We thank Klaus Munkholm for his comments on our meta-analysis of studies (comprising three different study designs) comparing long-acting injectable antipsychotics (LAIs) with oral antipsychotics.1Kishimoto T Hagi K Kurokawa S Kane JM Correll CU Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre–post studies. Although randomised controlled trials (RCTs) are usually the gold standard, comparing the efficacy of LAIs with oral antipsychotics might be an exception to this rule, because even RCTs are subject to potential biases because of the nature of the populations, treatments, and outcomes assessed. Therefore, we included cohort and pre–post studies in our evidence synthesis.Munkholm emphasised the absence of a statistical difference between LAIs and oral antipsychotics in RCTs with regard to the outcome of relapse alone. However, our primary endpoint of relapse or hospitalisation (with hospitalisation used preferentially over relapse) was statistically lower with LAIs than with oral antipsychotics. Relapse definitions differ across studies, but most include hospitalisation as one criterion. Importantly, relapse definitions using psychopathology ratings bias results towards individuals returning for study visits. Hospitalisation is an objective outcome including all patients.2Kishimoto T Hagi K Nitta M et al.Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies.Munkholm also comments on risk of bias and the Cochrane rule for judging risk of bias and certainty of the results. Following meta-analytic standards, we assessed risk of bias for the primary outcome. Importantly, insufficient blinding or the absence of blinding was the main reason for high risk of bias in most non-RCTs, and blinding is inherently difficult with LAI studies, increasing the value of hospitalisation as a key outcome. To optimally mask patients and clinicians in RCTs, a double-dummy design that provides patients with both injections and oral antipsychotics (one of which is placebo) is necessary. However, this approach further reduces the generalisability of the findings in RCTs versus clinical practice. RCTs can alter the ecology of care, and when adherence is a focus it can lead to bias. For example, in the PROACTIVE study,3Buckley PF Schooler NR Goff DC et al.Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study. LAIs and oral antipsychotics did not differ with regard to relapse risk, but investigators handed participants their oral antipsychotics instead of relying on them to fill their prescription at a pharmacy, which differs from usual care.

In conclusion, considering biases within each study design, the results are consistent and favour LAIs over oral antipsychotics on the outcome of hospitalisation or relapse, and other key outcomes in schizophrenia.

TK reports personal fees from Banyu, Eli Lilly, Janssen, Kyowa Pharmaceutical Industry, Lundbeck, Novartis, Otsuka, Sumitomo Dainippon Pharma, and Takeda, and grants from Sumitomo Dainippon Pharma and Otsuka, outside the submitted work. KH is an employee of Sumitomo Dainippon Pharma. SK reports personal fees from Sumitomo Dainippon Pharma , Meiji Seika Pharma, and Mochida Pharmaceutical, outside the submitted work. JMK reports personal fees from Alkermes, Acadia, Sumitomo Dainippon Pharma, Intra-Cellular Therapies, Merck, Neurocrine, Reviva, Roche, Saladex, Sunovion, Takeda, Teva, and LB Pharma, and grants and personal fees from H Lundbeck, Janssen, and Otsuka, outside the submitted work. JMK is also a shareholder of LB Pharma and The Vanguard Research Group. CUC reports personal fees from Acadia, Alkermes, Allergan, Angelini, Axsome, Bristol Myers Squibb, Gedeon Richter, Intra-Cellular Therapies, Janssen, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedinCell, Medscape, Merck, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Rovi, Servier, Sumitomo Dainippon Pharma, Sunovion, Supernus, Takeda, and Teva, and royalties from UpToDate, outside the submitted work. CUC is also a stock option holder of LB Pharma. TK and KH contributed equally to this Comment.

References1.Kishimoto T Hagi K Kurokawa S Kane JM Correll CU

Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre–post studies.

Lancet Psychiatry. 8: 387-4042.Kishimoto T Hagi K Nitta M et al.

Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies.

Schizophr Bull. 44: 603-6193.Buckley PF Schooler NR Goff DC et al.

Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study.

Schizophr Bull. 41: 449-459Article InfoPublication HistoryIdentification

DOI: https://doi.org/10.1016/S2215-0366(21)00203-0

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ScienceDirectAccess this article on ScienceDirect Linked ArticlesLong-acting injectable versus oral antipsychotics for schizophrenia

In their systematic review of long-acting injectable (LAI) versus oral antipsychotics, Taishiro Kishimoto and colleagues included randomised trials, cohort studies, and pre–post studies.1 On the basis of their findings, which included a lower risk of hospitalisation or relapse (their primary outcome) with LAIs than with oral antipsychotics, they suggested that increased use of LAIs could improve outcomes in schizophrenia. I would like to comment on some methodological issues.

Full-Text PDF Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre–post studies

Although study designs have strengths and weaknesses, including potential low quality of observational studies, we consistently identified significant benefit with LAIs versus oral antipsychotics in preventing hospitalisation or relapse, in settings ranging from restricted research (RCTs) to real-word application (cohort and pre–post studies). Our findings suggest that increased clinical use of LAIs could improve outcomes in schizophrenia.

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