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Cariprazine as a broad-spectrum treatment

    During the 15th World Congress of Biological Psychiatry, Gedeon Richter and Recordati organised a satellite symposium that aimed at exploring the broad-spectrum treatment of schizophrenia and cariprazine’s role in addressing wide-ranging needs, as supported by both clinical data and real-life experience.
     
    The ‘Cariprazine as broad-spectrum treatment’ symposium was chaired by Professor Christoph Correll, Professor of Psychiatry at The Zucker School of Medicine at Hofstra/Northwell, in New York, USA and Professor and Chair of the Department of Child and Adolescent Psychiatry at Charité University Medicine in Berlin, Germany.

    The concept of broad-spectrum treatment in schizophrenia

    “If we knew what the exact schizophrenias are, in terms of pathway into it and treatment response, we could devise more precise treatment –  but we don’t have that” – opened his presentation Professor Correll, the first speaker of the symposium. He gave a brief overview on the “different faces of schizophrenia”, highlighting the interaction between the five symptoms1, as well as the need for effective treatment options that target both negative2 and cognitive3 symptoms, as they have been most associated with reduced quality of life.
     
    Broad-concept approaches
    Next, Professor Correll outlined how the main treatment targets in schizophrenia have evolved: initially, antipsychotics were viewed as tranquilisers that reduce aggression and self-harm.4 Quickly, the observation was made that they reduce positive symptoms, i.e. hallucinations and delusions, which then became the focus of treatment, including relapse prevention with first-generation agents.4 Next, second-generation antipsychotics had less extrapyramidal symptoms and secondary negative symptoms, but other side-effects emerged, like cardiovascular illness, which were then attenuated with newer antipsychotics.4 More recently, higher order goals of quality of life, functionality and recovery – which includes symptoms stability with functionality – have become a major focus.4
     
    Recovery can be best achieved if symptoms remit early5 – continued Professor Correll – so, effective treatments are needed. Effective treatments can achieve symptoms stability, but they are not enough for recovery, as “there are no skills in pills”. Although effective antipsychotic treatment forms the basis of symptom stability, psychosocial interactions and psychosocial interventions are then required to teach patients skills that enable functional recovery.6,7
     
    When discussing functionality, the interaction of cognitive and negative symptoms needs to be noted – added Professor Correll. Negative symptoms impact on community activities, while cognition is even more relevant for communication and work skills.8 The capacity to engage in an activity is driven by cognitive abilities and the alertness of the brain, but actually executing this capacity and performing an activity has to do with anticipation of reward, drive and hedonic value – matters hindered by negative symptoms.8
     
    Furthermore, the acute treatment of patients with medication is not enough – in order to keep patients stable, relapse prevention comes into play in which antipsychotics have an important role.9 Maintenance care needs to be done with medications that have little side-effects as well as (ideally) long half-lives. Importantly, noted Professor Correll, among oral antipsychotics, cariprazine has the longest half-life.10 He then presented the findings of a study where relapse prevention was examined in patients who stopped their antipsychotic medication; the relapse rate at week 4 was only 5% in cariprazine patients, while it was around 8-34% in patients who were on an antipsychotic with shorter half-life.10 Looking at a 5% greater risk of relapse than continuing medication after discontinuation, drugs with shorter half-life achieved this greater risk after 1-4 weeks, while it took 6-7 weeks with cariprazine treatment.10 On a 10% separation, it was 12 weeks for cariprazine, compared to 2-7 weeks with other antipsychotics.10 These findings suggest that longer half-life medications, like cariprazine, are optimal choices for relapse prevention.
     
    Keeping the body in mind
    Finally, the last part of Professor Correll’s lecture focused on keeping the body in mind, since “efficacy is just the beginning of the treatment journey”; tolerability is crucial to improve adherence and alliance, which then enhances the higher order outcomes we want, like subjective well-being, quality of life and functional capacity.11 This was confirmed by the findings of a study where patients reported that activating or sedating side-effects, weight gain and sexual dysfunction are among the top-rated undesirable side-effects that impact their functioning negatively.12
     
    Studies have also confirmed that controlling the side-effects of medication impact positively on treatment adherence: EPS was the top factor reducing adherence by 43%, weight gain by 36%, sexual dysfunction by 31% and sedation can reduce adherence by 30%.13 Furthermore, these findings were supported by another study, where among 39 risk factors, only two were independently associated with relapse: higher PANSS score and metabolic syndrome.14
     
    In addition to poor adherence, physical illnesses have also been shown to have a negative impact on the brain. Metabolic syndrome, diabetes and hypertension have been associated with poor cognitive outcomes in patients with schizophrenia15, so “by keeping the body in mind, we strengthen the body and the mind” – concluded his presentation Professor Correll.

    Fulfilling wide-ranging with cariprazine

    After learning about the concept of broad-spectrum treatment of schizophrenia, Professor Koen Demyttenaere, Professor at the Faculty of Medicine of the University of Leuven in Belgium and Academic coordinator of the University Psychiatric Center KU Leuven at Campus Gasthuisberg in Leuven, Belgium, confirmed on the potential of cariprazine in broad-spectrum treatment by presenting the findings of numerous clinical trials.
     
    Professor Demyttenaere first introduced the findings of a 6-month trial comparing cariprazine to risperidone in patients with predominant negative symptoms.1 Results of this trial revealed that cariprazine proved to be more effective in reducing negative symptoms than risperidone from week 14 onwards.16 Furthermore, when looking at 20% responder rates, an 11% superiority of cariprazine was observed over risperidone, while for the 30% responder rates, a 13% superiority of cariprazine was detected.16
     
    “However, it’s not only about symptoms, we should also look at social functioning” – continued Professor Demyttenaere – since they are greatly impacted by negative symptoms. In the cariprazine versus risperidone trial by Nemeth et al., Personal and Social Performance (PSP) was further investigated – and findings confirmed that patients were quite impaired in their social functioning at baseline.16 Nonetheless, patients in the cariprazine group showed statistically significantly greater improvements in their social functioning compared to patients in the risperidone group from week 10 onwards.16 When looking at the 4 subscales of the PSP, cariprazine significantly outperformed risperidone in 3 subdomains.16 Furthermore, according to both the Clinical Global Impression (CGI) Severity and Improvement scales, cariprazine patients showed greater functional improvements.16
     
    The authors of the study also checked for pseudospecificity effects – continued Professor Demyttenaere – showing that positive symptoms, depression and extrapyramidal symptoms do not account for the improvement in negative symptoms.16
     
    Professor Demyttenaere then dived into discussing the short-term efficacy studies of cariprazine in patients with acute exacerbation of schizophrenia. Three pivotal studies revealed that cariprazine outperformed placebo in acute patients17,18,19, and so did risperidone17 and aripiprazole18, as shown by changes in Positive and Negative Syndrome Scale (PANSS) Total score.
     
    The effects of cariprazine were then checked to see whether the reduction was just an overall PANSS reduction, so the PANSS-derived Marder domains were examined separately.20 The findings showed that cariprazine was effective in reducing positive symptoms, and this effect was driven by 6 of the 8 subdomains.20 Cariprazine further outperformed placebo in improving negative symptoms (effect driven by 6 of 7 subdomains), affective symptoms (effect driven by 3 of 4 subdomains) and hostility (effect driven by all subdomains).20
     
    Lastly, Professor Demyttenaere presented the post-hoc analysis of the previously described 6-week treatment in acute patients, but looking at a subpopulation of patients with persistent predominant negative symptoms.21 According to the findings, cariprazine was statistically superior over placebo in reducing the predominant negative symptoms of patients, while aripiprazole and risperidone only reached statistical significance at certain timepoints. However, after adjusting for positive symptoms, cariprazine remained statistically significant over placebo, but aripiprazole and risperidone, although numerally greater, did not reach statistical significance in the reduction of negative symptoms compared to placebo.21 These observations suggest that cariprazine has a direct effect on predominant negative symptoms (both primary and secondary), while the other antipsychotics might show efficacy in reducing negative symptoms, but mainly on the secondary ones.
     
    To conclude his presentation, Professor Demyttenaere summarised briefly the main findings of the presented studies and concluded that cariprazine shows a broad ‘overall’ efficacy in different symptom domains of schizophrenia.

    Real-world clinical experience with cariprazine treatment

    The last presenter of the symposium, Dr Johan Sahlsten Schölin, Doctor of Psychiatry at the Department of Psychosis at the Sahlgrenska University Hospital in Gothenburg, Sweden, translated clinical data into real-world experience. He described two patients who received cariprazine treatment, elaborating on how cariprazine helped alleviate their disabling symptoms.

    Cod: 300021/R64. Submitted to AIFA on 03/12/2021

    References title

    1. Young, J. W. & Geyer, M. A. Developing treatments for cognitive deficits in schizophrenia: The challenge of translation. J. Psychopharmacol. 29, 178–196 (2015).
    2. Millan, M. J., Fone, K., Steckler, T. & Horan, W. P. Negative symptoms of schizophrenia: Clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment. Eur. Neuropsychopharmacol. 24, 645–692 (2014).
    3. Millan, M. J. et al. Cognitive dysfunction in psychiatric disorders: Characteristics, causes and the quest for improved therapy. Nat. Rev. Drug Discov. 11, 141–168 (2012).
    4. Correll, C. U. Pharmacotherapy of schizophrenia. Nervenarzt 91, 34–42 (2020).
    5. Lambert, M. et al. Rates and predictors of remission and recovery during 3 years in 392 never-treated patients with schizophrenia. Acta Psychiatr. Scand. 118, 220–229 (2008).
    6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edition. (Washington DC, 2000).
    7. Burns, T. & Patrick, D. Social functioning as an outcome measure in schizophrenia studies. Acta Psychiatr. Scand. 116, 403–418 (2007).
    8. Bowie, C. R. et al. Predicting Schizophrenia Patients’ Real World Behavior with Specific Neuropsychological and Functional Capacity Measures. Biol. Psychiatry 63, 505–511 (2008).
    9. Leucht, S. et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: A systematic review and meta-analysis. Lancet 379, 2063–2071 (2012).
    10. Correll, C. U. 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. 15, 2537–2550 (2019).
    11. Correll, C. U. What are we looking for in new antipsychotics? J. Clin. Psychiatry 72, 9–13 (2011).
    12. Tandon, R. et al. The impact on functioning of second-generation antipsychotic medication side effects for patients with schizophrenia: A worldwide, cross-sectional, web-based survey. Ann. Gen. Psychiatry 19, 1–11 (2020).
    13. DiBonaventura, M., Gabriel, S., Dupclay, L., Gupta, S. & Kim, E. A patient perspective of the impact of medication side effects on adherence: Results of a cross-sectional nationwide survey of patients with schizophrenia. BMC Psychiatry 12, (2012).
    14. Godin, O. et al. Metabolic syndrome and illness severity predict relapse at 1-year follow-up in schizophrenia: The FACE-SZ cohort. J. Clin. Psychiatry 79, (2018).
    15. Hagi, K. et al. Association between Cardiovascular Risk Factors and Cognitive Impairment in People with Schizophrenia: A Systematic Review and Meta-analysis. JAMA Psychiatry 78, 510–518 (2021).
    16. Németh, G. et al. Cariprazine versus risperidone monotherapy for treatment of predominant negative symptoms in patients with schizophrenia: a randomised, double-blind, controlled trial. Lancet 389, 1103–1113 (2017).
    17. Durgam, S. 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. 152, 450–457 (2014).
    18. Durgam, S. et al. Cariprazine in acute exacerbation of schizophrenia: A fixed-dose, phase 3, randomized, double-blind, placebo- and active-controlled trial. J. Clin. Psychiatry 76, e1574–e1582 (2015).
    19. Kane, J. M. et al. Efficacy and Safety of Cariprazine in Acute Exacerbation of Schizophrenia: Results from an International, Phase III Clinical Trial. J. Clin. Psychopharmacol. 35, 367–373 (2015).
    20. 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. 29, 127–136 (2019).
    21. Earley, W. et al. Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia: A post hoc analysis of pooled data. Schizophr. Res. 204, 282–288 (2019).
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