Which antidepressant doses are optimal?
Authors: Fredrik Hieronymus
Journal: The Lancet Psychiatry (2019)

In the most exhaustive investigation to date—an important contribution because of its broad scope and methodological rigour—Toshi A Furukawa and colleagues1Furukawa TA Cipriani A Cowen PJ Leucht S Egger M Salanti G Optimal dose of selective serotonin reuptake inhibitors, venlafaxine and mirtazapine in major depression: systematic review and dose-response meta-analysis.Lancet Psychiatry. 2019; (published online June 6.)http://dx.doi.org/10.1016/S2215-0366(19)30217-2Summary Full Text Full Text PDF PubMed Scopus (122) Google Scholar report findings that resonate well with earlier efforts: selective serotonin reuptake inhibitors (SSRIs) display dose-dependent beneficial effects up to the low-to-medium end of their licensed doses,2Papakostas GI Charles D Fava M Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebo-controlled, dose-finding studies in major depressive disorder.World J Biol Psychiatry. 2010; 11: 300-307Crossref PubMed Scopus (29) Google Scholar, 3Jakubovski E Varigonda AL Freemantle N Taylor MJ Bloch MH Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder.Am J Psychiatry. 2016; 173: 174-183Crossref PubMed Scopus (122) Google Scholar, 4Hieronymus F Nilsson S Eriksson E A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors.Transl Psychiatry. 2016; 6: e834Crossref PubMed Scopus (58) Google Scholar and so do mirtazapine and venlafaxine. Offsetting this beneficial effect is the well-known increase in dropouts due to side-effects, which comes with higher doses.1Furukawa TA Cipriani A Cowen PJ Leucht S Egger M Salanti G Optimal dose of selective serotonin reuptake inhibitors, venlafaxine and mirtazapine in major depression: systematic review and dose-response meta-analysis.Lancet Psychiatry. 2019; (published online June 6.)http://dx.doi.org/10.1016/S2215-0366(19)30217-2Summary Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 2Papakostas GI Charles D Fava M Are typical starting doses of the selective serotonin reuptake inhibitors sub-optimal? A meta-analysis of randomized, double-blind, placebo-controlled, dose-finding studies in major depressive disorder.World J Biol Psychiatry. 2010; 11: 300-307Crossref PubMed Scopus (29) Google Scholar, 3Jakubovski E Varigonda AL Freemantle N Taylor MJ Bloch MH Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder.Am J Psychiatry. 2016; 173: 174-183Crossref PubMed Scopus (122) Google Scholar On balance, Furukawa and colleagues conclude that the lower range of licensed doses is likely to yield the best (achievable) balance between efficacy, tolerability, and acceptability.1Furukawa TA Cipriani A Cowen PJ Leucht S Egger M Salanti G Optimal dose of selective serotonin reuptake inhibitors, venlafaxine and mirtazapine in major depression: systematic review and dose-response meta-analysis.Lancet Psychiatry. 2019; (published online June 6.)http://dx.doi.org/10.1016/S2215-0366(19)30217-2Summary Full Text Full Text PDF PubMed Scopus (122) Google Scholar The Article by Furukawa and colleagues includes data for five SSRIs: citalopram, escitalopram, fluoxetine, paroxetine, and sertraline. Efficacy plateaus at about 30–40 mg of citalopram, 10–15 mg of escitalopram, 20–30 mg of fluoxetine, 20–30 mg of paroxetine, and 75–100 mg of sertraline. Mirtazapine shows peak efficacy at 30 mg, whereas venlafaxine displays increasing efficacy up to 375 mg. Thus, with the possible exception of venlafaxine, low-to-medium doses appear to be optimal. These figures come with a caveat concerning the manner in which fixed-dose trials are designed. As Furukawa and colleagues state,1Furukawa TA Cipriani A Cowen PJ Leucht S Egger M Salanti G Optimal dose of selective serotonin reuptake inhibitors, venlafaxine and mirtazapine in major depression: systematic review and dose-response meta-analysis.Lancet Psychiatry. 2019; (published online June 6.)http://dx.doi.org/10.1016/S2215-0366(19)30217-2Summary Full Text Full Text PDF PubMed Scopus (122) Google Scholar the common use of rapid or no titration can lead to an increase in early dropouts, confounding efficacy with tolerability because participants tend to improve over time. Flexible-dose trials, which commonly use doses above those found to be optimal by Furukawa and colleagues, have been reported to yield larger drug–placebo differences than fixed-dose trials,5Khan A Khan SR Walens G Kolts R Giller EL Frequency of positive studies among fixed and flexible dose antidepressant clinical trials: an analysis of the food and drug administration summary basis of approval reports.Neuropsychopharmacology. 2003; 28: 552-557Crossref PubMed Scopus (148) Google Scholar suggesting that optimisation of the dose on the basis of the patient's need and tolerability, and occasionally using quite high doses when doing so appears tolerable, might be beneficial. Could it thus be that the doses Furukawa and colleagues found to be optimal might be spuriously low, and that higher doses might be the most effective if used judiciously? Dose escalation should, at the very least, yield some additional benefit for select patients because of individual differences (eg, in metabolism or pharmacodynamic responsiveness).6Huezo-Diaz P Perroud N Spencer EP et al.CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP.J Psychopharmacol. 2012; 26: 398-407Crossref PubMed Scopus (53) Google Scholar The available dose-escalation literature, however, is unanimous on this issue, in that little is gained by increasing SSRI doses above those found to be optimal (ie, low-to-medium).7Dold M Bartova L Rupprecht R Kasper S Dose escalation of antidepressants in unipolar depression: a meta-analysis of double-blind, randomized controlled trials.Psychother Psychosom. 2017; 86: 283-291Crossref PubMed Scopus (29) Google Scholar Additionally, one might consider that because most flexibly dosed acute-phase trials have a rather tight post-randomisation visit schedule (usually once a week), it is not clear how well a flexible dosing implementation translates to clinical reality in which follow-up visits might be considerably less frequent. It is unfortunate that no dose-escalation studies have been done for venlafaxine. Some details of the current Article might seem surprising, particularly that the point estimates indicate roughly double efficacy for the most effective venlafaxine doses (relative risk [RR] 1·64, 1·25–2·14) as compared with the most effective SSRI (RR 1·29, 1·21–1·36) or mirtazapine (RR 1·28, 1·03–1·58) doses. This finding is particularly remarkable if one considers that in an earlier study,8Cipriani 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; 91: 1357-1366Summary Full Text Full Text PDF Scopus (1336) Google Scholar by the same group, in which flexible dosing studies were also included, mirtazapine was found to have a higher odds ratio (OR) of response than venlafaxine. Similarly, the dose-response curves in the Article by Furukawa and colleagues indicate that, at optimal doses, citalopram is roughly twice as effective as escitalopram, whereas in the complete dataset escitalopram had a higher point estimate of efficacy (OR 1·68, 95% CI 1·50–1·87) than citalopram (OR 1·52, 1·33–1·74).8Cipriani 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; 91: 1357-1366Summary Full Text Full Text PDF Scopus (1336) Google Scholar Escitalopram has shown statistical superiority over citalopram for the response outcome when considering head-to-head comparisons only (OR 1·44, 1·18–1·75).9Montgomery S Hansen T Kasper S Efficacy of escitalopram compared to citalopram: a meta-analysis.Int J Neuropsychopharmacol. 2011; 14: 261-268Crossref PubMed Scopus (29) Google Scholar Although the wide CIs for each individual drug should generally dissuade us from drawing conclusions regarding comparative efficacy, inconsistencies such as these illustrate an inherent problem with meta-analytical investigations. When effort is primarily directed at being all-encompassing with regards to coverage, the effect of confounding factors that invariably vary across studies and thus also by compound (for example study duration, number of treatment arms, intensity of follow-up, and the effect of baseline severity or comorbidities) tends to increase, while the validity of the point estimates decrease.10Papakostas GI Ostergaard SD Iovieno N The nature of placebo response in clinical studies of major depressive disorder.J Clin Psychiatry. 2015; 76: 456-466Crossref PubMed Scopus (47) Google Scholar, 11Salanti G Chaimani A Furukawa TA et al.Impact of placebo arms on outcomes in antidepressant trials: systematic review and meta-regression analysis.Int J Epidemiol. 2018; 47: 1454-1464Crossref PubMed Scopus (22) Google Scholar In summary, one possible reading of the Article by Furukawa and colleagues1Furukawa TA Cipriani A Cowen PJ Leucht S Egger M Salanti G Optimal dose of selective serotonin reuptake inhibitors, venlafaxine and mirtazapine in major depression: systematic review and dose-response meta-analysis.Lancet Psychiatry. 2019; (published online June 6.)http://dx.doi.org/10.1016/S2215-0366(19)30217-2Summary Full Text Full Text PDF PubMed Scopus (122) Google Scholar is that medium doses are optimal. It is difficult to imagine a confounder that would inflate the efficacy of medium (as compared with low or high) doses and converging evidence (from dose-escalation and fixed-dose studies) discourages us from routinely using high dose. Thus, regularly aiming for a dose close to the upper boundaries identified by Furukawa and colleagues as optimal,1Furukawa TA Cipriani A Cowen PJ Leucht S Egger M Salanti G Optimal dose of selective serotonin reuptake inhibitors, venlafaxine and mirtazapine in major depression: systematic review and dose-response meta-analysis.Lancet Psychiatry. 2019; (published online June 6.)http://dx.doi.org/10.1016/S2215-0366(19)30217-2Summary Full Text Full Text PDF PubMed Scopus (122) Google Scholar while being attentive to intolerable side-effects, might be the optimal strategy for most patients. I have received speakers' fees from Lundbeck and Servier. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysisFor the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression. Full-Text PDF Open Access