Dose-dependent Effects of Antipsychotics on Efficacy and Adverse Effects in Schizophrenia

Background: Antipsychotics are a cornerstone of pharmacological treatment of schizophrenia. Improved understanding of the dose-response relationship of antipsychotics in terms of efficacy, adverse effects, and mortality can help to optimize the pharmacological treatment of schizophrenia.

Methods: This narrative literature review summarizes current evidence on the relationship of antipsychotic dose with efficacy, adverse effects, and mortality in patients with schizophrenia.

Results: The efficacy of antipsychotics generally appeared to be highly dose-dependent in the acute phase of schizophrenia, with each antipsychotic having a specific dose-response curve. The presence or absence of dose-dependency and its extent varied according to the type of adverse effect. Parkinsonism, hyperprolactinemia, weight gain, and neurocognitive impairment appeared to be dose-related. The following adverse effects might be at least somewhat dose-dependent: akathisia, tardive dyskinesia, osteoporosis, sexual dysfunction, diabetes mellitus, myocardial infarction, stroke, thromboembolism, QT interval prolongation, anticholinergic adverse effects, somnolence, pneumonia, hip fracture, and neuroleptic malignant syndrome. In contrast, the relationships of antipsychotic dose with dyslipidemia, hypotension, seizure, sialorrhea, and neutropenia and agranulocytosis remained unclear due to mixed findings and/or limited data. Although a higher lifetime cumulative antipsychotic dose might contribute to higher mortality, it is still difficult to conclude whether mortality increases in a dose-dependent manner.

Conclusion: These findings could help clinicians to optimize antipsychotic treatment in patients with schizophrenia by balancing risks and benefits in clinical practice. However, further investigations with larger sample sizes and more robust study designs that focus on each antipsychotic agent are needed.