Antipsychotic-induced hyperprolactinemia (AP-induced HPRL) occurs overall in up to 70% of patients with schizophrenia, which is associated with hypogonadism and sexual dysfunction. We summarized the latest evidence for the benefits of prolactin-lowering drugs. We performed network meta-analyses to summarize the evidence and applied Grading of Recommendations Assessment, Development, and Evaluation frameworks (GRADE) to rate the certainty of evidence, categorize interventions, and present the findings. The search identified 3,022 citations, 31 studies of which with 1999 participants were included in network meta-analysis. All options were not significantly better than placebo among patients with prolactin (PRL) less than 50 ng/ml. However, adjunctive aripiprazole (ARI) (5 mg: MD = −64.26, 95% CI = −87.00 to −41.37; 10 mg: MD = −59.81, 95% CI = −90.10 to −29.76; more than 10 mg: MD = −68.01, 95% CI = −97.12 to −39.72), switching to ARI in titration (MD = −74.80, 95% CI = −134.22 to −15.99) and adjunctive vitamin B6 (MD = −91.84, 95% CI = −165.31 to −17.74) were associated with significant decrease in AP-induced PRL among patients with PRL more than 50 ng/ml with moderated (adjunctive vitamin B6) to high (adjunctive ARI) certainty of evidence. Pharmacological treatment strategies for AP-induced HPRL depends on initial PRL level. No effective strategy was found for patients with AP-induced HPRL less than 50 ng/ml, while adjunctive ARI, switching to ARI in titration and adjunctive high-dose vitamin B6 showed better PRL decrease effect on AP-induced HPRL more than 50 ng/ml.

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QTc interval prolongation is one of the most common antipsychotic-induced side effects which could lead to ventricular tachycardia or Torsade de Pointes, even cardiac arrest. There is very limited understanding on the genetic factors that associated with antipsychotic-induced QTc interval change. We conducted a genome-wide association study (GWAS) of antipsychotic-induced QTc interval change among patients with schizophrenia. A total of 2040 patients with schizophrenia were randomly assigned to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and first-generation antipsychotics; first-generation antipsychotics including haloperidol or perphenazine were also assigned randomly) and received 6-week antipsychotic treatment. We identified two novel loci (rs200050752 in ATAD3B and rs186507741 in SKIL) that were associated with antipsychotic-induced QTc interval change at a genome-wide significance level. The combination of polygenic risk score (PRS), based the GWAS of myocardial infarction from BioBank Japan project, and clinical data (sex, heart rate and QTc interval at baseline) could be applied to predict whether patients with schizophrenia have QTc interval prolongation (10 ms was applied as threshold, P < 0.001, area under the curve [AUC] was 0.797), especially for the first episode patients (P < 0.001, AUC was 0.872). We identified two loci located within genes related to mitochondrial function and cell growth and differentiation, which were both associated with schizophrenia and heart function. The combination of PRS and clinical data could predict whether patients with schizophrenia have the side effect of QTc interval prolongation, which could fundamentally guide the choice of antipsychotic in patients with schizophrenia, especially for the first-episode patients.

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