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BackgroundDifferent effectiveness profiles among antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to impact on long-term outcome. The aim of this study is to compare the clinical effectiveness of olanzapine, risperidone, haloperidol, aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up.MethodFrom February 2001 to January 2011, 2 phases of a prospective, randomized, open-label study were undertaken. A total of 376 first-episode drug-naïve patients were randomly assigned to olanzapine (n = 55), risperidone (n = 63), haloperidol (n = 56), aripiprazole (n = 78), ziprasidone (n = 62), or quetiapine (n = 62) and followed up for 3 years. The primary effectiveness measure was all cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy.ResultsThe overall dropout rate at 3 years reached 20.75%. Treatment discontinuation rates were significantly different among treatment groups (olanzapine = 69.09, risperidone = 71.43, aripiprazole = 73.08%, ziprasidone = 79.03%, haloperidol = 89.28%, and quetiapine = 95.53%) (χ2 = 79.86; P = .000). Statistically significant differences in terms of lack of efficacy, adherence, and tolerability were observed among treatment groups along the 3-year follow-up, determining significant differences in time to all-cause discontinuation (log-rank = 92.240; P = .000). Significant differences between treatments were found in the categories of sleepiness/sedation, increased sleep duration, akinesia, weight gain, ejaculatory dysfunction, extrapyramidal-symptoms, and amenorrhea.ConclusionsOlanzapine, risperidone, and aripiprazole presented advantages for the first-line treatment of first episode of psychosis in terms of effectiveness. Identifying different discontinuation patterns may contribute to optimize treatment selection after first episode of psychosis.ClinicalTrials.gov Identifier: NCT02526030 https://clinicaltrials.gov/show/NCT02526030

In a pragmatic trial involving older persons with treatment-resistant depression, augmentation of existing antidepressants with aripiprazole was better than augmentation with bupropion or a switch to bupropion.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = −17.39 (1.3) ( p  = 0.015) but not aripiprazole augmentation (score change (se) = −14.9 (1.1) ( p  = 0.069) was superior to switch (score change (se) = −13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = −37.79 (2.9) ( p  = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = −42.96 (3.6) ( p  = 0.031) was superior to switch (mean change (se) = −34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression. Trial registration: ClinicalTrials.gov, NCT02977299

RationaleThe 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.ObjectivesWe aimed to explore the effect of AATA discontinuation on the major depressive disorder (MDD) recurrence risk in patients with remitted MDD after AATA.MethodsThis 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.ResultsTwenty-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.ConclusionsDefinitive 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.

Aripiprazole as a long-acting injectable (LAI) is initiated in oral aripiprazole-stabilised patients and needs, after first injection, 14 days supplementation of oral aripiprazole (one-injection start, OIS). Recently, an alternative two-injection start (TIS) was advanced, involving two 400 mg injections with a single 20 mg oral supplementation of aripiprazole. We tested the two regimens in patients with schizophrenia (SCZ, n = 152, 90 men and 62 women) with (SUD+; n = 93) or without (SUD–; n = 59) substance use disorders (SUDs), comparing OIS (n = 66) with TIS (n = 86) and SUD+ vs. SUD–. For 26 patients, we measured weekly for one month, aripiprazole + dehydroaripiprazole (active moiety) levels. Patients were followed for three months after LAI with psychopathology and quality-of-life scales (BPRS, CGI-S, ACES, BIS-11, and WHOQOL). All groups improved in psychopathology with no differences between OSI and TIS and between SCZ–SUD+ and SCZ–SUD–. The TIS group was associated with serum blood levels of the active moiety within the therapeutic window, while the OIS group showed peaks above the window, possibly exposing patients to toxicity. Treatments were well-tolerated. Here we showed no disadvantages for TIS vs. OIS and possibly increased safety. Shifting the initiation of aripiprazole LAIs to the TIS modality may be safe and pharmacokinetically advantageous.

BackgroundThis analysis evaluated potential differences in subjective well-being (SW) among patients with early-phase schizophrenia (SZ) randomized to treatment with either long-acting injectable (LAI) or oral aripiprazole or paliperidone within the “European Long-acting Antipsychotics in Schizophrenia Trial” (EULAST).MethodsA total of 478 patients were followed for up to 19 months. SW was measured using the Subjective Well-being under Neuroleptic Treatment scale (SWN). Linear mixed-effects models assessed treatment differences. Comprehensive analyses included age, sex, symptomatology (Positive and Negative Syndrome Scale [PANSS]), and side effects (Systematic Monitoring of Adverse Events Related to Treatments [SMARTS] and St. Hans rating scale [SHRS] for extrapyramidal syndromes) on SWN changes.ResultsOverall, SW improved over the course of the study. No significant differences emerged between LAI and oral administration (p = 0.1533) or between aripiprazole and paliperidone (p = 0.2008). Similarly, age and sex were not relevant in this regard. In contrast, negative, positive, and affective symptoms (all p < 0.0001) as well as the overall side effect burden (SMARTS sum-score, p < 0.0001) showed significant inverse associations with SW. Certain SHRS subscales correlated with SW in partial models, but associations disappeared in the fully adjusted model.ConclusionsPatients with SZ initiating LAI or oral treatment with aripiprazole or paliperidone reported comparable SW improvements. Findings emphasize that treatment choice should be guided less by formulation or substance and more by individual patient needs, prioritizing symptom control while minimizing adverse effects. A patient-centered approach remains essential to optimize both clinical outcomes and subjective well-being in early-phase SZ.

Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150–300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1–3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5–81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Introduction The use of second-generation antipsychotics (SGA) has been associated with metabolic changes. However, there are differences in the metabolic profile between SGAs. We have previously observed that ziprasidone had a more benign early metabolic profile compared to aripiprazole and quetiapine. However, a long-term follow-up is preferred to detect clinically relevant impairment in metabolic parameters. We aimed to compare the effect of aripiprazole, ziprasidone, and quetiapine on metabolic measures in first-episode non-affective psychosis patients after 1 year of treatment. Material and methods One hundred and sixty-five drug-naïve patients, suffering from a first episode of non-affective psychosis, were randomly assigned to receive quetiapine, ziprasidone, or aripiprazole. Weight and glycemic/lipid parameters were recorded at baseline and after 1 year of treatment. Results After 1 year of antipsychotic treatment, we found significant increments in weight, BMI, total cholesterol, LDL-cholesterol, triglycerides, and the triglyceride/HDL index in the sample as a whole. These changes produced a significant rise in the percentage of patients with obesity, hypercholesterolemia, and hypertriglyceridemia. However, when comparing the differential effect of each antipsychotic medication, we found no significant differences in any of the metabolic parameters between antipsychotics groups after 1 year of treatment. Conclusion We concluded that the antipsychotics studied present similar metabolic profiles. However, the primary exposure to SGAs during the first year of psychosis was associated with significant increases in weight and metabolic parameters, leading to increments in obesity, hypertriglyceridemia, and hypercholesterolemia.

Abstract Background The antipsychotic aripiprazole is mainly metabolized by the cytochrome P450 (CYP) 2D6. The main objective of this study was to evaluate the influence of CYP2D6 phenotypes on aripiprazole plasma levels and treatment duration. Design 466 patients treated with aripiprazole for up to 12 months and with at least one aripiprazole plasma level in steady-state condition were selected. CYP2D6 genotypes and phenoconversion to poor metabolizer status due to strong CYP2D6 inhibition were considered. Aripiprazole plasma level-to-dose ratios and treatment duration up to discontinuation, defined as switching to another psychotropic drug and/or stopping the follow-up, were analyzed using robust linear models and Cox regression, respectively. Akaike variable selection was applied. Results CYP2D6 poor metabolizers (genetically determined n = 19 and phenoconverted, n = 52) showed higher aripiprazole concentration-to-dose (P < .001) and aripiprazole plus dehydroaripiprazole concentration-to-dose (P < .001) ratios when compared to normal metabolizers (n = 255). CYP2D6 extreme metabolizers (ie, poor and ultrarapid metabolizers) had higher risk of treatment discontinuation versus intermediate and normal metabolizers after 3, 6, and 12 months of treatment (HR: 2.08, 1.75, 1.59, respectively; P = .013, P = .019, and P = .047, respectively). For a pharmacogenetic-guided treatment, the number of patients needed to genotype to prevent 1 patient from aripiprazole discontinuation was 15. Conclusion CYP2D6 poor metabolism was associated with increased aripiprazole and aripiprazole plus dehydroaripiprazole concentrations-to-dose. CYP2D6 extreme phenotypes were associated with increased risk of treatment discontinuation over 1 year of treatment. This finding supports the applicability of pre-emptive CYP2D6 genotyping, which is expected to decrease aripiprazole adverse events and inefficacy that would probably lead to treatment discontinuation.

Background Aripiprazole once-monthly (AOM), a long-acting injectable antipsychotic, is increasingly used in managing schizophrenia. However, to date, there has been no disclosure of pharmacokinetic data for AOM long-acting injection in the Chinese population. The present study aimed to evaluate the pharmacokinetics of AOM of Chinese patients with schizophrenia. Methods The single-administration part of the study was single-center and multiple-dose, in which 300/400-mg AOM was administered to 24 patients with schizophrenia. In the multiple-administration part of the study, 400-mg of AOM was administered once every 4 weeks for 20 consecutive weeks to 12 subjects. Pharmacokinetic parameters (e.g., e.g., Cmax, tmax, AUC0-∞, t1/2, and CL/F) were derived via non-compartmental analysis using actual sampling times, with bootstrap-derived confidence intervals for non-normal data. Safety evaluation included monitoring of adverse events (AEs), physical examinations, vital signs, and clinical laboratory tests. Results Following single administration of AOM (300-mg or 400-mg), maximum plasma concentration (C max ) values of aripiprazole were 85.05 ± 42.11 and 175.25 ± 67.84 ng/mL, respectively; median times to achieve C max (t max ) were 816.17 and 588.84 h, respectively; and elimination half-life (t 1/2 ) values were 647.18 ± 234.59 and 547.17 ± 258.48 h, respectively. Following multiple administration of AOM, the C max of aripiprazole was 270.18 ± 113.37 ng/mL, the median t max was118.83, and the t 1/2 was 1138.78 ± 998.77 h. In vivo exposure to aripiprazole increased with the AOM dose. No severe AEs were observed in single- or multiple-administration studies. Conclusions The pharmacokinetics of AOM support its clinical use as a 4-week injectable regimen, with favorable tolerability and safety profiles observed in Chinese patients with schizophrenia. Trial registration ClinicalTrials.gov Identifier: Single-administration NCT03287505 first submitted on 15 May 2017, Multiple-administration NCT03285503 first submitted on 11 Sep 2017.