Cariprazine Research Articles

Cariprazine and Cognition in Patients with Schizophrenia and Bipolar Disorder: A Systematic Review.

Cariprazine (CAR), an antipsychotic with partial agonism at the D3 receptor and higher affinity than dopamine, has shown significant procognitive effects in preclinical animal studies. This study systematically reviews CAR's effects on cognitive measures in patients with schizophrenia and bipolar disorder. Two independent reviewers systematically searched PubMed, Web of Science, Scopus, and the Cochrane Library up to May 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Additional studies were found by hand searching the references of included studies. Eligible studies were randomized controlled trials (RCTs) in English that assessed CAR's effects on cognition in patients with schizophrenia or bipolar disorder. Quality was assessed using the Jadad scale. Out of 139 reports, 5 studies (involving 6,104 patients with schizophrenia or bipolar disorder) were included. In schizophrenia, CAR showed better cognitive outcomes (mainly indirect measures) than placebo (PBO) in both early and late stages. It also outperformed risperidone and aripiprazole in attention-related cognitive tests. In bipolar disorder, CAR improved cognition compared to PBO (also using indirect measures). Most studies found the greatest cognitive benefits with low doses of CAR (1.5-3 mg/d). CAR improved cognitive measures compared to PBO and other D2 antagonists or partial agonists in RCTs, especially in patients with greater baseline impairment. Thus, CAR may be a promising option for enhancing cognition in schizophrenic and bipolar patients; though, more trials using specific cognitive assessment tools are needed. PROSPERO CRD42023485028.

Quality by Design Approach for the Development of Cariprazine Hydrochloride Loaded Lipid-Based Formulation for Brain Delivery via Intranasal Route.

Cariprazine (CPZ) is a third-generation antipsychotic medication that has been approved for treating schizophrenia. This study aimed to develop a cariprazine-loaded nanostructured lipid carrier (CPZ-NLCs) to prevent first-pass metabolism and improve bioavailability and site-specific delivery from the nose to the brain. The CPZ-NLCs were prepared using melt emulsification. The formulation was optimized using the Box-Behnken design (BBD); where the influence of independent variables on critical quality attributes, such as particle size and entrapment efficiency, was studied. The optimized batch (F6) had a particle size of 173.3 ± 0.6 nm and an entrapment efficiency of 96.1 ± 0.57%, respectively. The in vitro release showed >96% release of CPZ from NLC within 30 min. The optimized formulation's ex vivo studies revealed significantly increased CPZ permeability (>75%) in sheep nasal mucosa compared to the CPZ suspension (~26%). The ciliotoxicity study of the nasal mucosa revealed that the CPZ-NLC formulation did not affect the nasal epithelium. The intranasal administration of the formulation achieved 76.14±6.23 μg/ml concentration in the brain which was significantly higher than the oral CPZ suspension administration (30.46±7.24 μg/ml). The developed formulation was stable for 3 months. The study concluded that the developed CPZ-NLC could significantly improve the bioavailability with quick delivery to the brain.

Enhancing 7-dehydrocholesterol suppresses brain ferroptosis and tissue injury after neonatal hypoxia–ischemia

Neonatal hypoxic-ischemic brain injury (HIBI) results in part from excess reactive oxygen species and iron-dependent lipid peroxidation (i.e. ferroptosis). The vitamin D precursor 7-dehydrocholesterol (7-DHC) may inhibit iron-dependent lipid peroxidation. Primary neurons underwent oxygen and glucose deprivation (OGD) injury and treatment with 7-DHC-elevating medications such as cariprazine (CAR) or vehicle. Postnatal day 9 mice underwent sham surgery or carotid artery ligation and hypoxia and received intraperitoneal CAR. In neurons, CAR administration resulted in significantly increased cell survival compared to vehicle controls, whether administered 48 h prior to or 30 min after OGD, and was associated with increased 7-DHC. In the mouse model, malondialdehyde and infarct area significantly increased after HIBI in the vehicle group, which were attenuated by post-treatment with CAR and were negatively correlated with tissue 7-DHC concentrations. Elevating 7-DHC concentrations with CAR was associated with improved cellular and tissue viability after hypoxic-ischemic injury, suggesting a novel therapeutic avenue.

Relapse prevention with cariprazine in patients with early-stage schizophrenia

IntroductionRelapse is defined as the return of psychotic symptoms after a period of improvement/stability. Relapse is often associated with the disruptive re-hospitalization of patients. Importantly, relapse history is a strong predictor of subsequent relapses and poorer outcomes. Therefore, relapse prevention in the beginning of the disorder is especially important. Cariprazine, a novel D3-D2 partial agonist, has been effective in preventing relapse compared to placebo in stabilized patients with schizophrenia.ObjectivesTo present the efficacy of cariprazine in preventing relapse in patients with early-stage schizophrenia.MethodsPost-hoc analysis of data from a ˜96 weeks, multicentre, randomized, double-blind, placebo-controlled, parallel-group study in adults with schizophrenia. The study was composed of two parts: a 20-week open-label treatment phase and a double-blind treatment phase up to 72 weeks. During the open-label phase, patients were stabilized with cariprazine 3.0-9.0 mg/day. Then, they were randomized to continue cariprazine (fixed dosing: 3.0, 6.0, or 9.0 mg/day) or receive placebo. Relapse was defined as a deterioration of symptom scores as measured by the Positive Negative Syndrome Scale (PANSS), admission to a psychiatric hospital, exhibiting aggressive behaviour, or risk of suicide. In the present analysis, patients with a schizophrenia diagnosis history of 0-5 years were defined as early-stage patients. Baseline characteristics, and risk ratios (after the double-blind phase) with number-needed-to-treat (NNT) were calculated.ResultsOf 200 patients, 71 (35.5%) met the early-stage criteria: 32 patients in the cariprazine (CAR) and 39 in the placebo (PBO) arm. The mean age was 31.6 years in both groups with an average illness duration of 2.51+/-1.03 years in the CAR and 2.75+/-1.24 years in the PBO arm. 47% of patients in the CAR arm and 77% in the PBO arm were men. The average number of previous hospitalisations was comparable in the two groups (CAR: 2.3; PBO: 2.6), as was the severity of illness: mean PANSS Total score: 89.2 (CAR), 90.4 (PBO). Patients in both groups were highly compliant (pill-count: CAR: 98.2%; PBO: 99.5%). The main reported adverse effects were headache (CAR: 11.3%, PBO: 7.0%), insomnia (CAR: 5.6%, PBO: 4.2%), and increased triglycerides (CAR: 5.6%, PBO: 1.4%), discontinuation due to adverse event was 3.1% in the CAR and 2.6% in the PBO group. Altogether, 9.4% of patients relapsed in the cariprazine group compared to 48.7% on placebo (risk ratio=0.19 (95% confidence interval (CI): 6.3-59.2%, p=0.0041;NNT: 2.5 (95%CI: 1.7-5.1).ConclusionsIn this post-hoc analysis of patients within the first five years of schizophrenia, the relative risk of relapse was 81% reduced with cariprazine with prevention of one additional relapse after each third patient exposed to cariprazine vs placebo. Cariprazine seems to be a good treatment option for early-stage patients for preventing relapse.Disclosure of InterestC. Correll Consultant of: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellularTherapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Takeda, Teva, Tolmar, Vertex, and Viatris., Z. Dombi Employee of: Gedeon Richter Plc., P. Herman Employee of: Gedeon Richter Plc., Á. Barabássy Employee of: Gedeon Richter Plc.

Functional single nucleotide polymorphisms in dopaminergic receptors D2 predict clinical response to Cariprazine.

Cariprazine (CAR) is an antipsychotic drug for the treatment of schizophrenia (SCZ) and bipolar disorder (BD), and it acts as a partial agonist on the dopamine receptors (DR), D2, and D3. Although many single nucleotide polymorphisms (SNPs) in genes coding for these receptors are known to influence response to antipsychotics, to date, no study on CAR pharmacogenetics exists. In this pilot study, we investigated the relationship between SNPs in DRD2 (rs1800497 and rs6277) and DRD3 (rs6280), and response to CAR treatment, evaluated by the psychometric Brief Psychiatric Rating Scale (BPRS), in a cohort of Caucasian patients. We found a significant association between DRD2 rs1800497 and rs6277 and response to CAR treatment. When genotypes were combined into an arbitrary score, the receiver operating characteristic curve analysis showed that using a cut-off value of -2.5 the response to CAR treatment could be predicted with a positive likelihood ratio of 8.0. Our study report, for the first time, a correlation between SNPs in DRD2 and response to CAR treatment. After confirmation in a larger cohort of patients, our results could open the way for the identification of new tools for the provision of response to CAR treatment.

Categorical Improvement in Depressive Symptom Severity: Results From a Randomized Controlled Trial of Cariprazine for Adjunctive Treatment of MDD

AbstractBackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy alone and may require adjunctive treatment to provide adequate symptom relief. Cariprazine (CAR) is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with schizophrenia and manic, mixed, or depressive episodes of bipolar I disorder. Post hoc analysis of data from a randomized controlled trial evaluated clinically relevant improvements in depressive symptom severity with adjunctive cariprazine in patients with MDD and inadequate response to ADT monotherapy.MethodsPost hoc analysis evaluated data from a randomized, double-blind, placebo-controlled MDD trial (NCT03738215) in patients treated with CAR (1.5 mg/d or 3 mg/d) + ADT or placebo + ADT; the primary outcome was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Post hoc analysis evaluated category shifts from baseline to week 6 in MADRS severity (normal <6, mild 7–19, moderate 20–34, severe ≥35). MADRS severity shifts were reported as the percentage of patients with no change or worsened severity, 1 category improvement, ≥1 category improvement, and ≥2 category improvement. Examples of categorical shifts in depressive symptoms at week 6 include change from severe at baseline to moderate (1 category improvement) and change from severe at baseline to mild (2 category improvement).ResultsOf the 751 patients in the intent-to-treat (ITT) population (CAR: 1.5 mg/d=250, 3.0 mg/d=252; placebo=249), baseline MADRS severity was mild in 1.5%, moderate in 64%, and severe in 35%. Fewer CAR + ADT patients compared to placebo + ADT had no change or worsened MADRS severity at week 6 (CAR: 1.5 mg/d=32%, 3.0 mg/d=33%; placebo=42%). Approximately 68% of patients treated with CAR + ADT demonstrated a MADRS severity improvement of 1 category or greater by week 6 (CAR: 1.5 mg/d=68%, 3.0 mg/d=67%; placebo=58%). A greater percentage of patients in the CAR 1.5 mg/d group also had a 2 or greater category improvement versus CAR 3.0 mg/d or placebo 6 (CAR: 1.5 mg/d=28%, 3.0 mg/d=17%; placebo=19%).ConclusionsIn this post hoc analysis, CAR + ADT was associated with a greater proportion of patients with improvements in depressive symptom severity categories compared with placebo + ADT. These results may suggest that CAR + ADT is associated with clinically meaningful depressive symptom improvement in MDD patients.FundingAbbVie

Cariprazine for the Adjunctive Treatment of Major Depressive Disorder: Results of a Randomized Phase 3 Placebo-Controlled Study (Study 301)

AbstractBackgroundPatients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy; adjunctive treatment is often used to address this unmet need. Cariprazine (CAR), a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with manic, mixed, or depressive episodes of bipolar I disorder, is under investigation as adjunctive therapy for patients with MDD.MethodsThis randomized, double-blind, phase 3 placebo (PBO)-controlled study assessed the efficacy, safety, and tolerability of CAR 1.5 and 3 mg/d as an adjunct to ADT in adult patients with MDD (18–65 years) and inadequate response to ADT alone (NCT03738215). The primary endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impressions (CGI) were also assessed. Treatment response was defined as at least 50% decrease in MADRS total score at week 6.ResultsPatients (n=751) in the modified intent-to-treat population were randomly assigned to CAR 1.5 mg/d+ADT (n=250), CAR 3 mg/d+ADT (n=252), or PBO+ADT (n=249). Mean age was 44.8 years and 73.4% were female; mean baseline total scores were: MADRS=32.5, HAMD-17=25.9, HAM-A= 21.4. Overall, 89.7% of patients completed the study; rates of discontinuation due to adverse events (AEs) and lack of efficacy were 3.6% and 0.5%, respectively. The difference in MADRS total score change from baseline to week 6 was statistically significant after multiplicity adjustment for CAR 1.5 mg/d vs PBO (-14.1 vs -11.5; adjusted P=.0050), but not for CAR 3 mg/d (-13.1; P=.0727). Differences for CAR 1.5 mg/d vs PBO were observed by week 2 (nominal P=.0453) and maintained at weeks 4 (nominal P<.0001) and 6 (nominal P=.0025). At week 6, more CAR 1.5 mg/d patients (44%) than PBO patients (34.9%) responded to treatment (nominal P=.0446). Greater improvement in the CGI-I scores was observed for CAR 1.5 (nominal P=.0026) and 3 mg/d (nominal P=.0076) vs PBO. At week 6, improvement in HAMD-17 total score reached nominal significance for CAR 1.5 mg/d vs PBO (-13.1 vs -11.1; nominal P=.0017), but not for CAR 3 mg/day (-12.2; P=.0783). HAM-A improvement was greater for CAR 1.5 mg/d vs PBO (nominal P=.0370). There were no deaths; 2 serious AEs occurred in each group (CAR: kidney infection, social stay hospitalization; PBO: depression, multiple sclerosis). The most common CAR AEs (≥5% and twice PBO) were akathisia and nausea.ConclusionCariprazine 1.5 mg/d was effective as adjunctive treatment in adults with MDD and inadequate response to ADT. Cariprazine was generally well tolerated, with a safety profile that was consistent with other indications. Together with results from a prior flex-dose study, these results suggest that adjunctive cariprazine may be an effective option for patients with inadequate response to ADT alone.FundingAbbVie

Cariprazine’s efficacy in treating depressive symptoms – pooled data from schizophrenia, bipolar depression and major depression trials

IntroductionDepressive symptoms are a common feature of schizophrenia (SCH) and define bipolar disorder and major depressive disorder (MDD). Their emergence is related to altered neurotransmission at the serotonin receptors and potentially at dopamine D3 receptors.ObjectivesThe aim of this analysis was to examine the efficacy of cariprazine (CAR) in treating depressive symptoms in SCH, bipolar depression (BD) and MDD.MethodsClinical trials with randomised, double-blind, placebo (PLB)-controlled designs were included in these analyses. Data from 3 SCH [NCT00694707, NCT01104766, NCT01104779; 1.5-9 mg/d] and 3 BD [NCT01396447, NCT02670538, NCT02670551; 1.5-3 mg/d] studies were pooled. In MDD, add-on CAR to antidepressant treatment was evaluated against PLB in two studies [NCT03738215: 1.5 and 3 mg/d; NCT01469377: 1-2 mg/d and 2-4.5 mg/d).Least square (LS) mean changes were analysed using Mixed Model Repeated Measures: from baseline (BL) to Week 6 in the Positive and Negative Syndrome Scale (PANSS)-derived Marder anxiety/depression factor items (schizophrenia); from BL to Week 6 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (bipolar depression); and from BL to Week 6 [NCT03738215] and Week 8 [NCT01469377] in MADRS total score (major depressive disorder).ResultsAltogether, 1466 SCH (PLB=442, CAR=1024) patients were included in the pooled analysis. In the BD analysis, data from 1383 (PLB=460, CAR=923) patients were pooled. In the MDD trials, there were 502 CAR (1.5mg/d=250, 3 mg/d=252) and 249 PLB-treated patients [NCT03738215], and 544 CAR (1-2 mg/d=273, 2-4.5 mg/d=271) and 264 PLB patients in the other study [NCT01469377]. In SCH, CAR achieved significantly greater reductions than PLB on the Marder anxiety/depression factor domain (LS mean change: PLB= -2.66, CAR= -3.26, p<0.01): the effect was driven by 3 out of 4 items. In BD, CAR yielded significantly greater improvement on the MADRS compared to PLB (LS mean change: PLB= -12.05, CAR= -14.69, p<0.001), which was driven by 9 out of 10 items. In MDD [NCT03738215], CAR 1.5 mg/d add-on significantly alleviated depressive symptoms compared to PLB (LS mean change: PLB= -11.5, CAR 1.5mg/d= -14.1, p<0.01), while in the other MDD trial [NCT01469377], CAR 2-4.5 mg/d add-on produced significantly greater reductions than PLB (LS mean change: PLB= -12.5, CAR 2-4.5 mg/d= -14.6, p<0.01).ConclusionsThese findings indicate that CAR is an effective treatment option for the treatment of depressive symptoms independent of disease (in SCH, BD and MDD), being a transdiagnostic broad-spectrum treatment option.Disclosure of InterestR. McIntyre Grant / Research support from: CIHR/GACD/National Natural Science Foundation of China (NSFC), the Milken Institute, Consultant of: Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Gedeon Richter, Recordati, Atai Life Sciences, Speakers bureau of: Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Gedeon Richter, Recordati, Atai Life Sciences, R. Csehi Employee of: Gedeon Richter Plc., G. Németh Employee of: Gedeon Richter Plc.

A MINI REVIEW ON PROPERTIES, MECHANISM OF ACTION, PHARMACOKINETIC AND PHARMACODYNAMICS AND ANALYTICAL METHODS OF CARIPRAZINE

Cariprazine (CPZ) being a “D2/D3 receptor partial agonist” is used for schizophrenia treatment. CPZ illustrate different functional study at “dopamine receptors depending on the assay system”. This study elaborate review summarizes the structure–activity relationship (SAR), Mechanism of action (MOA), pharmacokinetics, pharmacodynamics and analytical methods published. CPZ was found to be more effective than risperidone. It was analogus with a remarkably longer time to deteriorate than inactive drug in a long-term, phase III,-deteriorate prevention study. This study elaborate the activating and solemn or sedative properties of first-line oral second generation antipsychotics by explore the rates of adverse effect in product labelling for the indications of schizophrenia and ancillary treatment of major depressive disorder (MDD). The common adverse events reported were extrapyramidal disorder, insomnia, dizziness, solemn, anxiety, vomiting and constipation in “fixed dose study of tested 1.5, 3.0, and 4.5 mg/day”. The presented review explains about biological properties, pharmacokinetics, pharmacodynamics, and analytical methods of CPZ.

Benzodiazepine use during cariprazine treatment in acute schizophrenia

IntroductionAlthough antipsychotics are first-line treatments for schizophrenia, benzodiazepines (BZDs) are often used as concomitant medications in acutely exacerbated patients due to their anxiolytic and sedative effects. Cariprazine (CAR), a D3-preferring dopamine D2/D3 partial agonist antipsychotic, has been examined in many clinical studies for the treatment of acute schizophrenia, with and without benzodiazepines.ObjectivesTo delineate the effects of benzodiazepine-use during cariprazine treatment in acute schizophrenia.MethodsPooled data of cariprazine-treated (1.5-6mg/day) and placebo-treated patients from four short-term, randomised, double-blind trials (NCT00404573, NCT01104766, NCT01104779, NCT00694707) were analysed. Baseline characteristics (age, duration of illness) and efficacy outcome parameters (Total and Hostility Factor Score of the Positive and Negative Syndrome Scale [PANSS]) were compared in patients receiving benzodiazepines (for more ≥3 consecutive days) and not receiving benzodiazepines (<3 consecutive days).ResultsAltogether, 36.7% and 40.7% of the CAR-treated and PBO-treated patients required BZDs. BZD-taking was associated with a higher age in both the CAR-treated (p=0.0002) and PBO-treated (p<0.0001) patients, and with longer illness-duration in both treatment groups (p<0.0001). PANSS Total Score at baseline was similar for BZD users and non-users (CAR: LS Mean=96.36 and 96.27; PBO: LS Mean=95.55 and 96.66). Change from baseline in the PANSS Total Score was greater for patients who did not use BZD vs those who did (CAR: LS Mean= -23.8 vs LS Mean 17.2, p<0.0001; PBO: LS Mean= -14.0 vs LS Mean 12.9, p=0.5776).ConclusionsThese findings may suggest that requiring benzodiazepines is a potential indicator of longer illness duration and poorer response in acute schizophrenia.DisclosureI am an employee of Gedeon Richter Plc.

Remission of Persistent Negative Symptoms and Psychosocial Consequences by Combined Clozapine and Cariprazine Treatment in a Patient With Long-Standing Treatment-Resistant Schizoaffective Disorder.

This patient case report describes a 45-year old white unmarried man with disability pension due to schizoaffective disorder, diagnosed at the age of 24. He lives in an apartment and has housing support. Retrospectively, the patient displayed prodromal markers of a disorder within the schizophrenia spectrum many years before the onset of frank psychosis, indeed since childhood. Over the years several symptoms and signs across schizophrenia domains have been manifest: positive, negative, cognitive, and affective, among which the negative and affective symptoms and signs were the earliest to appear. While the positive, disorganized, and catatonic symptoms responded to treatment – when duly tested and complied with – the negative and affective symptoms have been notoriously difficult to handle. We now report on the successful introduction of cariprazine (CAR) to his ongoing clozapine (CLZ) medication, the result of which has been a near-complete remission of his persistent negative and psychosocial issues. We interpret this remarkable alleviation of the patient's disease – and concomitant improvement of his quality of life – in terms of neuroreceptor target complementarity between CLZ and CAR, with particular emphasis on the contributions from the D3 and D2 receptor partial agonist components of the latter agent.

Improving Mood and Cognitive Symptoms in Huntington's Disease With Cariprazine Treatment.

In Huntington's disease (HD), the main clinical symptoms include depression, apathy, cognitive deficits, motor deficiencies and involuntary movements. Cognitive, mood and behavioral changes may precede motor symptoms by up to 15 years. The treatment of these diverse symptoms is challenging. Tetrabenazine and deutetrabenazine are the only medications specifically approved for Huntington's chorea, but they do not affect the non-motor symptoms. For these, antidepressants, antipsychotics, and benzodiazepines have demonstrated benefit in some cases and can be used off-label. These drugs, due to sedative side effects, may negatively influence cognition. Sixteen patients having HD received a 12-week off-label cariprazine (CAR) treatment (1.5–3 mg/day). Cognitive performance and behavioral changes were measured by the Addenbrooke Cognitive Examination (ACE) test, the Cognitive and Behavioral part of the Unified Huntington's Disease Rating Scale (UHDRS), and the Beck Depression Inventory (BDI). Mixed model for repeated measures was fitted to the data, with terms of visit, baseline (BL) and their interaction. Cariprazine treatment resulted in the following changes from BL to week 12, respectively: the mean score of BDI decreased from 17.7 ± 10.7 to 10.0 ± 10.7 (p <0.0097), while the Behavioral Assessment score of the UHDRS decreased from 54.9 ± 11.3 to 32.5 ± 15.4 (p < 0.0001); ACE score increased from 75.1 ± 11.0 to 89.0 ± 9.3 (p < 0.0001); Cognitive Verbal Fluency score from 6.2 ± 2.5 to 7.7 ± 2.7 (p < 0.0103); Symbol Digit Test from 9.2 ± 6.9 to 12.3 ± 8.9 (p < 0.0009). Mild akathisia was the most frequent side effect, presenting in 2 out of 16 patients (12.5%). We conclude that CAR had a positive effect on depressive mood, apathy and cognitive functions in patients with early stage of HD. Based on the neurobiological basis of these symptoms, CAR can improve the dopamine imbalance of the prefrontal cortex. This draws attention to the transdiagnostic approach which supports the further understanding of the similar symptomatology of different neuropsychiatric disorders and helps to identify new indications of pharmaceutical compounds.

Assessing the Benefit-Risk Ratio of Approved Treatments for Bipolar Depression Using Likelihood to be Helped or Harmed (LHH) Analyses

Four medications are FDA approved for bipolar depression: lurasidone (LUR), cariprazine (CAR), quetiapine IR & XR (QUE), and olanzapine-fluoxetine combination (OFC). Indirect comparisons for efficacy using Number Needed to Treat (NNT) and for tolerability using Number Needed to Harm (NNH) can be useful clinical benchmarks to aid treatment decisions. Benefit and risk may also be examined using the Likelihood to be Helped or Harmed (LHH). In this post-hoc analysis, we examined the benefit-risk ratio of the four treatments using LHH. Individual and pooled monotherapy data from short-term clinical registration trials of patients with bipolar depression were assessed for LUR, CAR, pooled QUE (300 and 600 mg), and pooled OFC (considered as monotherapy for this study at fixed doses of 6/25, 6/50, 12/50 mg) data. NNT estimates were calculated using the proportions of MADRS responders (defined as ≥ 50% improvement at study endpoint) and MADRS remitters (defined as a score of ≤ 10 [for LUR and CAR] and ≤ 12 [for QUE and OFC]) at study endpoint. NNH data were calculated for the proportions of patients who discontinued due to an adverse event (AE) and for individual AEs commonly associated with each treatment. LHH was calculated as the ratio of NNH/NNT to determine the benefit-risk ratio. The NNT estimates for response vs. placebo were: 5 for both LUR 20-60 mg and 80-120 mg; 10 for both CAR 1.5 mg and 3.0 mg; 6 for QUE; and 4 for OFC. The NNTs for remission vs placebo were: 7 for LUR 20-60 mg and 9 for LUR 80-120 mg; 10 for CAR 1.5 mg and 13 for CAR 3.0 mg; 6 for QUE; and 5 for OFC. The NNH estimates for discontinuations due to AEs were: 642 for LUR 20-60 mg and -151 for LUR 80-120 mg; 298 for CAR 1.5 mg and 31 for CAR 3.0 mg; 10 for QUE; and -37 for OFC. NNH values that were negative were assigned a value of 1000 to permit LHH to be calculated. The LHHs for response vs discontinuation due to an AE were: 128.4 for LUR 20-60 mg and 200 for LUR 80-120 mg; 29.8 for CAR 1.5 mg and 3.1 for CAR 3.0 mg; 1.7 for QUE; and 250 for OFC. The LHHs for response vs akathisia were: 3.6 for LUR 20-60 mg and 2.4 for LUR 80-120 mg; 3.6 for CAR 1.5 mg and 1.3 for CAR 3.0 mg; 34 for QUE; and not available (NA) for OFC. The LHHs for response vs EPS were: 8 for LUR 20-60 mg and 3.2 for LUR 80-120 mg; 5 for CAR 1.5 mg and 2.5 for CAR 3.0 mg; NA for QUE; and NA for OFC. The LHH for response vs weight gain was 5.8 for LUR 20-60 mg and 1110 for LUR 80-120 mg; 5 for both doses of CAR; 2.7 for QUE; and 1.5 for OFC. LHH can illustrate the trade-offs regarding potential benefits versus potential harms. Across a variety of measures, the lower-dose groups for both LUR and CAR generally evidenced a better benefit-risk profile than the higher-dose groups. While quetiapine and OFC demonstrated robust efficacy, their reduced tolerability resulted in a more marginal benefit-risk ratio for some of the outcomes. Sunovion Pharmaceuticals Inc.

Altered Cholesterol Biosynthesis Affects Drug Metabolism

The last step of cholesterol biosynthesis is the conversion of 7-dehydrocholesterol (7-DHC) into cholesterol, a reaction catalyzed by dehydrocholesterol reductase 7 (DHCR7). Investigation of the effect of Dhcr7 single-allele mutations on the metabolism of aripiprazole (ARI) and cariprazine (CAR) in maternally exposed transgenic pups revealed that ARI, CAR, and their active metabolites were decreased in the liver and brain of Dhcr7+/–. This difference in the drug and metabolite levels resulted in an increased turnover of ARI and CAR in tissues from Dhcr7+/– animals, indicating an enhanced metabolism, which was at least partially due to increased levels of Cyp2d6 in the liver of Dhcr7+/– mice. Finally, experiments with both WT and DHCR7+/– human fibroblasts revealed lower drug levels in DHCR7+/– heterozygous cells. Our findings have potential clinical implications, as DHCR7 heterozygosity is present in 1–3% in the human population, and these individuals might have reduced therapeutic levels of Cyp2d6-metabolized medications and are putatively more susceptible to unwanted side effects.

Leki przeciwpsychotyczne II generacji w terapii objawów negatywnych schizofrenii

Farmakoterapia schizofrenii jest trudnym i złożonym procesem, szczególnie w kontekście objawów negatywnych. Konieczne jest właściwe rozpoznanie grup pacjentów, a w szczególności indywidualnych pacjentów ― w zależności czy objawy negatywne są pierwotne, czy wtórne, przeważające czy znaczące, czy też przeważające i przetrwałe. Piśmiennictwo dotyczące oceny skuteczności różnych leków przeciwpsychotycznych II generacji w leczeniu objawów negatywnych jest niejednorodne, a ocena objawów negatywnych, oparta na różnych metodologiach, dotyczy przede wszystkim różnorodnych grup pacjentów, którzy najprawdopodobniej w zróżnicowany sposób reagują na badane leki, w zależności od tego, czy wykazują znaczące, przeważające lub też przeważające i przetrwałe objawy negatywne. Dodatkowo zdecydowana większość badań dotyczy ogólnej populacji chorych na schizofrenię, wśród których oceniano między innymi nasilenie objawów negatywnych. W związku z tym ocena tych badań i ich porównanie między sobą jest praktycznie niemożliwe. Wybór leku przeciwpsychotycznego II generacji, który wykazywałby zdecydowaną przewagę nad innymi, jest również trudny. W ramach niniejszego opracowania wykonano przegląd literatury dotyczącej badań randomizowanych bezpośrednio porównujących kluczowe leki przeciwpsychotyczne II generacji stosowane w terapii objawów negatywnych. W większości analizowanych badań nie wykazano istotnych statystycznie różnic pomiędzy analizowanymi lekami (porównanie risperidonu, amisulprydu, arypiprazolu, olanzapiny pomiędzy sobą). Tylko w pojedynczych badaniach wykazano przewagę olanzapiny nad risperidonem w ocenie wpływu obu tych leków na objawy negatywne. Należy jednak podkreślić, że wyniki cechowały się ograniczoną wiarygodnością w zakresie możliwości wnioskowania o bezpośrednim wpływie leków na objawy negatywne. Przyczynę takiego stanu rzeczy należy upatrywać między innymi w tym, że w badaniach tych nie korygowano uzyskiwanych efektów o czynniki zakłócające, których wpływ na objawy negatywne został potwierdzony. Natomiast w grupie chorych z przeważającymi i przetrwałymi objawami negatywnymi stwierdza się przewagę kariprazyny nad risperidonem. Uzupełniająca analiza opracowań wtórnych dla analizowanych leków wykazała wyższą skuteczność leków II generacji nad lekami I generacji i placebo w różnych grupach pacjentów z objawami negatywnymi. Należy jednak podkreślić, że badania ze względu na swoją niejednorodność są trudne do porównania. Dodatkowym problemem, który pojawia się w kontekście badań klinicznych, a także codziennej praktyki, jest właściwa diagnoza i odróżnienie pierwotnych objawów negatywnych od wtórnych objawów negatywnych.

Maternal cariprazine exposure inhibits embryonic and postnatal brain cholesterol biosynthesis

Cariprazine (CAR) is a strong inhibitor of the Dhcr7 enzyme, the last enzyme in the cholesterol biosynthesis pathway. We assessed the effects of CAR on maternally exposed Dhcr7+/− and wild-type mouse offspring, and tested the biochemical effects of CAR in human serum samples. Dhcr7+/− and wild-type time-pregnant mice were exposed to vehicle or 0.2 mg/kg CAR from E12 to E19. Levels of CAR, CAR metabolites, sterols, and oxysterols were measured in the brain of maternally exposed offspring at various time points using LC-MS/MS. Embryonic exposure to CAR significantly increased levels of 7-DHC in all organs of exposed embryos, with a particularly strong effect in the brain. Detectable levels of CAR and elevated 7-DHC were observed in the brain of newborn pups 14 days after drug exposure. In addition, CAR altered sterol metabolism in all animals analyzed, with the strongest effect on the brain of Dhcr7+/− pups born to Dhcr7+/− dams. Furthermore, CAR elevated toxic oxysterols in the brain of maternally exposed Dhcr7+/− offspring to levels approaching those seen in a mouse model of Smith–Lemli–Opitz syndrome. Finally, we observed that patients taking CAR have elevated 7-DHC in their serum. In summary, maternal DHCR7 heterozygosity, combined with offspring DHCR7 heterozygosity might represent a vulnerability factor to medications that interfere with sterol biosynthesis. Due to the conserved sterol biosynthesis between mice and humans, we suggest that the 1–3% of patient population with single-allele DHCR7 mutations might not be ideal candidates for CAR use, especially if they are nursing, pregnant or plan to become pregnant.

Effects of Cariprazine, Aripiprazole, and Olanzapine on Mouse Fibroblast Culture: Changes in Adiponectin Contents in Supernatants, Triglyceride Accumulation, and Peroxisome Proliferator-Activated Receptor-γ Expression.

Background and Objectives: The use of the dopamine-partial agonist subclass (also termed dopamine stabilizers) of atypical antipsychotics for the treatment of negative schizophrenia symptoms and some mood disorders has increased recently. Similar to other second-generation antipsychotics (SGAs), aripiprazole (ARI) and cariprazine (CAR) also influence food intake, but the peripheral effects of these drugs on adipose–tissue homeostasis, including adipokine secretion as well as lipo- and adipogenesis, are not fully elucidated. In this study, we explored the adipocyte-related mechanisms induced by second-generation antipsychotics (SGAs), leading to changes in peripheral signals involved in energy homeostasis. Materials and Methods: CAR, a new SGA, was compared with ARI and olanzapine (OLA), using cell cultures to study adipogenesis, and the expression levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) was measured in adipocytes derived from mouse fibroblasts, by western blotting on days 7, 14, and 21 postinduction. The triglyceride (TG) content of the cells was also evaluated on day 15 using Oil Red O staining, and the adiponectin (AN) content in the cell culture supernatants was quantified on days 7 and 15 by enzyme-linked immunosorbent assay. Cells were treated with two concentrations of ARI (0.5 and 20 µg/mL), OLA (1 and 20 µg/mL), and CAR (0.1 and 2 µg/mL). Results: Both concentrations of ARI and OLA, as well as the lower concentration of CAR, significantly increased the TG contents. The AN levels in the supernatants were significantly increased by the higher concentration of ARI on days 7 and 15 (p < 0.05). Although PPAR-γ levels were not significantly affected by ARI and OLA, the lower concentration of CAR induced a significant time-dependent decrease in PPAR-γ expression (p < 0.05). Conclusions: The in vitro adipogenesis considered from TG accumulation, AN secretion, and PPAR-γ expression was differently influenced by ARI, CAR, and OLA. Understanding the adipocyte-related mechanisms of antipsychotics could contribute to understanding their weight-influencing effect.

17. Effects of Cariprazine on Negative Symptoms, Cognitive Impairment, and Prosocial Functioning in Patients With Predominant Negative Symptoms: Post Hoc Analysis of a Phase III, Placebo-, and Active-Controlled Study

Abstract Background: Negative symptoms and cognitive deficits are core symptoms of schizophrenia that have proven to be difficult to treat and are associated with poor social/vocational functioning. Cariprazine (CAR), a D3/D2 receptor partial agonist, is approved in the United States for the treatment of schizophrenia in adults. This post hoc analysis of a Phase 3, randomized, double-blind, placebo- and active-controlled CAR study in adults with acute exacerbation of schizophrenia evaluated the effects of CAR on positive, negative, cognitive, and prosocial functioning domains in a subset of patients with predominant negative symptoms (PNS). Methods: Randomized patients received 6 weeks of double-blind treatment with CAR 3 mg/d, CAR 6 mg/d, aripiprazole 10 mg/d (ARI), or placebo (PBO). For post hoc analyses, patients with PNS were identified using baseline Positive and Negative Syndrome Scale factor scores (PANSS-FS) for positive symptoms (score ≤19; mild to moderate), negative symptoms (score ≥24; moderate to severe), and cognitive impairment (score ≥27; severe). Efficacy parameters included change from baseline to Week 6 in PANSS total score and PANSS-FS for negative, cognitive, and prosocial domains. Results: In all, 131 of 604 randomized patients met criteria for PNS (placebo = 35; CAR 3 mg/d = 27; CAR 6 mg/d = 34; ARI = 35). For CAR 6 mg/d, least squares mean differences (LSMDs) of change from baseline to Week 6 versus placebo were statistically significant on the PANSS total score (-13.9, P = .0132), and negative (-3.3, P = .0112), cognitive (-1.6, P = .0092), and prosocial (-2.9, P = .0035) factor scores. For CAR 3 mg/d, LSMDs versus placebo at Week 6 were statistically significant on the PANSS total score (-14.0; P = .0156), and cognitive (-1.5, P = .0164) and prosocial (-2.5, P = .0187) factor scores. For the negative symptoms factor score, numerical improvement was seen for CAR 3 mg/d over placebo, but the LSMD was not statistically significant at Week 6 (-2.6, P = .0515). In contrast, LSMDs for aripiprazole versus placebo were not statistically significant on PANSS total score (-9.6, P = .0800), negative (-0.6, P = .6449), cognitive (-0.6, P = .3108), or prosocial factor scores (-1.1, P = .2482). In addition, on PANSS-FS for negative symptoms, the LSMD between CAR 6 mg/d and ARI met statistical significance (-2.8, P = .0315). Conclusion: Cariprazine significantly improved overall schizophrenia symptoms, as well as negative, cognitive, and prosocial function versus placebo, in a subset of patients with PNS. These results suggest that cariprazine may be an effective treatment option for the negative symptoms of schizophrenia and its associated domains. Limitations of this analysis include the short duration (6 weeks) for evaluation of negative symptom improvement and the potential that improvements in at least some of the negative symptoms may have been secondary to improvements in positive symptoms.

Cariprazine: New antipsychotic offers patients another option

Cariprazine: New antipsychotic offers patients another option