Reply

We thank Chen et al ^{Reference Chen, Liang, Tseng and Hsu1} for their thoughtful commentary on our recent systematic review and meta-analysis examining the transdiagnostic efficacy of the atypical antipsychotic lurasidone on depressive symptoms. ^{Reference Ghenciulescu, Pearse, Minichino, Sampogna, De Giorgi and Fiorillo2} In our original study, we synthesised evidence from randomised controlled trials in patients with schizophrenia, bipolar disorder and depression, demonstrating a reduction in depressive symptom severity across diagnostic domains with lurasidone (standardised mean difference, SMD −0.26, 95% CI −0.37, −0.15). We also noted a high degree of heterogeneity among the studies (I ² = 72.07%), particularly within the schizophrenia subgroup, and noted that this may in part reflect differences in dosing regimens across trials. ^{Reference Ghenciulescu, Pearse, Minichino, Sampogna, De Giorgi and Fiorillo2} In their response, Chen et al conducted a dose–response meta-analysis of the schizophrenia trials included in our review, which suggests that the antidepressant effects of lurasidone in schizophrenia start at higher doses (≥60 mg/day), with minimal additional benefits beyond an optimal range of 80–120 mg/day. ^{Reference Chen, Liang, Tseng and Hsu1}

We commend Chen et al for undertaking this secondary analysis, which expands upon our findings and addresses a source of heterogeneity by applying a dose–response modelling approach. Their results are consistent with previous dose–response evidence for lurasidone ^{Reference Leucht, Crippa, Siafis, Patel, Orsini and Davis3} while also reflecting a relative paucity of data at the upper end of the dose range. Of note, earlier work estimated an effective dose (ED) 95 of approximately 150 mg/day for psychotic symptoms, with the dose–efficacy curve indicating that effects at higher doses remain incompletely characterised. ^{Reference Leucht, Crippa, Siafis, Patel, Orsini and Davis3} Interestingly, recent meta-analytic work on causes of discontinuation in antipsychotic studies, including lurasidone, suggests that failure to achieve meaningful symptom improvement rather than adverse effects remains the main driver of dropout in schizophrenia trials. ^{Reference Kishi, Matsuda, Sakuma, Okuya and Iwata4} In this context, identifying dose ranges more likely to confer clinical benefit may help explain attenuated effects and high attrition seen in some trials, as well as inform the optimisation of dosing strategies for specific symptom domains targeted in clinical practice. Incorporating dose–response analyses such as the one presented by Chen et al can therefore improve the interpretability and practical relevance of pooled efficacy estimates and support more robust transdiagnostic approaches to evaluating pharmacological treatment options across diagnoses.

Several caveats should, however, be considered when interpreting these findings. First, we did not pre-specify a dose–response analysis in our original protocol, and our meta-analysis was not powered to examine dose effects but relied on pooled averages across flexible and fixed dosing regimens. As such, the results of this post hoc dose–response modelling should be interpreted with caution and regarded as hypothesis-generating, as Chen et al point out. More generally, dose–response meta-analyses are susceptible to bias, particularly when aggregating data from trials which employ flexible dosing (as in our case), where mean daily dose may be confounded by symptom severity, early response or different tolerability. In addition, Chen et al propose that discrepancies in lurasidone dose required to achieve antidepressant effects across diagnoses could be explained by differential engagement of dopaminergic and serotonergic pathways. While intriguing, such mechanistic inferences cannot reliably be drawn from clinical efficacy data and require clarification with empirical evidence from pharmacodynamics investigations or receptor occupancy studies. ^{Reference Potkin, Keator, Kesler-West, Nguyen, van Erp and Mukherjee5,Reference Lan6} Importantly, though, the observation that higher doses of lurasidone are needed to target depressive symptoms in schizophrenia compared with bipolar depression is consistent with the pattern seen with other augmentation strategies, such as quetiapine, where antidepressant effects occur at lower dose ranges than those used in the treatment of psychotic symptoms. ^{Reference Leucht, Crippa, Siafis, Patel, Orsini and Davis3,Reference Yildiz, Siafis, Mavridis, Vieta and Leucht7}

Overall, we agree with Chen et al’s conclusion that dose-sensitive analyses can enhance the interpretability of meta-analytic studies into the efficacy of pharmacologically versatile agents such as lurasidone. Our findings, complemented by their extension, will encourage future transdiagnostic work in which symptom dimensions can be meaningfully compared across diagnoses, while allowing for diagnosis-specific optimisation of treatment strategies, including dose.