Challenging pharmacotherapy management of a psychotic disorder due to a delicate pharmacogenetic profile and drug-drug interactions: a case report and literature review.

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.

Initiating Aripiprazole Lauroxil: Post Hoc Analysis of Safety and Tolerability of 1-Day and 21-Day Regimens.

Objective: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic, has 2 initiation options: 1-day (AL NanoCrystal Dispersion [ALNCD] 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 ALNCD 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.

Medication burden reduction and early clinical benefit through aripiprazole once monthly in schizophrenia patients with polypharmacy.

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.

Long-term metabolic side effects of second-generation antipsychotics in Chinese patients with schizophrenia: A within-subject approach with modelling of dosage effects.

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.

Remission in schizophrenia spectrum disorders: A randomized trial of amisulpride, aripiprazole and olanzapine.

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.

Aripiprazole dose associations with metabolic adverse effect: Results from a longitudinal study.

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.

Bioequivalence prediction with small-scale biphasic dissolution and simultaneous dissolution-permeation apparatus-An aripiprazole case study.

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 (Cmax) 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 Cmax 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.

Aripiprazole for treating delirium: A systematic review-Is it a valid yet understudied treatment?

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.

Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2-Month Ready-to-Use Long-Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder.

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.

Antipsychotic medications and sleep problems in patients with schizophrenia.

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.

Dual Atypical Antipsychotics in Treatment-Resistant Schizophrenia: A Correctional Case Report and Review of Literature.

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.

Comparative Efficacy of Dopamine Partial Agonists by Doses for Treatment-Resistant Depression: A Systematic Review and Dose-Response Model-Based Network Meta-analysis.

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.

Switching from paliperidone palmitate 3-monthly long-acting injection to oral aripiprazole in a pregnant woman with schizophrenia: a case report and short review.

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.

Impact of Preoperative Aripiprazole on Postoperative Analgesia in Laparoscopic Hysterectomy: A Randomized Double-blind Placebo-controlled Trial.

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.

Impact of aripiprazole discontinuation in remitted major depressive disorder: a randomized placebo-controlled trial.

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.

Long-acting second-generation injectable antipsychotics for the maintenance treatment of bipolar disorder: a narrative review.

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.

A comparison of recurrence rates after discontinuation of second-generation antipsychotic long-acting injectable versus corresponding oral antipsychotic in the maintenance treatment of bipolar disorder: A systematic review.

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.

Optimal dose of aripiprazole for augmentation therapy of antidepressant-refractory depression: preliminary findings based on a systematic review and dose-effect meta-analysis.

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.