Examples of positive symptoms include persistent delusions, hallucinations, disorganised thinking, speech, and behaviour. Negative symptoms include for example avolition, blunted or flat affect, psychomotor disturbances as well as experiences of passivity and control. Positive symptoms tend to diminish naturally over time, whereas negative symptoms often persist and are associated with a poor prognosis.³ 

Cognitive domains affected include sustained attention, early information processing, contextual processing, memory, verbal and non-verbal ability, executive functioning, abstraction, and conceptual organisation.⁴ 

 Affective symptoms (eg depression and anxiety) are common in patients living with schizophrenia. Studies report that as many as 80% of patients experience depressive symptoms while the prevalence of any anxiety disorder is estimated to ~38%, with social anxiety disorder being the most common.^4,5,6 

What is different about cariprazine? 

According to Dr Barabassy, there are currently more than 20 antipsychotics available on the market to treat patients living with schizophrenia. So what differentiates cariprazine from other antipsychotics?²  

She explained that there are five important factors that differentiate cariprazine from other antipsychotics:

1. 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.⁷  

 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. 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 hydroxy tryptamine(5-HT).^1,8,9 

 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.^7,10  

 Furthermore, blocking D3 receptors can enhance acetylcholine release in the prefrontal cortex, which contribute to improvement in cognitive function.⁷  

2. 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).^2,11 

 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.¹¹ 

 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.¹¹ 

 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.¹¹  

 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.¹¹  

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.¹⁰  

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.¹⁰ 

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, he states.¹⁰  

3. Broad-spectrum efficacy across symptom domains 

Several studies examined the safety and efficacy of cariprazine in managing acute symptoms in patients living with schizophrenia. Durgam et al evaluated the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia.¹²  

 Patients (n=732) were randomised to receive placebo, cariprazine 1.5mg/day, cariprazine 3mg/day, cariprazine 4.5mg/day, or risperidone 4mg/d (for assay sensitivity) for six weeks of double-blind treatment and two weeks of safety follow-up.¹²   

 Positive and Negative Syndrome Scale (PANSS) score improvement at week six was statistically significant versus placebo for cariprazine 1.5mg/d, 3.0 mg/d, and 4.5 mg/d (least squares mean difference [LSMD]: -7.6, -8.8, -10.4, respectively) and risperidone (-15.1, p <0.001, LOCF). Furthermore, significant improvement on Global Impressions-Severity of Illness Scores (CGI-S) was demonstrated for all active treatments.¹²   

 The results of this study support the efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia, concluded the authors.¹² 

 Németh et al evaluated the efficacy of cariprazine in adult patients (n=460) with predominantly negative symptoms. Patients were randomised (1:1) to 26 weeks of monotherapy with fixed-dose oral cariprazine (n=230, 3mg/day, 4.5mg/day [target dose], or 6mg/day) or risperidone (n=231) 3mg/day, 4mg/day [target dose], or 6mg/day).¹³  

 The authors report that patients in the cariprazine group showed greater least squares mean change in PANSS from baseline to week 26 compared to those in the risperidone group (-8.90 vs -7.44).¹³ 

4. Relapse prevention and delay 

Durgam et al evaluated the efficacy, safety, and tolerability of cariprazine for relapse prevention in adult patients (n=765). Symptoms were treated/stabilised with cariprazine 3mg/day-9mg/day.¹⁴  

 The primary efficacy endpoint was time to relapse (worsening of symptom scores, hospitalisation, aggressive/violent behaviour, or suicidal risk). Time to relapse was significantly longer in the cariprazine group versus the placebo groups. Relapse occurred in 24.8% of patients in the cariprazine groups vs 47.5% in the placebo group.¹⁴   

 Cornell et al explored the timing of relapse following drug discontinuation and its relationship to estimated plasma levels and elimination half-life by comparing data from a randomised, placebo-controlled discontinuation study of cariprazine with those from similarly designed and conducted randomised control trials of other oral atypical antipsychotics.¹⁵  

 Data from a long-term, randomised, double-blind, placebo-controlled relapse prevention study in participants with schizophrenia were analysed. Similarly designed, published studies of other atypical antipsychotics were used for comparison.¹⁵  

 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 atypical antipsychotic and placebo curves.¹⁵  

 The Kaplan–Meier curve for cariprazine showed a time to drug-placebo relapse separation at six to seven weeks after randomisation, compared to the Kaplan–Meier curves for the other atypical antipsychotics, which showed earlier separation at one to four weeks.¹⁵  

 The placebo relapse rates at four weeks after randomisation were 5% for cariprazine and 8%-34% for other atypical antipsychotics. Geometric mean values of model-predicted plasma concentrations for total active cariprazine moieties (sum of cariprazine, DCAR, and DDCAR) were 20nM and 6.1nM at two and four weeks after discontinuation, respectively.¹⁵  

 Elimination half-lives of other atypical antipsychotics and their active metabolites (<4 days) suggest that plasma concentrations would be low or negligible at two to four weeks after the last dose.¹⁵  

 Discontinuation of cariprazine treatment appeared to be associated with a delayed incidence of relapse compared with other atypical antipsychotics, which may be due to the longer half-life of cariprazine and its active metabolites.¹⁵ 

5. More favourable side effect profile compared to first- and second-generation agents 

The most common AEs associated with cariprazine include extrapyramidal symptoms and akathisia. Dr Barabassy pointed out that the above-mentioned AEs are a class and dose effect associated with all antipsychotics and usually dissipates after two weeks of treatment.^1,2 

 More than 7% of patients living with schizophrenia experience clinically important weight increase after starting therapy with an antipsychotic. Weight gain is a concern for patients because it contributes to type 2 diabetes mellitus, dyslipidaemia, and hypertension, which increase the risk for cardiovascular events. Excessive weight can also have important effects on adherence to treatment.^16,17  

 Some antipsychotics are clearly more likely to induce weight gain than others, but no drug is completely free of a weight gain effect, and none causes weight gain in every patient.¹⁷  

 The incidence of clinically significant weight increase associated with atypical antipsychotic treatment has been reported in a range from 8.1% (aripiprazole) to 22.2% (olanzapine).¹⁹  

As with all antipsychotics, changes in body weight have been observed with cariprazine treatment. In short-term studies, there were slightly greater mean increases in body weight in the cariprazine group compared to the placebo group (1kg vs 0.3kg).²⁰  

In a long-term maintenance of effect study, there was no clinically relevant difference in change of body weight from baseline to end of treatment (1.1kg for cariprazine vs 0.9kg for placebo). Collectively, data suggest that cariprazine is on the lower end of the atypical antipsychotic weight gain hierarchy.^19,20 

Along with its good weight profile, cariprazine does not appear to have clinically relevant adverse effects on metabolic variables. Cariprazine had a neutral metabolic profile. In short-term studies, fewer patients treated with cariprazine compared to placebo-treated patients shifted from normal to high levels of low-density lipoprotein-cholesterol (LDL-C) (2.9% vs 4.9%) and fasting triglyceride (6.7% vs 8.3%).²¹ 

Furthermore, more patients treated (6.7%) shifted from normal to high levels of fasting glucose compared to placebo-treated patients (3.6%). In long-term studies, similar percentages of cariprazine- and placebo-treated patients shifted from normal to high levels of LDL-C (2.0% vs 2.0%) and fasting triglyceride (10.7% vs 12.5%), while more cariprazine-treated patients (6.2%) than placebo-treated patients (1%) again shifted from normal to high levels of fasting glucose.²¹  

Cariprazine did not show human ether-a-go-go related gene (hERG) inhibitory activity in vitro at concentrations well above therapeutic concentrations.²¹  

In a clinical study evaluating QT prolongation, no QT prolongation was observed even at supratherapeutic doses (9mg/day and 18mg/day, respectively). Only a few cases of not severe QT prolongation have been reported in clinical trials.²¹  

In a pooled analysis of eight cariprazine clinical studies four short-term, two open-label safety, one relapse prevention, the incidence of potentially clinically significant QT prolongation measured by the Fridericia formula (QTcF >500ms or QTcF increase >60ms), a better predictor of severe cardiac consequences than the Bazett formula (QTcB), was low in both treatment groups (cariprazine = 0.2%, placebo = 0.3%).²¹  

Cariprazine is not associated with hyperprolactinemia. On the contrary, high, or high-normal baseline prolactin levels decreased to reference range values for cariprazine (−12.9ng/ml) and placebo (−8.2ng/ml).²¹ 

Further, sexual dysfunction treatment-emergent adverse events (TEAEs) occurred in only a slightly higher percentage of cariprazine-treated patients (1%) than placebo-treated patients (0.3%), with higher rates noted in the active controls risperidone (2.7%) and aripiprazole (2%).²¹  

The most common sexual dysfunction TEAEs for cariprazine 3mg/day–6mg/day were erectile dysfunction (0.4%), decreased libido (0.3%), amenorrhoea (0.2%), and female orgasmic disorder (0.2%).²¹ 

Patients with hypersensitivity to cariprazine have been known to experience dermatological effects (rash, urticaria), and angioedema events (oedema of the tongue, face, and pharynx). Known interactions involve strong CYP3A4 inhibitors, in which case the dosage should be reduced by half. Withdrawal of the CYP3A4 inhibitor may require an increase in cariprazine dosage.¹ 

Five key messages 

1. Cariprazine differs from all other atypical antipsychotics in having a greater affinity for the D3 receptor (~10-fold higher) than dopamine itself, thereby exhibiting a functional D3 partial agonism in the human brain.^7,8  
2. Cariprazine has a unique pharmacokinetic profile. It has been shown to have the longest half-life of any atypical antipsychotic.¹⁰ 
3. Cariprazine has a broad-spectrum efficacy across symptom domains and has been shown to be superior in the treatment of negative and extrapyramidal symptoms.^1,12,13 
4. Cariprazine is effective in preventing or delaying relapse.^14,15 
5. Cariprazine has a more favourable side effect profile compared to first- and second-generation agents.¹ 

References 

1. Edinoff A, Ruoff MT, Ghaffar YT, et al. Cariprazine to Treat Schizophrenia and Bipolar Disorder in Adults. Psychopharmacol Bull, 2020 Sep 14;50(4):83-117. PMID: 33012874; PMCID: PMC7511151. 
2. Dr Agota Barabassy presentation. Adcock Ingram, 13 April 2023. 
3. Masinga N, Nyamaruze P, Akintola, O. A retrospective study exploring how South African newspapers framed Schizophrenia and other psychotic disorders over an 11-year period (2004–2014). BMC Psychiatry 22, 667 (2022). https://doi.org/10.1186/s12888-022-04276-5 
4. Srisudha B, Kattula D, Devika S, Rachana A. Cognitive dysfunction, and disability in people living with schizophrenia. J Family Med Prim Care, 2022 Jun;11(6):2356-2362. doi: 10.4103/jfmpc.jfmpc_396_21. Epub 2022 Jun 30.  
5. Morrissette DA, Stahl SM. Affective symptoms in schizophrenia. 
6. Drug Discovery Today: Therapeutic Strategies, Volume 8, Issues 1–2, 
7. doi.org/10.1016/j.ddstr.2011. 
8. Temmingh H, Stein DJ. Anxiety in Patients with Schizophrenia: Epidemiology and Management. CNS Drugs, 2015;29(10):819-32. doi: 10.1007/s40263-015-0282-7. PMID: 26482261. 
9. Stahl S. Drugs for psychosis and mood: unique actions at D3, D2,and D1 dopamine receptor subtypes. CNS Spectrums (2017), 22, 375–384. doi:10.1017/S1092852917000608 
10. 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, April 2010, 333 (1) 328-340; DOI: https://doi.org/10.1124/jpet.109.160432 
11. 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 Oct;233(19-20):3503-12. doi: 10.1007/s00213-016-4382-y. Epub 2016 Aug 15. PMID: 27525990; PMCID: PMC5035321. 
12. Stahl S. (2016). Mechanism of action of cariprazine. CNS Spectrums, 21(2), 123-127. doi:10.1017/S1092852916000043 
13. 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 Jan 14;10:327-38. doi: 10.2147/DDDT.S95100. PMID: 26834462; PMCID: PMC4716719. 
14. Durgam S, Starace A, Li D, et al. An evaluation of the safety and efficacy of cariprazine in patients with acute exacerbation of schizophrenia: a phase II, randomized clinical trial. Schizophr Res, 2014 Feb;152(2-3):450-7. doi: 10.1016/j.schres.2013.11.041. Epub 2014 Jan 10. PMID: 24412468. 
15. 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 Mar 18;389(10074):1103-1113. doi: 10.1016/S0140-6736(17)30060-0. Epub 2017 Feb 7.  
16. Durgam S, Earley W, Li R, et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial. Schizophr Res, 2016 Oct;176(2-3):264-271. doi: 10.1016/j.schres.2016.06.030. Epub 2016 Jul 15.  
17. Correll CU, Jain R, Meyer JM, et al. 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. Neuropsychiatr Dis Treat, 2019 Aug 30;15:2537-2550. doi: 10.2147/NDT.S210340. PMID: 31507322; PMCID: PMC6719841. 
18. Kapur S, Marques TR. Dopamine, striatum, antipsychotics, and questions about weight gain. JAMA Psychiatry 73, 107–108 (2016). 
19. Perkins AJ, Khandker R, Overley A, et al. Association of Antipsychotic-Related Weight Gain With Treatment Adherence and Switching Using Electronic Medical Records Data. The Primary Care Companion for CNS Disorders, 2023. 
20. Musil R, Obermeier M, Russ P, Hamerle M. Weight gain and antipsychotics: a drug safety review. Expert Opin Drug Saf, 2015 Jan;14(1):73-96. doi: 10.1517/14740338.2015.974549. Epub 2014 Nov 15. PMID: 25400109. 
21. 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. International Clinical Psychopharmacology, 2017 Nov;32(6):319-328. DOI: 10.1097/yic.0000000000000187. PMID: 28692485; PMCID: PMC5625952. 
22. European Medicine Agency. Product Information. Reagila, INN-cariprazine. [Internet]. Available from: https://www.ema.europa.eu/en/documents/product-information/reagila-epar-product-information_en.pdf. Accessed 13 June 2023. 
23. Laszlovszky I, Barabássy Á, Németh G. Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety. Adv Ther, 2021 Jul;38(7):3652-3673. doi: 10.1007/s12325-021-01797-5. Epub 2021 Jun 6. PMID: 34091867; PMCID: PMC8279990. 

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