Initial lurasidone dosing in acute schizophrenia: Pragmatic and trajectory-aware clinical implications

Abstract

Selecting the initial antipsychotic dose is a high-impact decision in acute schizophrenia. A randomized study found that starting lurasidone at 80 mg/day for 1 week (then flexible titration) produced earlier reductions in Positive and Negative Syndrome Scale positive symptoms than 40 mg/day, without higher discontinuations for adverse events or a metabolic penalty over 6 weeks. These data support an individualized approach: Start at 80 mg/day when rapid control of positive symptoms or agitation is needed and tolerance permits; start at 40 mg/day when akathisia risk or patient preference argues for caution, with a planned day-7 review for up-titration. The open-label design, dose convergence after week 1, and the lack of stratified randomization limit attribution of longer-term advantages to starting dose. Even so, the trial reframes initial dose as a modifiable lever for the early course rather than a one-size-fits-all rule and warrants confirmation in larger, double-blind randomized trials.

Key Words: Lurasidone; Schizophrenia; Antipsychotic agents; Treatment outcome; Akathisia; Body weight

Core Tip: Choosing a starting dose may influence the early clinical trajectory in acute schizophrenia. In a pragmatic randomized study, 80 mg/day for the first week led to more rapid improvement in Positive and Negative Syndrome Scale positive symptoms than 40 mg/day, with similar discontinuation for adverse events and no short-term metabolic penalty. Clinicians may prioritize speed with 80 mg/day when tolerated, or start at 40 mg/day when akathisia risk is a concern, coupled with a day-7 review for escalation. Open-label design and dose convergence temper causal claims, but initial dose selection may shape the early trajectory.

TO THE EDITOR

Initial antipsychotic dosing policies often default to “start low, go slow”[1], yet acute psychosis is a time-critical condition in which therapeutic momentum in the first 1-2 weeks can influence engagement, management needs, and downstream adherence[2,3]. Lurasidone, an atypical antipsychotic with a favorable metabolic profile, has label-permitted dose ranges that allow either 40 mg/day or 80 mg/day as a starting point in routine practice[4]. The randomized multicenter study under discussion (Liu et al[5]) directly tests these two initial strategies in acute schizophrenia with a design that mirrors real-world sequencing: A 7-day fixed-dose phase, followed by adjustments based on response and tolerability.

Mechanistic rationale for initial-dose effects

Lurasidone is an atypical antipsychotic whose early effects are plausibly mediated by D2 receptor occupancy within a therapeutic range (approximately 60%-80%), complemented by serotonin 2A antagonism; 5-hydroxytryptamine receptor 1A partial agonism may lessen anxiety and agitation, while minimal H1/M1 activity limits sedation and anticholinergic burden[6-9]. When tolerability permits, an 80 mg/day start, taken with food (≥ 350 kcal), may increase the probability of reaching therapeutic D2 occupancy during the initial fixed-dose week and thereby accelerate early improvement in positive symptoms[10]. Conversely, a 40 mg/day start is reasonable for patients with prior extrapyramidal symptoms/akathisia, marked anxiety, or frailty; a systematic reassessment at day 7 should be integrated into care, with up-titration if response is insufficient[11]. Early monitoring for extrapyramidal symptom/akathisia is advised, with short-term adjuncts (e.g., a beta-blocker or benzodiazepine) as needed[12].

Commentary and practice implications

(1) Safety, discontinuation due to adverse events (AEs) did not differ between starting doses, 3/99 (3.03%) for 40 mg/day vs 5/98 (5.10%) for 80 mg/day (P = 0.707); AE-related dose reductions occurred in 4/99 (4.0%) vs 12/98 (12.2%); and treatment-emergent AEs in 64/99 (64.6%) vs 70/98 (71.4%). These data may reassure clinicians when a faster start is considered in the context of acute agitation or risk; (2) Early trajectory, positive symptoms, per-arm sample sizes were 40 mg/day (n = 99) and 80 mg/day (n = 98). Despite broadly similar Positive and Negative Syndrome Scale (PANSS) total trajectories, the 80 mg/day arm showed greater early improvement on the PANSS positive subscale at weeks 1 and 2, a period when dose selection may be most clinically actionable. At week 1, PANSS positive least squares mean (LSM) (SE) change was -4.1 (0.46) for 40 mg/day vs -5.6 (0.48) for 80 mg/day; LSM difference 1.6 (SE 0.67), 95% confidence interval (CI): 0.23-2.88; P = 0.022. At week 2, LSM (SE) change was -6.7 (0.49) vs -8.4 (0.52); LSM difference 1.7 (SE 0.72), 95%CI: 0.25-3.08; P = 0.022. This pattern is consistent with pharmacologic considerations (e.g., D2 receptor occupancy and serotonin 2A modulation) that may support earlier stabilization, even though later titration narrows between-arm differences; (3) Global symptom change and clinical impression, beyond positive symptoms, group differences were modest: PANSS total change, PANSS negative and general psychopathology subscales did not differ; nominal advantages for the 80 mg/day start appeared in selected 5-factor domains at specific visits, and Clinical Global Impression-Severity showed greater improvement at week 2 (LSM difference 0.3; 95%CI: 0.01-0.66; P = 0.044); and (4) Weight and metabolic profile, ≥ 7% weight gain was numerically less frequent after an 80 mg/day start (4.1% vs 12.1%) in this short-term study; however, these differences should be interpreted cautiously given baseline imbalances, small sample sizes, and the possibility of chance, and do not establish a dose-dependent metabolic advantage. Overall, the short-term metabolic footprint appeared modest and comparable between strategies over 6 weeks.

Conclusion

Within approved labeling and local protocols, initial dose selection may influence the early clinical trajectory, particularly in the first week. In this pragmatic randomized study, an 80 mg/day lurasidone start was associated with more rapid improvement in positive symptoms during weeks 1-2 vs 40 mg/day, without higher AE-related discontinuation; however, global outcomes converged by week 6 with subsequent titration. These findings should be interpreted with caution given the open-label design, the lack of stratified randomization, and the short, 6-week follow-up, which limit generalizability and preclude inferences about longer-term efficacy, safety, or metabolic effects. When rapid symptom control is prioritized and tolerability permits, an 80 mg/day start may be considered with early monitoring; conversely, a 40 mg/day start may be appropriate when tolerability is paramount, with a planned reassessment at day 7-14 to guide titration. Confirmation in larger, double-blind randomized trials is warranted before practice guidelines are modified.