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.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. 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.First, because randomised trials are more likely to provide unbiased estimates of the effects of interventions than are other study designs, they should generally be preferred over non-randomised studies, such as some of the studies included by Kishimoto and colleagues, when synthesising the evidence to guide appropriate patient care.2Collins R Bowman L Landray M Peto R The magic of randomization versus the myth of real-world evidence. The validity of non-randomised studies, and hence syntheses including them, such as those done in this review, is inherently threatened by biases, especially confounding and selection bias.2Collins R Bowman L Landray M Peto R The magic of randomization versus the myth of real-world evidence., 3Bias and causal associations in observational research. On the basis of the randomised trials alone (27 studies, 7407 participants), the authors found no significant difference in relapse rates between participants receiving LAIs and those receiving oral antipsychotics—an outcome that is arguably more relevant to patients than the composite primary outcome of hospitalisation or relapse.Second, Kishimoto and colleagues assessed the risk of bias of the randomised trials, but it was not clear for which outcome this assessment was made, and they did not make an overall risk-of-bias judgment for each trial. They judged 24 (75%) of the 32 trials to be at high risk of bias for at least one domain and 30 (94%) were judged as either at high risk of bias in at least one domain or at unclear risk of bias for multiple domains. Using the judgments by Kishimoto and colleagues, and following guidance in the Cochrane Handbook for Systematic Reviews of Interventions for reaching an overall risk-of-bias judgment,4Higgins JPT Savović J Page MJ Elbers RG Sterne JAC Chapter 8: Assessing risk of bias in a randomized trial. 30 (94%) of the included randomised trials should potentially be judged as having an overall high risk of bias.Third, the authors did not assess the certainty of the evidence for any outcomes. On the basis of the randomised trials alone and assuming that their risk-of-bias assessment applied to the outcome of relapse, the certainty of the evidence for that outcome using the GRADE framework5Schünemann H Brożek J Guyatt G Oxman A GRADE handbook for grading quality of evidence and strength of recommendations. should arguably be rated as very low, due to downgrading for risk of bias, heterogeneity (I2=54·5), and indirectness, since the antipsychotics differed between the LAI and oral antipsychotic groups in most included studies. A similar rating would probably apply to the primary efficacy outcomes. The certainty of the evidence from non-randomised studies is, if possible, likely to be rated even lower.Taken together, the evidence presented by Kishimoto and colleagues1Kishimoto 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. does not appear to support conclusions regarding whether outcomes in schizophrenia would improve by increased use of LAIs or not.

I declare no competing interests. Cochrane Denmark is funded by the Danish Government.

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.Collins R Bowman L Landray M Peto R

The magic of randomization versus the myth of real-world evidence.

N Engl J Med. 382: 674-6783.

Bias and causal associations in observational research.

Lancet. 359: 248-2524.Higgins JPT Savović J Page MJ Elbers RG Sterne JAC

Chapter 8: Assessing risk of bias in a randomized trial.

in: Higgins JPT Thomas J Chandler J Cumptson M Li T Page MJ Welch VA Cochrane handbook for systematic reviews of interventions. 2nd edn. John Wiley & Sons, Chichester, UK: 205-2285.Schünemann H Brożek J Guyatt G Oxman A

GRADE handbook for grading quality of evidence and strength of recommendations.

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DOI: https://doi.org/10.1016/S2215-0366(21)00200-5

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ScienceDirectAccess this article on ScienceDirect Linked ArticlesLong-acting injectable versus oral antipsychotics for schizophrenia – Authors' reply

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.1 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.

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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