REVIEW OF: Srisurapanont M et al, Sci Rep 2021:11(1):5571

STUDY TYPE: Network meta-analysis

Lurasidone is FDA approved in schizophrenia, but we lack good evidence to guide its dosage. This study compared the efficacy, safety, and acceptability of lurasidone at different doses to establish a dose-response relationship for its therapeutic and adverse effects.

The study was a network meta-analysis of 10 randomized controlled trials with a total of 3336 adult patients with acute schizophrenia. The selected trials used fixed-dose lurasidone and lasted 4–16 weeks. Studies with a crossover design or flexible dosing were excluded. The primary outcomes were overall reduction in psychotic symptoms as measured by the Positive and Negative Syndrome Scale (PANSS) and all-cause dropout rates. These data allowed the investigators to compare 10 independent treatments at various doses of lurasidone (20, 40, 80, 120, and 160 mg/day) against a placebo or four comparator antipsychotics.

The analysis found that all doses except the 20 mg/day were effective in acute schizophrenia. The highest dose (160 mg/day) outperformed all of the lower doses on the primary outcome of improvement in the PANSS. The “effective dose 50,” which estimates the dose that produces the desired effect in at least half the population, was at least 80 mg/day.

An interesting finding arose when the investigators attempted to find the maximum effective dose by graphing the results. The graphs for psychotic symptoms, negative symptoms, and depressive symptoms continued to rise without plateauing up to the maximum approved dose of 160 mg/day, suggesting that lurasidone’s maximum effective dose may be higher than that. Most side effects rose in concert with the dose, particularly sedation and EPS, but all-cause dropouts were similar across the 40–160 mg/day dose range. This suggests that the tolerability problems may be outweighed by the benefits in the higher dose range.

TCPR’S Take
Lurasidone requires higher dosing to reach maximum efficacy in schizophrenia, up to the official maximum of 160 mg/day and possibly beyond that. High doses did not lead to higher dropout rates, but in our experience, one particular side effect is lessened with a slow titration: akathisia.