Cariprazine Orodispersible Tablet: A New Formulation for Cariprazine.

INTRODUCTION: Cariprazine is an atypical dopamine receptor partial agonist antipsychotic available in the form of capsules. Although capsules are one of the most desirable routes of administration, there are certain situations (e. g., in an acute psychiatric setting, or when swallowing difficulties, or liquid shortages are present) when they cannot be administered. Therefore, alternative solutions like orodispersible tablets are needed. This study aimed to investigate the bioequivalence of a newly developed orodispersible tablet to the commercially available hard gelatine capsule of cariprazine 1.5 mg. METHODS: This was a phase I, open-label, randomized, single-dose bioequivalence study. It had a 2-period, 2-sequence, cross-over design, where each subject received one test and one reference product in a randomized sequence, separated by a wash-out period of 55 days. Blood sampling was performed over 72 h after dosing. Cariprazine concentrations were analyzed by a validated HPLC-MS/MS method. Standard bioequivalence statistics was applied to PK parameters calculated by non-compartmental analysis. Safety measures were analyzed descriptively. RESULT: Pharmacokinetic data of 43 healthy volunteers and safety data of 54 subjects was analyzed. Cariprazine AUC0-72h and Cmax geometric mean ratios were 117.76% and 100.88%, respectively. The 90% confidence intervals were within the pre-defined bioequivalence acceptance limits of 80.00% - 125.00%. Safety data was in line with the Summary of Product Characteristics of Cariprazine. DISCUSSION: The result of this clinical trial proved the bioequivalence of the new orodispersible tablet formulation when compared to hard gelatine capsules, enabling an alternative option for treatment of those suffering from schizophrenia.

Comparing the latent state-trait structure of the PANSS in cariprazine-medicated and placebo-controlled patients with acute schizophrenia.

After over a hundred years of research, the question whether the symptoms of schizophrenia are rather trait-like (being a relatively stable quality of individuals) or state-like (being substance to change) is still unanswered. To assess the trait and the state component in patients with acute schizophrenia, one group receiving antipsychotic treatment, the other not. Data from four phase II/III, 6-week, randomized, double-blind, placebo-controlled trials of similar design that included patients with acute exacerbation of schizophrenia were pooled. In every trial, one treatment group received a third-generation antipsychotic, cariprazine, and the other group placebo. To assess symptoms of schizophrenia, the Positive and Negative Symptom Scale (PANSS) was applied. Further analyses were conducted using the five subscales as proposed by Wallwork and colleagues. A latent state-trait (LST) model was developed to estimate the trait and state components of the total variance of the observed scores. All symptom dimensions behaved more in a trait-like manner. The proportions of all sources of variability changed over the course of the observational period, with a bent around weeks 3 and 4. Visually inspected, no major differences were found between the two treatment groups regarding the LST structure of symptom dimensions. This high proportion of inter-individual stability may represent an inherent part of symptomatology that behaves independently from treatment status.

Single trajectory treatment response for predominant negative symptoms: Post-hoc analysis of a clinical trial with cariprazine and risperidone.

Examining the heterogeneity of negative symptoms of schizophrenia contributes to the identification of available treatment targets. Generally, prior evidence classified three to four symptom treatment response trajectory groups over the course of positive symptoms, yet, no evidence exists regarding the heterogeneity of medium-term response to predominant negative symptoms. The current post-hoc analysis aims to identify the heterogeneity in negative symptom treatment response trajectories among patients with predominant negative symptoms who received either cariprazine or risperidone for 26 weeks. Treatment response was analyzed based on the: the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), and the Clinical Global Impression Severity (CGIS) and Improvement (CGII) scales. To identify subgroups of patients with a similar course of treatment response, group-based trajectory modelling was utilized. Results demonstrated that in comparison with competing models, a single trajectory best described the treatment response of patients with predominant negative symptoms. The results indicate that patients with predominant negative symptoms with over ten years of schizophrenia respond rapidly to adequate treatment and follow a course of steady improvement.

The efficacy and safety of cariprazine in the early and late stage of schizophrenia: a post hoc analysis of three randomized, placebo-controlled trials.

BACKGROUND: 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). METHODS: 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. RESULTS: 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 P < .001) and late stage (LSMD -6.7, P < .01) subpopulation. Early stage patients experienced similar amount of TEAEs (CAR 67.3%, PBO 54.1%) as patients in the late stage (CAR 69.6%, PBO 65.6%). CONCLUSION: In conclusion, cariprazine, a potent D3-D2 partial agonist has been found to be safe and effective in the treatment of early and late stage schizophrenia.

What Is the Minimum Clinically Important Change in Negative Symptoms of Schizophrenia? PANSS Based Post-hoc Analyses of a Phase III Clinical Trial.

Introduction: Minimum clinically important difference (MCID) is a measure that defines the minimum amount of change in an objective score of a clinical test that must be reached for that change to be clinically noticeable. We aimed to find the MCID for patients with predominantly negative symptoms of schizophrenia at its earliest occurrence. Methods: Data of a 26-week long, double-blind study with 454 patients [Positive and Negative Symptom Scale Negative Factor Score (PANSS-FSNS) ≥24, Positive and Negative Symptom Scale Positive Factor Score (PANSS-FSPS) ≤ 19] treated with cariprazine 4.5 mg/d or risperidone 4 mg/d were analyzed. The Clinical Global Impression-Improvement scale was used to quantify minimum improvement (CGI-I = 3) and no clinical change (CGI-I = 4) on the PANSS-FSNS, and the MCID was estimated with the following methods: as the mean PANSS-FSNS changes corresponding to the first instance of minimal improvement across all visits (MCID1); as the difference between the PANSS-FSNS change associated with the first instance and the PANSS-FSNS changes associated with the last recorded clinically unchanged status across all visits (MCID2); with the effect size approach (MCID3); as the Youden Index based cut-off value between no clinical change and minimal improvement (MCID4); as the relative likelihood of minimal improvement (MCID5). Results: The MCID1 and MCID2 resulted in, respectively, a 3.8-point (18.5%) and a 1.5-point (7.3%) decrease from baseline severity on the PANSS-FSNS. Greater values were required for the MCID at later evaluation times. The cut-off between minimum improvement and no clinical change defined by the Youden Index was a-3-point (15%) change in the PANSS-FSNS. The effect size approach indicated the 1.5-point difference between minimally improved and unchanged patients to be a medium effect (ES = 0.6). Conclusion: Applying different methods led to different results, ranging between 7.3 and 18.5% improvement from the baseline for the MCID at its earliest occurrence in patients with predominantly negative symptoms of schizophrenia.

The burden of caring for someone with schizophrenia: A cross country report from Bulgaria, the Czech Republic, Hungary and Russia.

INTRODUCTION: People with schizophrenia often need long-term support in their everyday life. Thus, caregivers are vital factors to support their recovery and long-term functioning. In turn, however, the caregiver role is highly burdensome and may lead to severe distress and burnout, imposing further hardness on patients and their family. The aim of this paper was to map the caregivers' situation and their possible needs in Bulgaria, the Czech Republic, Hungary, and Russia. METHODS: 225 caregivers of schizophrenic patients completed a questionnaire in Bulgaria (n=50), the Czech Republic (n=50), Hungary (n=50) and Russia (n=75) about their sociodemographic status, financial, emotional and subjective challenges that arise from the caregiver duty. RESULTS: Caregivers are mainly married (56%), women (72%) entering their 50's, working full time (48%). The average time they spend taking care of someone with schizophrenia is 26 hours weekly. This duty often limits their indepen - dence (59%), recreational activities (56%), financial security (47%) and social life (47%). Thirty-nine percentage reported health-related issues, while sadness and anxiety were also commonly experienced. Caregivers felt left alone with their struggles (56%), longing for both disease-related information and self-help support. As a result, 21% felt fully or mostly dissatisfied with their life. CONCLUSION: Taking care of someone with schizophrenia represents a high burden, affecting one's social and economic status, as well as mental and physical health. Caregivers often feel alone with their struggles and would welcome tailored support to help them cope with the multidimensional burden they carry.

Reducing Addiction in Bipolar Disorder via Hacking the Dopaminergic System.

The dopaminergic system plays a central and decisive role in substance use disorder (SUD), bipolar disorder (BD), and possibly in a subgroup of patients with refractory depression. Common genetic markers and underlying cellular processes, such as kindling, support the close link between these disorders, which is also expressed by the high rate of comorbidity. Although partial dopamine agonists/antagonists acting on D2 and D3 receptors have an established role in treating BD, their usefulness in SUD is less clear. However, dopamine D3 receptors were shown to play a central role in SUD and BD, making D2/D3 partial agonists/antagonists a potential target for both disorders. This narrative review examines whether these substances bear the promise of a future therapeutic approach especially in patients with comorbid BD and SUD.

Disentangling the symptoms of schizophrenia: Network analysis in acute phase patients and in patients with predominant negative symptoms.

BACKGROUND: The Positive and Negative Syndrome Scale (PANSS) is widely used in schizophrenia and has been divided into distinct factors (5-factor models) and subfactors. Network analyses are newer in psychiatry and can help to better understand the relationships and interactions between the symptoms of a psychiatric disorder. The aim of this study was threefold: (a) to evaluate connections between schizophrenia symptoms in two populations of patients (patients in the acutely exacerbated phase of schizophrenia and patients with predominant negative symptoms [PNS]), (b) to test whether network analyses support the Mohr 5 factor model of the PANSS and the Kahn 2 factor model of negative symptoms, and finally (c) to identify the most central symptoms in the two populations. METHODS: Using pooled baseline data from four cariprazine clinical trials in patients with acute exacerbation of schizophrenia (n = 2193) and the cariprazine-risperidone study in patients with PNS (n = 460), separate network analyses were performed. Network structures were estimated for all 30 items of the PANSS. RESULTS: While negative symptoms in patients with an acute exacerbation of schizophrenia are correlated with other PANSS symptoms, these negative symptoms are not correlated with other PANSS symptoms in patients with PNS. The Mohr factors were partially reflected in the network analyses. The two most central symptoms (largest node strength) were delusions and uncooperativeness in acute phase patients and hostility and delusions in patients with PNS. CONCLUSIONS: This network analysis suggests that symptoms of schizophrenia are differently structured in acute and PNS patients. While in the former, negative symptoms are mainly secondary, in patients with PNS, they are mainly primary. Further, primary negative symptoms are better conceptualized as distinct negative symptom dimensions of the PANSS.

Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety.

Schizophrenia is characterized by positive, negative, cognitive, and affective symptoms. Antipsychotic medications, which work by blocking the dopamine D2 receptor, are the foundation of pharmacotherapy for schizophrenia to control positive symptoms. Cariprazine is a dopamine D3 receptor-preferring D3/D2 partial agonist antipsychotic that is approved for the treatment of schizophrenia (USA and European Union [EU]) and manic and depressive episodes associated with bipolar I disorder (USA). Partial agonist agents have a lower intrinsic activity at receptors than full agonists, so they act as either functional agonists or functional antagonists depending on the surrounding neurotransmitter environment. Beyond efficacy against positive symptoms, the unique D3-preferring partial agonist pharmacology of cariprazine suggests potential advantages against negative symptoms, and cognitive and functional impairment, which are challenging to treat. The efficacy and safety of cariprazine in adult patients with schizophrenia have been demonstrated in four short-term randomized, double-blind, placebo-controlled clinical trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study versus the active comparator risperidone. Additional post hoc investigations have supported efficacy across individual symptoms and domains in schizophrenia, as well as in diverse areas of interest including cognition, functioning, negative symptoms, hostility, and global well-being. This comprehensive review of cariprazine summarizes its pharmacologic profile, clinical trial evidence, and post hoc investigations. Collective evidence suggests that the pharmacology of cariprazine may offer broad-spectrum efficacy advantages for patients with schizophrenia, including effects against difficult-to-treat negative and cognitive symptoms, as well as functional improvements. Cariprazine was generally safe and well tolerated in patients with short- and long-term exposure and no new safety concerns were associated with longer-duration treatment.Trial registration ClinicalTrials.gov identifiers, NCT00404573, NCT00694707, NCT01104766, NCT01104779, NCT01412060, NCT00839852, NCT01104792.

Cariprazine and akathisia, restlessness, and extrapyramidal symptoms in patients with bipolar depression.

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

Safety and Tolerability of Cariprazine in Patients with Schizophrenia: A Pooled Analysis of Eight Phase II/III Studies.

BACKGROUND: Long-term treatment with antipsychotic agents is indicated for patients with schizophrenia, but treatment is associated with adverse events (AEs) that contribute to medication discontinuation and nonadherence. Understanding drug safety profiles is critical to avoid unwanted side effects. Cariprazine is a potent dopamine D3/D2 receptor partial agonist that is approved for the treatment of adults with schizophrenia (EU, US) and acute manic/mixed and depressive episodes associated with bipolar I disorder (US). METHODS: Post hoc analyses were conducted to characterize the safety profile of cariprazine within the recommended 1.5-6 mg/d dose range for schizophrenia; data from 8 short- or long-term clinical trials were analyzed. RESULTS: In the pooled cariprazine-treated safety population (n=2048), the rate of study completion was 52.8%, with withdrawal of consent, insufficient response, and AEs the most common reasons for premature discontinuation. The most commonly reported AEs (>10%) in the overall cariprazine-treatment group were akathisia (14.6%), insomnia (14.0%), and headache (12.1%); most AEs were considered mild (71.0%) or moderate (26.5%). Most akathisia was mild/moderate (97.5%) and >93% of patients remained on treatment; akathisia events were managed by rescue medications (56.3%) or dose reduction (18.3%). The metabolic profile of cariprazine was neutral in patients with short- and long-term exposure; mean weight gain was 1 kg for overall cariprazine, with an AE of weight increased reported for 5.1%. Other AEs of special interest that occurred at >3% for overall cariprazine were extrapyramidal disorder (7.0%), sedation (3.7%), and somnolence (3.1%); prolactin elevation, cognition impairment, sexual dysfunction, suicidality, and QT prolongation occurred at ≤1%. CONCLUSION: Akathisia, the most common cariprazine-related AE, was mild/moderate and resulted in few study discontinuations; symptoms were well managed and most patients remained on treatment. Results of this analysis indicated that cariprazine in the recommended dose range was safe and generally well tolerated in patients with schizophrenia. TRIAL REGISTRATION: Studies registered with ClinicalTrials.gov (NCT00404573, NCT01104779, NCT00694707, NCT01104766, NCT01104792, NCT00839852, and NCT01412060) and EudraCT (2012-005485-36).

The effectiveness and safety of cariprazine in schizophrenia patients with negative symptoms and insufficient effectiveness of previous antipsychotic therapy: an observational study.

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.

Dosing Cariprazine Within and Beyond Clinical Trials: Recommendations for the Treatment of Schizophrenia.

Although the optimal dosing of an antipsychotic medication is known to be essential in the long-term management of schizophrenia, in case of novel drugs such as cariprazine, determining the right dosing strategy is not that simple. Without decades of experience with a particular compound, evidence regarding dosing and titration comes primarily from double-blind, placebo controlled clinical trials that are not necessarily mirroring the real-life experiences of doctors. Via summarizing data from both clinical data (n = 3275) and real-world evidence (observational study n = 116, case studies n = 29), this perspective paper aims to shed a light on the appropriate dosing strategies of cariprazine from treatment initiation through switching strategies to concomitant medications.

Cariprazine Safety in Adolescents and the Elderly: Analyses of Clinical Study Data.

Schizophrenia is a life-long mental disorder, affecting young adolescents to elderly patients. Antipsychotic treatment is indicated for all patients with schizophrenia, including the very young and old as well. Developmental issues in the young and decline in organ functioning in the elderly could influence reactions to the drug, and require different dosing regimens. The aim of the present article was to examine the safety profile and dosing requirements in adolescent (13 to less than 18) and elderly (65 and above) patients treated with cariprazine. Data from two clinical studies (one pharmacokinetic pediatric study and one phase III clinical trial) on 49 adolescent patients and 17 elderly patients (65 years of age or above) treated with cariprazine was examined. Safety measures included assessment of adverse events (AEs), clinical laboratory values, physical examinations, extrapyramidal symptom (EPS)-, depression-, and suicidality rating scales. Safety parameters were summarized using descriptive statistics. Results indicate that cariprazine was generally safe and well tolerated. Adverse events in the marginal age populations were comparable to the adult population, except for less insomnia in the young and no reports of akathisia in the elderly. Laboratory parameters, vital sign values and EEG parameters were comparable to previously published data in the adult population. In conclusion, cariprazine in the approved adult dose-range of 1.5-6 mg might be a safe treatment option also in adolescent and elderly patients with schizophrenia. Further studies are need to verify these preliminary findings.

[Cariprazine, a new type - dopamine D3 receptor preferring - partial agonist atypical antipsychotic for the treatment of schizophrenia and the primary negative symptoms]. / Kariprazin, egy új típusú ­ dopamin D3 receptort preferáló ­ parciális agonista atípusos antipszichotikum a szkizofrénia és primer negatív tüneteinek kezelésére.

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.

Relationship between the timing of relapse and plasma drug levels following discontinuation of cariprazine treatment in patients with schizophrenia: indirect comparison with other second-generation antipsychotics after treatment discontinuation.

OBJECTIVE: To explore the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomized, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomized control trials of other oral atypical antipsychotics (AAPs). METHODS: Data from a long-term, randomized, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia (NCT01412060) were analyzed. Similarly designed, published studies of other AAPs were used for comparison. Time to drug-placebo relapse separation and relapse rates were estimated from Kaplan-Meier curves and evaluated descriptively. Separation was defined as a sustained difference of ≥5% incidence of relapse between the AAP and placebo curves. RESULTS: The Kaplan-Meier curve for cariprazine showed a time to drug-placebo relapse separation at 6-7 weeks after randomization, compared to the Kaplan-Meier curves for the other AAPs, which showed earlier separation at 1-4 weeks. The placebo relapse rates at 4 weeks after randomization were 5% for cariprazine and 8-34% for other AAPs. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, desmethyl-cariprazine, and didesmethyl-cariprazine) were 20.0 and 6.1 nM at 2 and 4 weeks after discontinuation, respectively. Elimination half-lives of other AAPs and their active metabolites (<4 days) suggest that plasma concentrations would be low or negligible at 2-4 weeks after last dose. CONCLUSION: Discontinuation of cariprazine treatment appeared to be associated with a delayed incidence of relapse compared with other AAPs, which may be due to the longer half-life of cariprazine and its active metabolites.

Linking PANSS negative symptom scores with the Clinical Global Impressions Scale: understanding negative symptom scores in 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.

The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors.

BACKGROUND: Negative symptoms in schizophrenia are heterogeneous and multidimensional; effective treatments are lacking. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was significantly more effective than risperidone in treating negative symptoms in a prospectively designed trial in patients with schizophrenia and persistent, predominant negative symptoms. METHODS: Using post hoc analyses, we evaluated change from baseline at week 26 in individual items of the Positive and Negative Syndrome Scale (PANSS) and PANSS-derived factor models using a mixed-effects model for repeated measures (MMRM) in the intent-to-treat (ITT) population (cariprazine = 227; risperidone = 227). RESULTS: Change from baseline was significantly different in favor of cariprazine versus risperidone on PANSS items N1-N5 (blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal, difficulty in abstract thinking) (P < .05), but not on N6 (lack of spontaneity/flow of conversation) or N7 (stereotyped thinking). On all PANSS-derived negative symptom factor models evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), statistically significant improvement was demonstrated for cariprazine versus risperidone (P < .01). Small and similar changes in positive/depressive/EPS symptoms suggested that negative symptom improvement was not pseudospecific. Change from baseline was significantly different for cariprazine versus risperidone on PANSS-based factors evaluating other relevant symptom domains (disorganized thoughts, prosocial function, cognition; P < .05). CONCLUSIONS: Since items representing different negative symptom dimensions may represent different fundamental pathophysiological mechanisms, significant improvement versus risperidone on most PANSS Negative Subscale items and across all PANSS-derived factors suggests broad-spectrum efficacy for cariprazine in treating negative symptoms of schizophrenia.

Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder.

Lack of treatment response is a critical problem in major depressive disorder (MDD). Cariprazine is a D3-preferring dopamine D3/D2 receptor partial agonist and 5-HT1A partial agonist. This phase 3, multicenter, open-label, long-term (26-week), flexible-dose (1.5-4.5 mg/day) study assessed the long-term safety and tolerability of cariprazine used adjunctively with antidepressant therapy in adult patients with MDD who had either completed a lead-in study (n=311) or had been newly recruited (n=131). A higher percentage of continuing patients (66.2%) than new patients (35.9%) completed the study. The most common reason for discontinuation was adverse events (AEs; 13.9%); 79% of patients experienced a treatment-emergent AE [most common: akathisia (15.9%,) headache (11.6%)]. Serious AEs occurred in 2% of patients; two deaths occurred (one traffic accident, one completed suicide, both considered unrelated to treatment). The mean changes in clinical laboratory, cardiovascular, and ophthalmologic parameters were generally not clinically relevant. The mean (SD) changes from the open-label baseline in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity score at week 26 were -7.3 (9.5) and -1.0 (1.2), respectively. By week 26, 53.3% of patients were in remission (Montgomery-Åsberg Depression Rating Scale total score≤10). The results suggest that cariprazine was generally safe and well tolerated as adjunctive therapy to treat MDD.