14 minute read
Cariprazine holds promise for transforming the clinical landscape of schizophrenia
This article summarises the presentations made by four prominent local psychiatrists and will highlight the five key advantages of cariprazine.
Cape Town
Prof Lebo Phahladira, psychiatrist and senior lecturer, is a member of the Psychosis Research Programme of the Department of Psychiatry at Stellenbosch University
Prof Dana Niehaus, Head: Psychogeriatric Unit at Stikland Hospital and Stellenbosch University
Cariprazine’s unique pharmacological profile
Antipsychotics are classified according to which dopamine receptors (D1, D2, D3) they bind to. The neurobiological mechanism and clinical effects of agents depend on which dopamine receptor subtype they exert their action.1
Cariprazine is a dopamine D3 and D2 receptor partial agonist and has a ~10-fold higher affinity for D3 receptors. D3 receptors are highly expressed in areas of the brain that play a role in the regulation of motivation and reward-related behaviour.2,3
Studies show clinical antipsychotic efficacy with cariprazine is attained at about 60% to 75% occupancy of dopamine D2 receptors. Cariprazine also has a high affinity for serotonin or 5-hydroxytryptamine (5-HT).2,4
According to Stahl, cariprazine is unique because of its high affinity for D3 receptors. Cariprazine works by blocking the release of D3 receptors, which is thought to improve dopaminergic neurotransmission.1,5
Furthermore, blocking D3 receptors can enhance acetylcholine release in the prefrontal cortex, which contribute to improvement in cognitive function.1
Cariprazine has the longest half-life of any atypical antipsychotic
Cariprazine is a once-daily oral agent, which can be taken with, or without food. It has two major active metabolites, desmethyl cariprazine (DCAR) and didesmethyl cariprazine (DDCAR).6
Nakamura et al evaluated the pharmacokinetics of cariprazine, metabolites, and total active moieties (sum of cariprazine and two metabolites), as well as efficacy and safety. Participants were randomised to 3mg, 6mg, or 9mg/day. The study duration was 28-weeks.6
They found that a steady state was reached within one to two weeks for cariprazine and DCAR, four weeks for DDCAR, and three weeks for total active moieties. Exposure was dose-proportional over the range of 3mg/day–9mg/day.6
Cariprazine and DCAR levels decreased by >90% within one week after the last dose, DDCAR decreased by ~50% at one week, and total active moieties decreased by ~90% within four weeks.6
The terminal half-lives of cariprazine, DCAR, and DDCAR ranged from 31.6 to 68.4, 29.7 to 37.5, and 314 to 446 hours, respectively. The effective half-life (calculated from time to steady state) of total active moieties was about a week.6
According to Stahl, cariprazine has the longest half-life of any atypical antipsychotic. As a result, it takes about five half-lives to get to steady state, which means that the effective dose continues to rise over the course of a few weeks following initiation, even if the daily dose stays the same.5
Stahl does caution that an unsuspecting clinician may increase the dose before arriving at steady state and overshoot the ideal dose, requiring some down-titration later.5
Furthermore, when stopping treatment with cariprazine, it will be many weeks before the active drug is washed out. That could be a potential advantage in schizophrenia, a condition known to be characterised by poor adherence to treatment.5
City of Tshwane
Dr Franco Colin, psychiatrist in private practice and part time consultant to the Department of Psychiatry, University of Pretoria
Cariprazine is a broad-spectrum treatment effective in managing positive and negative symptoms
The symptomatology of schizophrenia includes various clusters, including negative symptoms (such as blunted affect, anhedonia, and avolition), cognitive impairments, and mood disturbances (like depression). Symptoms may persist even in clinically stable patients, contributing to impaired social and occupational functioning, thus significantly impacting their daily lives.7
A limitation of currently approved antipsychotics is that they are only effective in addressing positive symptoms of schizophrenia and have limited efficacy in managing other symptom domains.7
So, apart from having to manage symptoms with agents that have limited efficacy, individuals living with schizophrenia also face a high burden of adverse effects (AEs) associated with older generation antipsychotics including weight gain, metabolic disruptions, and sexual dysfunction, leading to medication non-adherence that can potentially worsen symptoms, stressed Dr Colin.8
The limitations of traditional antipsychotics underscored the urgent need for the development of innovative therapeutic approaches to effectively address the diverse symptoms of the disorder while minimising the adverse effects on patients’ well-being, added Dr Colin.8
Enter cariprazine, a broad-spectrum antipsychotic that has been shown to effectively manage positive and negative symptoms. Marder et al evaluated the mean change from baseline to week six in Positive and Negative Syndrome Scale (PANSS)-derived symptom factors. Positive, negative, cognitive (eg disorganised thought), hostility (uncontrolled hostility/excitement), and affective (anxiety/depression) symptoms were analysed and the effects of cariprazine were compared to placebo.7
In the pooled analyses at week six, the difference in mean change from baseline was statistically significant in favour of cariprazine (1.5mg/d-9mg/d) compared to placebo across all five PANSS factors.7
The largest treatment effect was observed in the disorganised thought factor (effect size [ES]=0.47, P<0.0001). Similar treatment effects were found for the negative symptom (ES=0.39, P<0.0001), positive symptom (ES=0.37, P<0.0001), and uncontrolled hostility/excitement (ES=0.34, P<0.0001) factors.7
A dose-response analysis was conducted using pooled data from two fixed-dose studies. The difference in mean change from baseline in PANSS total score, negative symptom factor score, and disorganised thought factor score was statistically significant in favour of all doses of cariprazine (1.5mg/d, 3mg/d, 4.5mg/d and 6mg/d) compared to placebo.7
Slightly larger treatment effects were observed with cariprazine 4.5mg/d and 6mg/d than with cariprazine 1.5mg/d and 3mg/d on PANSS total, negative symptom, positive symptom, and disorganised thought factor scores.7
On the PANSS positive factor, the differences between the three highest doses of cariprazine and placebo were statistically significant, while all doses except cariprazine 4.5mg/d were significantly different from placebo on the uncontrolled hostility/excitement factor.7
Cariprazine is the only antipsychotic with proven efficacy in the treatment of predominant negative symptoms of schizophrenia
Németh et al conduced a randomised, double-blind, phase IIIb trial, enrolling adults living with stable schizophrenia and predominant negative symptoms (>6 months) at 66 study centres in 11 European countries.9
Participants (n=533) were randomly assigned (1:1) to 26 weeks of monotherapy with fixed-dose oral cariprazine (3mg, 4.5mg [target dose], or 6mg/d) or risperidone (3mg, 4mg [target dose], or 6mg/d). Previous medication was discontinued over two weeks.9
The primary outcome was the change from baseline to week 26 or end of treatment on the PANSS-factor score for negative symptoms (PANSS-FSNS), analysed in a modified intention-to-treat population of patients who had follow-up assessments within five days after the last receipt of study agents.9
Cariprazine led to greater least squares mean change in PANSS-FSNS from baseline to week 26 than 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).9
The authors concluded that their results support the efficacy of cariprazine in the treatment of predominant negative symptoms of schizophrenia.9
Dr Colin concluded that cariprazine has the potential to change clinical practice by providing a treatment option for patients with predominant negative symptoms of schizophrenia. Treatment with cariprazine monotherapy not only improved predominant negative symptoms in patients with schizophrenia, but the effect was also clinically meaningful, as shown by improvement in patient functioning.8
Johannesburg
Dr Viresh Chiman, a psychiatrist practising at Akeso Parktown
Modern psychopharmacology is increasingly emphasising the importance of pharmacotherapy’s tolerability to enhance the quality of life (QoL) for individuals living with schizophrenia. This focus includes factors such as functionality, sustained remission, and overall recovery, noted Dr Chiman.10
He emphasised that poor adherence rates to antipsychotic treatment is high among individuals living with schizophrenia, with adherence rates ranging between 56% and 60%.11
Non-adherence is the most frequent cause of exacerbation, relapse (75% to 90%), re-hospitalisation, or increased use of emergency psychiatric services, functional decline, and an increased risk of death, as well as increasing the care burden on their families.11
Non-adherence tends to occur more frequently when patients disagree with the necessity of treatment. Furthermore, complex treatment regimens and the presence of AEs deemed ‘unbearable and unacceptable’ by patients contribute significantly to non-adherence, said Dr Chiman.10
Furthermore, when looking at it from the patient perspective, they rated metabolic consequences of medication as contributing to morbidity, low QoL, and low satisfaction with care and from a caregiver perspective, sedation and weight gain were rated as important factors contributing to non-adherence, said Dr Chiman.10
Cariprazine’s safety profile
Numerous studies have assessed the safety and tolerability of cariprazine in a wide spectrum of patient subgroups. Earley et al (2017) conducted a post-hoc safety and tolerability analysis using data from four acute trials within the cariprazine schizophrenia clinical development programme.12
The analysis included the overall safety population, comprising all patients who received at least one dose of the study drug, as well as modal daily dose subgroups (1.5mg/d–3mg/day, 4.5mg/d–6mg/day, and 9mg/d–12mg/day).12
The study found that cariprazine was generally well tolerated. The incidence of treatment-emergent AEs compared to placebo was similar for the 1.5mg/d–3mg/day subgroup, but higher for the 4.5mg/d–6mg/day and 9mg/d–12mg/day subgroups.12
A dose-response relationship was observed for akathisia, extrapyramidal symptoms, and diastolic blood pressure. However, the mean changes in metabolic parameters were generally similar between cariprazine-treated and placebo-treated patients.12
Notably, there were no increases in prolactin levels or QTc values greater than 500ms. Small increases in mean body weight (~1kg-2kg) were observed compared to placebo.12
To further elucidate the long-term safety profile of cariprazine, Nasrallah et al (2017) conducted post-hoc analyses by pooling data from two 48-week open-label, flexible-dose extension studies. These analyses focused on outcomes in the pooled safety population, comprising patients who received at least one dose of cariprazine during an open-label extension period. Descriptive statistics were utilised to summarise findings for the overall cariprazine group and modal daily dose subgroups (1.5mg/d–3mg/day, 4.5mg/d–6mg/day, and 9mg/day).13
AEs such as akathisia, insomnia, weight increased, and headache were reported in ≥10% of the overall population. Notably, mean prolactin levels decreased across all dose groups (overall −15.4ng/mL).13
Clinically insignificant changes in aminotransferase levels and alkaline phosphatase were observed, with no evident dose-response relationship observed.13
Additionally, metabolic parameters, including total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels, exhibited mean decreases, without any dose-response relationship noted. Moreover, changes in cardiovascular parameters, including blood pressure and pulse, were generally deemed not clinically significant.13
AEs related to extrapyramidal symptoms occurred in ≥5% of patients, including akathisia, tremor, restlessness, and extrapyramidal disorder. Nasrallah et al concluded that these post-hoc pooled analyses demonstrated the overall safety and tolerability of cariprazine.13
Barabássy et al (2021) conducted post-hoc analyses to assess the safety profile of cariprazine within the recommended dose range of 1.5mg/d-6 mg/d for schizophrenia, using data (n=2048) from eight clinical trials.14
The most reported AEs (>10%) in patients treated with cariprazine included akathisia (14.6%), insomnia (14.0%), and headache (12.1%). Most AEs were considered mild (71.0%) or moderate (26.5%). Akathisia, the most common cariprazine-related AE, was predominantly mild/moderate (97.5%) and managed with rescue medications (56.3%) or dose reduction (18.3%).14
The metabolic profile of cariprazine showed minimal weight gain (mean of 1kg) and an AE of weight increased reported for 5.1% of patients. Other AEs of special interest that occurred at >3% included extrapyramidal disorder (7%), sedation (3.7%), and somnolence (3.1%). Prolactin elevation, cognition impairment, sexual dysfunction, suicidality, and QT prolongation were reported at ≤1%.14
The authors concluded that cariprazine within the recommended dose range demonstrated a favourable safety profile and was generally well tolerated in individuals living with schizophrenia.14
Dr Chiman pointed out that longer-terms studies (76 weeks) showed an average of only 1kg weight gain.10 A 2020 meta-analysis of 83 studies compared 18 different antipsychotics (18 750 patients) with placebo (4210 patients). The authors found no evidence of weight gain with cariprazine when compared with placebo.15
Ten key messages
Receptor Affinity and Function: Antipsychotics are categorised by their binding affinity to dopamine receptors (D1, D2, D3). Cariprazine is unique as a dopamine D3 and D2 receptor partial agonist, showing a ~10-fold higher affinity for D3 receptors.
D3 receptor Role: D3 receptors are prominently expressed in brain regions associated with motivation and reward-related behaviors, making cariprazine particularly effective in these areas.
Clinical efficacy: Studies demonstrate that cariprazine achieves clinical antipsychotic efficacy at 60% to 75% occupancy of dopamine D2 receptors. Additionally, it has a high affinity for serotonin or 5-HT receptors.
Mechanism of action: Cariprazine’s high affinity for D3 receptors and its partial agonism are thought to enhance dopaminergic neurotransmission, thereby improving symptoms of schizophrenia.
Cognitive Benefits: Blocking D3 receptors with cariprazine can increase acetylcholine release in the prefrontal cortex, contributing to better cognitive function.
Long half-life: Cariprazine boasts the longest half-life among atypical antipsychotics, with its active metabolites maintaining therapeutic levels for extended periods, which aids in maintaining steady-state levels and potentially improving treatment adherence.
Dosing and metabolism: Cariprazine is taken once daily and can be consumed with or without food. Its active metabolites, DCAR and DDCAR, contribute to its prolonged action and efficacy.
Treatment of negative symptoms: Cariprazine has shown efficacy in treating both positive and negative symptoms of schizophrenia, setting it apart from many antipsychotics that primarily address positive symptoms.
Safety profile: Cariprazine is generally well-tolerated, with common adverse events being mild to moderate. It shows minimal metabolic side effects, such as slight weight gain, and has a low impact on prolactin levels and QTc intervals.
Impact on clinical practice: Cariprazine’s efficacy in treating predominant negative symptoms and its favourable safety profile position it as a potential game-changer in clinical practice, offering a comprehensive treatment option for schizophrenia with fewer side effects and better patient adherence.
Cariprazine’s mode of action
Discover how cariprazine works to manage the symptoms of schizophrenia. In this short video, we delve into its unique mode of action, exploring its high affinity for D3 receptors and how this translates to potential cognitive, antidepressant, and symptom-relief benefits. Click here.
References
Stahl S. Drugs for psychosis and mood: unique actions at D3, D2, and D1 dopamine receptor subtypes. CNS Spectrums, 2017.
Kiss B, Horvath A, Nemethy Z, et al. Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile. Journal of Pharmacology and Experimental Therapeutics, 2010.
Girgis RR, Slifstein M, D’Souza D, et al. Preferential binding to dopamine D3 over D2 receptors by cariprazine in patients with schizophrenia using PET with the D3/D2 receptor ligand [(11)C]-(+)-PHNO. Psychopharmacology (Berl), 2016.
Edinoff A, Ruoff MT, Ghaffar YT, et al. Cariprazine to Treat Schizophrenia and Bipolar Disorder in Adults. Psychopharmacol Bull, 2020.
Stahl S. Mechanism of action of cariprazine. CNS Spectrums, 2016.
Nakamura T, Kubota T, Iwakaji A, et al. Clinical pharmacology study of cariprazine (MP-214) in patients with schizophrenia (12-week treatment). Drug Des Devel Ther, 2016.
Marder S, et al. Efficacy of cariprazine across symptom domains in patients with acute exacerbation of schizophrenia: Pooled analyses from 3 phase II/III studies. Eur Neuropsychopharmacol, 2019.
Franco C. Now Available in South Africa – Reagila® (Cariprazine): A New Atypical Broad-spectrum Antipsychotic with a unique pharmacological profile. Presentation, [date].
Németh G, Laszlovszky I, Czobor P, et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet, 2017
Chiman V. Now Available in South Africa – Reagila® (Cariprazine): A New Atypical Broad-spectrum Antipsychotic with a unique pharmacological profile. Presentation, 15 May 2024.
Chauhan N, Chakrabarti S, Grover S. Detecting medication non-adherence in schizophrenia: A comparison of different methods among outpatients from a North Indian center. Ind Psychiatry J, 2023.
Earley W, Durgam S, Lu K, et al. Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies. Int Clin Psychopharmacol, 2017.
Nasrallah HA, Earley W, Cutler AJ, et al. The safety and tolerability of cariprazine in long-term treatment of schizophrenia: a post hoc pooled analysis. BMC Psychiatry, 2017
Barabássy Á, Sebe B, Acsai K, et al. Safety and Tolerability of Cariprazine in Patients with Schizophrenia: A Pooled Analysis of Eight Phase II/III Studies. Neuropsychiatr Dis Treat, 2021.
Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry, 2020.
