% for the maximum plasma concentration (C max ). In the fed state, AUC 0-t , AUC 0-∞ , and C max were 92.23%-100.20%, 91.73%-100.14%, and 95.91%-105.13%, respectively. The 90%CIs of the test/reference AUC ratio and C max ratio were within the acceptance range of 80.00%-125.00% for bioequivalence. Neither the maximum peak plasma concentration (t max ) nor the terminal elimination half-life (t 1/2 ) showed any significant difference. No serious adverse events) were encountered during the study. The test and reference formulations were bioequivalent under both fasting and fed conditions and were found to be safe and tolerated., (© 2021, The American College of Clinical Pharmacology.)

Abstract: Acute dystonic reactions are a worrying reason for presentation to the pediatric emergency department and the pediatric neurology clinic in childhood. It must be diagnosed and treated quickly. The aim of this study was to examine the clinical presentations, etiological factors, and prognosis of patients presenting to our regional tertiary pediatric neurology clinic with a diagnosis of acute dystonic reactions in children.Nine pediatric patients who were treated for acute dystonic reactions between May, 2018 and May, 2020 and had adequate follow-up were included in the study. Medical record data were reviewed age, gender, etiology, features of family, treatment, and results.Three of the patients were female and 6 were male. Their average age was 11 years (4-17). All patients were evaluated as a drug-induced acute dystonic reaction. Of the 9 patients, 5 were due to metoclopramide, 3 were due to risperidone, and 1 was due to aripiprazole. It was learned that a similar situation against other drugs developed in the family history of 3 patients. As a treatment, all of them were intramuscularly applied biperiden suitable for their weight and 30 minutes dramatic improvement was observed. Additional dose had to be administered in only 1 case. All cases were discharged for 24 hours. No problem was observed in their follow-up.Drug-induced acute dystonic reaction can be diagnosed and has a clinical picture that completely resolves when effective treatment is applied. However, it should not be forgotten that it can reach life-threatening dimensions clinically., Competing Interests: The author has no funding and conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Few studies have evaluated the influence of valproate on the deterioration of the lipid profile in psychiatric patients. This observational study aimed to compare the evolution of metabolic parameters in a sample of adult patients starting valproate (n = 39) with a control group (n = 39) of patients starting aripiprazole, a drug associated with a low risk of metabolic deterioration. Data were obtained from a prospective study including psychiatric patients with metabolic parameters monitored during the first year of treatment. During the first month of treatment with valproate (median: 31 days [IQR: 25-36]), mean body mass index increased significantly (from 24.8 kg/m 2 at baseline to 25.2 kg/m 2 after one month; P = .03) and mean HDL-C levels decreased significantly (from 1.39 mmol/L to 1.27 mmol/L; P = .02). In comparison, these metabolic variables remained stable during the first month of treatment with aripiprazole. The proportion of patients with early (ie during the first month of treatment) HDL-C decrease of ≥ 5% was significantly higher under valproate (54%) than aripiprazole (15%) treatment (P < .001). These findings remind the importance of a prospective metabolic monitoring in patients who initiate valproate treatment. Further research should be conducted on larger samples and should focus on finding effective interventions to prevent such metabolic adverse effects., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Most studies investigating antipsychotic effectiveness report either total psychopathology or symptom cluster findings. Studies focusing on a separate symptom, such as hallucinations, a hallmark symptom in schizophrenia, are scarce.Therefore, the current study aims to compare the antihallucinatory effectiveness of 3 pharmacologically different antipsychotics: olanzapine, amisulpride, and aripiprazole., Methods: The present study is part of the Bergen-Stavanger-Innsbruck-Trondheim study, a 12-month prospective, randomized, pragmatic antipsychotic drug trial in active-phase schizophrenia spectrum disorders. The primary outcome of the present study was change of hallucinations as measured by item P3 (hallucinatory behavior) from the Positive and Negative Syndrome Scale in the subgroup with hallucinations at baseline. Primary analyses were intention to treat., Results: A total of 144 participants were included in the study, where 105 (72%) had a score of 3 or more on the Positive and Negative Syndrome Scale P3 item at baseline, indicating the presence of hallucinations (HALL subgroup).In the HALL subgroup, a significantly less reduction of hallucinations was revealed for participants using olanzapine in weeks 12, 26, 39, and 52 when compared with amisulpride and in weeks 26 and 52 when compared with aripiprazole. In subanalyses for participants never exposed to antipsychotic drugs (antipsychotic-naive) and those who had used antipsychotics before entering the study, antihallucinatory differences were revealed only in the latter group., Conclusions: A differential antihallucinatory effect of the 3 study drugs was present. The inferior effect of olanzapine seems to be driven by the subgroup of participants exposed to antipsychotic treatment before entering the study., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose/background: This study aimed to explore the discontinuation rate of aripiprazole long-acting injection (LAI) in a naturalistic clinical setting., Methods/procedures: A retrospective cohort study of 1 year duration was conducted on the first 200 patients registered to receive aripiprazole LAI in Sussex, UK. Rate of discontinuation and the association of robustly recorded clinical variables with discontinuation or a new acute care episode were explored., Findings/results: Of 200 registered, 173 patients initiated aripiprazole LAI and 40% discontinued this by 1 year. Mean discontinuation time was 18 weeks. The commonest discontinuation reason was "patient choice," independent of efficacy or adverse effects. Not having a diagnosis of schizophrenia spectrum was the only variable significantly associated with treatment continuation after 1 year. No single diagnostic group accounted for this, although a greater continuation rate was observed in those with bipolar disorder. Illness severity factors at baseline, including apparent treatment resistance, had no impact on later aripiprazole LAI discontinuation or on acute service use over the year. Medication-related variables had no identified impact on acute service use., Implications/conclusions: This study supports the clinical utility of aripiprazole LAI for its licensed indications. The 1-year discontinuation rate is equivalent to that in reports of similarly designed studies of paliperidone LAI. Further exploration of nonmedication factors influencing LAI discontinuation is required. Preferential use of aripiprazole LAI over other medications may be supported due to fewer associated metabolic adverse effects., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Cocaine addiction is a severe mental disorder for which few treatment options are available. The underlying mechanisms include facilitation of monoamine-neurotransmission, particularly dopamine. Here, we tested the hypothesis that the monoamine stabilizers, (-)-OSU6162 ((3S)-3-(3-methylsulfonylphenyl)-1-propylpiperidine) and aripiprazole (7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one), prevent cocaine-induced behaviors. Male Swiss mice received injections of (-)-OSU6162 or aripiprazole and cocaine and were tested for cocaine-induced hyperlocomotion, locomotor sensitization, and acquisition and expression of conditioned place preference (CPP). The increase in the distance traveled induced by cocaine (20 mg/kg) was prevented by pretreatment with aripiprazole (1 and 10 mg/kg), whereas (-)-OSU6162 (3 mg/kg) exerted a minor effect. Aripiprazole, however, also impaired spontaneous locomotion. Neither (-)-OSU6162 nor aripiprazole interfered with the locomotor sensitization and expression of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 (3 mg/kg), but not aripiprazole, prevented the acquisition of CPP induced by cocaine (15 mg/kg). (-)-OSU6162 exerts a minor effect in reducing cocaine-induced stimulatory activity and context-related memories, which are responsible for triggering drug seeking. Further studies are required to establish whether (-)-OSU6162 could be a candidate drug for the treatment of cocaine addiction.

Antipsychotics, including amisulpride (AMI), quetiapine (QUE), aripiprazole (ARI), and olanzapine (OLA), are used to treat mental illnesses associated with psychotic symptoms. The effect of these drugs on c-Fos expression in vasopressinergic (AVP) and oxytocinergic (OXY) neurons was studied in the hypothalamic paraventricular nucleus (PVN) of rats. The presence of c-Fos in AVP and OXY perikarya was investigated in seven PVN cells segregations: the anterior (Ant), dorsal cup (Dc), wing-shaped (Wi), periventricular zone (Pe), circle-shaped core (Co) and shell of core (Sh), and the posterior (pPVN) after an acute treatment with AMI-20 mg/kg, QUE-15 mg/kg, ARI-10 mg/kg, and OLA-5 mg/kg/bw in rats. Ninety min after treatments, the animals were sacrificed by transcardial perfusion with fixative and the PVN area sliced into 35 μm thick coronal sections for immunohistochemistry. The c-Fos was processed by avidin-biotin-peroxidase complex intensified with nickel-enhanced 3,3'-diaminobenzidine tetrahydrochloride. Visualization of AVP- and OXY-synthesizing neurons was achieved by a fluorescent marker Alexa Flour 568. The c-Fos-AVP and c-Fos-OXY colocalizations were evaluated from c-Fos stained sections merged with AVP or OXY ones. AMI, QUE, ARI, and OLA, single administration distinctly increased the c-Fos expression in each of the PVN cells segregations. QUE induced the highest magnitude of activation of AVP and OXY neurons, while OLA and AMI had only moderate effects. Incontestable variabilities detected in c-Fos expression in PVN AVP and OXY neurons extend the knowledge of selected antipsychotics extra-striatal actions and may also be helpful in a presumption of their possible functional impact., (Copyright © 2021. Published by Elsevier Ltd.)

Rationale: Beneficial effects of aripiprazole on cognition in schizophrenia have been previously reported, but not in recent onset schizophrenia. Cognitive impairments have also been associated with catechol-O-methyltransferase (COMT), methylenetetrahydrofolate reductase (MTHFR), and serotonin transporter (SERT) gene polymorphisms which were earlier implicated in the pathophysiology of schizophrenia., Objectives: This study examined the short-term influence of aripiprazole long-acting injectable (LAI) as well as of COMT, MTHFR, and SERT gene polymorphisms and their interactions on clinical features and cognitive functions in inpatients with recent onset schizophrenia., Methods: This study included 98 inpatients suffering from recent onset schizophrenia diagnosed according to DSM-5 criteria. Three months after initiating aripiprazole LAI, the severity of symptoms was assessed by the Positive and Negative Syndrome Scale (PANSS), while cognitive functions were measured by 5-KOG test for cognition. Genotypes of SERT, MTHFR, and COMT gene were determined by different polymerase chain reaction (PCR) methods., Results: Three-month aripiprazole LAI treatment was associated with a statistically significant change of PANSS total (p<0.001) and subscale scores as well as cognitive parameters of delayed recall (p<0.03), attention (p<0.01), and executive functions in the form of less perseverations (p<0.03), without influencing other examined cognitive functions. However, it significantly influenced composite cognitive score (p<0.02). In regard to the investigated genetic polymorphisms, we established a positive association between the COMT polymorphism (M/M allele carriers) and attention (p<0.01). Additionally, we also established a positive association between the COMT - MTHFR interaction and attention (p<0.02), as well as perseveration item belonging to executive functions (p<0.01). Two other investigated polymorphisms (MTHFR and SERT) were not significantly associated with cognitive indices. Investigated genetic polymorphisms and their interactions were not associated with PANSS scores., Conclusions: Our findings suggest that aripiprazole LAI improves individual cognitive functions in recent onset schizophrenia. Investigated COMT polymorphism (Met/Met genotype), as well as the COMT-MTHFR interaction, were positively associated with attention and executive functioning (perseveration), potentially implying COMT's biomarker potential in terms of cognition in schizophrenia.

Psychotropic medication treatment can cause elevated serum prolactin levels and hyperprolactinaemia (HPRL). Reports have suggested that aripiprazole may decrease elevated prolactin. The aim of this review was to assess evidence for the efficacy of adjunct aripiprazole in the treatment of psychotropic-induced HPRL. PubMed and Google Scholar were searched to identify randomised placebo-controlled trials (RCTs) of adjunct aripiprazole in patients with HPRL attributed to primary psychotropic medications. Data for individual patients from case studies, chart reviews and open-label studies were also identified and assessed. Six RCTs, with a total of 609 patients, met inclusion criteria. Primary psychotropics included risperidone, haloperidol, paliperidone, fluphenazine and loxapine. Reductions in prolactin from baseline, before the introduction of aripiprazole, were significantly greater for adjunct aripiprazole than for adjunct placebo in all the studies (p = 0.04 to p < 0.0001). Normalisation of serum prolactin levels was significantly more likely with adjunct aripiprazole than adjunct placebo (p = 0.028 to p < 0.001, data from three studies). Improvement or resolution of HPRL-related symptoms (galactorrhoea, oligomenorrhoea, amenorrhoea and sexual dysfunction) were reported in three studies. Prolactin levels decreased in all case reports and in both of two open-label studies; they normalised in 30/41 patients (73.2%) in case studies and 12/29 (41.4%) in the open-label studies. Adjunct aripiprazole was statistically significantly effective in treating elevated serum prolactin levels in six RCTs. Evidence from case reports and open-label studies suggests a degree of effectiveness in most patients.

Objective: This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses., Methods: The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation ("acceptability"). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation)., Results: Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone)., Conclusions: LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.

Purpose/background: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation., Methods/procedures: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2)., Findings/results: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES., Implications/conclusions: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Non-response to first-line treatment for major depressive disorder (MDD) is common; for such individuals, quality of life (QoL) impairments can be severe. Identifying predictors of QoL changes may support the management of cases with persistent depressive symptoms despite adequate initial pharmacological/psychological treatment., Objective: The present study aimed to explore predictors of domain-specific QoL improvement following adjunctive aripiprazole treatment for inadequate response to initial antidepressant therapy., Methods: We evaluated secondary QoL outcomes from a CAN-BIND (Canadian Biomarker Integration Network in Depression) study in patients with MDD who did not respond to an initial 8 weeks of escitalopram and received a further 8 weeks of adjunctive aripiprazole (n = 96). Physical, psychological, social, and environmental QoL domains were assessed using the World Health Organization QoL Scale Brief Version (WHOQOL-BREF). Clinician-rated depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Functioning was measured with the Sheehan Disability Scale (SDS). Satisfaction with medication was assessed with a single item from the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Exploratory t-tests were used to describe domain score changes. A hierarchical linear regression was used to explore demographic, clinical, and treatment-related predictors of improvement., Results: Across domains, QoL improved with adjunctive aripiprazole treatment. Satisfaction with medication and MADRS and SDS scores similarly improved. Symptom reduction was a predictor for positive change to physical and psychological QoL; functioning improvements were predictive of increases to all QoL domains. Satisfaction with medication predicted improvements to physical and psychological domains, whereas number of medication trials was a predictor of worsening QoL in the physical domain., Conclusion: The final model explained the most variance in psychological (68%) and physical (67%) QoL. Less variance was explained for environmental (43%) and social QoL (33%), highlighting a need for further exploration of predictors in these domains. Strategies such as functional remediation may have potential to support QoL for individuals with persistent depressive symptoms., Clinical Trials Registry: ClinicalTrials.gov identifier: NCT016557.

Background: Aripiprazole has been linked to cases of problem gambling (PBG), but evidence supporting this association remains preliminary. Additionally, data specific to PBG in individuals with first-episode psychosis (FEP) receiving aripiprazole are limited to a few case reports, even though aripiprazole is widely used among this population that might be especially vulnerable to PBG., Methods: To examine this association, a nested case-control study was conducted in a cohort of 219 patients followed at a FEP program located in the Quebec City, Quebec, Canada, metropolitan area. Fourteen cases meeting the PBG criteria according to the Problem Gambling Severity Index were identified and matched for gender and index date to 56 control subjects., Results: In the univariable conditional logistic regression analysis, the use of aripiprazole was associated with an increased risk of PBG (odds ratio [OR] 15.2; 95% confidence interval [CI] 2.1-670.5). Cases were more likely to have a prior gambling history (either recreational or problematic) than controls at admittance in the program; they were also more frequently in a relationship and employed. After adjustment for age, relationship status, employment and Cluster B personality disorders, the use of aripiprazole remained associated with an increased risk of PBG (OR 8.6 [95% CI 1.5-227.2])., Conclusions: Findings from this study suggest that FEP patients with a gambling history, problematic or not, may be at increased risk of developing PBG when receiving aripiprazole. They also highlight the importance of systematically screening for PBG all individuals with psychotic disorders, as this comorbidity hinders recovery. While the results also add credence to a causal association between aripiprazole and PBG, further prospective studies are needed to address some of the limitations of this present study.

Background: Pharmacogenetics study was added into 2 bioequivalence trials of aripiprazole. The correlation between CYP2D6 polymorphisms and aripiprazole pharmacokinetics (PK) was analyzed. Materials & methods: A total of 140 subjects were included. A total of 26 CYP2D6 gene alleles were detected. The plasma concentration of aripiprazole was measured by liquid chromatography-tandem mass spectrometry. SPSS Statistics 21 was used to analyze the correlation between CYP2D6 polymorphisms and aripiprazole PK parameters. Results: All of the four PK parameters were significantly influenced by CYP2D6 rs1058164 and rs28371699 . t 1/2 and area under the concentration-time curve exhibited significant difference between CYP2D6 extensive metabolizers and intermediate metabolizers. Conclusion: Aripiprazole PK was greatly influenced by CYP2D6 . Attention should be paid to the possible dose adjustment for CYP2D6 intermediate metabolizer population when the drug is used in Chinese patients.

Fifty-one patients suffering an acute episode of schizophrenia and treated with aripiprazole long-acting injectable (ALAI) were chosen to elaborate an observational study in two in-patient units in Spain, in order to examine the effects of early administration during a hospital admission. When treatment with ALAI is administered in the first week of admission (in 31 patients, 60.78%), hospitalization time is significantly reduced, 12.1 days on average. It can be concluded that ALAI is an effective treatment for these patients. Analysis in economic terms and comparison with other LAI antipsychotics are interesting lines for further research., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

The present study pursued the systematic development of a stable solid self-emulsifying drug delivery system (SMEDDS) of an atypical antipsychotic drug, aripiprazole (APZ), which exhibits poor aqueous solubility and undergoes extensive p-glycoprotein efflux and hepatic metabolism. Liquid SMEDDS excipients were selected on the basis of solubility studies, and the optimum ratio of surfactant/co-surfactant was determined using pseudo-ternary phase diagrams. The prepared formulations were subjected to in vitro characterization studies to facilitate the selection of optimum liquid SMEDD formulation containing 30% Labrafil® M 1944 CS, 46.7% Cremophor® EL and 23.3% PEG 400 which were further subjected to solidification using maltodextrin as a hydrophilic carrier. The optimized solid SMEDDS was extensively evaluated for stability under accelerated conditions, dissolution at various pH and pharmacokinetic profile. Solid-state attributes of the optimized solid SMEDDS indicated a marked reduction in crystallinity of APZ and uniform adsorption of liquid SMEDDS. Stability study of the solid SMEDDS demonstrated that the developed formulation retained its stability during the accelerated storage conditions. Both the optimized liquid and solid SMEDDS exhibited enhanced dissolution rate which was furthermore independent of the pH of the dissolution medium. Oral bioavailability studies in Sprague-Dawley rats confirmed quicker and greater extent of absorption with solid SMEDDS as evident from the significant reduction in T max in case of solid SMEDDS (0.83 ± 0.12 h) as compared with commercial tablet (3.33 ± 0.94 h). The results of the present investigation indicated the development of a stable solid SMEDDS formulation of APZ with enhanced dissolution and absorption attributes.

Background: Antipsychotic drugs are well established to alter serum prolactin levels, often resulting in adverse effects including amenorrhea, galactorrhea, osteoporosis, and loss of libido. There is growing preclinical evidence that prolactin-elevating drugs can instigate the progression of precancerous lesions to breast cancer and that genes activated by prolactin are associated with the development and proliferation of breast cancer. Current guides advise a cautious approach (weighing risks and benefits) to the administration of prolactin-elevating antipsychotic drugs in women with a previously detected breast cancer. Aripiprazole is known to be a prolactin-sparing antipsychotic; however, data regarding its effects on prolactin and estrogens in postmenopausal women are lacking., Methods: We examined serum hormone levels in n = 66 women who participated in a randomized, double-blind, placebo-controlled, multicenter trial of aripiprazole (high and low doses) added to an antidepressant in adults older than 60 years. Aripiprazole or placebo tablets were administered for 12 weeks as an augmentation strategy in venlafaxine-treated women. The primary outcomes were the difference in prolactin and estrogen levels., Results: There was no significant effect of aripiprazole treatment on prolactin or estrogen levels, including in models that divided groups into low and high doses: prolactin (P = 0.075), estrone (P = 0.67), and estradiol (P = 0.96)., Conclusions: Aripiprazole addition to an antidepressant did not alter serum estrogens or prolactin. These findings may be relevant in the treatment of some postmenopausal women with depression., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To assess adverse events (AEs) and safety of aripiprazole (ARI) and olanzapine (OLA) treatment., Methods: Twenty-four healthy volunteers receiving five daily oral doses of 10 mg ARI and 5 mg OLA in a crossover clinical trial were genotyped for 46 polymorphisms in 14 genes by qPCR. Drug plasma concentrations were measured by high-performance liquid chromatography tandem mass spectrometry. Blood pressure (BP) and 12-lead electrocardiogram were measured in supine position. AEs were also recorded., Results: ARI decreased diastolic BP on the first day and decreased QTc on the third and fifth day. OLA had a systolic and diastolic BP, heart rate and QTc lowering effect on the first day. Polymorphisms in ADRA2A, COMT, DRD3 and HTR2A genes were significantly associated to these changes. The most frequent adverse drug reactions (ADRs) to ARI were somnolence, headache, insomnia, dizziness, restlessness, palpitations, akathisia and nausea while were somnolence, dizziness, asthenia, constipation, dry mouth, headache and nausea to OLA. Additionally, HTR2A, HTR2C, DRD2, DRD3, OPRM1, UGT1A1 and CYP1A2 polymorphisms had a role in the development of ADRs., Conclusions: OLA induced more cardiovascular changes; however, more ADRs were registered to ARI. In addition, some polymorphisms may explain the difference in the incidence of these effects among subjects., (© 2020 John Wiley & Sons Ltd.)