Some schizophrenia patients with therapeutic compromise experience issues with their antipsychotic medication due to either ineffectiveness of the medication itself or non-compliance.¹ These patients usually require a switch in their antipsychotic medication.¹ Instability of the underlying condition and the risk of relapse is high in this patient population, due to poor treatment compliance, even in patients who are otherwise treatment-responsive.¹ This population also includes treatment-resistant patients who do not improve because their medication is inefficacious.²
 
Inadequate treatment response to AP medications
Poor treatment response to antipsychotic medication is reported in 20 to 30% of patients³ and includes persistent and impairing positive, negative or mood symptoms, as well as limited or no improvement in patients’ psychosocial functioning.¹
 
Other factors
Non-adherence resulting in therapeutic compromise may also be due to complex dosing schedules, misinformation concerning AP medication, doubts regarding pharmacotherapy in general and an underappreciation of illness severity.¹ On average, 50% of patients are non-compliant with their oral antipsychotic medication⁴, and they take 58% of the recommended amount of medication with a range of 24-90%.⁵

Managing treatment response: broad-spectrum efficacy
A broad spectrum of patient symptoms need to be further improved, including positive, negative, cognitive and mood symptoms and psychosocial functioning.⁶ It is also necessary to identify appropriate therapy options for treatment-resistant patients.² Apart from the potential switch in AP medication, patients need to be involved in psychosocial interventions as adjunctive treatment to pharmacotherapy.⁶ For instance, social skill training has been seen to improve positive and negative symptoms; CBT can improve positive symptoms; and cognitive remediation therapy has the potential to improve deficient cognitive capabilities (e.g. attention, memory, executive functioning).⁶
 
Managing other factors: Improving non-adherence
Psychoeducation provides patients and their family with in-depth knowledge regarding schizophrenia by explaining its aetiology, course, management etc. with the aim of increasing patients’ treatment compliance by highlighting the importance of medication and other interventions and explaining the severity of the illness and the detrimental consequences of non-adherence.⁶ In addition, medication regimens should be simplified for patients who are non-adherent due to a complex regimen.¹

Managing treatment response: broad-spectrum efficacy
Cariprazine was found to be effective in reducing all 5 symptom domains of schizophrenia (positive, negative, anxiety/depression, uncontrolled hostility/excitement, disorganised thought) compared to placebo, making it a valuable treatment option for patients with efficacy-related therapeutic compromise.⁷

Adapted from: 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).
 
Compared to placebo, cariprazine was found to be more effective in reducing overall negative symptoms: the effect was driven by 6 of 7 subdomains.⁷

Adapted from: 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).
 
These data were also supported by a specifically designed study to examine the efficacy of cariprazine on negative symptoms of schizophrenia versus risperidone. The study showed that the improvement in the symptoms and functioning of patients with negative symptoms obtained with cariprazine was significantly better than that achieved with risperidone.⁸ 

Adapted from: 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).
 
Cariprazine was shown to decrease overall affective (anxiety/depression) symptoms with statistically significant superiority over placebo.⁷

Adapted from: 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).
 
Cariprazine was more effective in improving quality of life, with statistically significant superiority over placebo.⁹

Adapted from: Kahn, R. Effects of Cariprazine on Health‑Related Quality of Life in Patients with Schizophrenia. Am. Psychiatr. Assoc. Annu. Meet. Poster Present.
 
 
Managing other factors: Improving non-adherence, minimising the risk of relapse
Cariprazine has a long half-life, due mainly to the presence of an active metabolite, didesmethyl-cariprazine (DDCAR), that has an extended half-life of 1-3 weeks.¹⁰ The predicted plasma concentration of total cariprazine in studies implies that patients who have discontinued cariprazine treatment may still have a substantial D2 occupancy after 2 weeks and moderate D2 occupancy after 4 weeks from the last dose; furthermore, D3 receptor occupancy is substantial 2 and 4 weeks after the last dose of cariprazine.¹⁰ Therefore, as cariprazine is eliminated from the body in 3-4 weeks, patients do not experience a relapse if they skip a few doses due to medication non-adherence.¹⁰
 
Time to relapse was significantly longer in the cariprazine group than in the placebo group (p=0.001).¹¹ The 25^th percentile for time to relapse was 92 days in the placebo group, versus 224 days in the cariprazine group.¹¹

Adapted from: Durgam, S. et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial. Schizophr. Res. 176, 264–271 (2016).
 
Long-term cariprazine treatment was significantly more effective than placebo for preventing relapse in patients with schizophrenia: relapse occurred in 24.8% of cariprazine- and 47.5% of placebo-treated patients.¹¹

Adapted from: Durgam, S. et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial. Schizophr. Res. 176, 264–271 (2016).
 
Cariprazine treatment was significantly more effective than placebo for the long-term relapse prevention in subacute patients.¹²

Adapted from: Correll, C. U. et al. Long-term remission with cariprazine treatment in patients with schizophrenia: A post hoc analysis of a randomized, double-blind, placebo-controlled, relapse prevention trial. J. Clin. Psychiatry 80, 1–7 (2019).
 
Cariprazine was associated with significantly longer sustained remission and an increased likelihood of sustaining remission for ≥ 6 consecutive months versus placebo.¹²

Adapted from: Correll, C. U. et al. Long-term remission with cariprazine treatment in patients with schizophrenia: A post hoc analysis of a randomized, double-blind, placebo-controlled, relapse prevention trial. J. Clin. Psychiatry 80, 1–7 (2019).
 
Cariprazine treatment of acutely ill patients was associated with a robust increase in functionality during the stabilisation phase. This improvement was maintained over time.¹¹

Adapted from: Durgam, S. et al. Long-term cariprazine treatment for the prevention of relapse in patients with schizophrenia: A randomized, double-blind, placebo-controlled trial. Schizophr. Res. 176, 264–271 (2016).
 
Switching
In patients with therapeutic compromise, slower switching strategies and gradual cross-titration may be indicated.¹ Weekly dose-increases of cariprazine by 1.5 mg increments represent a slower up-titration of cariprazine in stable patients with schizophrenia.⁸ On the other hand, dose decreases of the previous antipsychotics at any time (1 week¹³, 2 weeks⁸, 3 weeks¹³) up to 4 weeks¹³ – or even a full dose overlap for a certain time – are recommended when switching stable patients.¹⁴

Note: The recommended starting dose is 1.5 mg once a day. The dose can be increased by 1.5 mg at a time up to a maximum of 6 mg per day.

COD. 300021/R58. Submitted to AIFA on 19/11/2021