With over 2 dozen FDA-approved antidepressants on the market, it is reasonable to ask: which antidepressants are most effective? After decades of clinical experience and literally millions of prescriptions written over the years, it stands to reason that 1 or 2 agents have risen from the pack to outshine the rest.
Unfortunately, clinical experience shows this not to be the case. The general consensus is that despite their different mechanisms of action, all current antidepressants seem to have more or less the same effect. The functional equivalency of antidepressants is highlighted in practice guidelines and, understandably, serves as justification for restricted formulary access to more expensive agents.1 As a result, most psychiatrists choose antidepressants not on the basis of efficacy, but rather on the basis of insurance coverage, adverse-effect profiles, or particular clinical features of depression (eg, melancholic, atypical, anxious features), for which some differences in efficacy do exist.
Efficacy vs effectiveness
The question of how well antidepressants work for the routine treatment of depression can be answered in terms of efficacy or effectiveness. An efficacy trial asks the question, Does the drug work under ideal circumstances? Although such trials are usually brief (6 to 8 weeks) and interventions are standardized and rarely flexible, they serve as the basis for the FDA’s approval of drugs.
“Effectiveness” concerns the success or failure of drugs in the real world. A true effectiveness study asks the question, Does the drug work under usual conditions? Effectiveness trials enroll a more heterogeneous population, often with comorbid mental illness, substance abuse, or other psychiatric diagnoses, and health care professionals are often free to offer concurrent therapies. As a result, effectiveness trials tend to have more generalizability, or external validity, to real patient populations.
Effectiveness trials help clinicians and policymakers select which medications work best for a given indication in real-world conditions. Surprisingly, despite decades of experience with antidepressants, information on their relative effective-ness is lacking, while health care costs continue to escalate. As a result, more emphasis is being placed on comparative effectiveness research, in which alternative treatments are compared under real-world conditions, and costs and adverse effects are measured in addition to clinical outcomes.
Effectiveness trials are often large, expensive, and time-consuming. They sometimes take the form of a practical clinical trial in which multiple clinically relevant treatment regimens are compared across a large population of subjects. One such landmark study is the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. In this NIMH-funded study, more than 4000 depressed patients in outpatient psychiatry and primary care practices received citalopram for up to 12 weeks; those who did not improve advanced to later phases that offered augmentation with, or a switch to, a second antidepressant or psychotherapy.2
Remission rates in step 1 were low (28%) and decreased further with additional steps. Cumulatively, two-thirds of patients entered remission after 4 steps.3 Direct comparison of the effectiveness of antidepressants was not possible because of the overall lack of randomization and poor statistical power.4 Despite the scope and initial aims of the study, no single antidepressant strategy or combination appeared more advantageous than any other.
Other effectiveness trials have yielded similar results. A 24-week trial that randomized patients to sertraline or citalopram found no significant difference between groups.5 Another 24-week trial of 234 patients randomized to receive sertraline or fluoxetine also found no significant difference.6 In a 2001 study, 573 patients were randomized to 1 of 3 SSRIs for 9 months; sertraline, paroxetine, and fluoxetine were equally effective.7 Patients admitted to a German psychiatric hospital for treatment of depression were followed up for 10 weeks, and response and remission rates were 68.9% and 51.9%, respectively, again with no difference among individual antidepressant agents.8 Effectiveness trials, therefore, seem to confirm the conventional wisdom that no single antidepressant works better than—or worse than—any other.
Dr Balt is Diplomate of the American Board of Psychiatry and Neurology, Diplomate of the American Board of Addiction Medicine, Editor in Chief of The Carlat Psychiatry Report, and Supervising Psychiatrist at John Muir Behavioral Health in Concord, Calif. He reports no personal conflicts of interest concerning the subject matter of this article; however, his wife is employed by Otsuka America, Inc.
1. American Psychiatric Association. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. Arlington, VA: American Psychiatric Association; 2010.
2. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Psychiatr Clin North Am. 2003;26:457-494, x.
3. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
4. Baghai TC, Blier P, Baldwin DS, et al; Section of Pharmacopsychiatry, World Psychiatric Association. General and comparative efficacy and effectiveness of antidepressants in the acute treatment of depressive disorders: a report by the WPA section of pharmacopsychiatry. Eur Arch Psychiatry Clin Neurosci. 2011;261(suppl 3):207-245.
5. Ekselius L, von Knorring L, Eberhard G. A double-blind multicenter trial comparing sertraline and citalopram in patients with major depression treated in general practice. Int Clin Psychopharmacol. 1997;12:323-331.
6. Sechter D, Troy S, Paternetti S, Boyer P. A double-blind comparison of sertraline and fluoxetine in the treatment of major depressive episode in outpatients. Eur Psychiatry. 1999;14:41-48.
7. Kroenke K, West SL, Swindle R, et al. Similar effectiveness of paroxetine, fluoxetine, and sertraline in primary care: a randomized trial. JAMA. 2001;286:2947-2955.
8. Seemüller F, Riedel M, Obermeier M, et al. Outcomes of 1014 naturalistically treated inpatients with major depressive episode. Eur Neuropsychopharmacol. 2010;20:346-355.
9. Gartlehner G, Hansen RA, Thieda P, et al. Comparative Effectiveness of Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression. Rockville, MD: Agency for Healthcare Research and Quality, US Dept of Health and Human Services; 2007.
10. Gartlehner G, Hansen RA, Morgan LC, et al. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. Rockville, MD: Agency for Healthcare Research and Quality, US Dept of Health and Human Services; 2011.
11. Gartlehner G, Hansen RA, Morgan LC, et al. Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis. Ann Intern Med. 2011;155:772-785.
12. Cipriani A, Furukawa TA, Salanti G, et al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746-758.
13. Turner EH, Matthews AM, Linardatos E, et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med. 2008;358:252-260.
14. Sinyor M, Schaffer A, Smart KA, et al. Sponsorship, antidepressant dose, and outcome in major depressive disorder: meta-analysis of randomized controlled trials. J Clin Psychiatry. 2012;73:e277-e287.
15. Goldacre B, Heneghan C. Improving, and auditing, access to clinical trial results. BMJ. 2014;348:g213.
16. Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and meta-analysis. J Clin Psychiatry. 2011;72:156-167.
17. Goldney RD. From mania and melancholia to the bipolar disorders spectrum: a brief history of controversy. Aust N Z J Psychiatry. 2012;46:306-312.
18. Fournier JC, DeRubeis RJ, Hollon SD, et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA. 2010;303:47-53.
19. Nemeroff CB, Heim CM, Thase ME, et al. Differential responses to psychotherapy versus pharmacotherapy in patients with chronic forms of major depression and childhood trauma [published correction appears in Proc Natl Acad Sci U S A. 2005;102:16530]. Proc Natl Acad Sci U S A. 2003;100:14293-14296.
20. Ghaemi SN. Why antidepressants are not antidepressants: STEP-BD, STAR*D, and the return of neurotic depression. Bipolar Disord. 2008;10:957-968.
21. Rush AJ, Trivedi MH, Stewart JW, et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am J Psychiatry. 2011;168:689-701.
22. Bschor T, Bauer M. Efficacy and mechanisms of action of lithium augmentation in refractory major depression. Curr Pharm Des. 2006;12:2985-2992.
23. Spielmans GI, Berman MI, Linardatos E, et al. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Med. 2013;10:e1001403.
24. Tansey KE, Guipponi M, Hu X, et al. Contribution of common genetic variants to antidepressant response. Biol Psychiatry. 2013;73:679-682.
25. GENDEP Investigators, MARS Investigators, STAR*D Investigators. Common genetic variation and antidepressant efficacy in major depressive disorder: a meta-analysis of three genome-wide pharmacogenetic studies. Am J Psychiatry. 2013;170:207-217.
26. Tansey KE, Guipponi M, Perroud N, et al. Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis. PLoS Med. 2012;9:e1001326.
27. Kocsis JH, Leon AC, Markowitz JC, et al. Patient preference as a moderator of outcome for chronic forms of major depressive disorder treated with nefazodone, cognitive behavioral analysis system of psychotherapy, or their combination. J Clin Psychiatry. 2009;70:354-361.
28. Winter SE, Barber JP. Should treatment for depression be based more on patient preference? Patient Prefer Adherence. 2013;7:1047-1057.
29. Sneed JR, Rutherford BR, Rindskopf D, et al. Design makes a difference: a meta-analysis of antidepressant response rates in placebo-controlled versus comparator trials in late-life depression. Am J Geriatr Psychiatry. 2008;16:65-73.
30. McKay KM, Imel ZE, Wampold BE. Psychiatrist effects in the psychopharmacological treatment of depression. J Affect Disord. 2006;92:287-290.