Antipsychotic drugs for the treatment of acute schizophrenia after the first episode

Abstract

Background: Antipsychotic drugs (APDs) represent the treatment of choice for psychotic disorders, but uncertainty surrounds the optimal selection of agents. Methodology: This was a mixed method study which included a systematic review and psychiatrists’ opinion survey. The systematic review focused on comparative analysis of APDs, regardless of being typical or atypical, which are used for the treatment of schizophrenia, to determine their relative efficacy, rate and causes of discontinuations and potential side-effects. The review followed the PRISMA-P© statement and checklist and used the RevMan© statistical analysis tool to report on the findings. PubMed©, CINHAL© and ScienceDirect™ were searched for suitable studies. The primary outcomes of interest were clinical response measured by symptoms improvement, tolerance to side effects and discontinuation rate and reasons. The study analyses were presented as forest plots, with 95% confidence intervals and p value of 0.05 or less as significant. The selected study population was adults who were APD-naïve or only a short history of APD use (<16 weeks). A cross-sectional survey of psychiatrists from the UK and India was conducted to understand their opinions regarding their choice of APDs, their experience with tolerance and efficacy in managing psychosis in patients diagnosed with acute schizophrenia after first episode of psychosis. Both categorical and qualitative data was collected and analysed. The survey was opened from 26 April 2022 to 31 July 2022. Findings: Twenty one RCTs were included in the systematic review. There was better individual patients’ response to aripiprazole vs. ziprasidone (CDSS p=0.04), aripiprazole vs. quetiapine (BPRS p=0.02, YMRS p=0.001) and ziprasidone vs. quetiapine (CGI p=0.02, CDSS p=0.02) in the study sample. In the short term APDs use, the difference between aripiprazole and risperidone was statistically significant for diminished sexual desire (p=0.01). Long term APDs use, the difference between aripiprazole and ziprasidone was significant for increased duration of sleep (p=0.003), rigidity (p=0.02), erectile dysfunction (p=0.005), ejaculatory dysfunction (p=0.02) and weight gain (p=0.01); aripiprazole and quetiapine for sleepiness (p<0.001), increased duration of sleep (p=0.001), tremors (p=0.04), erectile dysfunction (p=0.002), akathisia (p=0.05); quetiapine and ziprasidone for rigidity (p=0.03), vertigo (p=0.05), weight gain (p=0.003) and akathisia (p=0.005); olanzapine and quetiapine for weight gain (p<0.001), risperidone and quetiapine for increased duration of sleep (p=0.02), olanzapine and risperidone for weight gain (p=0.03), olanzapine and haloperidol for weight gain (p<0.001) and akathisia (p=0.0003), haloperidol and quetiapine for akathisia (p=0.02), haloperidol and ziprasidone for weight gain (p=0.03) and olanzapine and ziprasidone weight gain (p<0.001). Total discontinuation after short term use for quetiapine vs. aripiprazole, ziprasidone vs. olanzapine, ziprasidone vs. quetiapine, ziprasidone vs. olanzapine and aripiprazole vs. risperidone was not significantly different (p>0.05) but it was for ziprasidone vs. olanzapine (p=0.02). After long term use of APDs, total discontinuation rate difference was significantly different in six pairs: p=0.03 for quetiapine vs. olanzapine, p<0.001 for quetiapine vs. ziprasidone, p<0.001 for quetiapine vs. aripiprazole, p=0.02 for olanzapine vs. ziprasidone, p=0.002 for haloperidol vs. olanzapine, p=0.05 for haloperidol vs. ziprasidone. However the difference was not significantly different (p>0.05) between quetiapine vs. risperidone, haloperidol vs. quetiapine, ziprasidone vs. aripiprazole, risperidone vs. olanzapine, ziprasidone vs. risperidone haloperidol vs. risperidone. Discontinuation reasons were possible to analyse only with long term APDs use and 12 pairs were compared. The difference was significant between olanzapine and risperidone due to the lack of efficacy (p<0.001), quetiapine and ziprasidone due to lack of efficacy (p<0.001) and side effects (p<0.001), quetiapine and haloperidol due to side effects (p=0.01), quetiapine and aripiprazole due to lack of efficacy (p<0.001) and drop-out (p=0.04), aripiprazole and ziprasidone due to side effects (p<0.001) and lack of compliance (p=0.0005), olanzapine and haloperidol due to lack of efficacy (p<0.001) and side effects (p=0.001), haloperidol and ziprasidone due to lack of compliance (p=0.01) and olanzapine and ziprasidone due to lack of efficacy (p=0.01), side effects (p<0.001) and lack of compliance (p=0.05). For risperidone vs. olanzapine, risperidone vs. ziprasidone vs. risperidone, quetiapine vs. risperidone vs. haloperidol, there was no significant difference in reported reasons (p>0.05). The most selected first line APDs in both countries were olanzapine (47.5%), risperidone (42.8%) and aripiprazole (25.3%). 60% of psychiatrists from India (60%) and 48% from UK (48%) selected that ‘medication efficacy’ as the main reason for choosing specific APD. Switching one APD to another within 4-6 weeks from initiation was selected by 53.7% of psychiatrists and 3-6 months was selected by 11.6%. The main reasons for switching APDs indicated were poor clinical efficacy (69%) and lack of tolerability (45%). Poor efficacy was the most selected reason by the Indian practitioners (68%) and the UK practitioners(71%) for switching APDs. When one APDs did not control the symptoms, 35% of the UK psychiatrists waited 3-6 months and 47% of Indian psychiatrists waited for 4-6 weeks before adding another APDs to manage poor efficacy. Nonadherence was the most common reason for relapse (90% UK psychiatrist and 70% Indian psychiatrist) followed by elicit drug use (27.6%). The most reported side effects which led to nonadherence were weight gain (10.8%), drowsiness (10.4%), erectile dysfunction and movement disorders (equally 8.7%). Weight gain (8.1%), movement disorders (7.7%) and hyperprolactinaemia (7%) were the highest reported side effects that caused psychiatrist to switch to another APDs. Similarly, weight gain (11.4%) was the most common side effects prompting patients to seek termination of the treatment, followed by drowsiness (10.3%) and erectile dysfunction (9.4%). Life threatening rare side effects was the main reason to discontinue the use of APDs (10.5%). Conclusion: Olanzapine, risperidone and aripiprazole were the most selected as initial treatment choice by psychiatrists from India and UK and are perceived as widely effective and/or widely tolerated. It was concluded that no single antipsychotic stands out as uniquely effective or free of side effects for all treated individuals. Individual patient clinical response, tolerance to side effects or life threatening side effects remain the most reliable basis for continuing the use of APD. relevant However, lack of clinical effect or intolerable side effects lead to therapy being reviewed, APD switched or ceased.