Treatments for major depression

Here we raise several concerns regarding the Review by Steven Marwaha and colleagues.1Marwaha S Palmer E Suppes T Cons E Young AH Upthegrove R Novel and emerging treatments for major depression.Lancet. 2022; 401: 141-153Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar First, the concept of treatment-resistant depression does not have reliable criteria for research and is conceptually empty. The key question remains whether the disorder is resistant to treatment, or whether treatments are less effective. For example, an individual participant level of analysis of clinical trial data revealed small average differences between antidepressants and placebo.2Stone MB Yaseen ZS Miller BJ Richardville K Kalaria SN Kirsch I Response to acute monotherapy for major depressive disorder in randomized, placebo controlled trials submitted to the US Food and Drug Administration: individual participant data analysis.BMJ. 2022; 378e067606PubMed Google Scholar Second, regarding emerging treatments, the US Food and Drug Administration even decreased the bar for evidence, granting approval for esketamine and brexanolone via expedited approval pathways with the vague designation of breakthrough therapy. For both approvals, there was scarce evidence of the benefits outweighing the harms, and many open questions.3Cristea IA Naudet F US Food and Drug Administration approval of esketamine and brexanolone.Lancet Psychiatry. 2019; 6: 975-977Summary Full Text Full Text PDF PubMed Scopus (53) Google Scholar Wisely, brexanolone is not approved in Europe and the National Institute for Health and Care Excellence did not recommend esketamine. Third, the phrase “evidence exists”1Marwaha S Palmer E Suppes T Cons E Young AH Upthegrove R Novel and emerging treatments for major depression.Lancet. 2022; 401: 141-153Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar used in table 1 of the Review appears overly positive and can obfuscate questionable evidence. For example, there are documented concerns about the internal validity of the entire body of evidence of repetitive transcranial magnetic stimulation.4Brini S Brudasca NI Hodkinson A et al.Efficacy and safety of transcranial magnetic stimulation for treating major depressive disorders: an umbrella review and re-analysis of published meta-analyses of randomised-controlled trials.Clin Psychol Rev. 2022; 100102236PubMed Google Scholar For deep brain stimulation, the largest randomised trial to date, stopped for futility, was not cited.5Holtzheimer PE Husain MM Lisanby SH et al.Subcallosal cingulate deep brain stimulation for treatment-resistant depression: a multisite, randomised, sham-controlled trial.Lancet Psychiatry. 2017; 4: 839-849Summary Full Text Full Text PDF PubMed Scopus (332) Google Scholar As narrative reviews generally reach more positive conclusions compared with systematic reviews, emergent treatments for depression should have been reviewed systematically and rigorously, preferably by authors free of considerable financial conflicts of interest. In our opinion, novel treatments should exhibit a net positive benefit to harm ratio at high evidentiary standards before raising the hopes of patients and clinicians. We declare no competing interests. Treatments for major depression – Authors' replyAlain Braillon and colleagues outline several judgements about novel treatments for depression and argue that treatment-resistant depression does not have reliable research criteria. Although we are aware of the debate concerning multiple treatment-resistant depression1 definitions, their specificity, and precision, we used the widely accepted definition of not responding to at least two treatments that is consistent with approximately 50% of definitions that are used in the literature.2 We believe this was a pragmatic and reasonable choice, as the alternative is to not investigate therapy for people who have not responded to serial treatments before having an internationally agreed research criterion (clearly desirable). Full-Text PDF