Meta-analysis of optimal dosing for antipsychotic drugs in schizophrenia

28 Oct 2021

Schizophrenia is a chronic and severe mental disorder affecting more than 20 million people worldwide.1 It is characterized by distorted thoughts, perception, emotions, language, sense of self and behavior, associated with considerable disabilities which affect the educational and occupational performances.1 In most patients, schizophrenia is a long-term disease with high relapse rates. Patients who are non-compliant with their medications are particularly prone to relapse in case of treatment discontinuation. Hence, developing a regimen that promotes good medication adherence could be an effective way to prevent relapse of schizophrenia.2

Medical adherence to antipsychotic medications, such as second-generation antipsychotic (SGA) drugs, is difficult. The side effects such as anticholinergic effects, dyslipidemia, extrapyramidal symptoms (EPS), hyperprolactinemia, neuroleptic malignant syndrome (NMS), postural hypotension, QT prolongation, sedation, seizures, sexual dysfunction, weight gain and type 2 diabetes mellitus (T2DM), always discourage patients from taking the drugs on schedule.3 Therefore, research is required to determine the optimal dose of antipsychotic drugs for minimizing the side effects and sustaining the remission period.4

In a recent meta-analysis conducted by Dr. Stefan Leucht, Department of Psychiatry and Psychotherapy, Technical University of Munich, School of Medicine, Munich of Germany and his fellows, the optimum doses of various antipsychotic medications in patients with stable schizophrenia to reduce relapse occurrence have been extrapolated.4 Trials with fixed dose, randomized, blinded, or open trials that lasted for more than 3 months were selected in the meta-analysis, and the data pool had spread across 72 arms of 26 studies, resulting in a total of 4,776 patients being recruited.4 Incidences of rehospitalization, positive, negative syndrome scale, brief psychiatric rating scale total score reduction from baseline, all-cause discontinuation, and dropouts due to adverse events were also measured as the secondary outcomes.4

The antipsychotic medications analyzed in the study, which included oral aripiprazole, aripiprazole long-acting injectable (LAI), fluphenazine LAI, oral haloperidol, haloperidol decanoate, lurasidone, oral olanzapine, olanzapine LAI, paliperidone LAI, quetiapine, risperidone LAI, ziprasidone, and zotepine, were translated into their respective equivalent doses in terms of risperidone.4 Regarding the study design, Dr. Leucht noted that using a dose-response meta-analysis could provide a curve that showed how the effect evolved with different doses, instead of the traditional meta-analysis with ‘arbitrary’ cut off points.5

Findings have shown that low doses of antipsychotics, equivalent to 2.5mg risperidone, was sufficient to reduce relapse rate by 40%.4 There was no extra benefit in association with efficacy beyond doses that were equivalent to 5mg risperidone.4 In a subgroup analysis of patients in remission, doses equivalent to 2.5mg were sufficient for many population groups.4 The analysis reminded clinicians to be cautious when reducing the dosage of antipsychotic medications because further decrease of dosage to the lower end of the dose range may be accompanied by a disproportionally higher risk of relapse.4

Dr. Leucht concluded that there is large interindividual variability in the measured outcomes of the analysis.4 Ultimately, the patients’ preference will be key to determining the dosage as some patients might value the reduced chances of relapse, while others might instead prefer the quality-of-life increased from the reduced side effects.4 He advised clinicians to take patients’ characteristics into consideration, such as whether they have other psychiatric comorbidities or substance abuse problems, as well as the severity of past relapses and the properties of individual drugs.4

In response to the analysis, Dr. Thomas Sedlak, Director of the Schizophrenia and Psychosis Consult Clinic and Assistant Professor of Psychiatry and Behavioral Sciences at Johns Hopkins School of Medicine in the United States, cautioned that severely ill patients may be underrepresented in clinical trials because they are too impaired to participate.5 As such, further studies are required as this analysis might not reflect the optimal dosage for those populations or when to switch to clozapine in those severe cases.5

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