cariprazine and Schizophrenia

Early treatment of psychotic illness improves outcomes, reduces relapse rates and should not be delayed. Cariprazine is a promising antipsychotic drug and may be a valuable resource when clinicians are in doubt if psychotic symptoms are due to schizophrenia or bipolar disorder.. We conducted a systematic review and meta-analysis that included seven studies (n = 2896) analyzing the effect of cariprazine in psychotic symptoms assessed by the positive and negative symptoms scale (PANSS).. We found cariprazine to be significantly superior to placebo (Hedges' g = 0.40; 95% CI 0.32-0.49) for acute psychosis independently of primary psychiatric diagnosis and also to be superior to placebo for both schizophrenia (Hedges' g = 0.39; 95% CI 0.29-0.50) and bipolar patients (Hedges' g = 0.43; 95% CI 0.27-0.58).. We propose that cariprazine may be useful in treating psychosis independently of nosological differentiation at the beginning of the treatment Key pointsEarly treatment of psychotic illness with antipsychotic medications improves outcomes and reduces relapse rates.Cariprazine was found to be significantly superior to placebo for acute psychosis independently of primary psychiatric diagnosis.Cariprazine may be useful in treating psychosis independently of nosological differentiation between schizophrenia and bipolar disorder at the beginning of the treatment.

Topics: Acute Disease; Antipsychotic Agents; Humans; Piperazines; Psychotic Disorders; Schizophrenia; Treatment Outcome

Cariprazine is a newer 3rd generation antipsychotic acting as partial agonist for dopamine receptors with unique higher affinity for D3 than D2 receptors. This review article summarizes key data from preclinical and clinical studies of cariprazine including pharmacodynamics, pharmacokinetics, clinical efficacy and safety/acceptability in acute short-term and long-term maintenance and relapse prevention therapy in patients with schizophrenia. Efficacy and safety of cariprazine in patients schizophrenia with predominantly negative symptoms resistant to previous antipsychotic therapy is discussed as well.. В обзоре представлены обобщенные данные преклинических и клинических исследований карипразина — новейшего антипсихотика третьего поколения, частичного агониста дофаминовых рецепторов с уникальным предпочтительным взаимодействием с D3 относительно D2 рецепторов. Проводится последовательный анализ параметров фармакодинамики, фармакокинетики, клинической эффективности, переносимости и безопасности на всех этапах терапии шизофрении, включая купирующую терапию манифестных приступов и экзацербаций, профилактику рецидивов и длительную поддерживающую терапию. Обсуждается также эффективность карипразина при замене других антипсихотиков при терапии шизофрении с преобладанием негативных расстройств.

Topics: Antipsychotic Agents; Humans; Piperazines; Receptors, Dopamine D2; Schizophrenia; Treatment Outcome

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Humans; Piperazines; Schizophrenia

Schizophrenia and schizoaffective disorder are treated with antipsychotic drugs. Some patients show treatment-resistant forms of psychotic disorders, and in this case, they can be treated with clozapine. Based on the previous reviews on novel antipsychotic drugs, it is important to know whether the add-on therapy with the new drugs can ameliorate the positive and negative schizophrenic scale (PANSS) total score.. The aim of this review is to suggest an appropriate treatment for patients with treatment-resistant forms of psychotic disorders. A combination of the currently available antipsychotic drugs with novel antipsychotic or modulating drugs might improve negative schizophrenic symptoms and cognitive function and thereby social functioning and quality of life.. The mechanisms of action, the therapeutic effects, and the pharmacokinetic profiles of novel antipsychotic drugs such as cariprazine, brexipiprazole, and lumateperone have been updated. Published case reports of patients with treatment-resistant psychoses have also been discussed in this study. These patients were treated only with clozapine, as a result of which a high PANSS total score was observed. Only the add-on therapy with cariprazine improved the score, and above all, the negative schizophrenic symptoms and cognitive functions were improved. For the ensurance of a constant antipsychotic drug concentration, long-acting injectable antipsychotic drugs might be a choice for the maintenance therapy in schizophrenia. New modulating drugs, such as receptor positive allosteric modulators (N-methyl-D-aspartate receptor; subtype 5 of the metabotropic glutamatergic receptor) and encenicline, an alpha7 nicotinic cholinergic receptor agonist, have been investigated in preclinical and clinical trials.. In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know whether combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total score. In schizophrenia, long-acting injectable antipsychotic drugs are safe and tolerable maintenance therapy. In further clinical studies, it should be investigated whether patients with treatment-resistant forms of psychoses can improve negative schizophrenic symptoms and cognitive functions by the add-on therapy with cognitionenhancing drugs.

Topics: Antipsychotic Agents; Cognition; Humans; Pharmaceutical Preparations; Piperazines; Quality of Life; Schizophrenia; Treatment Outcome

The dose-response relationships of antipsychotic drugs for schizophrenia are not well defined, but such information would be important for decision making by clinicians. The authors sought to fill this gap by conducting dose-response meta-analyses.. A search of multiple electronic databases (through November 2018) was conducted for all placebo-controlled dose-finding studies for 20 second-generation antipsychotic drugs and haloperidol (oral and long-acting injectable, LAI) in people with acute schizophrenia symptoms. Dose-response curves were constructed with random-effects dose-response meta-analyses and a spline model. The outcome measure was total score reduction from baseline on the Positive and Negative Syndrome Scale or the Brief Psychiatric Rating Scale. The authors identified 95% effective doses, explored whether higher or lower doses than the currently licensed ones might be more appropriate, and derived dose equivalencies from the 95% effective doses.. Sixty-eight studies met the inclusion criteria. The 95% effective doses and the doses equivalent to 1 mg of oral risperidone, respectively, were as follows: amisulpride for patients with positive symptoms, 537 mg/day and 85.8 mg; aripiprazole, 11.5 mg/day and 1.8 mg; aripiprazole LAI (lauroxil), 463 mg every 4 weeks and 264 mg; asenapine, 15.0 mg/day and 2.4 mg; brexpiprazole, 3.36 mg/day and 0.54 mg; haloperidol, 6.3 mg/day and 1.01 mg; iloperidone, 20.13 mg/day and 3.2 mg; lurasidone, 147 mg/day and 23.5 mg; olanzapine, 15.2 mg/day and 2.4 mg; olanzapine LAI, 277 mg every 2 weeks and 3.2 mg; paliperidone, 13.4 mg/day and 2.1 mg; paliperidone LAI, 120 mg every 4 weeks and 1.53 mg; quetiapine, 482 mg/day and 77 mg; risperidone, 6.3 mg/day and 1 mg; risperidone LAI, 36.6 mg every 2 weeks and 0.42 mg; sertindole, 22.5 mg/day and 3.6 mg; and ziprasidone, 186 mg/day and 30 mg. For amisulpride and olanzapine, specific data for patients with predominant negative symptoms were available. The authors have made available on their web site a spreadsheet with this method and other updated methods that can be used to estimate dose equivalencies in practice.. In chronic schizophrenia patients with acute exacerbations, doses higher than the identified 95% effective doses may on average not provide more efficacy. For some drugs, higher than currently licensed doses might be tested in further trials, because their dose-response curves did not plateau.

Topics: Acute Disease; Administration, Oral; Antipsychotic Agents; Aripiprazole; Clozapine; Delayed-Action Preparations; Dose-Response Relationship, Drug; Haloperidol; Humans; Imidazoles; Indoles; Isoxazoles; Lurasidone Hydrochloride; Olanzapine; Paliperidone Palmitate; Piperazines; Piperidines; Quetiapine Fumarate; Quinolones; Risperidone; Schizophrenia; Schizophrenic Psychology; Thiazoles; Thiophenes

Aripiprazole, brexpiprazole and cariprazine differ from all other second-generation antipsychotics due to partial agonism at the dopamine D2 and D3 receptors. In contrast to aripiprazole, brexpiprazole has lower intrinsic dopamine D2 activity and higher affinity for the serotonin 5-HT1A and 5-HT2A receptors, while cariprazine has the highest affinity for the dopamine D3 receptor, and the longest half-life. The main adverse effect of dopamine receptor partial agonists (DRPAs) is akathisia of low-to-moderate severity, which occurs in a small proportion of patients, usually in the first few weeks of treatment. While definitive conclusions concerning differences between the DRPAs require head-to-head comparison studies, on the available evidence, akathisia is probably least likely to occur with brexpiprazole and most likely with cariprazine; the risk of akathisia with aripiprazole lies in between. Weight-gain risk is low with aripiprazole and cariprazine, but moderate with brexpiprazole. Risk of sedation is low with DRPAs, as is risk of insomnia and nausea. Partial dopamine agonism leads to a low risk for hyperprolactinaemia (and probably a low risk of sexual dysfunction). Prolactin concentrations fall in some patients (particularly those with elevated levels prior to initiating the drugs). Rates of discontinuation due to adverse effects in pivotal studies were low, and on the whole, DRPAs are well tolerated. Aripiprazole has been implicated in pathological gambling and other impulse control behaviours, likely due to partial dopamine agonist activity (there have been no reports with brexpiprazole and cariprazine). The risks for diabetes and tardive dyskinesia with DRPAs are unknown, but are likely to be low. On the basis of tolerability, DRPAs should be considered as first-line treatment options, particularly in patients with early schizophrenia.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Dopamine Agonists; Humans; Piperazines; Quinolones; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Thiophenes

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

Cariprazine is a new atypical antipsychotic drug (APD) with a unique pharmacodynamic profile, different from both typical and atypical APDs. Specifically, cariprazine acts as a partial agonist at the dopamine (DA) D2 and D3 receptors and serotonin 5-HT1A receptors, and as an antagonist at the 5-HT2B receptors. Moreover, it shows moderate affinities for adrenergic, histaminergic, and cholinergic receptors that are involved in mediating the side effects characteristic of typical APDs. In this review, we discuss the contribution of DA D3 receptors (D3Rs) in the etiology and pathophysiology of schizophrenia and the potential benefits that may be associated with a more selective targeting of D3R by APDs, as compared to other dopaminergic and non-dopaminergic receptor subtypes. Cariprazine, by acting on D3Rs, ameliorates anhedonia and cognitive deficits in animal models based on environmental or pharmacological manipulation. The reviewed results support the potential benefits of cariprazine in treating negative symptoms and cognitive deficits of schizophrenia, and therefore representing a promising approach in addressing the unmet clinical needs for the improved treatment of this serious neuropsychiatric disorder.

Topics: Animals; Antipsychotic Agents; Dopamine Agonists; Humans; Piperazines; Receptors, Dopamine D3; Schizophrenia

Since 2018, cariprazine has been available for the treatment of schizophrenia on the Dutch and Belgian markets.
AIM: To give an overview of the indications, effectiveness and side effects of cariprazine. To make an inventory of the advantages and disadvantages of this new antipsychotic drug.
METHOD: A clinically oriented literature review of published clinical studies and pharmacodynamic and -kinetic publications.
RESULTS: Cariprazine is unique because of its preferential D3 receptor partial agonist affinity and has, in theory, a beneficial effect on negative symptoms. The antipsychotic has two active metabolites: desmethylcariprazine and didesmethylcariprazine. The long half-life of cariprazine indicates that, in theory, the drug should not be given daily. Cariprazine is metabolized by cyp3a4 and to a lesser extent by cyp2d6 enzymes. Extrapyramidal symptoms and akathisia are relatively frequent side effects. In contrast, metabolic side effects and weight gain have been reported rarely.
CONCLUSION: Cariprazine can be an effective treatment option for schizophrenia. The final positioning of this antipsychotic drug will have to be based on future research.

Topics: Antipsychotic Agents; Dopamine Agonists; Humans; Piperazines; Schizophrenia; Treatment Outcome

There are many psychotropic drugs available for treatment of schizophrenia. The clinician's choice of the most effective first-line antipsychotic treatment for patients with schizophrenia should balance considerations of differential efficacy of antipsychotics against the relative risk of different side effects.. We reviewed recent studies using meta-analytic techniques and additional studies of new antipsychotics which quantitatively evaluate the efficacy of side effects of first- and second-generation antipsychotics and studies of the efficacy on add-on secondary medications. We present an integrated summary of these results to guide a clinician's decision-making.. Recent meta-analyses have suggested that antipsychotics are not equivalent in efficacy. Clozapine (effect size [SMD] 0.88 vs. placebo), amisulpride (effect size 0.6 vs placebo), olanzapine (effect size 0.59 vs. placebo), and risperidone (effect size 0.56 vs placebo) show small but statistically significant differences compared to a number of other antipsychotics on measures of overall efficacy (effect sizes 0.33-0.50). However, increasing placebo response remains a concern in interpreting these data. Amisulpride (effect size 0.47 vs placebo) and cariprazine (effect size in one trial compared to risperidone 0.29) have the strongest evidence indicating greater efficacy for treating primary negative symptoms relative to other antipsychotics. In terms of side effects, clozapine and olanzapine have among the highest weight gain potential and sertindole and amisulpride have more effects on QTc prolongation than other commonly used antipsychotics. Prolactin elevation is highest with paliperidone, risperidone, and amisulpride. Adjunctive treatment with an antidepressant drug may improve response in patients with schizophrenia who also have severe depressive or negative symptoms. For multi-episode patients with an inadequate response to an adequate dose and duration of the initial antipsychotic choice, switching to another antipsychotic, with a different receptor profile, may improve response, although evidence is very limited. In first-episode patients, a recent study on switching to another antipsychotic, with a different receptor profile after 4 weeks demonstrated no beneficial effects. There is little evidence to support using doses above the therapeutic range other than in exceptional circumstances.. Our review of recent studies using meta-analytic techniques has provided evidence that all antipsychotics are not equal in the severity of different side effects and in some measures of clinical efficacy. Comparative analysis and rankings from network meta-analyses can provide guidance to clinicians in choosing the most appropriate antipsychotic for first-line treatment, if used in conjunction with available information of the patient's history of previous clinical response or higher risks for specific side effects.

Topics: Amisulpride; Antidepressive Agents; Antipsychotic Agents; Clozapine; Depression; Humans; Imidazoles; Indoles; Olanzapine; Piperazines; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

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

The purpose of this study was to assess the efficacy and acceptability of cariprazine treatment in acute exacerbation of schizophrenia.. This review included randomized controlled trials of patients with acute exacerbation of schizophrenia in relation to efficacy and acceptability. The efficacy outcomes were assessed by pooling standardized mean differences (SMDs) calculated from the difference in the reduction in the mean of the Positive and Negative Syndrome Scale (PANSS) total score, PANSS positive and negative scores, and response rate. The primary acceptability outcomes were determined by pooling the risk ratios (RRs) of discontinuation for any reason, the incidence of serious adverse events, and treatment emergent events.. Four randomized controlled trials consisting of 1843 patients met all inclusion and exclusion criteria. Efficacy analysis showed significant positive effects in relation to cariprazine therapy (SMD: -0.37, P < 0.00001 for PANSS total score change; SMD: -0.32, P < 0.00001 for PANSS positive score change; SMD: -0.32, P < 0.0001 for PANSS negative score change; RR, 1.41; 95% confidence interval [CI], 1.19-1.67; P < 0.0001 for response rate). For primary acceptability outcomes, less patients taking cariprazine discontinued treatment for any reason compared with patients receiving placebo (RR, 0.90; 95% CI, 0.78-1.04; P = 0.16). Significantly less patients on cariprazine had serious adverse events during the double-blind treatment period compared with patients taking placebo (RR, 0.55; 95% CI, 0.34-0.89; P = 0.01). Significantly more patients on cariprazine had treatment emergent events compared with those receiving placebo (RR, 1.10; 95% CI, 1.03-1.18; P = 0.006).. Results suggest that cariprazine may be an effective and acceptable treatment for schizophrenia and future research is warranted.

Topics: Acute Disease; Antipsychotic Agents; Humans; Patient Acceptance of Health Care; Piperazines; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult patients. It is typically administered orally once a day (a dose range 1.5 - 6 mg/day), does require titration, and may be given with or without food. It has a half-life of 2 - 4 days with an active metabolite that has a terminal half-life of 2 - 3 weeks. Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. This article is based on the available literature with respect to the preclinical and clinical findings and product labels of cariprazine. Expert opinion: Cariprazine shows highest affinity toward D

Topics: Adult; Animals; Antipsychotic Agents; Dose-Response Relationship, Drug; Drug Development; Drug Discovery; Drug Evaluation, Preclinical; Half-Life; Humans; Piperazines; Schizophrenia

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

Although the development of second-generation antipsychotics was a cornerstone in the treatment of schizophrenia, several unmet treatment needs in the field still exist. It is particularly important to note that available antipsychotics have limited efficacy in the treatment of negative symptoms and cognitive impairment. At this point, it should be noted that primary negative symptoms, i.e., those that are not due to depression, extrapyramidal symptoms or psychotic withdrawal, might affect even one-fourth of patients with schizophrenia and are associated with poor clinical and functional outcomes. Cariprazine, is an emerging antipsychotic drug, D3/D2 receptor partial agonist, with affinity to several serotonin receptors. In this article, we provide an overview of pharmacokinetic and pharmacodynamic properties of cariprazine, showing its unique receptor profile. Next, we discuss results of double-blind, placebo-controlled, randomized clinical trials and post hoc analyses of cariprazine that have been published to date. These studies have provided evidence for efficacy of cariprazine in the treatment of schizophrenia exacerbations compared to placebo, with safety and good tolerability. In addition, one clinical trial published to date revealed superior efficacy of cariprazine compared to risperidone in the treatment of predominant negative symptoms that had been also associated with concomitant improvement of functional performance. Overall, current evidence in the field supports the use of cariprazine in exacerbation of schizophrenia and suggests promising efficacy in the treatment of predominant negative symptoms.

Topics: Antipsychotic Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Medication Adherence; Piperazines; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Treatment Outcome

Cariprazine, a potent dopamine D3 and D2 receptor partial agonist antipsychotic with preferential binding to D3 receptors, is Food and Drug Administration approved for treating schizophrenia and manic or mixed episodes of bipolar I disorder. A post-hoc safety/tolerability analysis of data from the four acute trials in the cariprazine schizophrenia clinical development program (NCT00404573; NCT00694707; NCT01104766; NCT01104779) was carried out using the overall safety population (all patients who received ≥1 dose of study drug) and modal daily dose subgroups (1.5-3, 4.5-6, and 9-12 mg/day). These exploratory findings were summarized using descriptive statistics. Cariprazine was generally well tolerated. The incidence of treatment-emergent adverse events versus placebo was similar for cariprazine 1.5-3 mg/day and higher for cariprazine 4.5-6 and 9-12 mg/day; a dose-response relationship was observed for akathisia, extrapyramidal symptoms, and diastolic blood pressure. The mean changes in metabolic parameters were generally similar in cariprazine-treated and placebo-treated patients. There was no prolactin level increase or QTc value greater than 500 ms; small increases in mean body weight (∼1to2 kg) versus placebo were observed. Within the Food and Drug Administration-approved dose range (1.5-6 mg/day), cariprazine was generally safe and well tolerated in patients with schizophrenia.

Topics: Acute Disease; Antipsychotic Agents; Basal Ganglia Diseases; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dopamine Agonists; Double-Blind Method; Headache; Humans; Piperazines; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Cariprazine is a new dopamine D2 and D3 receptor partial agonist antipsychotic. Meta-analytic evidence of efficacy in acute schizophrenia and specific groups of patients is lacking. We carried out a meta-analysis in patients with acute schizophrenia to evaluate the efficacy of cariprazine over placebo and active comparators in overall symptoms, positive and negative symptoms and quality of life. Low and high (≥6 mg/day) doses were tested separately. The possible effect of clinical-demographic modulators was also tested. Four studies (2144 patients) were included. Both high and low cariprazine doses proved superior to placebo in all symptom domains. The standardized mean difference (SMD) to placebo showed a modest impact on overall symptoms compared with meta-analytic results for other antipsychotics (SMD was similar to lurasidone, asenapine, ziprasidone and aripiprazole, but lower than risperidone, quetiapine and olanzapine). The SMD to placebo on negative symptoms was superior to many antipsychotics including aripiprazole, with a slightly more relevant effect of cariprazine low doses. This effect was probably on secondary negative symptoms since the short-term follow-up of the studies included. Meta-regression data further refined the compound clinical profile, suggesting that cariprazine may be particularly useful in young patients with a relatively short duration of disease.

Topics: Acute Disease; Antipsychotic Agents; Dopamine Agonists; Humans; Piperazines; Randomized Controlled Trials as Topic; Regression Analysis; Schizophrenia; Treatment Outcome

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

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

There are several new and emerging medication interventions for both the acute and maintenance treatment phases of schizophrenia. Recently approved are 2 new dopamine receptor partial agonists, brexpiprazole and cariprazine, as well as 2 new long-acting injectable antipsychotic formulations, aripiprazole lauroxil and 3-month paliperidone palmitate. Although differences in efficacy compared to other available choices are not expected, the new oral options offer different tolerability profiles that may be attractive for individual patients who have had difficulties with older medications. The new long-acting injectable options provide additional flexibility in terms of increasing the time interval between injections. In Phase III of clinical development is a novel antipsychotic, lumateperone (ITI-007), that appears to have little in the way of significant adverse effects. Deutetrabenazine and valbenazine are agents in Phase III for the treatment of tardive dyskinesia, a condition that can be found among persons receiving chronic antipsychotic therapy. On the horizon are additional injectable formulations of familiar antipsychotics, aripiprazole and risperidone, that may be more convenient than what is presently available.

Topics: Antipsychotic Agents; Aripiprazole; Delayed-Action Preparations; Humans; Injections, Intramuscular; Paliperidone Palmitate; Piperazines; Quinolones; Schizophrenia; Tetrabenazine; Thiophenes; Valine

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 an atypical antipsychotic in clinical development for the treatment of schizophrenia and bipolar mania/mixed episodes.. The purpose of this review is to describe the chemistry, pharmacodynamic profile, pharmacokinetics, and clinical profile of cariprazine.. Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist. Doses ≥ 1.5 mg/d yielded 69 - 75% D2/D3 receptor occupancy as measured in positron emission tomography scans. Mean half-life for cariprazine was 2 - 5 d over a dose range of 1.5 - 12.5 mg. Cariprazine produces two clinically relevant metabolites: desmethyl-cariprazine and didesmethyl-cariprazine, the latter having a longer half-life than cariprazine. Exposure to didesmethyl-cariprazine exceeded that of the parent drug. Cariprazine is metabolized by CYP3A4 and to a lesser extent by CYP2D6. The efficacy and safety of cariprazine have been so far investigated only in a few short-term (unpublished) clinical trials; however, three studies in schizophrenia and three studies in bipolar mania/mixed episodes evidenced a statistically significant therapeutic effect compared to placebo for cariprazine at doses ranging from 1.5 to 12 mg/d. There does not appear to be clinically relevant adverse effects of cariprazine on metabolic variables. Commonly encountered adverse events associated with cariprazine include insomnia, extrapyramidal symptoms, akathisia, sedation, nausea, dizziness, and constipation.

Topics: Animals; Antipsychotic Agents; Clinical Trials as Topic; Humans; Piperazines; Schizophrenia; Treatment Outcome

Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist in late-stage clinical development for the treatment of schizophrenia, as well as for bipolar disorder (manic/mixed and depressive episodes), and as an adjunctive agent for the treatment of major depressive disorder. Four phase 2 or 3, 6-week, randomized controlled trials in acute schizophrenia have been completed and reported as poster presentations or in press releases by the manufacturer. Superiority over placebo on the Positive and Negative Syndrome Scale total score was evidenced for cariprazine in daily doses of 1.5, 3.0, 4.5, 6.0, 1.5-4.5, 3.0-6.0, and 6.0-9.0 mg. A randomized controlled trial for the prevention of relapse of schizophrenia is ongoing. In short-term, randomized controlled trials, cariprazine does not appear to adversely impact metabolic variables, prolactin, or the electrocardiogram (ECG) QT interval. In the fixed-dose study of cariprazine that tested 1.5, 3.0, and 4.5 mg/day, the most commonly encountered adverse events were insomnia, extrapyramidal disorder, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation. However, 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. 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 second-generation antipsychotics.

Topics: Antipsychotic Agents; Humans; Piperazines; Randomized Controlled Trials as Topic; Receptors, Dopamine D3; Schizophrenia; Treatment Outcome

The dopamine system plays a crucial role in the pathophysiology of many neuropsychiatric disorders. Altough there is sufficient information and knowledge about several dopamine receptor subtypes and their functions, until the last decade the role of the D3 receptor was almost unclear. Recent research data proved that the D3 receptor might have a significant role in fine tuning the modulation of dopaminergic neurotransmission. Cariprazine is a novel agent developed in Hungary, its activity on the dopamine D3 receptor might open up new dimensions in the pharmacotherapy of schizophrenia and affective disorders.

Topics: Animals; Antipsychotic Agents; Humans; Hungary; Mood Disorders; Piperazines; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Synaptic Transmission

The aim of the post hoc analysis was to better understand the efficacy and safety of cariprazine in patients with schizophrenia for less than 5 years (early stage) and for more than 15 years (late stage).. Data from three phase II/III randomized, double-blind, placebo-controlled trials with similar design in patients with acute exacerbation of schizophrenia were pooled and patients with early and late stage of schizophrenia were determined. A mixed-effects model for repeated measures approach was applied and least square (LS) mean changes from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) total and factor scores were reported. Descriptive statistics were used for safety analyses including treatment emergent adverse events (TEAEs) and discontinuation rates.. Overall, 460 patients were identified as being in the early and 414 in the late stage of schizophrenia. The pooled analysis evaluating mean change from baseline to week 6 in the PANSS total score indicated statistically significant difference between cariprazine and placebo in favor of cariprazine in both the early (LS mean difference [LSMD] -7.5. In conclusion, cariprazine, a potent D

Topics: Antipsychotic Agents; Double-Blind Method; Humans; Piperazines; Schizophrenia; Treatment Outcome

Although currently approved antipsychotics exert efficacy on positive symptoms of schizophrenia, treatments for negative symptoms remain a major unmet need. Post hoc analyses were used to investigate the possible efficacy of cariprazine in patients with moderate/severe negative symptoms of schizophrenia and no predominance of positive symptoms. Data were pooled from 2 randomized, double-blind, placebo- and active-controlled cariprazine studies in patients with acute schizophrenia (NCT00694707, NCT01104766). Analyses included data from a subset of patients with a Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) ≥24, PANSS factor score for positive symptoms (PANSS-FSPS) ≤19, and scores of ≥4 on ≥2 of 3 PANSS items (blunted affect [N1], passive/apathetic social withdrawal [N4], lack of spontaneity/flow of conversation [N6]). Changes from baseline to week 6 in PANSS-FSNS were evaluated in the following treatment groups: placebo (n = 79), cariprazine 1.5-3 (n = 94) and 4.5-6 mg/d (n = 66), risperidone 4 mg/d (n = 34), or aripiprazole 10 mg/d (n = 44). Significant differences were observed versus placebo for cariprazine (1.5-3 mg/d, P = .0179; 4.5-6 mg/d, P = .0002) and risperidone (P = .0149), but not aripiprazole (P = .3265), and versus aripiprazole for cariprazine 4.5-6 mg/d (P = .0197). After adjusting for positive symptom changes, differences versus placebo remained statistically significant for cariprazine (1.5-3 mg/d, P = .0322; 4.5-6 mg/d, P = .0038) but not for risperidone (P = .2204). PANSS-FSNS response (≥20% reduction from baseline) rates were significantly higher with cariprazine (1.5-3 mg/d = 54.3%, P = .0194; 4.5-6 mg/d = 69.7%, P = .0001) than placebo (35.4%). In patients with acute schizophrenia and moderate/severe negative symptoms, cariprazine was associated with significantly greater improvement in negative symptoms compared with placebo and aripiprazole, warranting further exploration of the efficacy of cariprazine on negative symptoms.

Topics: Acute Disease; Adolescent; Adult; Antipsychotic Agents; Aripiprazole; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Piperazines; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Young Adult

Long-term remission is an important treatment goal in schizophrenia. Cariprazine, a dopamine D₃/D₂ receptor and serotonin 5-HT1A receptor partial agonist, is approved in the United States and Europe to treat adults with schizophrenia.. Post hoc analyses of data from a long-term cariprazine relapse prevention study (NCT01412060; September 27, 2011-September 3, 2014) investigated the efficacy of cariprazine for maintaining remission in clinically stable patients with DSM-IV-TR-defined schizophrenia. Patients were stabilized with open-label cariprazine (20 weeks), then randomized 1:1 to cariprazine (3, 6, or 9 mg/d) or placebo for double-blind treatment (up to 72 weeks). Symptomatic remission was defined as scores ≤ 3 on 8 items from the General, Positive, and Negative Symptoms subscales of the Positive and Negative Syndrome Scale (PANSS). Sustained remission included meeting remission criteria at the current and all prior double-blind visits or for ≥ 6 consecutive months.. At randomization, 169/200 patients (84.5%) met symptomatic remission criteria. During double-blind treatment, time to loss of sustained remission was significantly longer (P = .0020) for cariprazine versus placebo (hazard ratio = 0.51); 60.5% of cariprazine-treated and 34.9% of placebo-treated patients sustained remission through the final visit (odds ratio [OR] = 2.85; P = .0012; number needed to treat [NNT] = 4). Almost twice as many cariprazine-treated (39.6%) as placebo-treated (21.2%) patients met symptomatic remission criteria at all visits ≥ 6 consecutive months immediately before/including the final double-blind visit (OR = 2.44; P = .0057; NNT = 6). More cariprazine-treated (41.6%) than placebo-treated (27.3%) patients sustained remission for any ≥ 6 consecutive month period (OR = 1.90, P = .0379; NNT = 7).. Cariprazine was associated with significantly longer sustained remission, higher remission rates, and increased likelihood of sustaining remission for ≥ 6 consecutive months versus placebo.. ClinicalTrials.gov identifier: NCT01412060.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Piperazines; Schizophrenia; Secondary Prevention; Time Factors; Treatment Outcome; Young Adult

Cariprazine, a dopamine D3/D2 partial agonist atypical antipsychotic with preferential binding to D3 receptors, is approved for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of cariprazine was established in three randomized, double-blind, placebo-controlled, 6-week trials in patients with acute exacerbation of schizophrenia. This 53-week study evaluated the long-term safety and tolerability of cariprazine in patients with schizophrenia.. This was a multicenter, open-label, flexible-dose study of cariprazine 3-9 mg/d in adults with schizophrenia. Participants included new patients and patients who had completed one of two phase III lead-in studies (NCT01104766, NCT01104779). Eligible patients entered a no-drug screening period of up to 1 week followed by 48 weeks of flexibly dosed, open-label cariprazine treatment (3-9 mg/d) and 4 weeks of safety follow-up.. A total of 586 patients received open-label cariprazine treatment, ~39% of whom completed the study. No unexpected safety issues or deaths were reported. The most common (≥10%) adverse events (AEs) observed were akathisia (16%), headache (13%), insomnia (13%), and weight gain (10%). Serious AEs occurred in 59 (10.1%) patients, and 73 (12.5%) patients discontinued the study due to AEs during open-label treatment. Mean changes in metabolic, hepatic, and cardiovascular parameters were not considered clinically relevant. Mean body weight increased by 1.5 kg during the study, prolactin levels decreased slightly, and measures of efficacy remained stable.. Long-term cariprazine treatment at doses up to 9 mg/d appeared to be generally safe and well tolerated in patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Female; Headache; Humans; Male; Maximum Tolerated Dose; Middle Aged; Piperazines; Psychomotor Agitation; Schizophrenia; Sleep Initiation and Maintenance Disorders; Weight Gain

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

Our study aimed at estimating differences in quality-adjusted life year (QALY) gain for patients with predominant negative symptoms of schizophrenia treated with cariprazine compared with risperidone.. A Markov model was built, based on the Mohr-Lenert approach and data derived from clinical trials, to estimate potential QALY gains of patients.. Patients had higher probability of reaching better health states treated with cariprazine compared with risperidone. In the model, this resulted in an estimated QALY gain of 0.029 per patient, after 1 year of treatment.. Cariprazine, which showed clinically meaningful improvement in the symptoms, and personal and social performance, can also provide significant QALY gain in the treatment of patients with predominant negative symptoms of schizophrenia compared with risperidone.

Topics: Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Quality-Adjusted Life Years; Risperidone; Schizophrenia; Treatment Outcome

Although predominant negative symptoms of schizophrenia can be severe enough to cause persistent impairment, effective treatment options are lacking. We aimed to assess the new generation antipsychotic cariprazine in adult patients with predominant negative symptoms.. In this randomised, double-blind, phase 3b trial, we enrolled adults aged 18-65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres (mainly hospitals and university clinics, with a small number of private practices) in 11 European countries. Patients were randomly assigned (1:1) by an interactive web response system to 26 weeks of monotherapy with fixed-dose oral cariprazine (3 mg, 4·5 mg [target dose], or 6 mg per day) or risperidone (3 mg, 4 mg [target dose], or 6 mg per day); previous medication was discontinued over 2 weeks. The primary outcome was change from baseline to week 26 or end of treatment on the Positive and Negative Syndrome Scale factor score for negative symptoms (PANSS-FSNS) analysed in a modified intention-to-treat population of patients who had follow-up assessments within 5 days after last receipt of study drugs with a mixed-effects model for repeated measures. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, number 2012-005485-36.. Between May 27, 2013, and Nov 17, 2014, 533 patients were screened and 461 (86%) patients were randomised to treatment (230 for cariprazine and 231 for risperidone); 460 were included in the safety population (one patient discontinued before study drug intake). 227 (99%) of 230 patients in the cariprazine group and 229 (99%) of 230 patients in the risperidone group were included in the modified intention-to-treat population (178 [77%] in each group completed 26 weeks of treatment). Mean daily doses were 4·2 mg (SD 0·6) for cariprazine and 3·8 mg (0·4) for risperidone. Treatment-emergent adverse events (eg, insomnia, akathisia, worsening of schizophrenia, headache, anxiety) were reported in 123 (54%) patients treated with cariprazine and 131 (57%) patients treated with risperidone. Use of cariprazine led to a greater least squares mean change in PANSS-FSNS from baseline to week 26 than did risperidone (-8·90 points for cariprazine vs -7·44 points for risperidone; least squares mean difference -1·46, 95% CI -2·39 to -0·53; p=0·0022; effect size 0·31). One patient in the risperidone group died of a cause regarded as unrelated to treatment.. Our results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia.. Gedeon Richter Plc.

Topics: Adult; Antipsychotic Agents; Behavioral Symptoms; Double-Blind Method; Female; Humans; Male; Middle Aged; Piperazines; Risperidone; Schizophrenia; Schizophrenic Psychology; Treatment Outcome

This 6-week, double-blind, placebo-controlled, proof-of-concept study evaluated the efficacy, safety, and tolerability of low-dose (1.5-4.5 mg/day) and high-dose (6-12 mg/day) cariprazine in patients with acute exacerbation of schizophrenia (NCT00404573). The primary efficacy measure was change in the Positive and Negative Syndrome Scale (PANSS) total score, analyzed using a last observation carried forward approach. Other efficacy measures included the Clinical Global Impression-Severity (secondary) and PANSS subscales (additional). There were no significant differences between the two doses of cariprazine and placebo in PANSS total score change or any other efficacy parameter after multiplicity adjustment. However, low-dose cariprazine versus placebo showed significantly greater reductions in PANSS total (P=0.033) and PANSS negative (P=0.027) scores without multiplicity adjustment. Common treatment-emergent adverse events (incidence≥5% and twice that in the placebo group in either cariprazine dose group) were akathisia, restlessness, tremor, back pain, and extrapyramidal disorder. In this study, the overall cariprazine treatment effect was not statistically significant, but patients treated with low-dose cariprazine showed significantly greater improvement in schizophrenia symptoms relative to placebo-treated patients. Cariprazine was generally well tolerated. Results of this study suggest that cariprazine may be effective in treating schizophrenia and future research is warranted.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology; Time Factors; Treatment Outcome; United States

Cariprazine is a potent dopamine D3-preferring D3/D2 receptor partial agonist in development for the treatment of schizophrenia, bipolar mania, and depression. Pharmacokinetics of cariprazine and the two clinically relevant metabolites (desmethyl- and didesmethyl-cariprazine) was evaluated in a clinical pharmacology study.. This was a multicenter, randomized, open-label, parallel-group, fixed-dose (3, 6, or 9 mg/day) study of 28-week duration (≤4-week observation, 12-week open-label treatment, and 12-week follow-up). Once-daily cariprazine was administered to 38 adult patients with schizophrenia. The pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites) was evaluated; efficacy and safety were also assessed.. Steady state was reached within 1-2 weeks for cariprazine and desmethyl-cariprazine, 4 weeks for didesmethyl-cariprazine, and 3 weeks for total active moieties. Cariprazine and desmethyl-cariprazine levels decreased >90% within 1 week after the last dose, didesmethyl-cariprazine decreased ~50% at 1 week, and total active moieties decreased ~90% within 4 weeks. Terminal half-lives of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. Effective half-life (calculated from time to steady state) of total active moieties was ~1 week. Incidence of treatment-emergent adverse events was 97.4%; 15.8% of patients discontinued due to adverse events. No abnormal laboratory values or major differences from baseline in extrapyramidal symptoms were observed.. Cariprazine and its active metabolites reached steady state within 4 weeks, and exposure was dose proportional over the range of 3-9 mg/day. Once-daily cariprazine was generally well tolerated in adult patients with schizophrenia.

Topics: Adult; Antipsychotic Agents; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Half-Life; Humans; Male; Middle Aged; Piperazines; Schizophrenia; Treatment Outcome

Cariprazine, a dopamine D3/D2 receptor partial agonist with preference for D3 receptors, has demonstrated efficacy in randomized controlled trials in schizophrenia. This multinational, randomized, double-blind, placebo-controlled, parallel-group study evaluated the efficacy, safety, and tolerability of cariprazine for relapse prevention in adults with schizophrenia; total study duration was up to 97weeks. Schizophrenia symptoms were treated/stabilized with cariprazine 3-9mg/d during 20-week open-label treatment consisting of an 8-week, flexible-dose run-in phase and a 12-week fixed-dose stabilization phase. Stable patients who completed open-label treatment could be randomized to continued cariprazine (3, 6, or 9mg/d) or placebo for double-blind treatment (up to 72weeks). The primary efficacy parameter was time to relapse (worsening of symptom scores, psychiatric hospitalization, aggressive/violent behavior, or suicidal risk); clinical measures were implemented to ensure safety in case of impending relapse. A total of 264/765 patients completed open-label treatment; 200 eligible patients were randomized to double-blind placebo (n=99) or cariprazine (n=101). Time to relapse was significantly longer in cariprazine- versus placebo-treated patients (P=.0010, log-rank test). Relapse occurred in 24.8% of cariprazine- and 47.5% of placebo-treated patients (hazard ratio [95% CI]=0.45 [0.28, 0.73]). Akathisia (19.2%), insomnia (14.4%), and headache (12.0%) were reported in ≥10% of patients during open-label treatment; there were no cariprazine adverse events ≥10% during double-blind treatment. Long-term cariprazine treatment was significantly more effective than placebo for relapse prevention in patients with schizophrenia. The long-term safety profile in this study was consistent with the safety profile observed in previous cariprazine clinical trials. ClincalTrials.gov identifier: NCT01412060.

Topics: Administration, Oral; Adolescent; Adult; Antipsychotic Agents; Double-Blind Method; Female; Follow-Up Studies; Humans; Internationality; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Schizophrenia; Secondary Prevention; Young Adult

This phase III study evaluated the efficacy and safety of cariprazine, a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, in patients with acute exacerbation of schizophrenia. Patients were randomized to 6-week double-blind treatment with placebo, cariprazine 3 to 6 mg/d, or cariprazine 6 to 9 mg/d. Primary and secondary efficacy: change from baseline to week 6 in Positive and Negative Syndrome Scale total and Clinical Global Impressions-Severity scores, respectively, analyzed using a mixed-effects model for repeated measures adjusting for multiple comparisons. Safety included treatment-emergent adverse events, clinical laboratory values, vital signs, electrocardiograms, ophthalmologic examination, Columbia-Suicide Severity Rating Scale, and extrapyramidal symptom scales. In the Safety Population (placebo, n = 147; cariprazine 3-6 mg/d, n = 151; cariprazine 6-9 mg/d, n = 148), 60.5% of patients completed the study. At week 6, statistically significant least squares mean differences in favor of cariprazine versus placebo were observed for Positive and Negative Syndrome Scale total score (3-6 mg/d: -6.8, P = 0.003; 6-9 mg/d: -9.9, P < 0.001) and Clinical Global Impressions-Severity (3-6 mg/d: -0.3, P = 0.012; 6-9 mg/d: -0.5, P < 0.001). Common treatment-emergent adverse events (≥5% and twice the rate of placebo) in both cariprazine groups were akathisia, extrapyramidal disorder, and tremor; most were mild to moderate in severity. Mean changes in metabolic parameters were generally small and similar between groups. Prolactin levels decreased in all groups. In conclusion, cariprazine 3 to 6 and 6 to 9 mg/d versus placebo demonstrated significant improvement on primary and secondary efficacy parameters. Cariprazine was generally well tolerated. These results suggest that cariprazine may be a new and effective treatment for schizophrenia.

Topics: Acute Disease; Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Hyponatremia; Internationality; Male; Middle Aged; Piperazines; Psychoses, Substance-Induced; Schizophrenia; Treatment Outcome

This phase 3 study evaluated the efficacy, safety, and tolerability of cariprazine in patients with acute exacerbation of schizophrenia.. This multinational, randomized, double-blind, placebo- and active-controlled study was conducted from April 2010 to December 2011. Patients who met DSM-IV-TR criteria for schizophrenia were randomized to placebo (n = 153), cariprazine 3 mg/d (n = 155), cariprazine 6 mg/d (n = 157), or aripiprazole 10 mg/d (n = 152) for 6 weeks of double-blind treatment. The primary and secondary efficacy parameters were mean change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total score and Clinical Global Impressions-Severity of Illness (CGI-S) score, respectively.. Least squares mean differences (LSMDs) in PANSS total score change at week 6 significantly favored cariprazine 3 and 6 mg/d versus placebo (LSMD [95% CI]: 3 mg/d, -6.0 [-10.1 to -1.9], adjusted P = .0044; 6 mg/d, -8.8 [-12.9 to -4.7], adjusted P < .0001). Cariprazine 3 and 6 mg/d were also associated with significant improvements relative to placebo in CGI-S scores (LSMD [95% CI]: 3 mg/d, -0.4 [-0.6 to -0.2], adjusted P = .0044; 6 mg/d, -0.5 [-0.7 to -0.3], adjusted P < .0001). Significant differences from placebo were also observed with aripiprazole on the PANSS (LSMD [95% CI]: -7.0 [-11.0 to -2.9], P = .0008) and CGI-S (LSMD [95% CI]: -0.4 [-0.6 to -0.2], P = .0001). Common treatment-emergent adverse events (≥ 10%) were insomnia (all groups), akathisia (cariprazine 6 mg/d), and headache (placebo, cariprazine 6 mg/d).. This study supports the efficacy, safety, and tolerability of cariprazine 3 and 6 mg/d in the treatment of patients with acute exacerbation of schizophrenia.. ClinicalTrials.gov identifier: NCT01104766.

Topics: Acute Disease; Adult; Antipsychotic Agents; Aripiprazole; Double-Blind Method; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Piperazines; Schizophrenia

Cariprazine is an orally active and potent D3 and D2 partial agonist with preferential binding to D3 receptors in development for the treatment of schizophrenia and bipolar mania. This study (NCT00694707) evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.. This study was a multinational, double-blind, randomized, placebo- and active-controlled, fixed-dose trial. Patients were randomized to receive placebo, cariprazine 1.5mg/d, cariprazine 3.0mg/d, cariprazine 4.5mg/d, or risperidone 4.0mg/d (for assay sensitivity) for 6 weeks of double-blind treatment and 2 weeks of safety follow-up. Primary and secondary efficacy parameters were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total and Global Impressions-Severity of Illness (CGI-S) scores, respectively. Safety parameters included adverse events (AEs), vital signs, laboratory measures, and extrapyramidal symptom (EPS) scales.. Of 732 randomized patients, 64% completed the study. PANSS total score improvement at Week 6 was statistically significant versus placebo for cariprazine 1.5mg/d, 3.0mg/d, and 4.5mg/d (least squares mean difference [LSMD]: -7.6, -8.8, -10.4, respectively; p<0.001; LOCF) and risperidone (-15.1, p<0.001; LOCF); significant improvement on CGI-S was demonstrated for all active treatments (p<0.05). The most frequent cariprazine AEs (≥ 5% and at least twice the rate of the placebo group) were insomnia, extrapyramidal disorder, akathisia, sedation, nausea, dizziness, and constipation. Mean changes in metabolic parameters were small and similar between groups.. The results of this study support the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Basal Ganglia Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Piperazines; Psychiatric Status Rating Scales; Schizophrenia; Time Factors; Treatment Outcome; Young Adult

Schizophrenia is a chronic mental health condition treated with antipsychotics. A significant number of patients fail to respond to standard treatment and develop treatment-resistant schizophrenia (TRS). The only current treatment for TRS is clozapine, which has significant side effects and may only be effective in 40% of cases. We describe two cases of patients with TRS who have failed multiple antipsychotic trials and have had extensive hospitalization history due to aggression/hostility. Both patients responded to dual antipsychotic therapy with a long-acting injectable antipsychotic plus cariprazine. Both patients demonstrated improvement in hostility and cognition/memory. Cariprazine's novel mechanism of action may allow it to be uniquely effective in dual antipsychotic therapy for TRS. Cariprazine has a higher affinity than dopamine for D3 receptors and has a 10-fold higher affinity for D3 than D2. This may contribute to its pro-cognitive and anti-hostility effects. Further studies are warranted to determine the role of cariprazine in TRS.

Topics: Antipsychotic Agents; Cognition; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant

Schizophrenia is a psychiatric disorder whose therapeutic objectives are aimed at reducing symptoms and improving patient's quality of life. First- and second-generation antipsychotics present numerous side effects. Recently introduced in the treatment of schizophrenia, cariprazine has shown to improve positive and negative symptoms as well as cognitive impairment, with good tolerability.. To assess the level of consensus among Italian psychiatrists in relation to the use of cariprazine in the treatment of schizophrenia by using the Delphi technique.. A Delphi study was undertaken between January and July 2022. Two questionnaires were consecutively sent to a panel of 97 psychiatrists from all over Italy, of which 81 actively participated, anonymously, in at least one of the two consultations with a sufficiently high response rate (83%).. Broad consensus in terms of the efficacy and safety of cariprazine in the treatment of schizophrenia during all phases of the disorder. The young first-episode schizophrenia patient with or without substance abuse seems to be an excellent candidate for cariprazine therapy. In addition, the lack of side effects makes cariprazine a suitable drug for adult and elderly patients with schizophrenia. However, there is still limited experience with the use of cariprazine, along with little knowledge of the most recent real-life data.. These results could encourage wider dissemination of evidence-based practices with the final aim of optimizing the clinical use of cariprazine in patients with schizophrenia.

Topics: Adult; Aged; Antipsychotic Agents; Drug-Related Side Effects and Adverse Reactions; Humans; Piperazines; Quality of Life; Schizophrenia

Cognitive deficits are associated with schizophrenia and show a progressive worsening, often being unresponsive to treatment. New antipsychotic molecules acting as antagonist at the serotoninergic 5-hydroxytryptamine receptor 7 (e.g. lurasidone) or partial agonists at dopamine D3 receptor (e.g. cariprazine) could have an impact on cognition in this patient group. The aim of the systematic review is to explore the efficacy of lurasidone and cariprazine in improving cognition in both animal models and human studies. The following terms: (lurasidone AND cognit*) OR (cariprazine AND cognit*) were searched in Web of Science from inception to December 2021. We included all studies that assessed changes in cognitive function after treatment with cariprazine or lurasidone. Of 201 selected articles, 36 were included. Twenty-four articles used animal models (rats, mice and marmosets), five evaluating the effects of cariprazine and 19 the effects of lurasidone. Twelve articles were clinical studies (cariprazine n = 2; lurasidone n = 10). In both animal and human studies lurasidone showed a greater efficacy on cognitive performance compared to placebo, quetiapine, ziprasidone or treatmentas- usual. Cariprazine was superior to other antipsychotics in improving cognitive functions in both animal and human studies. The cognitive effect of lurasidone could be explained by its potent antagonism at the 5-HT7 receptors combined with partial agonism at 5-HT1A receptors. The pro-cognitive effect of cariprazine is probably explained by its very high affinity for D3 receptors. Head-to-head studies comparing lurasidone and cariprazine are needed to establish the "first-choice" treatment for cognitive dysfunction associated with schizophrenia.

Topics: Animals; Antipsychotic Agents; Cognition; Humans; Lurasidone Hydrochloride; Mice; Rats; Schizophrenia

Topics: Animals; Antipsychotic Agents; Piperazines; Rats; Rats, Wistar; Receptors, Serotonin; Schizophrenia

Topics: Antipsychotic Agents; Clinical Trials as Topic; Humans; Piperazines; Risperidone; Schizophrenia

The aim of the study was to examine the effectiveness and safety of cariprazine in routine psychiatric settings on schizophrenia patients with negative symptoms who have been treated with antipsychotics previously but without sufficient success. This was an open-label, flexible-dose, 16-week, observational study in Latvia. The primary outcome measure was an array of anamnesis-based clinical questions on schizophrenia symptoms rated on a seven-point scale. Other outcome measurements were the clinical global impression improvement (CGI-I) and severity (CGI-S) scales. Safety parameters included spontaneous reports of adverse events and specific assessments of extrapyramidal side-effects. A mixed model for repeated measures was fit to the data to evaluate the mean change from baseline for all visits. A total of 116 patients enrolled in the study (completion: 83%). Change from baseline to termination in symptom control was statistically significant (-7.3; P < 0.001), with the most improvement in negative symptoms (-6.3; P < 0.001). Over 70% of patients improved minimally or much based on the CGI-I scores at the final visit, and the CGI-S scores indicated an overall improvement in severity from moderately to mildly ill. 40% of patients experienced treatment-emergent adverse events. Over 70% of doctors were satisfied with the effectiveness and tolerability of cariprazine. Cariprazine significantly improved negative symptoms in schizophrenia patients.

Topics: Antipsychotic Agents; Humans; Piperazines; Schizophrenia; 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

Obsessive-compulsive disorder is often associated with schizophrenia and may represent a significant challenge in the treatment as this comorbidity may not respond properly to antipsychotic medication and usually require a pharmacological and psychotherapeutic add-on. In the present case report, we present the case of a 26-year-old male blue-collar subject who developed obsessive-compulsive disorder after a year of complete remission of schizophrenia symptoms under paliperidone long-acting injection that rapidly resolved after low-dosage cariprazine add-on. No adverse effects were reported due to cariprazine- paliperidone long-acting injection combination.

Topics: Adult; Antipsychotic Agents; Comorbidity; Delayed-Action Preparations; Drug Therapy, Combination; Humans; Injections, Intramuscular; Male; Obsessive-Compulsive Disorder; Paliperidone Palmitate; Piperazines; Schizophrenia

Currently available antipsychotics have limited efficacy in the treatment of negative symptoms in schizophrenia and new drugs with wider spectrums of clinical efficacy are very desirable. Cariprazine is a newer antipsychotic acting as dopamine D3- and in lesser extent D2-receptor partial agonist found to be effective in the treatment of negative symptoms in schizophrenia.. To evaluate cariprazine early effects at the first stage of therapy of schizophrenia patients with predominantly negative symptoms.. Open-lable observational assessment of 60 adult schizophrenia patients (F20 on ICD-10, 49% males) with predominantly negative symptoms (PANSS-FSNS ≥15, PANSS-FSPS <19) treated by cariprazine (starting daily dose 1.5 mg followed by upward titration by 1.5 mg weekly up to 6 mg if needed) were assessed with PANSS, CAINS, CDSS and SAS scales at baseline and on week 1, 2, and 4. Efficacy criteria were.. Most patients (75%) improved during 28 days of cariprazine treatment. Negative symptoms mean total scores on PANSS-NS and CAINS significantly (. The study results preliminary suggest initial effect of cariprazine on negative symptoms at least in some schizophrenia patients with predominantly negative symptoms starting from 1-2 weeks of treatment and available for observation and assessment and could be useful for determination of early clinical predictors for efficacy. Considering limitations of observational open-lable design with no control groups these data need to be confirmed.. Эффективность антипсихотиков в коррекции негативных симптомов шизофрении остается неудовлетворительной, в связи с чем новые препараты с более широким спектром клинического действия особенно актуальны. Карипразин — новейший антипсихотик, частичный агонист дофаминовых рецепторов D3- и в меньшей степени D2-рецепторов с верифицированным свойством коррекции первичных негативных симптомов шизофрении.. Оценка инициального эффекта Карипразина в терапии пациентов с шизофренией с преобладанием негативных симптомов.. Наблюдательное открытое исследование 60 взрослых больных шизофренией с преобладающими негативными симптомами (баллы PANSS-FSNS ≥15 и PANSS-FSPS <19). Пациенты получали Карипразин начиная с 1,5 мг с последующей титрацией до максимальной дозы 6 мг/сут в зависимости от эффекта и переносимости. Клиническая и психометрическая оценка эффективности и переносимости (шкалы PANSS, CAINS, CDSS, SAS, регистрация побочных эффектов) проводилась на старте и далее на 7, 14 и 28-й дни терапии.. У большинства (75%) пациентов начиная с 1-й недели терапии отмечалась редукция негативных симптомов со статистически значимым (. Полученные данные позволяют предположить поддающийся выявлению и оценке ранний эффект Карипразина в редукции первичных негативных симптомов шизофрении. В случае подтверждения этих данных в более масштабных и методологически строгих исследованиях возможна разработка ранних предикторов последующей эффективности препарата.

Topics: Adult; Antipsychotic Agents; Female; Humans; Male; Piperazines; Receptors, Dopamine D2; Schizophrenia; Treatment Outcome

To conduct a comprehensive pharmacoeconomic evaluation of feasibility of treatment with cariprazine (reagila) in patients with schizophrenia.. A retrospective study using the pharmacoeconomic cost analysis, budget impact analysis, and cost-effectiveness analysis was performed. Data on cariprazine were compared to those on sertindole.. If cariprazine is used instead of sertindole, the cost saved will amount to 30.8% per patient per year. If sertindole is fully replaced with cariprazine, the costs related to treatment of patients with a second generation antipsychotics funded by the state will be reduced by 97.8 million rubles over 3 years (30.9%). Gradual replacement of sertindole with cariprazine will make it possible to reduce budget expenditures by 20.1% or 63.8 million rubles over 3 years. This replacement will make it possible to provide therapy to additional 44.6% of patients, or 561 people. In this case, the number of patients receiving therapy will increase from 1257 to 1818.. The results of the pharmacoeconomic analysis show that the registration of cariprazine (reagila) in the Russian Federation as therapeutic drug is economically feasible.. Цель исследования. Фармакоэкономическая оценка применения Карипразина (реагила) для лечения больных шизофренией. Материал и методы. Ретроспективное исследование с применением метода фармакоэкономического анализа затрат, 'влияния на бюджет' и показателя 'затраты-эффективность'. Данные, полученные при использовании Карипразина, сравнивали с таковыми Сертиндола. Результаты. Минимизация затрат при применении препарата Карипразин вместо сертиндола за 1 год на 1 пациента составит 30,8%. Полная замена Сертиндола на Карипразин позволит снизить затраты бюджетных средств на 97,8 млн руб. за 3 года (30,9%). Постепенная замена на Карипразин равными долями в течение 3 лет позволит сократить затраты бюджета за 3 года на 20,1%, или 63,8 млн руб. Эта замена позволит обеспечить терапией дополнительно 44,6% пациентов, или 561 человека. В этом случае число пациентов, обеспечиваемых терапией, возрастет с 1257 до 1818. Заключение. Результаты проведенного фармакоэкономического анализа позволяют заключить, что регистрация в РФ препарата Карипразин в качестве терапевтического средства экономически целесообразно.

Topics: Antipsychotic Agents; Humans; Piperazines; Retrospective Studies; Russia; Schizophrenia

Dopamine D₂ receptor partial agonists represent a new generation of atypical antipsychotics. Cariprazine, which has received centralized market authorization from the European Medicines Agency in 2017 for the treatment of adult patients with schizophrenia (including those with predominant negative symptoms of schizophrenia) differs from the other two partial agonist antipsychotics aripiprazole and brexpiprazole due to its unique features. Cariprazine is a dopamine D₃ preferring D₃/D₂ partial agonist with very similar dopamine receptor subtype selectivity as dopamine. It has proven efficacy in the treatment of positive and negative symptoms of schizophrenia, as well as for relapse prevention. Further phase-3 clinical studies proved the efficacy of cariprazine in the acute treatment of manic or mixed episodes associated with bipolar I disorder, as well as in bipolar depression. For the adjunctive treatment of major depressive disorder, phase 3 studies are in progress.

Topics: Antipsychotic Agents; Depressive Disorder, Major; Dopamine Agonists; Humans; Piperazines; Receptors, Dopamine D3; Schizophrenia

Understanding how rating scale improvement corresponds to a clinical impression in patients with negative symptoms of schizophrenia may help define the clinical relevance of change in this patient population. We conducted post hoc equipercentile linking analyses of Positive and Negative Syndrome Scale (PANSS) outcomes (e.g., PANSS-Factor Score for Negative Symptoms [FSNS]) with Clinical Global Impressions-Improvement (CGI-I) and -Severity (CGI-S) ratings on data from patients treated with cariprazine (n = 227) or risperidone (n = 229) in a clinical study evaluating negative symptoms in schizophrenia. Patients were prospectively selected for persistent, predominant negative symptoms of schizophrenia (PNS), and minimal positive/depressive/extrapyramidal symptoms. Linking results demonstrated that greater improvement on PANSS-derived measures corresponded to clinical impressions of greater improvement, as measured by the CGI-I, and less severe disease states, as measured by the CGI-S. For example, CGI-S scores of 1 (normal), 2, 3, 4, 5, and 6 (severely ill) corresponded to PANSS-FSNS scores of 7, 13, 19, 24, 29, and 35, respectively. Likewise, CGI-I scores of minimally improved, much improved, and very much improved corresponded to a change from baseline in PANSS-FSNS scores of -27%, -49%, and -100%, respectively. These are important findings for the interpretation of the results of trials in patients with persistent negative symptoms.

Topics: Adult; Antipsychotic Agents; Double-Blind Method; Female; Humans; Male; Middle Aged; Patient Outcome Assessment; Piperazines; Psychiatric Status Rating Scales; Psychometrics; Randomized Controlled Trials as Topic; Risperidone; Schizophrenia; Schizophrenic Psychology; Severity of Illness Index; Young Adult

Aberrant glutamatergic, dopaminergic, and GABAergic neurotransmission has been implicated in schizophrenia. Cariprazine reverses the behavioral effects observed in the rat phencyclidine (PCP)-induced model of schizophrenia; however, little is known about its in vivo neurochemistry.. The study aims to compare the effects of cariprazine and aripiprazole on PCP-induced changes in the extracellular levels of glutamate, dopamine, serotonin, noradrenaline, and GABA in the rat medial prefrontal cortex (mPFC), and on locomotor activation.. Microdialysis was performed in awake rats with probes placed into the mPFC. Rats (n = 7/group) received vehicle (saline), cariprazine (0.05, 0.2, or 0.8 mg/kg), or aripiprazole (3 or 20 mg/kg) via gavage. After 60 min, 5 mg/kg PCP was administered intraperitoneally (i.p.). Samples were taken before drug administration, during pretreatment, and after PCP injection. Locomotor activity recording and microdialysis sampling occurred simultaneously.. PCP treatment increased extracellular levels of all the neurotransmitters tested except GABA, for which there were no significant changes. Cariprazine and aripiprazole dose-dependently inhibited the PCP-induced increases of tested neurotransmitters. Overall effects were significant for higher cariprazine doses and both aripiprazole doses for glutamate and noradrenaline, for higher cariprazine doses and 20 mg/kg aripiprazole for dopamine, and for 0.8 mg/kg cariprazine and 20 mg/kg aripiprazole for serotonin and locomotor activity.. Both cariprazine and aripiprazole dose-dependently attenuated PCP-induced hyperlocomotion and acute increases in glutamate, dopamine, noradrenaline, and serotonin levels in the mPFC; cariprazine was approximately 5-fold more potent than aripiprazole.

Topics: Animals; Antipsychotic Agents; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Extracellular Fluid; gamma-Aminobutyric Acid; Glutamic Acid; Locomotion; Male; Microdialysis; Norepinephrine; Phencyclidine; Piperazines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Schizophrenia; Serotonin

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

Topics: Double-Blind Method; Humans; Piperazines; Recurrence; Schizophrenia; Secondary Prevention

To further characterize the long-term safety of cariprazine, data from two 48-week open-label, flexible-dose extension studies were pooled for post hoc analyses. Outcomes were evaluated in the pooled safety population (patients who received ≥1 dose of cariprazine during an open-label extension period); findings were summarized using descriptive statistics for the overall cariprazine group and in modal daily dose groups (1.5-3, 4.5-6, and 9 mg/d).. Of the 679 patients in the overall cariprazine safety population, 40.1% completed the study. The only adverse events (AEs) leading to discontinuation of ≥2% of patients in any dose group were akathisia, worsening of schizophrenia, and psychotic disorder. Treatment-emergent AEs (TEAEs) of akathisia, insomnia, weight increased, and headache were reported in ≥10% of the overall population. Mean prolactin levels decreased in all dose groups (overall, -15.4 ng/mL). Clinically insignificant changes in aminotransferase levels and alkaline phosphatase were observed; no dose-response relationship was observed across groups. Mean total (-5.3 mg/dL), low-density lipoprotein (-3.5 mg/dL), and high-density lipoprotein (-0.8 mg/dL) cholesterol levels decreased; no dose-response relationship was observed for metabolic parameters. Mean change in body weight was 1.58 kg; body weight increase and decrease ≥7% occurred in 27% and 11% of patients, respectively. Mean changes in cardiovascular parameters, including blood pressure and pulse, were generally not considered clinically significant. EPS-related TEAEs that occurred in ≥5% of patients were akathisia, tremor, restlessness, and extrapyramidal disorder.. In these post hoc pooled analyses of data from 2 long-term open-label studies, treatment with cariprazine was generally safe and well tolerated. Results support the safety and tolerability of cariprazine within the FDA-recommended dose range of 1.5-6 mg/d for schizophrenia.. NCT01104792, NCT00839852.

Topics: Adult; Akathisia, Drug-Induced; Antipsychotic Agents; Female; Humans; Male; Piperazines; Randomized Controlled Trials as Topic; Schizophrenia; Treatment Outcome

Negative symptoms and cognitive impairment associated with schizophrenia are strongly associated with poor functional outcome and reduced quality of life and remain an unmet clinical need. Cariprazine is a dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors, recently approved by the FDA for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder. The aim of this study is to evaluate effects of cariprazine in an animal model of cognitive deficit and negative symptoms of schizophrenia. Following sub-chronic PCP administration (2mg/kg, IP for 7 days followed by 7 days drug-free), female Lister Hooded rats were administered cariprazine (0.05, 0.1, or 0.25mg/kg, PO) or risperidone (0.16 or 0.1mg/kg, IP) before testing in novel object recognition (NOR), reversal learning (RL), and social interaction (SI) paradigms. As we have consistently demonstrated, sub-chronic PCP significantly impaired behavior in these tests. Deficits were significantly improved by cariprazine, in a dose dependent manner in the operant RL test with efficacy at lower doses in the NOR and SI tests. Locomotor activity was reduced at the highest doses of 0.1mg/kg and 0.25mg/kg in NOR and SI. Risperidone also reversed the PCP-induced deficit in all tests. In conclusion, cariprazine was effective to overcome PCP-induced deficits in cognition and social behavior in a thoroughly validated rat model in tests representing specific symptom domains in schizophrenia patients. These findings support very recent results showing efficacy of cariprazine in the treatment of negative symptoms in schizophrenia patients.

Topics: Animals; Antipsychotic Agents; Cognition; Cognition Disorders; Conditioning, Operant; Disease Models, Animal; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Exploratory Behavior; Female; Motor Activity; Nootropic Agents; Phencyclidine; Piperazines; Rats; Recognition, Psychology; Risperidone; Schizophrenia; Schizophrenic Psychology; Social Behavior

Current antipsychotic medication is largely ineffective against the negative and cognitive symptoms of schizophrenia. One promising therapeutic development is to design new molecules that balance actions on dopamine D2 and D3 receptors to maximise benefits and limit adverse effects. This study used two rodent paradigms to investigate the action of the dopamine D3-preferring D3/D2 receptor partial agonist cariprazine. In adult male rats, cariprazine (0.03-0.3 mg/kg i.p.), and the atypical antipsychotic aripiprazole (1-3 mg/kg i.p.) caused dose-dependent reversal of a delay-induced impairment in novel object recognition (NOR). Treating neonatal rat pups with phencyclidine (PCP) and subsequent social isolation produced a syndrome of behavioural alterations in adulthood including hyperactivity in a novel arena, deficits in NOR and fear motivated learning and memory, and a reduction and change in pattern of social interaction accompanied by increased ultrasonic vocalisations (USVs). Acute administration of cariprazine (0.1 and 0.3 mg/kg) and aripiprazole (3 mg/kg) to resultant adult rats reduced neonatal PCP-social isolation induced locomotor hyperactivity and reversed NOR deficits. Cariprazine (0.3 mg/kg) caused a limited reversal of the social interaction deficit but neither drug affected the change in USVs or the deficit in fear motivated learning and memory. Results suggest that in the behavioural tests investigated cariprazine is at least as effective as aripiprazole and in some paradigms it showed additional beneficial features further supporting the advantage of combined dopamine D3/D2 receptor targeting. These findings support recent clinical studies demonstrating the efficacy of cariprazine in treatment of negative symptoms and functional impairment in schizophrenia patients.

Topics: Analysis of Variance; Animals; Animals, Newborn; Antipsychotic Agents; Aripiprazole; Association Learning; Developmental Disabilities; Disease Models, Animal; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Interpersonal Relations; Locomotion; Male; Memory Disorders; Phencyclidine; Piperazines; Rats; Recognition, Psychology; Schizophrenia

Although most patients with schizophrenia are not aggressive, individuals with the disorder have increased risk of hostile behavior. Cariprazine, a dopamine D3 and D2 receptor partial agonist antipsychotic with preferential binding to D3 receptors, was evaluated for antihostility effects in patients with schizophrenia.. Post hoc analyses were conducted using pooled data from 3 positive randomized, placebo-controlled, phase 2/3 studies in inpatients (18-60 years) with acute exacerbation of schizophrenia according to DSM-IV-TR criteria; data were collected between 2008 and 2011. The principal post hoc outcome was mean change from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) hostility item (P7); separate analyses adjusted for certain PANSS positive symptoms and sedation covariates. Analyses were based on the pooled intent-to-treat population (N = 1,466) using a mixed-effects model for repeated measures approach; separate analyses were conducted in subgroups categorized by baseline hostility item scores (P7: ≥ 2, ≥ 3, ≥ 4).. The least squares mean difference (LSMD) in change from baseline to week 6 was statistically significant on all PANSS hostility item analyses in favor of cariprazine versus placebo: unadjusted (-0.28; P < .0001), adjusted for PANSS positive symptoms (-0.12; P < .05), adjusted for positive symptoms plus sedation (-0.12; P < .05). The magnitude of change for cariprazine increased with greater baseline hostility (LSMD vs placebo for ≥ 2, ≥ 3, ≥ 4 subgroups: -0.32, -0.37, -0.51, respectively; P < .01 all).. Significant improvement on the hostility item was seen in cariprazine- versus placebo-treated patients with schizophrenia; the effect of cariprazine increased with greater levels of baseline hostility.. ClinicalTrials.gov identifiers: NCT00694707, NCT01104766, and NCT01104779.

Topics: Adolescent; Adult; Antipsychotic Agents; Female; Hostility; Humans; Male; Meta-Analysis as Topic; Middle Aged; Piperazines; Randomized Controlled Trials as Topic; Schizophrenia; Schizophrenic Psychology; Treatment Outcome; Young Adult

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

Second-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia.. The purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia.. Using [(11)C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations.. A monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing.. This PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.

Topics: Adult; Antipsychotic Agents; Brain; Carbon Radioisotopes; Dopamine; Dopamine Agonists; Drug Partial Agonism; Female; Humans; Male; Middle Aged; Oxazines; Piperazines; Positron-Emission Tomography; Protein Binding; Radiopharmaceuticals; Receptors, Dopamine D2; Receptors, Dopamine D3; Schizophrenia; Young Adult

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