Benzodiazepine use during cariprazine treatment in acute schizophrenia
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ABSTRACT: Introduction
Although antipsychotics are first-line treatments for schizophrenia, benzodiazepines (BZDs) are often used as concomitant medications in acutely exacerbated patients due to their anxiolytic and sedative effects. Cariprazine (CAR), a D3-preferring dopamine D2/D3 partial agonist antipsychotic, has been examined in many clinical studies for the treatment of acute schizophrenia, with and without benzodiazepines. Objectives
To delineate the effects of benzodiazepine-use during cariprazine treatment in acute schizophrenia. Methods
Pooled data of cariprazine-treated (1.5-6mg/day) and
SUBMITTER: Correll C
PROVIDER: S-EPMC9564837 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Project description:Cariprazine is an oral antipsychotic approved in the US and EU for the treatment of schizophrenia. Cariprazine differs from other antipsychotics in that it is a dopamine D3- and D2-receptor partial agonist, with tenfold higher affinity for D3 receptors than for D2 receptors. Cariprazine is metabolized in two steps by CYP3A4 to didesmethyl-cariprazine (DDCAR). DDCAR has a long half-life of 1-3 weeks and is the predominant circulating active moiety. Efficacy and safety in persons with acute schizophrenia were assessed in four similarly designed, short-term, randomized, placebo-controlled clinical trials in nonelderly adults, with three studies considered positive and yielding a number needed to treat vs placebo for response (change from baseline ?30% in Positive and Negative Syndrome Scale total score) of ten for the approved dose range of cariprazine 1.5-6 mg/day. The most common adverse reactions were extrapyramidal symptoms (15% and 19% for 1.5-3 and 4.5-6 mg/day, respectively, vs 8% for placebo) and akathisia (9% and 12.5% for 1.5-3 and 4.5-6 mg/day, respectively, vs 4% for placebo). For the approved dose range, rates of discontinuation because of an adverse event were lower overall for patients receiving cariprazine vs placebo (9% vs 12%). Weight and metabolic profile appear favorable. Cariprazine does not increase prolactin levels or prolong the electrocardiographic QT interval. Cariprazine has also been found to be effective for the maintenance treatment of schizophrenia by delaying time to relapse when compared with placebo (HR 0.45). A 26-week randomized clinical trial evidenced superiority of cariprazine over risperidone for the treatment of predominantly negative symptoms in patients with schizophrenia. Cariprazine is also approved in the US for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and is being studied for the treatment of bipolar I depression and major depressive disorder.
| S-EPMC6179724 | biostudies-literature
Project description:Schizophrenia is characterized by positive, negative, cognitive, and affective symptoms. Antipsychotic medications, which work by blocking the dopamine D2 receptor, are the foundation of pharmacotherapy for schizophrenia to control positive symptoms. Cariprazine is a dopamine D3 receptor-preferring D3/D2 partial agonist antipsychotic that is approved for the treatment of schizophrenia (USA and European Union [EU]) and manic and depressive episodes associated with bipolar I disorder (USA). Partial agonist agents have a lower intrinsic activity at receptors than full agonists, so they act as either functional agonists or functional antagonists depending on the surrounding neurotransmitter environment. Beyond efficacy against positive symptoms, the unique D3-preferring partial agonist pharmacology of cariprazine suggests potential advantages against negative symptoms, and cognitive and functional impairment, which are challenging to treat. The efficacy and safety of cariprazine in adult patients with schizophrenia have been demonstrated in four short-term randomized, double-blind, placebo-controlled clinical trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study versus the active comparator risperidone. Additional post hoc investigations have supported efficacy across individual symptoms and domains in schizophrenia, as well as in diverse areas of interest including cognition, functioning, negative symptoms, hostility, and global well-being. This comprehensive review of cariprazine summarizes its pharmacologic profile, clinical trial evidence, and post hoc investigations. Collective evidence suggests that the pharmacology of cariprazine may offer broad-spectrum efficacy advantages for patients with schizophrenia, including effects against difficult-to-treat negative and cognitive symptoms, as well as functional improvements. Cariprazine was generally safe and well tolerated in patients with short- and long-term exposure and no new safety concerns were associated with longer-duration treatment.Trial registration ClinicalTrials.gov identifiers, NCT00404573, NCT00694707, NCT01104766, NCT01104779, NCT01412060, NCT00839852, NCT01104792.
| S-EPMC8279990 | biostudies-literature
Project description:Purpose of reviewAntipsychotics are the standard of care when it comes to the treatment of Schizophrenia, and they are often used in Bipolar as well. Their use can come with adverse effects such as extrapyramidal movements, metabolic complications as well as cardiovascular complications such as a prolonged QT interval. Treatment for these side effects ranges from the treatment of the complications up to the cessation of the medication, which could come at the expense of the user's stability. Both schizophrenia and bipolar disorder have an increased risk of suicide and increased morbidity. The purpose of this review presents the background, evidence, and indications for the use of the new second-generation antipsychotic Cariprazine, which has a primary function as a D3 and D2 partial agonist, with higher selectivity for the D3 receptor type.Recent findingsSchizophrenia is currently teated by dopamine antagonists and/or 5HT modulators, each with their own set of side effects. Bipolar disorder is mostly treated with mood stabilizers. Studies looking at the efficacy and safety of cariprazine have shown in two phase II trials and phase III trials the decrease in PANSS scores in schizophrenia. The most common adverse effects were akathisia, insomnia, constipation, and other extrapyramidal side effects. A unique side effect of Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following daily oral administration for 13 weeks and/or 1 year and retinal degeneration in rats following daily oral administration for 2 years. Another study showed that cariprazine had significant efficacy in preventing relapse in patients with schizophrenia. The time to the loss of sustained remission was significantly longer (P = .0020) for cariprazine compared to placebo (hazard ratio = 0.51) during the double-blind treatment. 60.5% of patients treated with cariprazine and 34.9% of patients treated with placebo sustained remission through the final visit (odds ratio [OR] = 2.85; P = .0012; number needed to treat [NNT] = 4. Another Phase IIIb study looked at negative symptoms and used the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), and it found that the use of cariprazine, from baseline to week 26, led to a greater least-squares mean change in PANSS-FSNS than did risperidone. Another study looked at the quality of life years with the treatment of cariprazine and showed those treated with cariprazine had superior quality of life compared to those treated with risperidone. In terms of bipolar disorder, it showed a decrease in depressive symptoms as measured by decreased MADRs scores with a dose of 3.0mg/day. A phase II study looked at the use of cariprazine in mania or mix states and showed cariprazine significantly decreased YMRS scores compared to placebo, least-square mean difference of -6.1 (p < 0.001). The metabolic parameters demonstrated comparable changes except for fasting glucose in which cariprazine was associated with elevations in glucose levels compared to placebo (p < 0.05). Another phase III study showed significant differences in YMRS total score mean change between cariprazine versus placebo-treated group. Changes in metabolic profiles in all mentioned studies were minimal.SummaryCariprazine, in recent studies, has shown some promise in being able to treat both bipolar disorder in manic, depressed, and mixed states as well as schizophrenia. Side effects noted as adverse events in these studies are similar in profile to the medications that were developed in the past. With better relapse prevention, cariprazine could be a reasonable alternative clozapine.
| S-EPMC7511151 | biostudies-literature
Project description:ImportanceIncreased use of benzodiazepines has resulted in increasing rates of misuse and adverse effects associated with these drugs. Little is known about the initial exposure and source of benzodiazepines among those who use them persistently.ObjectiveTo examine the frequency of use and persistent use of benzodiazepines among patients undergoing major and minor surgical procedures.Design, setting, and participantsThis cohort study included 2 509 599 adult patients who underwent 1 of 11 common surgical procedures in the United States from 2009 to 2017 and were recorded in the MarketScan database. The rates of perioperative and persistent benzodiazepine use were examined in benzodiazepine-naive patients. Data analysis was conducted from July to November 2020.Main outcomes and measuresReceipt of a perioperative benzodiazepine prescription and persistent use (ie, fill of a second prescription 90-180 days after surgery) among those who received a benzodiazepine perioperatively.ResultsAmong 2 509 599 included patients, the mean (SD) age was 54.4 (15.3) years, and 1 596 137 (63.6%) were women. Perioperative benzodiazepine use was noted in 63 931 patients (2.6%). The median (interquartile range) benzodiazepine supply was 10 (5-23) days. Among benzodiazepine-naive patients prescribed a perioperative benzodiazepine, the rate of persistent benzodiazepine use was 19.5% (95% CI, 19.2%-19.8%). During the 90 to 180-day period after surgery, 7013 of 12 468 patients (56.2%) received 1 prescription for benzodiazepines while 5455 (43.8%) received 2 or more prescriptions. Among patients prescribed a benzodiazepine, persistent use was more common in Medicaid recipients (vs patients with commercial insurance: adjusted rate ratio [aRR], 1.29; 95% CI, 1.03-1.62), patients 70 years or older (vs those aged 40-49 years: aRR, 1.14; 95% CI, 1.05-1.23), in women (vs men: aRR, 1.10; 95% CI, 1.06-1.15), in patients with more medical comorbidities (eg, Elixhauser comorbidity score ≥3 vs 0: aRR, 1.11; 95% CI, 1.04-1.19), and in those with diagnoses of anxiety, depression, insomnia or substance use disorder (eg, with vs without anxiety: aRR, 1.43; 95% CI, 1.37-1.50).Conclusions and relevanceIn this study, a relatively small percentage of surgical patients were prescribed benzodiazepines in the perioperative period; however, 1 in 5 of these patients went on to persistent benzodiazepine use.
| S-EPMC8176328 | biostudies-literature
Project description:The aim of our study was to evaluate the efficacy of cariprazine augmentation of clozapine in treatment-resistant schizophrenia in a retrospective chart review. Among 916 medical records of schizophrenia patients, we identified 12 individuals treated with a combination of those drugs for a duration of 3-60 weeks [median 32 (10-40)]. Clinical Global Impression-Improvement (CGI-I) scores were used to measure the treatment response between the introduction of cariprazine augmentation of clozapine and the last point of observation. The majority of the patients presented treatment response (9/12 patients, 75%) after 4-16 weeks of therapy [median 6 (4-12)]. Treatment was associated with the decrease in positive, negative, affective, and anxiety symptom severity, as well as improvement of patient global functioning. One patient discontinued the treatment due to side effects (akathisia), and two patients halted the therapy due to the exacerbation of psychotic symptoms. Our study presents a thorough clinical description of the largest number of treatment-resistant schizophrenia patients medicated using cariprazine augmentation of clozapine in a "real-world" setting. Our results suggest that the use of this combination may lead to the improvement in a broad range of symptoms of patients with this condition.
| S-EPMC10794393 | biostudies-literature
Project description:After over a hundred years of research, the question whether the symptoms of schizophrenia are rather trait-like (being a relatively stable quality of individuals) or state-like (being substance to change) is still unanswered. To assess the trait and the state component in patients with acute schizophrenia, one group receiving antipsychotic treatment, the other not. Data from four phase II/III, 6-week, randomized, double-blind, placebo-controlled trials of similar design that included patients with acute exacerbation of schizophrenia were pooled. In every trial, one treatment group received a third-generation antipsychotic, cariprazine, and the other group placebo. To assess symptoms of schizophrenia, the Positive and Negative Symptom Scale (PANSS) was applied. Further analyses were conducted using the five subscales as proposed by Wallwork and colleagues. A latent state-trait (LST) model was developed to estimate the trait and state components of the total variance of the observed scores. All symptom dimensions behaved more in a trait-like manner. The proportions of all sources of variability changed over the course of the observational period, with a bent around weeks 3 and 4. Visually inspected, no major differences were found between the two treatment groups regarding the LST structure of symptom dimensions. This high proportion of inter-individual stability may represent an inherent part of symptomatology that behaves independently from treatment status.
| S-EPMC11362189 | biostudies-literature
Project description:Background and hypothesisComplex schizophrenia symptoms were recently conceptualized as interactive symptoms within a network system. However, it remains unknown how a schizophrenia network changed during acute antipsychotic treatment. The present study aimed to evaluate the interactive change of schizophrenia symptoms under seven antipsychotics from individual time series.Study designData on 3030 schizophrenia patients were taken from a multicenter randomized clinical trial and used to estimate the partial correlation cross-sectional networks and longitudinal random slope networks based on multivariate multilevel model. Thirty symptoms assessed by The Positive and Negative Syndrome Scale clustered the networks.Study resultsFive stable communities were detected in cross-sectional networks and random slope networks that describe symptoms change over time. Delusions, emotional withdrawal, and lack of spontaneity and flow of conversation featured as central symptoms, and conceptual disorganization, hostility, uncooperativeness, and difficulty in abstract thinking featured as bridge symptoms, all showing high centrality in the random slope network. Acute antipsychotic treatment changed the network structure (M-test = 0.116, P < .001) compared to baseline, and responsive subjects showed lower global strength after treatment (11.68 vs 14.18, S-test = 2.503, P < .001) compared to resistant subjects. Central symptoms and bridge symptoms kept higher centrality across random slope networks of different antipsychotics. Quetiapine treatment network showed improvement in excitement symptoms, the one featured as both central and bridge symptom.ConclusionOur findings revealed the central symptoms, bridge symptoms, cochanging features, and individualized features under different antipsychotics of schizophrenia. This brings implications for future targeted drug development and search for pathophysiological mechanisms.
| S-EPMC9810008 | biostudies-literature
Project description:Abstract Background: Cariprazine (CAR) is a D3/D2 receptor partial agonist antipsychotic approved for treatment of adults with acute exacerbation of schizophrenia. Many patients with schizophrenia display a progressive worsening of symptomatology, a process that has the potential to impede treatment response. These post hoc analyses were performed to evaluate CAR efficacy in subsets of patients at different stages of disease progression. Methods: Data were pooled from 3 randomized, 6-week, double-blind, placebo (PBO)-controlled Phase II/III trials of CAR efficacy and safety in patients with schizophrenia (NCT01104766, NCT01104779, NCT00694707). For this post hoc analysis, data were grouped according to number of previous episodes (<5, 5–10, >10), duration of schizophrenia in years (≤5.1, 5.2–13.4, >13.4), or number of previous psychiatric hospitalizations (≤2, 3–6, >6). Efficacy outcomes were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score, PANSS Positive and Negative subscales, and Clinical Global Impression of Severity scale (CGI-S); data were analyzed using a mixed-effects model for repeated measures. Results: At all stages of illness, patients treated with CAR (n = 1024) showed a significantly greater improvement on PANSS and CGI-S total scores than did those treated with PBO (n = 442). Compared with PBO, CAR significantly reduced mean PANSS total score in patients regardless of number of previous episodes (<5: least squares mean difference [LSMD] −8.0, P < .0001; 5–10: LSMD −6.3, P = .0018; >10: LSMD −9.2, P = .0001), duration of schizophrenia (≤5.1 years: LSMD −7.6, P = .0002; 5.2–13.4 years: LSMD −8.5, P < .0001; >13.4 years: LSMD −7.6, P = .0003), or number of previous psychiatric hospitalizations (0–2: LSMD −5.6, P = .0030; 3–6: LSMD −9.7, P < .0001; >6: LSMD −9.6, P < .0001). CAR also significantly reduced mean CGI-S overall score relative to PBO in patients regardless of number of previous episodes (<5: LSMD −0.4, P = .0005; 5–10: LSMD −0.2, P = .0385; >10: LSMD −0.7, P < .0001), duration of schizophrenia (≤5.1 years: LSMD −0.3, P = .0041; 5.2–13.4 years: LSMD −0.5, P < .0001; >13.4 years: LSMD −0.3, P = .0017), or number of previous psychiatric hospitalizations (0–2: LSMD −0.3, P = .0133; 3–6: LSMD −0.4, P < .0001; >6: LSMD −0.6, P < .0001). Similar results were observed on the PANSS Positive and Negative subscales. Conclusion: Cariprazine was efficacious in the overall adult population. When stratified by number of previous episodes experienced, duration of schizophrenia, or number of previous psychiatric hospitalizations, no consistent trends in magnitude of efficacy were evident; however, cariprazine efficacy in patients at the later stages of illness was similar to or greater than that in patients at earlier stages, suggesting that cariprazine is effective in the treatment of schizophrenia in adults regardless of the stage of illness progression.
| S-EPMC5475603 | biostudies-literature
Project description:Real-world evidence fills in an important gap by providing data on the effectiveness and tolerability of new medications in everyday patients. In this data collection form a Spanish hospital, the effectiveness and tolerability of cariprazine were evaluated in 14 patients who were admitted to the hospital due to an acute episode of schizophrenia or schizoaffective disorder. The collected data included demographic characteristics, history of disorder and previous treatment, and details of cariprazine therapy such as dosing, side effects and measurements of effectiveness via scales. Difference between admission and discharge on the Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression-Severity (CGI-S) scale scores were evaluated using the Wilcoxon Signed-Rank test. Significant improvement was detected in nearly all patients (one patient dropped out) as measured by the BPRS Total, Negative symptom, Positive symptom, and Hostility scores. At admission, patients were markedly-moderately ill and at discharge the severity was reduced to borderline ill and normal according to the CGI-S. The CGI-Improvement scale also indicated very much and much improvement at discharge. Importantly, patients left the hospital with high doses of cariprazine, i.e., 7.5 mg/day or even 9.0 mg/day, but this did not cause safety problems; cariprazine well-tolerated as only a few patients experienced side effects such as akathisia. The results provide novel evidence regarding the tolerability and effectiveness of cariprazine in high doses patients on the schizophrenia spectrum.
| S-EPMC9998536 | biostudies-literature
Project description:Background and objectivesOlder adults receive benzodiazepines for agitation, anxiety, and insomnia after acute ischemic stroke (AIS). No trials have been conducted to determine if benzodiazepine use affects poststroke mortality in the elderly.MethodsWe examined the association between initiating benzodiazepines within 1 week after AIS and 30-day mortality. We included patients ≥65 years, admitted for new nonsevere AIS (NIH-Stroke-Severity[NIHSS]≤ 20), 2014-2020, with no recorded benzodiazepine use in the previous 3 months and no contraindication for use. We linked a stroke registry to electronic health records, used inverse-probability weighting to address confounding, and estimated the risk difference (RD). A process of cloning, weighting, and censoring was used to avoid immortal time bias.ResultsAmong 2,584 patients, 389 received benzodiazepines. The crude 30-day mortality risk from treatment initiation was 212/1,000 among patients who received benzodiazepines, while the 30-day mortality was 34/1,000 among those who did not. When follow-up was aligned on day of AIS admission and immortal time was assigned to the two groups, the estimated risks were 27/1,000 and 22/1,000, respectively. Upon further adjustment for confounders, the RD was 5 (-12 to 19) deaths/1,000 patients.ConclusionThe observed higher 30-day mortality associated with benzodiazepine initiation within 7 days was largely due to bias.
| S-EPMC10033385 | biostudies-literature