Subacute schizophrenia patients are subjects who transitioned from the acute to the subacute phase due to symptom remission (PANSS total score range is 50-75; moderately ill).¹ The delusions, hallucinations, disorganised thinking, and/or formal thought disorder that were more prominent in the acute phase may still be present in milder form.² However, negative symptoms can become more prevalent, along with cognitive impairments and limited social functioning, meaning patients remain functionally impaired.² These patients are usually hospitalised but may also be outpatients.² Subacute patients usually have better insight into their condition due to symptom remission; however, having greater insight after the acute phase may increase their risk of suicidality.²

The main treatment goals for subacute patients are to sustain symptom remission, reduce the likelihood of relapse as far as is possible, support patients’ adaptation to the community and promote recovery in general.²
 
Studies have shown that relapses are common in schizophrenia, and the more relapses patients experience, the worse their prognosis will be: each relapse leads to symptom-deterioration, with impaired cognition, decreased social functioning and poorer quality of life.³ Therefore, relapse prevention is of great importance in the management of the disease³, where patients in the subacute phase require extra support to live a normal life and function adequately in the community.² It is beneficial for inpatients to schedule an appointment with an outpatient psychiatrist before discharge from the hospital.² Adjustment to life in the community should be gradual, since overly ambitious expectations can induce stress and anxiety in patients, increasing their risk of relapse.²
 
Subacute patients should continue being treated with atypical antipsychotics to treat lingering positive symptoms, as early down-titration or discontinuation can result in symptom exacerbation, recurrence or even relapse.² Furthermore, the side effects of AP medication should be more closely monitored and pharmacotherapy should be adjusted accordingly, otherwise patients may become non-adherent to their medication, increasing their risk of relapse.²
 
Clinicians should continue engaging with the patients’ family and educate them on how to cope with schizophrenia, especially as the patient will soon be leaving or has already left the inpatient ward.² Due to the high risk of relapse in the subacute phase, patients and their families should be educated regarding the recognition and management of the early signs of relapse.²
 
Adjunctive medications, such as benzodiazepines for agitation, that may have been used in the acute phase should be reconsidered for continuation as the patient becomes increasingly stable.²  However, comorbid conditions, such as depression or obsessive-compulsive disorder, should be treated with concomitant medication.²

As subacute patients show improvements in their positive symptoms, it is important to monitor negative symptoms.² If negative symptoms develop and worsen, patients may benefit from switching to cariprazine if they are on another medication, as cariprazine is the only antipsychotic that has outperformed another (risperidone) in the treatment of negative symptoms.⁴
 
Cariprazine produced significantly greater improvements on 5 of 7 PANSS negative symptom items.⁵

Adapted from: Fleischhacker, W. et al. The efficacy of cariprazine in negative symptoms of schizophrenia: Post hoc analyses of PANSS individual items and PANSS-derived factors. Eur Psychiatry, 58, 1-9 (2019).⁵
 
 
Subacute patients taking cariprazine relapsed far later than those in the placebo group – 326 days versus 92 days, respectively.⁶

Adapted from: Reagila Summary of Product Characteristics⁶
 
Long-term cariprazine treatment was significantly more effective than placebo for relapse prevention: relapse occurred in 21.6% of cariprazine and 49% of placebo-treated patients.⁶

Adapted from: 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).⁷
 
Cariprazine treatment was significantly more effective than placebo for long-term relapse prevention in subacute patients.⁸

Adapted from: Correll, C.U. et al. Long-term remission with cariprazine treatment in patients with schizophrenia: A post-hoc analysis of a randomised, double-blind, placebo-controlled, relapse prevention trial. J Clin Psychiatry, 80, e1-e7 (2019).⁸
 
 
Cariprazine is associated with significantly longer sustained remission and increased likelihood of sustaining remission for at least 6 consecutive months versus placebo.⁸

Adapted from: Correll, C.U. et al. Long-term remission with cariprazine treatment in patients with schizophrenia: A post-hoc analysis of a randomised, double-blind, placebo-controlled, relapse prevention trial. J Clin Psychiatry, 80, e1-e7 (2019).⁸
 
 
A study has shown that cariprazine (3-9mg/day) patients had a significantly longer time to relapse and lower relapse rates than placebo (24.8% vs 47.5%).³ The 25th percentile for time to relapse was 92 days in the placebo group, compared to 224 days in the cariprazine group.³ These results suggest that cariprazine has the potential to delay or prevent relapse in schizophrenia.³
 
If non-adherence occurs in a subacute outpatient and doses of the antipsychotic medication are skipped, cariprazine is an excellent choice because of its long half-life.³
 
Furthermore, cariprazine was found to be superior to risperidone in improving patients’ day-to-day functioning.⁵
 
Dosing
In the acute phase, cariprazine was rapidly up-titrated (daily or every second day in 1.5mg increments). Once patients had stabilised and reached the subacute state, the dose was maintained.³

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/R57. Submitted to AIFA on 29/11/2021