Although the current generation of antidepressants extends back to the late 1980s, efforts to describe the dose-response relationship for treatment of major depressive disorder continue. More in this research update.
Second-generation antidepressants have served as first-line treatments for major depressive disorder (MDD) for over two decades. Nevertheless, the nature of the dose-response curve for contemporary antidepressants has proved surprisingly difficult to define.
Many early studies comparing the efficacy of fixed doses described a flat dose-response curve, a conclusion that seemed well aligned with receptor binding analyzed by positron emission tomography (PET) in which 80% serotonin transporter occupancy in the striatum appeared to be achieved at minimal therapeutic doses for most SSRIs and venlafaxine with only small incremental increases occurring at higher doses.1 More recent meta-analyses of published trials that used both fixed and flexible dosing strategies have somewhat modified assertions of a flat dose-response curve, suggesting modestly greater efficacy for higher doses yet still concluding that efficacy may plateau in the moderate dose range at around the equivalent of 40 mg to 50 mg of fluoxetine.2
In contrast, standard clinical practice has been to increase doses more assertively as tolerated, particularly in the setting of inadequate initial response to antidepressants,3 an approach that is also in line with the American Psychiatric Association (APA) guidelines for MDD treatment.4[PDF]âWading into this controversy, Furukawa and colleagues5 conducted the most sophisticated and comprehensive meta-analysis to date of fixed-dose, double-blind, randomized controlled trials of second-generation antidepressants, both published and unpublished, for the acute treatment of MDD.
Rather than limiting their analysis to efficacy (as assessed by 50% reduction in depression severity), the investigators also assessed treatment tolerability (as assessed by dropouts due to adverse effects) and treatment acceptability (as assessed by dropouts for any reason). In all the researchers analyzed 77 studies involving 19,364 participants. The mean age of participants was 42.5 years and 60.9% were female. The median length of antidepressant trial was 8 weeks. They conducted separate dose-response analyses for individual SSRIs as well as for venlafaxine and mirtazapine.
For SSRIs they found that the dose-response curve for efficacy showed a gradual increase in doses of 20 mg to 40 mg fluoxetine equivalents, with either asymptotic or decreasing efficacy at higher doses. At the same time, the dose-response curve for drop-outs due to adverse effects increased linearly across all doses studied. Overall, the relationship between dose and acceptability overall favored the 20 mg to 40 mg fluoxetine equivalents. The dose-response curve for efficacy for mirtazapine appeared to peak around 30 mg and then decline. In contrast, the dose-response curve for efficacy of venlafaxine, though most sharply increasing between 75 mg and 150 mg, continued to increase steadily up through 400 mg, the highest dose studied.
Nevertheless, dropouts due to adverse effects or other reasons increased with dose for both mirtazapine and venlafaxine indicating greater acceptability at low to moderate doses (around < 40 mg and < 200 mg respectively). Based on their overall findings, the authors conclude, “For the majority of patients receiving an SSRI, venlafaxine, and mirtazapine for the acute-phase treatment of their major depressive episode, the lower range of the licensed dose will probably achieve the optimal balance between efficacy, tolerability, and acceptability. Clinical guidelines need to incorporate these findings.”5
Where does this leave the clinician who values the evidence base yet recognizes the risks and burden of unremitted depression and not infrequently advocates for patients in their appeals to insurers reluctant to cover daily antidepressant doses above the usual range?
On balance, the study provides further evidence that for some patients there may be diminishing returns, and, indeed, potentially lower response rates at SSRI doses that exceed 20 mg to 40 mg of fluoxetine equivalents or at mirtazapine doses above 30 mg. For venlafaxine, the potential for response may continue to increase with dose escalation but so will the potential for dropout due to adverse effects. Nevertheless, this conclusion may well extend to only a subset of patients seen in psychiatric settings.
In a frequently cited study, Zimmerman and colleagues6 found that of 599 patients with unipolar nonpsychotic MDD, a remarkable 79.5% would have been excluded from RCTs by usual eligibility criteria such as medical or psychiatric comorbidity and severity. In this context, Furukawa and colleagues5 explicitly excluded studies of MDD in patients with medical comorbidity. Moreover, many RCTs included in their analysis excluded individuals with significant psychiatric comorbidity such as substance use disorders, posttraumatic stress disorder, or severe personality disorders with active suicidality, or with a history of non-response to antidepressants.
In addition, fixed-dose studies do not mimic usual clinical practice. Clinicians do not routinely start treatment with moderate to high doses of antidepressants in the way patients in fixed-dose studies are directly randomized to these higher doses vs. lower doses. Rather, those patients in clinical practice who get to higher doses are typically those who have already proven themselves to tolerate lower doses and yet to have not remitted. The question at that point is, given reasonable tolerability and incomplete response, what is the probability of tolerability and greater response at a higher dose? Patients without adverse effects or benefit at a lower dose may be individuals who are rapid metabolizers of the medication or whose receptors are less responsive to usual doses.
Furthermore, for individuals who may have tried and failed other antidepressants, an additional question is whether the profile of risks and benefits involved in exploring higher doses is more or less favorable than starting from scratch with a new agent, augmenting the initial antidepressant with other agents, or combining it with second antidepressants. The Furukowa study5 was not designed to address these questions. Finally, although efficacy and tolerability during acute treatment are key factors, in clinical practice, efficacy and tolerability during continuation and maintenance treatment for prevention of relapse and recurrence are also integral to the overall impact and success of depression treatment.
Clinical bottom line
The take home message is that, based on the most comprehensive and state-of-the-art meta-analysis of studies involving patients with MDD randomized to fixed doses of SSRIs mirtazapine or venlafaxine, the combined evaluation of efficacy, tolerability and acceptability, favors dosing in the low to moderate range in the simplest cases. Yet, as the evidence base does not extend well to the many patients with depressive symptoms seen in psychiatric practice with psychiatric or other medical comorbidity, before treatment resistance, or incomplete response but tolerability on a current antidepressant, the elegant meta-analysis by Furakawa5 does not provide sufficient reason to hold back on thoughtful dose increases as tolerated. Along with potential dose increases, in the setting of ongoing depression, the reassessment of diagnosis, comorbidity, and psychosocial factors together with consideration of augmentation and combination strategies, psychotherapy, and neuromodulation are also crucially important.
Dr Alpert is the Dorothy and Marty Silverman Chair of the Department of Psychiatry and Behavioral Sciences at Montefiore Medical Center and Albert Einstein College of Medicine where he is Professor of Psychiatry, Neuroscience, and Pediatrics. The author reports that he receives research support from Otsuka Pharmaceuticals, Axsome Therapeutics, and the Patient-Centered Outcomes Research Institute.
1. Meyer JH, Wilson AA, Sagrati S, et al. Serotonin transporter occupancy of five selective serotonin reuptake inhibitors at different doses: an [11C]DASB positron emission tomography study. Am J Psychiatry. 2004;161:826-35.
2. Jakubovski E, Varigonda AL, Freemantle N, et al. Systematic review and meta-analysis: dose-response relationship of selective serotonin reuptake inhibitors in major depressive disorder. Am J Psychiatry. 2016;173:174-183.
3. Ionescu DF, Rosenbaum JF, Alpert JE: Pharmacological approaches to the challenges of treatment-resistant depression. Dialogues Clin Neurosci. 2015;17:111-126.
4. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry. 2010;167(suppl):1-152.
5. Furukawa TA, Cipriani A, Cowen PJ, et al. Optimal dose of selective serotonin reuptake inhibitors, venlafaxine, and mirtazapine in major depression: a systematic review and dose-response meta-analysis. Lancet Psychiatry. 2019;6:601-609.
6. Zimmerman M, Chelminski I, Posternak MA. Generalizability of antidepressant efficacy trials: differences between depressed psychiatric outpatients who would or would not qualify for an efficacy trial. Am J Psychiatry. 2005;162:1370-1372.