cariprazine and Bipolar-Disorder

The treatment of bipolar depression is one of the most challenging needs in contemporary psychiatry. Currently, only quetiapine, olanzapine-fluoxetine combination, lurasidone, cariprazine, and recently lumateperone have been FDA-approved to treat this condition. The neurobiology of bipolar depression and the possible targets of bipolar antidepressant therapy remain elusive. The current study investigated whether the pharmacodynamic properties of cariprazine fit into a previously developed model which was the first to be derived based on the strict combination of clinical and preclinical data. The authors performed a systematic review of the literature to identify the pharmacodynamic properties of cariprazine. The original model suggests that a constellation of effects on different receptors is necessary and that serotonin reuptake inhibition does not appear to play a significant role in acute bipolar depression. On the contrary, norepinephrine activity seems to be necessary. Probably the early antidepressant effect can be achieved through an agonistic activity at 5HT-1A and antagonism at alpha1 noradrenergic and 5-HT2A receptors, but the presence of a norepinephrine reuptake inhibition appears essential to sustain it. Overall, the properties of cariprazine fit well the proposed model and add to its validity. A point that needs further clarification is norepinephrine reuptake inhibition which is not yet fully studied for cariprazine.

Topics: Antidepressive Agents; Antipsychotic Agents; Bipolar Disorder; Humans; Lurasidone Hydrochloride; Norepinephrine

Bipolar depression is the most prevalent phase of bipolar disorder (BD). There is a risk of inducing treatment-emergent affective switches (TEAS) with antidepressants (ADs). Hence, clinical guidelines do not recommend their use in monotherapy. Cariprazine is a dopamine-serotonin partial agonist, with a recent FDA approval as a monotherapy for BD type 1 (BD-I) depression. To our knowledge, there is no significant evidence of cariprazine-induced TEAS in bipolar depression. We describe three clinical cases of patients admitted to our acute psychiatric ward who developed manic episodes after the introduction of low doses of cariprazine. Two of the patients met the DSM-5 criteria for BD-I, and one for schizoaffective disorder, bipolar type. All patients were initially treated with low doses of cariprazine (1.5 mg) during a depressive phase. All three cases were simultaneously treated with mood stabilizers, regardless of which they switched to a manic episode when cariprazine was initiated. In our review of previous studies assessing the efficacy and side effects profile of cariprazine in BD-I, TEAS have not been found to be significant. However, according to our experience, cariprazine may induce affective switches in BD-I patients. Patients and psychiatrists should receive information regarding early warning symptoms and monitor possible cariprazine-induced mood switching.

Topics: Antipsychotic Agents; Bipolar Disorder; Humans; Mania; Piperazines

Depressive episodes, the most frequent episodes in bipolar disorder, contribute in large part to poor functional outcomes. Very few treatments, however, have been approved by the Food and Drug Administration for the treatment of bipolar depression. Cariprazine, a broad-spectrum dopamine antagonist/partial agonist with dopamine D3/D2 (preferring D3) and serotonin 5-HT1A receptor partial agonist properties, was recently approved. A review of the literature suggests that it is an effective and well-tolerated treatment for bipolar depression.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Depression; Dopamine Antagonists; Drug Partial Agonism; Humans; Piperazines

Cariprazine is a partial agonist at D2/D3 receptors that has been approved for the treatment of mania associated with bipolar disorder (BD). This meta-analysis aimed to assess the efficacy and tolerability of cariprazine in the treatment of BD.. Randomized controlled trials investigating the efficacy of cariprazine in BD were included. Of the 391 studies yielded by search, 7 were included. The PRISMA protocol was followed and a set of analyses involving random-effects model with restricted maximum-likelihood estimator were used to synthesize effect sizes.. Cariprazine was associated with a moderate and significant reduction of manic symptoms based on YMRS change scores (SMD: -0.52; 95%CI: -0.82 to -0.21; P = .018). Cariprazine resulted in significantly higher remission (OR: 2.05; 95%CI: 1.61-2.61; P = .006) and response rates (OR: 2.31; 95%CI: 1.35-3.95; P = .021) for manic and mixed episodes compared with placebo. Both cariprazine 1.5 mg and 3 mg doses were associated with small but significant reduction in depressive symptoms assessed with MADRS scores (SMD: -0.26, 95%CI: -0.49 to -0.02; P = .040) (SMD: -0.21, 95%CI: -0.41 to -0.01; P = .045), respectively. Cariprazine was significantly associated with the development of adverse effects but not with dropouts due to these adverse effects, when compared to placebo.. Cariprazine appears to be safe and efficacious in the treatment of acute mania and mixed episodes associated with BD. Cariprazine at doses of 1.5-3 mg/day is efficacious in acute bipolar depression but the effect sizes were smaller. Controlled studies evaluating its efficacy for prophylaxis are needed.

Topics: Antipsychotic Agents; Bipolar Disorder; Depression; Double-Blind Method; Humans; Mania; Piperazines; Receptors, Dopamine D2; Treatment Outcome

Antipsychotics 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.. Schizophrenia 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.. Cariprazine, 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.

Topics: Animals; Antipsychotic Agents; Bipolar Disorder; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dogs; Humans; Piperazines; Quality of Life; Randomized Controlled Trials as Topic; Rats; Schizophrenia; Treatment Outcome

Bipolar disorder is a chronic, disabling, and costly illness with frequent relapses and recurrences, high rates of co-morbid conditions, and poor adherence to treatment. Mood stabilizers and antipsychotics are the cornerstones of treatment. Dopamine receptor partial agonists are a novel class of antipsychotic agents with original pharmacodynamic properties. Among them, two have been approved by the US Food and Drug Administration for the treatment of bipolar disorder. Aripiprazole (oral formulation) has been approved as monotherapy for the treatment of manic/mixed episodes in adult and pediatric populations and for maintenance treatment in adults, and as adjunctive treatment to mood stabilizers, for the acute treatment of manic/mixed episodes and for maintenance in adults. An intramuscular formulation of aripiprazole has been approved for the treatment of agitation in mania and a long-acting injectable formulation has been approved as maintenance treatment. In the USA, cariprazine has been approved as monotherapy for the acute treatment of manic/mixed as well as bipolar depressive episodes. Brexpiprazole is not yet approved to treat bipolar disorder. The evidence supporting these indications is reviewed via an analysis of clinical registration trials as well as additional studies, on the basis of a systematic literature search. Further studies dealing with other aspects of bipolar illness are also presented. Aripiprazole and cariprazine are efficacious and generally well tolerated agents that have shown cost effectiveness, and may therefore enrich our therapeutic armamentarium for bipolar illness. Brexpiprazole, which displays an overall promising tolerability profile, deserves further efficacy studies.

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Dopamine Agonists; Humans; Piperazines; Receptors, Dopamine; United States; United States Food and Drug Administration

Akathisia is a common and distressing movement disorder that can be associated with the use of antipsychotics. It is characterized by a subjective (inner restlessness) and an objective (excessive movements) component. Akathisia can have a negative impact on clinical outcome and even lead to treatment discontinuation. Although medication-induced akathisia is more commonly associated with the use of first-generation antipsychotics (FGAs), it also occurs with second-generation antipsychotics (SGAs), including the newly approved antipsychotics (NAPs) asenapine, lurasidone, iloperidone, cariprazine, and brexpiprazole. Until now, no meta-analysis has been published on the risk of akathisia for all NAPs, as monotherapy or adjunctive treatment, in patients with a severe mental illness.. The primary objectives of this systematic review and meta-analysis were to (i) compare akathisia incidence rates of the NAPs, as monotherapy or adjunctive treatment, in adult patients with a severe mental illness (i.e., schizophrenia, bipolar disorder, or major depressive disorder), using data from published and unpublished randomized controlled trials; and (ii) examine the role of several study characteristics explaining differences in akathisia incidence rates between studies.. A systematic literature search, using the PubMed, EMBASE, and Cochrane Library databases (until October 2018), was conducted for English-language placebo- as well as active-controlled clinical trials, including subjective (percentage of patients reporting akathisia) and/or scale-defined medication-induced akathisia incidence rates with NAPs (as monotherapy or as adjunctive treatment) in adult patients with schizophrenia, bipolar disorder, or major depressive disorder. Additional unpublished clinical trials were identified through the ClinicalTrials.gov electronic database. Two meta-analyses (incidence rates and odds ratio [OR] [placebo vs. active] of medication-induced akathisia with NAPs) were performed to obtain an optimal estimation of akathisia risks of adult patients with a severe mental illness under these treatment conditions and to assess the role of study characteristics.. Two hundred and thirteen reports were selected as potentially eligible for our meta-analysis. Of these, 48 met the inclusion criteria. Eight records, identified through the ClinicalTrials.gov database and cross-referencing, and which fulfilled the inclusion criteria, were added, resulting in a total of 56 records (iloperidone = 5, asenapine = 11, lurasidone = 15, brexpiprazole = 13, cariprazine = 12). The estimated weighted mean incidence rate of akathisia was 7.7% (95% confidence interval [CI] 6.5-9.1), with estimates being 3.9% (95% CI 2.4-6.3) for iloperidone, 6.8% (95% CI 5.1-9.0) for asenapine, 10.0% (95% CI 7.4-13.5) for brexpiprazole, 12.7% (95% CI 10.1-16.1) for lurasidone, and 17.2% (95% CI 13.4-22.1) for cariprazine. After Tukey-adjustment for multiple testing, the incidence rate of akathisia was significantly (p < 0.05) lower for iloperidone than for brexpiprazole, lurasidone, and cariprazine. In addition, the incidence rate of akathisia was significantly (p < 0.05) lower for asenapine than for lurasidone and cariprazine. Finally, the incidence rate of akathisia was significantly (p < 0.05) lower for brexpiprazole than for cariprazine. Type of medication (p < 0.0001), diagnosis (p = 0.02), and race (p = 0.0003) significantly explained part of the heterogeneity of the incidence estimates of akathisia between studies. The estimated weighted OR of akathisia under medication, compared with placebo, was 2.43 (95% CI 1.91-3.10). The OR was smallest for iloperidone (OR 1.20; 95% CI 0.42-3.45) and increased for brexpiprazole (OR 2.04; 95% CI 1.09-3.83), asenapine (OR 2.37; 95% CI 1.32-4.27), lurasidone (OR 3.74; 95% CI 2.32-6.02), and cariprazine (OR 4.35; 95% CI 2.80-6.75). Only type of medication (p = 0.03) explained systematic differences in the OR for akathisia between placebo versus active treatment across studies. After Tukey-adjustment for multiple testing, no significant differences between these ORs were found. The severity of akathisia with NAPs generally is mild to moderate, only leading to treatment discontinuation in a minority of cases (< 5%).. The use of a NAP raises the akathisia risk more than two-fold when compared with patients receiving placebo. Although distinctions between the different NAPs were not clear in placebo-controlled trials, the results of our meta-analyses and systematic review generally indicate that these differences more than likely reflect real differences, with iloperidone showing the most and cariprazine showing the least benign akathisia profile. Moreover, due to patient characteristics and methodological issues, incidence rates of akathisia with NAPs found in this meta-analysis may even be an underestimation of true incidence rates.

Topics: Akathisia, Drug-Induced; Antipsychotic Agents; Bipolar Disorder; Depressive Disorder, Major; Humans; Lurasidone Hydrochloride; Piperazines; Randomized Controlled Trials as Topic; Schizophrenia; Severity of Illness Index

Cariprazine is an oral antipsychotic approved in the US for the treatment of schizophrenia, acute bipolar mania, and most recently, bipolar depression. The aim of this systematic review is to describe the efficacy, tolerability and safety of cariprazine for the treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults.. The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms "cariprazine" AND "bipolar" AND "depression," and by also querying the Web of Science commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information.. Double-blind placebo-controlled studies in adults with bipolar depression.. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were calculated from the available study reports and other sources of information.. Cariprazine differs from other antipsychotics in that it has a 10-fold higher affinity for dopamine D3 receptors than for D2 receptors. Cariprazine's principal active metabolite, didesmethyl-cariprazine (DDCAR), has a half-life of 1-3 weeks and at steady state DDCAR is the predominant circulating moiety. Four double-blind placebo-controlled studies of cariprazine for bipolar depression were found of which three were considered positive and provided data on efficacy; all four studies were used to assess tolerability. Rates of treatment response, defined by a ≥50% reduction from baseline on the Montgomery-Asburg Depression Ratting Scale (MADRS) total score at study endpoint, for the approved doses of 1.5 and 3.0 mg/d (pooled) vs placebo were 46.3% vs 35.9% (NNT 10, 95% CI 7-21). Corresponding rates for remission (defined as MADRS total score ≤10 at endpoint) were 30.2% vs 20.9% (NNT 11, 95% CI 8-22). Discontinuation rates because of an adverse event (AE) were 6.7% for cariprazine (all doses pooled) vs 4.8% for placebo (NNH 51, ns). Product labelling lists the most common AEs as nausea, akathisia, restlessness and extrapyramidal symptoms. Patients receiving cariprazine 3.0 vs 1.5 mg/d were more likely to experience AEs and discontinue the trials because of an AE.. Cariprazine is the fourth agent approved for bipolar depression in the US. The likelihood to experience a benefit (response or remission) is substantially greater than the likelihood to encounter a discontinuation because of an AE. Direct, head-to-head comparisons with the other approved choices for bipolar depression in the "real world" are needed.

Topics: Antipsychotic Agents; Bipolar Disorder; Clinical Trials as Topic; Double-Blind Method; Humans; Patient Selection; Piperazines; Treatment Outcome

Cariprazine is a piprazine derivative approved by the FDA in 2015 for the treatment of schizophrenia and bipolar manic or mixed episodes in adults. High affinity for D3 dopamine receptors and observed actions on 5HT1A, 5HT2A and alpha 1B receptors differentiate it pharmacologically from other antipsychotics. This review is a comprehensive and thorough summary of the most important findings on cariprazine use in bipolar mania and depression. Pharmacokinetics, pharmacogenetics, tolerability and safety adverse effects are discussed in this paper.. Moreover, the results from pivotal clinical trials are presented. Cariprazine represents an additional option for clinicians to treat patients with bipolar disorder. It shows a unique pharmacological profile and has demonstrated in randomized clinical trials efficacy and general tolerability compared to placebo in bipolar mania and seem to be a promising therapeutic option for bipolar depression.

Topics: Antipsychotic Agents; Bipolar Disorder; Humans; Piperazines

Cariprazine was approved for treating schizophrenia and bipolar disorder, and currently is being evaluated for treating depression in clinical trials in the United States. We systematically reviewed the literature on the efficacy and safety of cariprazine.. We performed a literature search of the PubMed, MEDLINE, PsycINFO, EMBASE, and Cochrane collaboration databases through August 31, 2016. The search was not restricted by patient age. Articles published in English or official English translations were included.. Eleven articles that evaluated the use of cariprazine in the treatment of psychiatric disorders were identified. Four trials evaluated the safety and efficacy of cariprazine in bipolar disorder. One trial investigated its use as an adjunct to antidepressants in major depressive disorder. Three trials evaluated its use in the treatment of acute exacerbations of schizophrenia. Two studies used risperidone or aripiprazole as comparators. Both low- and high-dose cariprazine were more effective than placebo in the treatment of acute mania, mixed episodes, and acute psychosis. Additionally, cariprazine showed efficacy as an adjunctive treatment for depression.. Our review indicates that cariprazine demonstrates superior efficacy and good tolerability, both at low and high doses, in the treatment of individuals with psychosis, mania, and depression.

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Depressive Disorder; Humans; Piperazines; Risperidone; Schizophrenia

Data from 3 bipolar mania and 3 schizophrenia trials were pooled by indication (bipolar disorder = 1033; schizophrenia = 1466). Cariprazine- and placebo-treated patients were categorised by baseline CGI-S scores; the proportion of patients who improved from more severe categories at baseline to less severe categories at end-point was evaluated using a logistic regression model. Correlations between Young Mania Rating Scale and Positive and Negative Syndrome Scale total score changes and category shifts were also evaluated.. In both disease states, more cariprazine- than placebo-treated patients had improved CGI-S scores at end-point; more placebo-treated patients had worse end-point scores. More cariprazine- vs placebo-treated patients shifted from the extremely/severely ill to mildly ill/better category (bipolar disorder = 55% vs 36%, odds ratio [OR] = 2.1; P = .09; schizophrenia = 42% vs 18%, OR = 3.4, P<.01). ORs was statistically significant in favour of cariprazine in shifts from marked and moderate illness to borderline/normal in both indications (P < .05). Correlations between rating scale improvement and category shift were greatest in patients with extreme/severe baseline illness for bipolar disorder (-0.853) and schizophrenia (-0.677).. Post hoc analyses showed that more cariprazine- than placebo-treated patients with bipolar mania or schizophrenia had statistically significant and clinically meaningful CGI-S improvement.

Topics: Antipsychotic Agents; Bipolar Disorder; Humans; Piperazines; Schizophrenia; Severity of Illness Index

To review the data regarding a new antipsychotic, cariprazine.. Cariprazine is a dopamine D3, D2 partial agonist, with greater affinity to D3. It has been examined for schizophrenia, bipolar mania, bipolar depression, and unipolar depression. It has demonstrated efficacy in schizophrenia and mania, and has recently been approved by the U.S. Food and Drug Administration. However, it has a more inconsistent effect in depression, both unipolar and bipolar. Adverse effects include extrapyramidal symptoms, akathisia, and gastrointestinal distress.. Cariprazine will be a promising addition in the treatment of patients with acute mania and schizophrenia.

Topics: Antipsychotic Agents; Bipolar Disorder; Dopamine Agonists; Humans; Piperazines

Cariprazine (RGH-188, MP-214, Vraylar[TM]) is a new dopamine receptor ligand developed for the treatment of several neuropsychiatric diseases including schizophrenia and bipolar disorders. Cariprazine displays higher affinity at dopamine D3 receptors and a similar affinity at D2 and 5-HT2B receptors. At variance with some atypical antipsychotics, its affinity at 5-HT1A, 5-HT2A and histamine H1 receptors is modest compared with its three main targets. Cariprazine could correspond to a biased agonist at dopamine receptors, displaying either antagonist or partial agonist properties depending on the signaling pathways linked to D2/D3 receptors. The compound crosses the blood-brain barrier, as revealed by positron emission tomography and pharmacokinetic studies in various species. Two main metabolites result mainly from the activity of CYP34A and display properties similar to those of the parent drug. Behavioral data report that cariprazine is efficacious in animal models addressing positive, negative and cognitive symptoms of schizophrenia with no extrapyramidal side effects. In September 2015, the FDA approved the use of cariprazine for the treatment of schizophrenia and type I bipolar disorder. The efficacy of cariprazine in other neuropsychiatric diseases is currently being evaluated in preclinical and clinical studies. Side effects have been observed in humans, including extrapyramidal side effects and akathisia of mild to moderate intensity.

Topics: Animals; Antipsychotic Agents; Bipolar Disorder; Humans; Piperazines; Schizophrenia

Topics: Administration, Oral; Animals; Antipsychotic Agents; Bipolar Disorder; Humans; Piperazines; Randomized Controlled Trials as Topic; Schizophrenia

Cariprazine (RGH-188) is a novel antipsychotic drug that exerts partial agonism of dopamine D2/D3 receptors with preferential binding to D3 receptor, antagonism of 5HT2B receptors and partial agonism of 5HT1A. Currently, cariprazine is in late-stage clinical development (phase III clinical trials) in patients with schizophrenia (S) and in patients with bipolar disorder (BD), as well as an adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. Cariprazine has completed phase III trials for the acute treatment of schizophrenia and bipolar mania, phase II trials for the bipolar depression and MDD whilst it is undergoing phase III trials as an adjunct to antidepressants. The present review aims at proving a comprehensive summary of the current evidence on the safety, tolerability and efficacy of cariprazine in the treatment of schizophrenia, BD (manic/mixed/ depressive episode) and MDD. A systematic search was conducted on PubMed/Medline/ Scopus and the database on Clinical Trials from inception until April 2015 by typing a set of specified keywords. Available evidence seems to support cariprazine efficacy in the treatment of cognitive and negative symptoms of schizophrenia. Preliminary findings suggest its antimanic activity whilst it is still under investigation its efficacy in the treatment of bipolar depression and MDD. Furthermore, the available data seems not to allow judgements about its antipsychotic potential in comparison with currently prescribed antipsychotics. Further studies should be carried out to better investigate its pharmacodynamic and clinical potential, particularly as alternative to current antipsychotic drugs.

Topics: Animals; Antipsychotic Agents; Bipolar Disorder; Depressive Disorder, Major; Humans; Piperazines; Schizophrenia

Cariprazine is an antipsychotic medication and received approval by the U.S. Food and Drug Administration for the treatment of schizophrenia in September 2015. Cariprazine is a dopamine D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors. The recommended dose range of cariprazine for the treatment of schizophrenia is 1.5-6 mg/d; the starting dose of 1.5 mg/d is potentially therapeutic. Cariprazine is administered once daily and is primarily metabolized in the liver through the CYP3A4 enzyme system and, to a lesser extent, by CYP2D6. There are two active metabolites of note, desmethyl-cariprazine and didesmethyl-cariprazine; the latter's half-life is substantially longer than that for cariprazine and systemic exposure to didesmethyl-cariprazine is several times higher than that for cariprazine. Three positive, 6-week, Phase 2/3, randomized controlled trials in acute schizophrenia demonstrated superiority of cariprazine over placebo. Pooled responder rates were 31% for cariprazine 1.5-6 mg/d vs. 21% for placebo, resulting in a number needed to treat (NNT) of 10. In a 26-72 week, randomized withdrawal study, significantly fewer patients relapsed in the cariprazine group compared with placebo (24.8% vs. 47.5%), resulting in an NNT of 5. The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) are extrapyramidal symptoms (number needed to harm [NNH] 15 for cariprazine 1.5-3 mg/d vs. placebo and NNH 10 for 4.5-6 mg/d vs. placebo) and akathisia (NNH 20 for 1.5-3 mg/d vs. placebo and NNH 12 for 4.5-6 mg/d vs. placebo). Short-term weight gain appears small (approximately 8% of patients receiving cariprazine 1.5-6 mg/d gained ≥7% body weight from baseline, compared with 5% for those randomized to placebo, resulting in an NNH of 34). Cariprazine is associated with no clinically meaningful alterations in metabolic variables, prolactin, or the ECG QT interval. Cariprazine is also approved for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Clinical trials are ongoing in patients with acute bipolar I depression and as adjunctive treatment to antidepressant therapy in patients with major depressive disorder.

Topics: Antipsychotic Agents; Bipolar Disorder; Depressive Disorder, Major; Dopamine Agonists; Drug Partial Agonism; Humans; Piperazines; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Treatment Outcome

Cariprazine is a novel antipsychotic agent recently approved for treating schizophrenia and bipolar mania in the USA. The sample sizes of published randomized controlled trials (RCTs) of the drug are small; previous meta-analyses included few RCTs and did not specifically investigate the tolerability/safety profile of cariprazine.. Our objective was to conduct a meta-analysis of published RCTs to systematically review the tolerability and safety of cariprazine versus placebo.. We searched the clinical trial registers (the metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform) and electronic databases (PubMed, Embase, PsycINFO and Cochrane library) up to June 2016 to identify phase II/III RCTs of cariprazine in patients with schizophrenia, bipolar disorder or major depressive disorder. We conducted a meta-analysis to investigate outcomes, including risks of discontinuation due to adverse events (AEs), extrapyramidal side effects (EPS) or related events, metabolic syndrome and cardiovascular-related events.. We included nine RCTs, with a total of 4324 subjects. The risk of discontinuation due to AEs for cariprazine was similar to that for placebo (risk ratio [RR] 1.13, 95 % confidence interval [CI] 0.77-1.66). Cariprazine was associated with higher risks of EPS-related events than was placebo, including risk of akathisia (RR 3.92, 95 % CI 2.83-5.43), tremor (RR 2.41, 95 % CI 1.53-3.79) and restlessness (RR 2.17, 95 % CI 1.38-3.40). The cariprazine treatment group was more likely to have clinically significant weight gain (RR 1.68, 95 % CI 1.12-2.52). No statistically significant differences in results were found in other metabolic parameters or cardiovascular-related events.. There was a statistically significant higher risk of EPS-related AEs and a slight increase in mean body weight with cariprazine. There were no statistically significant effects on prolactin level or cardiovascular parameters. EPSs were the main short-term adverse reactions reported in the limited number of patients studied. Further clinical and post-marketing pharmacovigilance studies are needed to investigate the long-term safety of cariprazine.

Topics: Antipsychotic Agents; Bipolar Disorder; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Depressive Disorder, Major; Humans; Piperazines; Psychotic Disorders; Schizophrenia

Topics: Antipsychotic Agents; Benzhydryl Compounds; Bipolar Disorder; Dopamine Agonists; Dopamine Plasma Membrane Transport Proteins; Drug Discovery; Humans; Isoindoles; Lurasidone Hydrochloride; Modafinil; Piperazines; Thiazoles

Cariprazine (RGH-188, trans-4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-N,N-dimethylcarbamoyl-cyclohexyl-amine hydrochloride), is a novel antipsychotic with dopamine D2 and D3 receptors antagonist-partial agonist properties. Cariprazine has also moderate affinity for serotonin 5-hydroxytryptophan (5-HT) 1A receptors, high affinity for 5-HT1B receptors with pure antagonism and low affinity for 5-HT2A receptors. Randomized, double blind, placebo controlled, flexible-dose (3-12 mg/day) studies have demonstrated cariprazine is effective in both schizophrenia and acute manic episodes associated with bipolar disorder. The incidence of serious adverse events in cariprazine arm was no different than in placebo arm in these studies. The most common adverse events were extrapyramidal symptoms, headache, akathisia, constipation, nausea, and dyspepsia which can be explained with cariprazine's partial dopamine agonism. Although cariprazine treatment was associated with a higher incidence of treatment-emergent adverse events, particularly akathisia and tremor, common side effects of marketed second generation antipsychotics such as weight gain, metabolic disturbances, prolactin increase or QTc prolongation were not associated with cariprazine, probably due to its moderate to low binding affinity for histamine H1 and 5-HT2C receptors. Animal studies show that cariprazine may have additional therapeutic benefit on impaired cognitive functioning with D3 receptor activity, however clinical data is still scarce. The aim of this article is to review the potential use of cariprazine for the treatment of acute manic episodes in the light of the preclinical and clinical trials reported to date.

Topics: Acute Disease; Animals; Antipsychotic Agents; Bipolar Disorder; Clinical Trials as Topic; Humans; Piperazines

Cariprazine is a novel drug with partial agonist activity at dopamine D2/3 receptors and six- to eightfold higher affinity for human dopamine D3 over D2 receptors. Results from several placebo-controlled Phase II/III trials in patients with a The Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of schizophrenia or bipolar I disorder suggest that cariprazine is superior to placebo with respect to antipsychotic and antimanic activity. Reports concerning safety and tolerability of cariprazine are mainly favorable, although the rates of treatment-associated adverse events, which most commonly included akathisia and extrapyramidal symptom, are rather high. However, only minor alterations of clinical laboratory values, prolactin concentrations and ECG parameters are reported in cariprazine-treated patients. A new drug application to the U.S. F DA for cariprazine for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar I disorder was submitted in November 2012. A more precise assessment of the clinical properties of this new drug will require additional studies, aimed to compare and contrast cariprazine with other antipsychotic agents.

Topics: Administration, Oral; Animals; Bipolar Disorder; Clinical Trials as Topic; Depressive Disorder; Dopamine Agonists; Drug Partial Agonism; Humans; Piperazines; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Schizophrenic Psychology

Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist in late-stage clinical development for the treatment of bipolar disorder (manic/mixed and depressive episodes), as well as for schizophrenia, and as an adjunctive agent for the treatment of major depressive disorder. Three phase 2 or 3, 3-week, randomized controlled trials in bipolar mania or mixed episodes have been completed and reported as poster presentations or in press releases by the manufacturer. Superiority over placebo on the Young Mania Rating Scale total score was evidenced for daily doses of cariprazine 3-12 mg/day. In short-term randomized controlled trials, cariprazine does not appear to adversely impact metabolic variables, prolactin, or the electrocardiogram (ECG) QT interval. The most commonly encountered adverse events in the mania trials were extrapyramidal disorder, akathisia, insomnia, vomiting, restlessness, sedation, vision blurred, and pain in extremity in the phase 2 trial where this was presented in a poster, and akathisia, extrapyramidal disorder, tremor, dyspepsia, vomiting, dizziness, diarrhea, somnolence, restlessness, and pyrexia for the phase 3 trial where this was presented in a poster. With the exception of akathisia and extrapyramidal disorder, the differences in incidence versus placebo for these events were generally small. If approved by regulatory authorities, cariprazine would join aripiprazole as the second dopamine receptor partial agonist antipsychotic available for clinical use in persons with bipolar mania or mixed episodes. Cariprazine differs from aripiprazole in terms of dopamine D3 receptor selectivity. Further studies would be helpful to discern the distinguishing features of cariprazine from other antimanic agents.

Topics: Antimanic Agents; Bipolar Disorder; Humans; Piperazines; Randomized Controlled Trials as Topic; Receptors, Dopamine D3; Treatment Outcome

Patients who experience bipolar depression have diverse demographic and clinical characteristics that have the potential to impact treatment. The efficacy of cariprazine in bipolar I depression was evaluated in patient subgroups defined by baseline demographic and clinical characteristics. Post hoc analyses of data from three randomized, double-blind, placebo-controlled trials in bipolar I depression (NCT01396447, NCT02670538 and NCT02670551) evaluated mean change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores for pooled cariprazine 1.5-3 mg/d versus placebo in subgroups defined by demographic and clinical characteristics. The least-squares mean difference in MADRS total score change from baseline was statistically significant for cariprazine 1.5-3 mg/d versus placebo in all patient subgroups analyzed (P < 0.05 all subgroups): demographic characteristics (age, sex, white or black race and obese/nonobese BMI); episode characteristics (defined by current episode duration, number of previous manic/mixed and depressive episodes, and prior bipolar disorder medication use) and disease severity (groups above and below Clinical Global Impressions-Severity and MADRS cutoff scores). Cariprazine 1.5-3 mg/d consistently improved depressive symptoms in all patient subgroups without regard to differences in baseline demographic and clinical characteristics, suggesting broad efficacy across a spectrum of patients with bipolar I depression.

Topics: Bipolar Disorder; Humans; Patients; Piperazines; Treatment Outcome

Mixed presentations, defined by simultaneous occurrence of depressive and manic symptoms, are difficult to treat. Antidepressants, although commonly used, have weak evidence of efficacy and may increase risk of mood destabilization. The aim of this pooled post hoc analysis was to evaluate the efficacy of cariprazine in the treatment of bipolar depression with or without concurrent manic symptoms.. Patients from 3 randomized, double-blind, placebo-controlled studies who met DSM-IV-TR or DSM-5 criteria for bipolar I disorder with a current major depressive episode were identified to have concurrent manic symptoms by baseline Young Mania Rating Scale total score ≥4. Efficacy was assessed in cariprazine 1.5 and 3 mg/day dose groups versus placebo; analyses included the least squares mean change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score.. Of 1383 patients randomized to treatment, 808 (58.4%) had concurrent manic symptoms. For patients with manic symptoms, mean reduction in MADRS total score from baseline to week 6 was significantly greater for both cariprazine 1.5 and 3 mg/day compared with placebo, with least squares mean differences (LSMDs) versus placebo of -2.5 (p = .0033) and -2.9 (p = .0010), respectively; for patients without manic symptoms, the LSMD was significant for 1.5 mg/day (-3.3; p = .0008), but not for 3 mg/day (-1.9; p = .0562).. The results of this post hoc analysis suggest that cariprazine may be an appropriate treatment option for patients with bipolar I depression with or without manic symptoms, with higher doses potentially more effective in patients with manic symptoms.

Topics: Adolescent; Adult; Antidepressive Agents; Bipolar Disorder; Dopamine Agonists; Female; Humans; Male; Mania; Middle Aged; Piperazines

To assess the efficacy, safety, and tolerability of cariprazine in the treatment of the depressed phase of bipolar I disorder in adults (NCT02670538).. In this phase 3 double-blind placebo-controlled study, adult patients with bipolar I disorder according to the Diagnostic and Statistical Manual - 5th Edition criteria and a current depressive episode were randomized to placebo (n = 167), cariprazine 1.5 mg/day (n = 168) or cariprazine 3.0 mg/day (n = 158). Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary) and Clinical Global Impressions - Severity (CGI-S) scores (secondary) from baseline to Week 6 compared to placebo. A mixed-model for repeated measures was used to estimate the least-squares mean differences (LSMD); P-values were adjusted for multiplicity. Adverse events (AEs), laboratory results, vital signs, and suicide risk were monitored.. Cariprazine 1.5 mg/day significantly reduced depressive symptoms on the primary (MADRS LSMD = -2.5; adjusted P = .0417) and secondary (CGI-S LSMD = -0.3; adjusted P = .0417) efficacy parameters vs placebo; differences were not statistically significant for cariprazine 3.0 mg/day. Common treatment-emergent AEs (≥5% in either cariprazine group and at least twice the incidence of placebo) were akathisia, restlessness, nausea, and fatigue. Mean metabolic parameter changes were low and generally comparable among groups; mean weight increases were ≤0.5 kg for all groups.. Cariprazine 1.5 mg/day significantly reduced depressive symptoms in adults with bipolar I depression compared to placebo, but differences were not significant for cariprazine 3.0 mg/day. The safety and tolerability profiles were similar to previous studies of cariprazine.

Topics: Adult; Antipsychotic Agents; Anxiety; Bipolar Disorder; Depression; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Psychomotor Agitation; Treatment Outcome

This double-blind placebo-controlled, fixed/flexible-dose phase 2 trial assessed the efficacy, safety, and tolerability of cariprazine vs. placebo for depressive episodes associated with bipolar I or II disorder. Primary endpoint was change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (baseline to week 8), and secondary endpoint was mean Clinical Global Impressions-Improvement score (week 8). Patients were randomized (N = 233) 1:1:1 to placebo, 'low-dose' 0.25-0.5 mg/day or 'high-dose' 1.5-3.0 mg/day cariprazine. Adverse events, laboratory results, vital signs, extrapyramidal symptoms, and suicide risk were monitored. Neither cariprazine group significantly separated from placebo in primary (mixed-effect model repeated measures MADRS least-squares mean differences: low-dose = -0.7, P = 0.7408; high-dose = 0.0, P = 0.9961) or secondary efficacy measures. No new safety signals with cariprazine were observed and common treatment-emergent adverse events (≥5% of cariprazine patients and twice the rate of placebo) included insomnia, akathisia, dry mouth, nausea, weight increased, diarrhea, restlessness, vomiting, musculoskeletal stiffness, migraine, and cough. Metabolic and weight changes were generally similar for cariprazine and placebo. Factors that may have affected the outcome of the trial were identified, which helped to inform the design and conduct of subsequent phase 2b/3 clinical trials of cariprazine in bipolar depression.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Treatment Outcome; Young Adult

Bipolar disorder is a complex mood disorder characterized by a chronic and subtle course of fluctuating manic/hypomanic and depressive symptoms. Cariprazine, a dopamine D₃-preferring D₃/D₂ receptor partial agonist with serotonin 5-HT1A receptor partial agonist and serotonin 5-HT2A antagonist properties, is approved to treat manic and depressive episodes of bipolar disorder. Post hoc analyses evaluated efficacy across symptoms in bipolar depression.. Pooled data were analyzed from 3 phase 2 or 3, randomized, double-blind, placebo-controlled studies of adults with bipolar disorder and a major depressive episode. Mean change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score and individual item scores were analyzed in individual dose groups (1.5 mg/d, 3 mg/d) and overall cariprazine (1.5-3 mg/d). Pooled safety was evaluated via adverse events.. A significantly greater difference in mean change from baseline in MADRS total score was seen for each cariprazine dose group versus placebo (least squares mean difference vs placebo: 1.5-3 mg/d = -2.6, 1.5 mg/d = -2.8, 3 mg/d = -2.4) (P < .001 all). Significant differences versus placebo were seen on all individual MADRS items except inner tension for the overall cariprazine group (P < .05). Cariprazine was generally well tolerated.. Cariprazine demonstrated broad efficacy across symptoms of depression in bipolar disorder. In previous post hoc analyses, cariprazine also demonstrated broad efficacy across manic symptoms, suggesting that it is effective across the wide range of symptoms on the bipolar spectrum. A 1.5-mg/d starting dose and slow titration resulted in lower rates of some adverse events in the bipolar depression studies versus the mania studies.. ClinicalTrials.gov identifiers: NCT01396447, NCT02670538, NCT02670551.

Topics: Adult; Bipolar Disorder; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Male; Middle Aged; Neurotransmitter Agents; Piperazines; Treatment Outcome

When bipolar I disorder (BP-I) mania is accompanied by subsyndromal depressive symptoms, a more complicated illness presentation results. To qualify for the mixed features specifier during mania, the DSM-5 requires ≥3 "non-overlapping" depressive symptoms (DS); notwithstanding, concerns of this definition's ecological validity and implications for timely diagnosis remain.. Herein, patients were pooled from three similarly-designed pivotal trials of cariprazine compared to placebo for BP-I mania (NCT00488618/NCT01058096/NCT01058668) in post hoc analyses of mixed features using three criteria: ≥3 DS (DSM-5), ≥2 DS, and Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≥10. Efficacy of cariprazine compared to placebo was assessed (Week 3) by Young Mania Rating Scale (YMRS) and MADRS scores and rates of mania response and remission.. In pooled patients (N = 1037), cariprazine significantly improved mean YMRS scores compared to placebo for each criterion; LSMDs were ≥3 DS = -3.79 (P = .0248), ≥2 DS = -2.91 (P = .0207), and ≥10 MADRS = -5.49 (P < .0001). More cariprazine- than placebo-treated patients met YMRS response and remission criteria, reaching significance for response in ≥2 DS (34% versus 47%; number-needed-to-treat [NNT] = 8, P = .0483) and ≥10 MADRS (31% versus 57%, NNT = 4, P < .0001) and for remission in ≥2 DS (27% versus 39%, NNT = 9, P = .0462), ≥10 MADRS (23% versus 44%, NNT = 5, P < .0001). Depressive symptoms were improved compared to placebo, reaching statistical significance in the MADRS ≥10 subgroup (LSMD = -1.59, P = .0082).. Post hoc analysis, MADRS  < 18 entry criterion may have prevented assessment of MADRS changes.. Cariprazine significantly reduced manic and depressive symptoms in patients with mixed features with differential efficacy across the subgroups analyzed herein.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Depression; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Treatment Outcome

We evaluated the safety/tolerability of longer-term open-label treatment with cariprazine in patients who had responded to cariprazine for acute bipolar mania.. In this multinational, multicenter study, open-label, flexible-dose, cariprazine 3-12mg/d was administered for up to 16 weeks to patients (18-65 years) with bipolar mania. Safety evaluations included adverse events (AEs), laboratory values, vital signs, and extrapyramidal symptom (EPS) scales. Symptom change was evaluated by Young Mania Rating Scale (YMRS) total score change from baseline using the last observation carried forward approach.. Of the 402 patients taking cariprazine, 33% completed the trial; the most frequent reasons for discontinuation were withdrawal of consent (20%), AEs (16%), and protocol violation (14%). Most common AEs leading to discontinuation were akathisia (4.7%) and depression (1.5%). Mean treatment duration was 57.7 days; mean cariprazine dose was 6.2mg/d. The incidence of serious AEs was 7.5% (most common: mania [2.2%], depression [1.2%]); 83.3% had treatment-emergent AEs, including akathisia (32.6%), headache (16.7%), constipation (10.7%), and nausea (10.4%). Mean body weight increased <1kg; 9.3% had ≥7% weight gain; 5.7% had sedation; 3% had somnolence. Mean changes in laboratory values, vital signs, ECGs, and ophthalmology parameters were not clinically significant. Mean YMRS total score decreased by -15.2 at week 16.. Uncontrolled, open-label design.. Open-label cariprazine 3-12 (mean 6.2) mg/d for up to 16 weeks was generally well tolerated, with low (<10%) rates of sedation and ≥7% weight gain. Although akathisia occurred in 33%, it yielded discontinuation in <5%.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Depression; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Treatment Outcome; Weight Gain

Rates of response and remission are measures that endorse the clinical significance of treatment. Cariprazine is FDA approved for the acute treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder in adults. Post hoc analyses of pooled data from 3 pivotal trials of cariprazine in manic/mixed episodes associated with bipolar I disorder were conducted to investigate the effect of cariprazine on various criteria of response and remission.. The constituent studies were 3-week randomized, double-blind, placebo-controlled, multicenter, parallel-group phase II/III studies in adult patients (age 18-65 years) with bipolar I disorder (NCT00488618, NCT01058096, NCT01058668). Post hoc analyses included Young Mania Rating Scale (YMRS) outcomes for response (≥50% decrease in score), remission (total score ≤12 and ≤8), cumulative remission, and global improvement. Additionally, composite remission (YMRS total score ≤12 plus Montgomery-Åsberg Depression Rating Scale total score ≤12) and worsening/switch to depression (MADRS total score ≥15) by week were investigated.. Rates of response and remission were significantly greater for cariprazine versus placebo on every measure evaluated (P < .01 all analyses); the estimated number needed to treat for each measure was ≤10. There was no evidence of worsening/switch to depression.. Post hoc analyses, short treatment duration, no active comparator.. Cariprazine-treated patients with bipolar I disorder attained clinically significant improvement in manic symptoms as shown by significantly greater rates of response and remission versus placebo; improvement in manic symptoms did not induce depressive symptoms.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Bipolar Disorder; Depression; Depressive Disorder; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Time Factors; Treatment Outcome; Young Adult

To evaluate the cost-effectiveness of aripiprazole once-monthly 400/300 mg (AOM 400) in maintenance monotherapy treatment of bipolar I disorder (BP-I).. A de novo lifetime Markov model was developed for BP-I using available data for AOM 400 and relevant comparators. Base-case analysis considered costs and outcomes from the US payer perspective.. The cost per quality-adjusted life year gained with AOM 400 versus comparators ranged from US$2007 versus oral asenapine to dominance (i.e., lower cost with quality-adjusted life gain) versus long-acting injectable risperidone, paliperidone palmitate, oral cariprazine and best supportive care. Patients treated with AOM 400 were estimated to have fewer mood episodes and hospitalizations per patient (5.37) than comparators (6.33, asenapine or cariprazine; 6.54, risperidone long-acting injectable; 7.64, paliperidone palmitate; and 8.93, best supportive care). Sensitivity analyses showed results were robust to parameter uncertainty.. AOM 400 may be considered cost effective in the maintenance monotherapy treatment of BP-I in adults.

Topics: Adolescent; Adult; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Cost-Benefit Analysis; Delayed-Action Preparations; Drug Administration Schedule; Drug Costs; Female; Humans; Injections, Intramuscular; Male; Markov Chains; Middle Aged; Paliperidone Palmitate; Piperazines; Quality-Adjusted Life Years; Risperidone; Schizophrenia; Young Adult

The authors evaluated the efficacy, safety, and tolerability of cariprazine, an atypical antipsychotic candidate, in adult patients with acute bipolar I depression.. This was an 8-week multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study in adult patients with bipolar I disorder experiencing a current major depressive episode. Patients were randomly assigned (1:1:1:1) to receive placebo or cariprazine at 0.75, 1.5, or 3.0 mg/day. The primary and secondary efficacy parameters were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions severity subscale (CGI-S), respectively, analyzed using a mixed-effects model for repeated measures on the modified intent-to-treat population.. The intent-to-treat population comprised 571 patients (141 in the placebo group and 140, 145, and 145 in the cariprazine 0.75-, 1.5-, and 3.0-mg/day groups). Cariprazine at 1.5 mg/day showed significantly greater improvement on MADRS total score change from baseline to week 6 compared with placebo; the least squares mean difference was -4.0 (95% CI=-6.3, -1.6; significant after adjustment for multiple comparisons). Cariprazine at 3.0 mg/day showed greater MADRS score reduction than placebo (-2.5, 95% CI=-4.9, -0.1; not significant when adjusted for multiple comparisons). The 0.75 mg/day dosage was similar to placebo. A similar pattern for significance was observed on the CGI-S (1.5 mg/day: least squares mean difference=-0.4, 95% CI=-0.6, -0.1; 3.0 mg/day: -0.3, 95% CI=-0.5, -0.0). The most common adverse events (≥10%) in cariprazine-treated patients were akathisia and insomnia; weight gain was slightly higher with cariprazine than with placebo.. Cariprazine at 1.5 mg/day demonstrated consistent efficacy compared with placebo across outcomes and was generally well tolerated, suggesting efficacy for the treatment of bipolar I depression.

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Depression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Treatment Outcome

Cariprazine, an orally active and potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, is being developed for the treatment of schizophrenia and bipolar mania. This Phase II trial evaluated the efficacy, safety, and tolerability of cariprazine versus placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder.. This was a multinational, randomized, double-blind, placebo-controlled, flexible-dose study of cariprazine 3-12 mg/day in patients with acute manic or mixed episodes associated with bipolar I disorder. Following washout, patients received three weeks of double-blind treatment. The primary and secondary efficacy parameters were change from baseline to Week 3 in Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S) scores, respectively. Post-hoc analysis evaluated changes on YMRS single items.. In each group, 118 patients received double-blind treatment; 61.9% of placebo and 63.6% of cariprazine patients completed the study. The overall mean daily dose of cariprazine was 8.8 mg/day. At Week 3, cariprazine significantly reduced YMRS and CGI-S scores versus placebo, with least square mean differences of -6.1 (p < 0.001) and -0.6 (p < 0.001), respectively. On each YMRS item, change from baseline to Week 3 was significantly greater for cariprazine versus placebo (all, p < 0.05). A significantly greater percentage of cariprazine patients than placebo patients met YMRS response (48% versus 25%; p < 0.001) and remission (42% versus 23%; p = 0.002) criteria at Week 3. Adverse events (AEs) led to discontinuation of 12 (10%) placebo and 17 (14%) cariprazine patients. The most common AEs (> 10% for cariprazine) were extrapyramidal disorder, headache, akathisia, constipation, nausea, and dyspepsia. Changes in metabolic parameters were similar between groups, with the exception of fasting glucose; increases in glucose were significantly greater for cariprazine versus placebo (p < 0.05). Based on Barnes Akathisia Rating Scale and Simpson-Angus Scale scores, more cariprazine than placebo patients experienced treatment-emergent akathisia (cariprazine: 22%; placebo: 6%) or extrapyramidal symptoms (parkinsonism) (cariprazine: 16%; placebo: 1%).. Cariprazine demonstrated superior efficacy versus placebo and was generally well tolerated in patients experiencing acute manic or mixed episodes associated with bipolar I disorder.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Basal Ganglia Diseases; Bipolar Disorder; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Treatment Outcome

This Phase III, randomized, double-blind, placebo-controlled study investigated the efficacy and tolerability of flexibly-dosed cariprazine in patients with acute manic or mixed episodes associated with bipolar I disorder.. Patients were randomized to 3 weeks of double-blind treatment with cariprazine 3-12mg/day (n=158) or placebo (n=154). The primary efficacy parameter was change from baseline to Week 3 in Young Mania Rating Scale (YMRS) total score. The secondary efficacy parameter was change from baseline to Week 3 in Clinical Global Impressions-Severity (CGI-S) score.. Mean change from baseline to Week 3 in YMRS total score was significantly greater for patients receiving cariprazine 3-12mg/day versus placebo (P=0.0004). Significant differences between groups in YMRS total score mean change were observed by Day 4 (first postbaseline assessment) and maintained throughout double-blind treatment (all assessments, P<0.01). Cariprazine also demonstrated statistically significant superiority over placebo on YMRS response (≥50% improvement: cariprazine, 58.9%; placebo, 44.1%; P=0.0097) and remission (YMRS total score≤12: cariprazine, 51.9%; placebo, 34.9%; P=0.0025) and mean change in CGI-S (P=0.0027) score and Positive and Negative Syndrome Scale (PANSS) (P=0.0035) total score. The most common cariprazine-related (≥10% and twice placebo) treatment emergent adverse events (TEAEs) were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting. Mean change from baseline in metabolic parameters were generally small and similar between groups.. Lack of active comparator arm; short duration of study.. In this study, cariprazine 3-12mg/day was effective and generally well tolerated in the treatment of manic and mixed episodes associated with bipolar I disorder.

Topics: Acute Disease; Adult; Aged; Akathisia, Drug-Induced; Antipsychotic Agents; Bipolar Disorder; Double-Blind Method; Drug Administration Schedule; Dyspepsia; Female; Humans; Male; Middle Aged; Piperazines; Severity of Illness Index; Treatment Outcome; Tremor; Vomiting

This phase 3 trial evaluated the efficacy, safety, and tolerability of low- and high-dose cariprazine in patients meeting DSM-IV-TR criteria for acute manic or mixed episodes associated with bipolar I disorder.. This multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed/flexible-dose study was conducted from February 2010 to December 2011. Patients were randomly assigned to placebo, cariprazine 3-6 mg/d, or cariprazine 6-12 mg/d for 3 weeks of double-blind treatment. Primary and secondary efficacy parameters were change from baseline to week 3 in Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions-Severity of Illness (CGI-S) score, respectively. Post hoc analysis examined change from baseline to week 3 in YMRS single items.. A total of 497 patients were randomized; 74% completed the study. The least squares mean difference (LSMD) for change from baseline to week 3 in YMRS total score was statistically significant in favor of both cariprazine groups versus placebo (LSMD [95% CI]: 3-6 mg/d, -6.1 [-8.4 to -3.8]; 6-12 mg/d, -5.9 [-8.2, -3.6]; P < .001 [both]). Both cariprazine treatment groups showed statistically significant superiority to placebo on all 11 YMRS single items (all comparisons, P < .05). Change from baseline in CGI-S scores was statistically significantly greater in both cariprazine groups compared with placebo (LSMD [95% CI]: 3-6 mg/d, -0.6 [-0.9 to -0.4]; 6-12 mg/d, -0.6 [-0.9 to -0.3]; P < .001 [both]). The most common (≥ 5% and twice the rate of placebo) treatment-related adverse events for cariprazine were akathisia (both groups) and nausea, constipation, and tremor (6-12 mg/d only).. Results of this study demonstrated that both low- and high-dose cariprazine were more effective than placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. Cariprazine was generally well tolerated, although the incidence of akathisia was greater with cariprazine than with placebo.. ClinicalTrials.gov identifier: NCT01058668.

Topics: Adolescent; Adult; Aged; Akathisia, Drug-Induced; Bipolar Disorder; Dopamine Agonists; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Placebos; Remission Induction; Severity of Illness Index; Treatment Outcome; Young Adult

Bipolar I disorder is a chronic disorder characterized by episodic recurrences of mania, depression, and mixed affective states interspersed with periods of full or partial remission; subsyndromal residual symptoms between episodes are common and disabling. Cariprazine, an atypical antipsychotic, is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. Post-hoc analyses of pooled data from 3 positive trials were conducted to evaluate the effect of cariprazine 3-12 mg/d on the symptoms of mania in inpatients (18-65 years) with bipolar I disorder and a current manic episode. Analyses were based on the pooled intent-to-treat (ITT) population (placebo=429; cariprazine=608). Mean change from baseline to the end of treatment on individual Young Mania Rating Scale (YMRS) items was analysed using a mixed-effects model for repeated measures (MMRM); categorical symptom severity shifts were analysed using logistic regression. Statistically significant improvement in mean change was seen for cariprazine versus placebo on all 11 YMRS items (p<0.0001); significantly more cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment on 11 YMRS items (p<0.0001) and concurrently on the 4 YMRS core symptoms (irritability, speech, content, and disruptive-aggressive behaviour) (p<0.0001). Significantly more cariprazine- versus placebo-treated patients shifted from a Moderate/Worse or Marked/Worse Symptoms categories to Mild/No Symptoms on all 11 (p<0.0001) and 9 of 11 YMRS items (p<0.05), respectively. Results suggest that cariprazine treatment improved mania across YMRS symptoms; a significant percentage of cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment.

Topics: Adolescent; Adult; Aged; Antimanic Agents; Bipolar Disorder; Double-Blind Method; Female; Follow-Up Studies; Humans; Inpatients; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Treatment Outcome; Young Adult

Akathisia is a neuropsychiatric syndrome that is commonly related to the use of dopamine receptor antagonists/partial agonists. The characteristics of cariprazine-related akathisia, restlessness, and extrapyramidal symptoms (EPS) were investigated in patients with bipolar I depression.. Akathisia-related data from 3 fixed-dose clinical studies of cariprazine 1.5 mg/d and 3 mg/d in bipolar depression were evaluated in pooled post hoc analyses. Outcomes related to treatment-emergent adverse events (TEAEs) included incidence, time to onset, time to resolution, severity, discontinuations, and rescue medication use.. The incidence of akathisia was 7.6% for overall cariprazine (1.5 mg/d=5.5%; 3 mg/d=9.6%) and 2.1% for placebo; acute EPS occurred in 4.5% of cariprazine-treated (1.5 mg/d=3.8%; 3 mg/d=5.1%) and 2.1% of placebo-treated patients. Findings were similar for restlessness. Most TEAEs were mild/moderate (>95%), occurred during the first 3 weeks of cariprazine initiation or dose increase, and resulted in few discontinuations (<3%); median time to resolution of an akathisia or EPS TEAE after the last dose of cariprazine was ~1 week. Rescue medication was used by <3% of patients to manage akathisia/EPS events.. Post hoc analyses; no active comparator.. In patients with bipolar depression, the incidence of cariprazine-related akathisia was higher than acute EPS or restlessness, with lower cariprazine doses associated with lower incidences of events. Akathisia and EPS TEAEs occurred early in treatment and were mild/moderate in severity. Few patients with akathisia or acute EPS discontinued treatment. Cariprazine-related akathisia and EPS can be minimized with conservative dosing and titration strategies.. ClinicalTrials.gov Identifiers: NCT01396447, NCT02670538, NCT02670551.

Topics: Antipsychotic Agents; Bipolar Disorder; Double-Blind Method; Humans; Piperazines; Psychomotor Agitation; Treatment Outcome

Topics: Adult; Antipsychotic Agents; Bipolar Disorder; Clinical Trials as Topic; Datasets as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Biological; Piperazines; Psychiatric Status Rating Scales; Risk Assessment; Schizophrenia; Treatment Outcome

Topics: Antipsychotic Agents; Bipolar Disorder; Humans; Piperazines

To estimate the budget impact (BI) of introducing aripiprazole once-monthly 400 mg/300 mg (AOM 400) in the maintenance monotherapy treatment of bipolar I disorder versus long-acting injectables, oral antipsychotics and best supportive care.. A BI model was developed from a US-payer perspective using treatment-related, hospitalization and adverse event management cost estimates for a hypothetical 1,000,000-member health plan over a 5-year period.. Market share of AOM 400 was predicted to increase from 0.6% in Year 1 (current scenario) to 1.3% in Year 5 (predicted scenario), with predicted increases for paliperidone palmitate, asenapine and cariprazine. Treatment-related costs explained the BI increase, while adverse event and hospitalization costs were reduced. The per member per month incremental cost ranged from US$0.06 to US$0.26 in Years 1-5. The largest increases were predicted for paliperidone palmitate.. As market shares of atypical antipsychotics are predicted to increase, payers may wish to re-evaluate their use.

Topics: Adult; Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Budgets; Cost-Benefit Analysis; Delayed-Action Preparations; Dibenzocycloheptenes; Drug Administration Schedule; Drug Costs; Health Care Costs; Heterocyclic Compounds, 4 or More Rings; Hospitalization; Humans; Injections, Intramuscular; Injections, Subcutaneous; Medication Adherence; Paliperidone Palmitate; Piperazines; Schizophrenia

Atypical antipsychotics have broad-spectrum efficacy against core symptoms of acute mania/mixed states in bipolar disorder; however, they are associated with clinically significant adverse effects (AEs).. This post hoc analysis evaluated the safety and tolerability of the atypical antipsychotic cariprazine in the treatment of adult patients with acute manic/mixed episodes of bipolar I disorder. Data were taken from three 3-week randomized, double-blind, placebo-controlled, flexible-dose trials of cariprazine 3-12mg/d. Patient subgroups categorized by modal daily dose (3-6mg/d; 9-12mg/d) were used to assess dose response.. The pooled safety population comprised 1065 patients (placebo=442; cariprazine 3-6mg/d=263; cariprazine 9-12mg/d=360). More cariprazine- than placebo-treated patients reported double-blind treatment-emergent AEs; the overall AE incidence was similar among cariprazine-dose groups. AEs reported in ≥5% of cariprazine patients overall with at least twice the incidence of placebo were akathisia, extrapyramidal symptoms, restlessness, and vomiting. The incidence of SAEs was low and similar between the placebo- and cariprazine-treatment groups. Metabolic parameter changes were small and generally similar between cariprazine and placebo groups; mean increases in fasting glucose levels were greater with cariprazine (3-6mg/d=6.6mg/dL; 9-12mg/d=7.2mg/dL) than placebo (1.7mg/dL). Mean weight change was 0.54kg and 0.17kg for cariprazine and placebo, respectively; weight increase ≥7% was <3% in all treatment groups. Cariprazine was not associated with clinically meaningful changes in electrocardiogram parameters.. Post hoc analysis, flexible-dose design, short trial duration.. Cariprazine was generally safe and well-tolerated in patients with manic/mixed episodes associated with bipolar I disorder.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Bipolar Disorder; Female; Humans; Male; Middle Aged; Piperazines; Randomized Controlled Trials as Topic

Cariprazine is a new therapeutic agent recently approved for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar disorder, and is under investigation for the treatment of both bipolar depression and major depressive disorder.

Topics: Antipsychotic Agents; Bipolar Disorder; Depressive Disorder, Major; Dopamine Agonists; Drug Partial Agonism; Humans; Piperazines; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Serotonin Receptor Agonists

Topics: Bipolar Disorder; Dopamine Agonists; Female; Humans; Male; Piperazines

In the only bipolar cycling in vitro model, rat hippocampal slices are treated with the sodium pump inhibitor ouabain, which induces epileptiform activity, followed by refractory activity loss that recovers and cycles back to epileptiform activity. Thus, clinical cycling seen in patients with bipolar disorder is modeled on a cellular level as alternating hyperactivity and hypoactivity interspersed with normal activity. In this study, we tested the ability of cariprazine a new antipsychotic candidate to block ouabain-induced changes in rat hippocampal slices. Cycling of population spikes and epileptiform bursts was evoked using an extracellular stimulation electrode located in the Schaeffer collaterals of 400-µm-thick rat hippocampal slices treated with ouabain (3.3μM) alone or in combination with cariprazine (1, 5, 25, and 50µM). Responses were recorded using an extracellular electrode placed in the cell body layer of the CA1 region. Cariprazine 25 and 50µM delayed ouabain-induced epileptiform burst onset and subsequent activity loss. Lower cariprazine concentrations were ineffective. Cariprazine delays the onset of ouabain-induced epileptiform bursts and the loss of spiking activity similarly to that previously demonstrated with the mood stabilizer lithium. These results suggest that cariprazine may have therapeutic potential for treatment of bipolar disorder.

Topics: Animals; Antipsychotic Agents; Bipolar Disorder; Evoked Potentials; Hippocampus; Male; Ouabain; Piperazines; Rats; Rats, Sprague-Dawley

Topics: Antipsychotic Agents; Aripiprazole; Bipolar Disorder; Depressive Disorder, Major; Dopamine Agonists; Drug Administration Schedule; Drug Interactions; Humans; Piperazines; Quinolones; Schizophrenia; Thiophenes

Cariprazine (Vraylar) is an oral atypical antipsychotic originated by Gedeon Richter. It is a potent dopamine D3 and D2 receptor partial agonist, which preferentially binds to the D3 receptor. Cariprazine also has partial agonist activity at serotonin 5-HT1A receptors. In September 2015, cariprazine received its first global approval in the USA for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is also in development in a variety of countries for the treatment of schizophrenia with predominant negative symptoms (phase III), as adjunctive therapy for major depressive disorder (phase II/III) and for the treatment of bipolar depression (phase II). This article summarizes the milestones in the development of cariprazine leading to this first approval for schizophrenia and manic or mixed episodes associated with bipolar I disorder.

Topics: Antipsychotic Agents; Bipolar Disorder; Depressive Disorder, Major; Drug Approval; Humans; Internationality; Patents as Topic; Piperazines; Schizophrenia

Cariprazine (RGH-188), which is being codeveloped by Gedeon Richter Ltd, Forest Laboratories Inc and Mitsubishi Tanabe Pharma Corp, is a novel putative antipsychotic drug that exerts partial agonism at dopamine D2/D3 receptors, with preferential binding to D3 receptors, and partial agonism at serotonin 5-HT1A receptors. Its activity at D2/D3 receptors may be lower than that of the prototype partial agonist aripiprazole. The antipsychotic activity of cariprazine was demonstrated in animal models, and data also suggest that the propensity for extrapyramidal side effects is low and that the drug may have procognitive properties. Cariprazine is rapidly absorbed, with high oral bioavailability and a long plasma elimination t1/2. Cariprazine is in phase III clinical trials in patients with schizophrenia and in patients with bipolar disorder. Data from phase II trials in patients with schizophrenia and bipolar mania indicate that the drug has antipsychotic and antimanic properties that are superior to placebo. With its unique receptor affinity profile, cariprazine may represent a potential enrichment of the therapeutic armamentarium for schizophrenia and affective disorders. Its activity against the cognitive deficits associated with schizophrenia has to be carefully investigated.

Topics: Administration, Oral; Animals; Antipsychotic Agents; Bipolar Disorder; Depression; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Patents as Topic; Piperazines; Receptors, Dopamine D3; Schizophrenia; Structure-Activity Relationship