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Clinical Global Impression of Cariprazine in Negative Symptom Schizophrenia Patients: Comparison of clinical trial data vs. real-world evidence
- E. Rancans, Z. B. Dombi, R. Csehi, G. Németh
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S641
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Introduction
There is an increasing need to understand the effectiveness of novel medications in real-world context since despite being the gold standard, double-blind trials have their own limitations as well. Clinical Global Impression is a simple tool for clinicians to assess the severity of an illness (CGI-Severity) as well as to rate how much the patient’s disorder has improved or worsened relative to baseline (CGI-Improvement). In this poster, cariprazine, a third-generation antipsychotic medication that was found to be effective in the treatment of negative symptoms in schizophrenia will be evaluated.
ObjectivesTo compare the effectiveness of cariprazine in clinical trial vs real-world setting via the CGI-S and CGI-I scales in negative symptom schizophrenia patients.
MethodsWe compared the results of a clinical trial (Németh et al. Lancet 2017; 389:1103-13) and an observational study (Rancans et al. Int Clin Psychopharmacol. 2021;36(3):154-161). The latter was an open-label, flexible-dose, 16-week, observational study of cariprazine involving 116 outpatients in Latvia. Adult patients who have been diagnosed with schizophrenia, exhibited negative symptoms based on clinical judgement, were at least mildly ill according to the CGI-S scale and have not previously received cariprazine were eligible to take part in the study. Dosing of cariprazine was based on clinical judgement. The clinical trial was a randomized, double-blind, multi-centred, 26-week study with adults aged 18–65 years with long-term (>2 year), stable schizophrenia and predominant negative symptoms (>6 months). Patients were randomly assigned to monotherapy with cariprazine 4.5 mg/day or risperidone 4.0 mg/day.
Results116 patients on flexible dose cariprazine (observational study) were compared with 227 patients on cariprazine 4.5 mg/day and 229 on risperidone 4.0 mg/day (clinical trial). Baseline severity of illness as measured by the CGI-S was between moderately and markedly ill in all three groups. By the end of the 26-week trial, cariprazine reduced the CGI-S score significantly (LS Mean Change: -0.9, p<0.01). In contrast, the risperidone group achieved only -0.7-point change from baseline. In the observational study, cariprazine also achieved significant change (-0.9, p<0.001) but by week 16. In terms of improvement, patients on cariprazine improved minimally to much in both the clinical trial and real-world setting.
ConclusionsThe effectiveness of cariprazine in clinical trial and real-world setting do not seem to differ as measured by the scales in negative symptom patients.
Disclosure of InterestE. Rancans Grant / Research support from: Gedeon Richter, Lundbeck, Consultant of: Abbvie, Gedeon Richter, Grindex, Janssen Cilag, Lundbeck, Servier, Zentiva, Speakers bureau of: Abbvie, Gedeon Richter, Grindex, Janssen Cilag, Lundbeck, Servier, Zentiva, Z. Dombi Employee of: Gedeon Richter Plc., R. Csehi Employee of: Gedeon Richter Plc., G. Németh Employee of: Gedeon Richter Plc.
Cariprazine’s efficacy in treating depressive symptoms – pooled data from schizophrenia, bipolar depression and major depression trials
- R. S. McIntyre, R. Csehi, G. Németh
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, pp. S297-S298
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Introduction
Depressive 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.
Defining the therapeutic reference range for cariprazine
- M. Kapás, A. Horváth, D. Djuric, R. Csehi, Á. Barabássy
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- Journal:
- European Psychiatry / Volume 66 / Issue S1 / March 2023
- Published online by Cambridge University Press:
- 19 July 2023, p. S559
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Introduction
According to the Consensus Guideline, the “therapeutic reference range” (TRR) defines ranges of drug blood concentrations that specify a lower limit below which a drug-induced therapeutic response is unlikely to occur and an upper limit above which tolerability decreases or the therapeutic improvement ceases. The TRR can be obtained from concentration measurements (trough (pre-dose) plasma concentration under steady-state conditions) in studies at therapeutically effective doses.
ObjectivesThe aim is to examine the TRR for cariprazine (CAR: 1.5 mg/day to 6 mg/day) in schizophrenia studies.
MethodsThe population based TRR for CAR is derived by PK/PD evaluation from phase 2/3 schizophrenia efficacy studies with sparse PK sampling. The population PK simulated TRR is compared to the actually measured values obtained from two PK studies. As the two active metabolites of cariprazine also contribute to the drug effect, plasma exposure is given for Total cariprazine (CAR + DCAR + DDCAR) and the parent drug (CAR).
ResultsPK/PD analyses demonstrated an increase in efficacy with increasing exposure. These efficacy results are related to Total cariprazine trough concentrations of ca. 30 nM and 100 nM that determine the lower and upper TRR limits. For the parent drug, the pre-dose mean plasma concentration at 6 mg/day was between 5.7-10 ng/mL in different studies, while at 1.5 mg/day it was 1.9 ng/mL.
ConclusionsThe TRR of the trough plasma levels at steady state is ca. 30 – 100 nM for Total cariprazine and ca. 2-10 ng/mL for the parent drug (unchanged drug) for schizophrenia treatment.
Disclosure of InterestM. Kapás Employee of: Gedeon Richter Plc., A. Horváth Employee of: Gedeon Richter Plc., D. Djuric Employee of: Gedeon Richter Plc., R. Csehi Employee of: Gedeon Richter Plc., Á. Barabássy Employee of: Gedeon Richter Plc.
Benzodiazepine use during cariprazine treatment in acute schizophrenia
- C. Correll, B. Sebe, R. Csehi, K. Acsai, Á. Barabássy
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- Journal:
- European Psychiatry / Volume 65 / Issue S1 / June 2022
- Published online by Cambridge University Press:
- 01 September 2022, p. S98
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Introduction
Although antipsychotics are first-line treatments for schizophrenia, benzodiazepines (BZDs) are often used as concomitant medications in acutely exacerbated patients due to their anxiolytic and sedative effects. Cariprazine (CAR), a D3-preferring dopamine D2/D3 partial agonist antipsychotic, has been examined in many clinical studies for the treatment of acute schizophrenia, with and without benzodiazepines.
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.