More data, more answers: picking the optimal antidepressant
Authors: Sagar V Parikh, Sidney H Kennedy
Journal: The Lancet (2018)

In an era of increasingly large datasets for health and emphasis on so-called big data analyses, key clinical questions remain unpretentiously simple. For example, do some antidepressants work better than others for depression? And are some more tolerable than others, at least as measured in dropout rates? A quick PubMed search of antidepressant meta-analyses yields more than 2000 hits, but the complexity of understanding which antidepressants are better or more tolerable than others is made particularly daunting by the fact that more than 40 antidepressants are available. Andrea Cipriani and colleagues1Cipriani A Furukawa TA Salanti G et al.Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatment meta-analysis.Lancet. 2009; 373: 746-758Summary Full Text Full Text PDF PubMed Scopus (1276) Google Scholar provided a novel answer to these questions originally in a paper published in The Lancet in 2009, introducing the new method of network meta-analysis to psychiatry and showing that four of the 12 then newer antidepressants were more efficacious than the rest. In that landmark study, the authors examined 117 trials with nearly 26 000 participants. 9 years later in The Lancet, Cipriani and colleagues2Cipriani A Furukawa TA Salanti G et al.Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.Lancet. 2018; (published online Feb 21.)https://doi.org/10.1016/S0140-6736(17)32802-7Summary Full Text Full Text PDF PubMed Scopus (1379) Google Scholar report their work applying a similar method to address the same question; this time they evaluated 21 antidepressants and placebo in 522 double-blind trials with 116 477 participants. Chief among the findings are detailed new results on efficacy (8-week outcomes) and acceptability (8-week dropout rates due to all causes). The study found that all antidepressants were more efficacious than placebo, with odds ratios (ORs) ranging from 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline to 1·37 (1·16–1·63) for reboxetine. Additionally, the study found reduced differences between antidepressants compared with the 2009 study, with ORs (usually with broad CrIs) from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability (tolerability). More specifically, head-to-head efficacy comparisons of antidepressants disclosed seven agents (agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine) as distinctly more effective and four agents (fluoxetine, fluvoxamine, reboxetine, and trazodone) to be somewhat less effective than the other antidepressants. As a method, network meta-analysis has emerged as a legitimate approach, as shown (via a simple MEDLINE search) by more than 900 network meta-analysis publications in the area of cancer based on this method, and more than 200 publications related to depression, although few are full network meta-analysis studies. In this latest paper, Cipriani and colleagues2Cipriani A Furukawa TA Salanti G et al.Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.Lancet. 2018; (published online Feb 21.)https://doi.org/10.1016/S0140-6736(17)32802-7Summary Full Text Full Text PDF PubMed Scopus (1379) Google Scholar carefully follow recommended procedures to optimise methodological rigour and identify potential sources of bias and error.3Mills EJ Thorlund K Ioannidis JP Demystifying trial networks and network meta-analysis.BMJ. 2013; 346: f2914Crossref PubMed Scopus (474) Google Scholar, 4Jansen JP Naci H Is network meta-analysis as valid as standard pairwise meta-analysis? It all depends on the distribution of effect modifiers.BMC Med. 2013; 11: 159Crossref PubMed Scopus (360) Google Scholar, 5Salanti G Del Giovane C Chaimani A Caldwell DM Higgins JP Evaluating the quality of evidence from a network meta-analysis.PLoS One. 2014; 9: e99682Crossref PubMed Scopus (724) Google Scholar, 6Hutton B Salanti G Caldwell DM et al.The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations.Ann Intern Med. 2015; 162: 777-784Crossref PubMed Scopus (3326) Google Scholar, 7Brignardello-Petersen R Bonner A Alexander PE et al.Advances in the GRADE approach to rate the certainty in estimates from a network meta-analysis.J Clin Epidemiol. 2018; 93: 36-44Summary Full Text Full Text PDF PubMed Scopus (290) Google Scholar They also sought to maximise clinical relevance by focusing not only on modern antidepressants but also including the two WHO recommended essential antidepressants, amitriptyline and clomipramine.8WHOWHO model lists of essential medicines. World Health Organization, Geneva2015http://www.who.int/medicines/publications/essentialmedicines/en/Google Scholar Special effort to minimise bias was achieved by obtaining additional unpublished data for more than half of the studies, and also by separate analyses to look for various potential contributors to bias including pharmaceutical sponsorship. Finally, for clinical relevance and face validity, although network meta-analysis was used to generate overall findings, results from head-to-head clinical studies were emphasised. The current study2Cipriani A Furukawa TA Salanti G et al.Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.Lancet. 2018; (published online Feb 21.)https://doi.org/10.1016/S0140-6736(17)32802-7Summary Full Text Full Text PDF PubMed Scopus (1379) Google Scholar used efficacy outcomes at 8 weeks, while dropout rates at 8 weeks served as a proxy for overall side-effect burden, termed acceptability. Although seven antidepressants had higher efficacy than the other antidepressants, after factoring in acceptability, three emerged as preferable: agomelatine, escitalopram, and vortioxetine. Three antidepressants had a poor profile of efficacy and acceptability: fluvoxamine, reboxetine, and trazodone. A direct clinical implication is that the three net efficacious antidepressants might be considered first choice, whereas the three less efficacious antidepressants might be avoided initially. Depression severity or other patient characteristics might also argue for first-line consideration of the remaining so-called superior agents in terms of efficacy—namely, amitriptyline and venlafaxine. A key question—raised in 2009—remains, what is the implication of superiority of outcomes at 8 weeks for long-term effects, particularly functional outcomes?9Parikh SV Antidepressants are not all created equal.Lancet. 2009; 373: 700-701Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar Although network meta-analysis is exemplary as a technique to combine aggregate data, such aggregation does not allow for analysis at the individual patient level and so cannot provide finer detail on who might preferentially respond or who might be more vulnerable to side-effects. An additional important facet missed by network meta-analysis involves the heterogeneity of response within major depressive disorder, identified by other statistical approaches. Using growth mixture modelling, distinct trajectories of responders (76%) and non-responders (24%) to duloxetine were identified.10Gueorguieva R Mallinckrodt C Krystal JH Trajectories of depression severity in clinical trials of duloxetine: insights into antidepressant and placebo responses.Arch Gen Psychiatry. 2011; 68: 1227-1237Crossref PubMed Scopus (86) Google Scholar Although clinical phenotyping on the basis of traditional specifiers of melancholia, atypical symptoms, and anxiety have not been helpful in predicting treatment response,11Arnow BA Blasey C Williams LM et al.Depression subtypes in predicting antidepressant response: a report from the iSPOT-D trial.Am J Psychiatry. 2015; 172: 743-750Crossref PubMed Scopus (114) Google Scholar the integration of clinical and biological markers shows more promise. One recent study12Drysdale AT Grosenick L Downar J et al.Resting-state connectivity biomarkers define neurophysiological subtypes of depression.Nat Med. 2017; 23: 28-38Crossref PubMed Scopus (1090) Google Scholar integrated clinical and neuroimaging markers to identify four distinct neurophysiological biotypes in more than 1000 patients with major depressive disorder on the basis of resting-state functional connectivity. These biotypes were linked to clinical dimensions of anhedonia and anxiety, and predicted response to repetitive transcranial magnetic stimulation. Ultimately, the field requires different research strategies to identify response at the level of the individual patient, not just network meta-analysis with larger sample sizes. Nevertheless, Cipriani and colleagues have made a major contribution. This study of antidepressant outcomes identified significant differences between antidepressants that are relevant to health-care economists and policy makers, clinicians, and patients. In everyday clinical practice, medications with the highest net efficacy and acceptability ratings merit discussion with patients for use as the first treatment. The demonstration of the extent of antidepressant superiority over placebo reassures patients and health-care professionals of the efficacy of treatment despite high placebo response rates. SVP has received research funding from the Ontario Brain Institute for biomarker research and knowledge translation activities in major depressive disorder (MDD), the Canadian Institutes of Health Research for biomarker research in MDD, the James and Ethel Flinn Foundation for evaluation of a depression education programme in schools, and Assurex Health for a randomised controlled trial of pharmacogenomics testing in MDD; honoraria from Mensante Corporation for website content development, Takeda for consulting on design of a new clinical trial, Lundbeck for consulting on design of a new clinical trial, and the Canadian Network for Mood and Anxiety Treatments (CANMAT) for a symposium presentation and authorship of a monograph on depression; and holds minor equity in Mensante (a provider of internet-based mental health software). SHK has received research funding from the Ontario Brain Institute for MDD biomarker research, the Ontario Research Fund for development and expansion of mobile health initiatives in MDD, the Canadian Institutes for Health Research for MDD biomarker research, Janssen for a study of relapse in MDD using m-health, and Abbott for a randomised controlled trial of deep brain stimulation for depression; honoraria from Allergan for consulting on clinical trial design for a new study of MDD, Bristol-Myers Squibb for dissemination of 2016 CANMAT MDD Guidelines, Lundbeck for consulting on clinical trial design for a new MDD study, Lundbeck Institute for education and dissemination of 2016 CANMAT MDD Guidelines, Otsuka consulting on clinical trial design for a new MDD study, Pfizer for consulting on clinical trial design for a new MDD study and a study of reward experience after MDD treatment, Servier for consulting on clinical trial design for a new MDD study, Sunovion for consulting on clinical trial design for a new MDD study, and Xian-Janssen for dissemination of 2016 CANMAT MDD Guidelines. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysisAll antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Full-Text PDF Open Access