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BMJ Case Reports May 2017Aripiprazole is an atypical antipsychotic agent commonly used in the management of schizophrenia. Aripiprazole has not been reported to have an association with...
Aripiprazole is an atypical antipsychotic agent commonly used in the management of schizophrenia. Aripiprazole has not been reported to have an association with interstitial lung disease. We describe a case of a 36-year-old woman who began to experience respiratory issues shortly after starting aripiprazole and presented to us 4 years later with progressive exertional shortness of breath. High-resolution CT of the chest showed a bilateral ground glass pattern. Video-assisted thoracoscopy with biopsy revealed alveolar septal thickening and an inflammatory infiltrate composed mainly of lymphocytes, suggestive of chronic hypersensitivity pneumonitis. After discontinuing aripiprazole and initiating prednisolone therapy, the patient's pulmonary symptoms improved. This case highlights that aripiprazole can cause hypersensitivity pneumonitis in susceptible individuals.
Topics: Adult; Alveolitis, Extrinsic Allergic; Antipsychotic Agents; Aripiprazole; Diagnosis, Differential; Female; Humans; Lung Diseases, Interstitial; Schizophrenia; Tomography, X-Ray Computed
PubMed: 28487307
DOI: 10.1136/bcr-2017-219929 -
CNS Drugs Apr 2023Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for gluteal administration every 2 months, currently... (Randomized Controlled Trial)
Randomized Controlled Trial
A Randomized, Open-Label, Multiple-Dose, Parallel-Arm, Pivotal Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Aripiprazole 2-Month Long-Acting Injectable in Adults With Schizophrenia or Bipolar I Disorder.
BACKGROUND
Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a new long-acting injectable antipsychotic formulation for gluteal administration every 2 months, currently being investigated for the treatment of schizophrenia and bipolar I disorder (BP-I). The objectives of this trial were to evaluate the safety and tolerability of Ari 2MRTU 960, and the similarity of aripiprazole plasma concentrations following administration of Ari 2MRTU 960 or aripiprazole once-monthly 400 mg (AOM 400), in adults with schizophrenia or BP-I.
METHODS
This was a 32-week open-label study. Eligible participants were randomized 1:1 to receive Ari 2MRTU 960 every 56 ± 2 days (four injections scheduled) or AOM 400 every 28 ± 2 days (eight injections scheduled). Participants received overlapping oral antipsychotic treatment with the first administration of study drug (there was no oral overlap for participants stabilized on AOM 400). Safety, tolerability, and pharmacokinetics (PK) were evaluated throughout the study. Primary safety endpoints included reported adverse events, injection site reactions, and extrapyramidal symptoms. Primary PK endpoints were plasma concentration of aripiprazole 56 days after the fourth dose of Ari 2MRTU 960 and 28 days after the eighth dose of AOM 400, and area under the concentration-time curve (AUC) from Day 0 to 56 postdose after the fourth dose of Ari 2MRTU 960, or AUC from Day 0 to 28 after the seventh and eighth doses of AOM 400.
RESULTS
Of the 266 participants enrolled (schizophrenia, n = 185; BP-I, n = 81), 132 were randomized to receive Ari 2MRTU 960 and 134 were randomized to receive AOM 400. The majority (66.2%) of participants were male; 72.9% were Black or African American, and mean age was 47.3 years; demographic characteristics and baseline disease characteristics were generally well balanced between groups. Study completion rate was 77.3% in the Ari 2MRTU 960 group and 68.7% in the AOM 400 group. The incidence of treatment-emergent adverse events (TEAEs) was similar between Ari 2MRTU 960 (71.2%) and AOM 400 (70.9%). The most frequently reported TEAEs were increased weight (Ari 2MRTU 960: 22.7%; AOM 400: 20.9%) and injection-site pain (Ari 2MRTU 960: 18.2%; AOM 400: 9.0%). The geometric means ratio (GMR) of aripiprazole plasma concentrations on the last day following the final dosing for Ari 2MRTU 960 versus AOM 400 was 1.011 (90% confidence interval [CI] 0.893-1.145), and the GMR of aripiprazole plasma exposure (area under the concentration-time curve) over the fourth Ari 2MRTU 960 dosing interval versus the seventh and eighth AOM 400 dosing intervals was 1.006 (90% CI 0.851-1.190).
CONCLUSIONS
Ari 2MRTU 960 was generally well tolerated in adults with schizophrenia or BP-I, with a safety profile comparable with that of AOM 400, and aripiprazole exposure equivalent to that with AOM 400 (ClinicalTrials.gov identifier: NCT04030143, registered on 23 July 2019).
Topics: Adult; Male; Humans; Female; Middle Aged; Aripiprazole; Schizophrenia; Antipsychotic Agents; Bipolar Disorder; Injections; Delayed-Action Preparations
PubMed: 36961650
DOI: 10.1007/s40263-023-00996-8 -
Molecular Psychiatry Jan 2022Cholesterol is essential for normal brain function and development. Genetic disruptions of sterol biosynthesis result in intellectual and developmental disabilities.... (Review)
Review
Cholesterol is essential for normal brain function and development. Genetic disruptions of sterol biosynthesis result in intellectual and developmental disabilities. Developing neurons synthesize their own cholesterol, and disruption of this process can occur by both genetic and chemical mechanisms. Many commonly prescribed medications interfere with sterol biosynthesis, including haloperidol, aripiprazole, cariprazine, fluoxetine, trazodone and amiodarone. When used during pregnancy, these compounds might have detrimental effects on the developing brain of the offspring. In particular, inhibition of dehydrocholesterol-reductase 7 (DHCR7), the last enzyme in the biosynthesis pathway, results in accumulation of the immediate cholesterol precursor, 7-dehydrocholesterol (7-DHC). 7-DHC is highly unstable, giving rise to toxic oxysterols; this is particularly pronounced in a mouse model when both the mother and the offspring carry the Dhcr7 genotype. Studies of human dermal fibroblasts from individuals who carry DCHR7 single allele mutations suggest that the same gene*medication interaction also occurs in humans. The public health relevance of these findings is high, as DHCR7-inhibitors can be considered teratogens, and are commonly used by pregnant women. In addition, sterol biosynthesis inhibiting medications should be used with caution in individuals with mutations in sterol biosynthesis genes. In an age of precision medicine, further research in this area could open opportunities to improve patient and fetal/infant safety by tailoring medication prescriptions according to patient genotype and life stage.
Topics: Animals; Aripiprazole; Brain; Cholesterol; Female; Humans; Mice; Neurons; Oxidoreductases Acting on CH-CH Group Donors; Pregnancy
PubMed: 33820938
DOI: 10.1038/s41380-021-01074-5 -
Schizophrenia Bulletin Jan 2024Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia. (Meta-Analysis)
Meta-Analysis
Long-Acting Injectable Second-Generation Antipsychotics vs Placebo and Their Oral Formulations in Acute Schizophrenia: A Systematic Review and Meta-Analysis of Randomized-Controlled-Trials.
BACKGROUND AND HYPOTHESIS
Long-acting injectable antipsychotic drugs (LAIs) are mainly used for relapse prevention but could also be advantageous for acutely ill patients with schizophrenia.
STUDY DESIGN
We conducted a systematic review and meta-analysis of randomized-controlled-trials (RCTs) comparing the second-generation long-acting injectable antipsychotics (SGA-LAIs) olanzapine, risperidone, paliperidone, and aripiprazole with placebo or their oral counterparts in acutely ill patients with schizophrenia. We analyzed 23 efficacy and tolerability outcomes, with the primary outcome being overall symptoms of schizophrenia. The results were obtained through random effects, pairwise meta-analyses, and subgroup tests. The study quality was assessed using the Cochrane-Risk-of-Bias-Tool version-1.
STUDY RESULTS
Sixty-six studies with 16 457 participants were included in the analysis. Eleven studies compared second-generation long-acting injectable antipsychotics (SGA-LAIs) with a placebo, 54 compared second-generation oral antipsychotics (SGA-orals) with a placebo, and one compared an SGA-LAI (aripiprazole) with its oral formulation. All 4 SGA-LAIs reduced overall symptoms more than placebo, with mean standardized differences of -0.66 (95% CI: -0.90; -0.43) for olanzapine, -0.64 (-0.80; -0.48) for aripiprazole, -0.62 (-0.76; -0.48) for risperidone and -0.42 (-0.53; -0.31) for paliperidone. The side-effect profiles of the LAIs corresponded to the patterns known from the oral formulations. In subgroup tests compared to placebo, some side effects were less pronounced under LAIs than under their oral formulations.
CONCLUSIONS
SGA-LAIs effectively treat acute schizophrenia. Some side effects may be less frequent than under oral drugs, but due to the indirect nature of the comparisons, this finding must be confirmed by RCTs comparing LAIs and orals head-to-head.
Topics: Humans; Antipsychotic Agents; Paliperidone Palmitate; Aripiprazole; Olanzapine; Risperidone; Delayed-Action Preparations; Schizophrenia
PubMed: 37350486
DOI: 10.1093/schbul/sbad089 -
Biology Direct Aug 2023Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder...
Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent 'third'-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~ 5 to 15% of patients. However, it is not fully understood how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adult Drosophila melanogaster consistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.
Topics: Animals; Mice; Aripiprazole; Antipsychotic Agents; Depressive Disorder, Major; Drosophila melanogaster; Electron Transport
PubMed: 37528429
DOI: 10.1186/s13062-023-00375-9 -
CNS Drugs Sep 2016Both the US FDA and the European Medicines Agency (EMA) have approved aripiprazole for use in adolescents for specific indications. Given the assumed favorable... (Review)
Review
BACKGROUND
Both the US FDA and the European Medicines Agency (EMA) have approved aripiprazole for use in adolescents for specific indications. Given the assumed favorable side-effect profile of aripiprazole, its use in children and adolescents has increased for both official and off-label indications (anxiety disorders, eating disorders, personality disorders). However, several cases of children and adolescents with new-onset extrapyramidal symptoms (EPS) after commencing treatment with aripiprazole have been reported, and a more systematic appraisal of this possible risk is lacking.
OBJECTIVE
We conducted a systematic review and a meta-analysis to assess the evidence for acute EPS (acute dystonia, akathisia, Parkinsonism) associated with the use of aripiprazole in children and adolescents.
METHOD
We searched the MEDLINE and Embase databases (2003-10 April 2016) for clinical trials in pediatric patients (aged 0-18 years) using the keywords 'aripiprazole' (regardless of the formulation) and 'extrapyramidal symptoms'. We evaluated the abstracts of papers using the following exclusion criteria: (1) study design: case report, letter to the editor, editorial, or poster presentation data; (2) unrelated PICOS (population, intervention, comparators, outcomes, study) structure. We performed a meta-analysis, in which we used effect sizes with 95 % confidence intervals (CIs). To examine the homogeneity of the effect size distribution, we used a Q-statistic. When we observed heterogeneity in effect sizes, we assessed the possible influence of moderator variables (age and sex, mean dose, study duration, and method of measuring EPS incidence) and evaluated the suitability of either a fixed or a random model. Finally, we assessed the incidence of EPS in children and adolescents treated with aripiprazole compared with placebo.
RESULTS
An initial search via PubMed and Embase yielded 328 hits. A manual search of the reference lists of review papers revealed seven additional relevant articles. We included 41 studies, with 2114 pediatric patients, in the meta-analysis. For the analysis of the mean incidence of EPS, data were provided by 24 studies, with a total of 1446 pediatric patients. Meta-analysis revealed a mean EPS incidence of 17.1 % (95 % CI 0.128-0.223). In terms of the incidence of various extrapyramidal side effects, overall, no significant effects of age, sex, mean dose, study duration, or measuring method could be demonstrated. The side effects 'EPS', 'parkinsonism', and 'tremor' were significantly more common in children and adolescents treated with aripiprazole than in those treated with placebo.
CONCLUSION
Our meta-analysis provides evidence for a non-negligible incidence of acute EPS in children and adolescents treated with aripiprazole. Although the study has several limitations and further investigation is needed, these findings may help clinicians make more balanced treatment choices and more closely monitor the use of this drug in youth.
Topics: Adolescent; Age Factors; Antipsychotic Agents; Aripiprazole; Basal Ganglia Diseases; Child; Dyskinesia, Drug-Induced; Humans; Incidence
PubMed: 27395403
DOI: 10.1007/s40263-016-0367-y -
Current Psychiatry Reports Nov 2023Despite clear evidence that sex differences largely impact the efficacy and tolerability of antipsychotic medication, current treatment guidelines for schizophrenia... (Review)
Review
PURPOSE OF REVIEW
Despite clear evidence that sex differences largely impact the efficacy and tolerability of antipsychotic medication, current treatment guidelines for schizophrenia spectrum disorders (SSD) do not differentiate between men and women. This review summarizes the available evidence on strategies that may improve pharmacotherapy for women and provides evidence-based recommendations to optimize treatment for women with schizophrenia.
RECENT FINDINGS
We systematically searched PubMed and Embase for peer-reviewed studies on three topics: (1) sex differences in dose-adjusted antipsychotic serum concentrations, (2) hormonal augmentation therapy with estrogen and estrogen-like compounds to improve symptom severity, and (3) strategies to reduce antipsychotic-induced hyperprolactinemia. Based on three database studies and one RCT, we found higher dose-adjusted concentrations in women compared to men for most antipsychotics. For quetiapine, higher concentrations were specifically found in older women. Based on two recent meta-analyses, both estrogen and raloxifene improved overall symptomatology. Most consistent findings were found for raloxifene augmentation in postmenopausal women. No studies evaluated the effects of estrogenic contraceptives on symptoms. Based on two meta-analyses and one RCT, adjunctive aripiprazole was the best-studied and safest strategy for lowering antipsychotic-induced hyperprolactinemia. Evidence-based recommendations for female-specific pharmacotherapy for SSD consist of (1) female-specific dosing for antipsychotics (guided by therapeutic drug monitoring), (2) hormonal replacement with raloxifene in postmenopausal women, and (3) aripiprazole addition as best evidenced option in case of antipsychotic-induced hyperprolactinemia. Combining these strategies could reduce side effects and improve outcome of women with SSD, which should be confirmed in future longitudinal RCTs.
Topics: Female; Humans; Male; Aged; Antipsychotic Agents; Schizophrenia; Aripiprazole; Hyperprolactinemia; Raloxifene Hydrochloride; Estrogens
PubMed: 37864676
DOI: 10.1007/s11920-023-01460-6 -
PloS One 2023Second-generation antipsychotics (SGAs) are frequently prescribed for the treatment of resistant anorexia nervosa. However, few clinical trials have been conducted so...
INTRODUCTION
Second-generation antipsychotics (SGAs) are frequently prescribed for the treatment of resistant anorexia nervosa. However, few clinical trials have been conducted so far and no pharmacological treatment has yet been approved by the Food and Drug Administration. The aim of this paper is to conduct a systematic scoping review exploring the effectiveness and safety of atypical antipsychotics in anorexia nervosa (AN).
METHOD
We conducted a systematic scoping review of the effectiveness and tolerability of SGAs in the management of AN. We included articles published from January 1, 2000, through September 12, 2022 from the PubMed and PsycInfo databases and a complementary manual search. We selected articles about adolescents and adults treated for AN by four SGAs (risperidone, quetiapine, aripiprazole or olanzapine). This work complies with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for scoping reviews (PRIMA-ScR) and was registered in the Open Science Framework (OSF) repository.
RESULTS
This review included 55 articles: 48 assessing the effectiveness of SGAs in AN and 7 focusing only on their tolerability and safety. Olanzapine is the treatment most frequently prescribed and studied with 7 randomized double-blind controlled trials. Other atypical antipsychotics have been evaluated much less often, such as aripiprazole (no randomized trials), quetiapine (two randomized controlled trials), and risperidone (one randomized controlled trial). These treatments are well tolerated with mild and transient adverse effects in this population at particular somatic risk.
DISCUSSION
Limitations prevent the studies both from reaching conclusive, reliable, robust, and reproducible results and from concluding whether or not SGAs are effective in anorexia nervosa. Nonetheless, they continue to be regularly prescribed in clinical practice. International guidelines suggest that olanzapine and aripiprazole can be interesting in severe or first-line resistant clinical situations.
Topics: Adult; Adolescent; Humans; Antipsychotic Agents; Olanzapine; Risperidone; Aripiprazole; Quetiapine Fumarate; Anorexia Nervosa; Benzodiazepines; Randomized Controlled Trials as Topic
PubMed: 36928656
DOI: 10.1371/journal.pone.0278189 -
Psychological Medicine Dec 2023Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is...
BACKGROUND
Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is known about the drugs' mortality risk or whether serious mental illness (SMI) diagnosis or race/ethnicity modify these effects.
METHODS
Authors created a retrospective cohort of non-elderly adults with SMI initiating monotherapy with an SGA (olanzapine, quetiapine, risperidone, and ziprasidone, aripiprazole) or haloperidol during 2008-2013. Three-year diabetes incidence or all-cause death risk differences were estimated between each drug and aripiprazole, the comparator, as well as effects within SMI diagnosis and race/ethnicity. Sensitivity analyses evaluated potential confounding by indication.
RESULTS
38 762 adults, 65% White and 55% with schizophrenia, initiated monotherapy, with haloperidol least (6%) and quetiapine most (26·5%) frequent. Three-year mortality was 5% and diabetes incidence 9.3%. Compared with aripiprazole, haloperidol and olanzapine reduced diabetes risk by 1.9 (95% CI 1.2-2.6) percentage points, or a 18.6 percentage point reduction relative to aripiprazole users' unadjusted risk (10.2%), with risperidone having a smaller advantage. Relative to aripiprazole users' unadjusted risk (3.4%), all antipsychotics increased mortality risk by 1.1-2.2 percentage points, representing 32.4-64.7 percentage point increases. Findings within diagnosis and race/ethnicity were generally consistent with overall findings. Only quetiapine's higher mortality risk held in sensitivity analyses.
CONCLUSIONS
Haloperidol's, olanzapine's, and risperidone's lower diabetes risks relative to aripiprazole were not robust in sensitivity analyses but quetiapine's higher mortality risk proved robust. Findings expand the evidence on antipsychotics' risks, suggesting a need for caution in the use of quetiapine among individuals with SMI.
Topics: Adult; Humans; Middle Aged; Antipsychotic Agents; Olanzapine; Risperidone; Quetiapine Fumarate; Aripiprazole; Haloperidol; Retrospective Studies; Benzodiazepines; Schizophrenia; Diabetes Mellitus
PubMed: 37753625
DOI: 10.1017/S0033291723001502 -
Molecular Psychiatry Sep 2023This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia...
This mirror-image study aimed to evaluate the real-life effectiveness of long-acting injectable antipsychotics (LAI) in schizophrenia. Patients with schizophrenia initiating LAIs January 2015-December 2016 were enrolled from the French National Health Data System (SNDS). Standardized mean differences (SMD > 0.1 deemed clinically significant) were calculated for psychiatric healthcare resource utilization measures assessed one year before (during oral AP treatment) and one year after LAI initiation. LAI effectiveness was analyzed overall and by age group, gender and compliance to oral AP, defined as exposure to an AP for at least 80% of the year before LAI initiation. 12,373 patients were included. LAIs were more frequently initiated in men (58.1%), young (18-34 years, 42.0%) and non-compliant (63.7%) patients. LAI initiation was effective in reducing the number and duration of psychiatric hospitalizations and psychiatric emergency department (ED) admissions in non-compliant patients (SMD = -0.19, -0.26 and -0.12, respectively), but not in compliant patients. First-generation LAIs, paliperidone and aripiprazole LAIs reduced psychiatric hospitalizations (SMD = -0.20, -0.24, -0.21, respectively) and ED admissions (SMD = -0.15, -0.13, -0.15, respectively). No differences in effectiveness were found for age or gender. In compliant patients, only aripiprazole LAI reduced the number of psychiatric hospitalizations (SMD = -0.13). Risperidone and paliperidone LAIs increased hospitalization duration (SMD = 0.15 and 0.18, respectively). The prescription of LAIs (except risperidone) should be recommended in all non-compliant patients, even in women and patients aged 35 or older. The lower frequency of administration of LAIs than of oral APs may improve compliance and hence reduce the risk of relapse. Aripiprazole LAI may represent a treatment of choice for compliant patients that should be further investigated.
Topics: Male; Humans; Female; Antipsychotic Agents; Schizophrenia; Risperidone; Paliperidone Palmitate; Aripiprazole; Injections; Administration, Oral
PubMed: 37479781
DOI: 10.1038/s41380-023-02175-z