Depression, a common disorder, affects one in eight adults during their lifetime (1) and incurs an annual financial burden of approximately $83 billion (2). Primary care physicians manage the majority of depressed patients presenting for care, and antidepressant medication treatment is the primary mode of care delivered. Second-generation antidepressants (SGAs)—antidepressants developed following the first generation of tricyclic and monoamine oxidase agents—have become the preferred antidepressant choice because of their greater tolerability, lower risk of lethality, and comparable efficacy.
As of this writing, 12 different types of SGAs exist, yet evidence-based data to guide selection of treatments has been limited. Because of the lack of available direct head-to-head comparisons, prior systematic reviews (3, 4) have been able to say little about differences between the medications. A recent comparative effectiveness review published by the Agency for Healthcare Research and Quality (AHRQ) compared the benefits and harms of SGAs for treatment of adult patients with major depressive disorder (MDD) (5). The analysis included evidence from both direct, head-to-head drug comparisons and adjusted indirect comparisons that used meta-regression and network meta-analysis of placebo- and active-controlled trials. Such mixed treatment comparisons have limitations, but nevertheless they provide the best evidence on the comparative efficacy of SGAs currently available. This review provided the foundation on which the American College of Physicians (ACP) based their current practice guidelines for using SGAs to treat depressive disorders (6). Below, we review the specific recommendations and their supporting evidence and comment on their applicability in actual clinical practice.
ACP Recommendations and Commentary
Recommendation 1: The American College of Physicians recommends that when clinicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preferences (Grade: strong recommendation; moderate-quality evidence).
Existing literature well supports this recommendation, given the lower risk of overdose and similar general efficacy of SGAs relative to the prior generation of tricyclic antidepressants and monoamine oxidase inhibitors (4). Although coexisting symptom clusters such as anxiety are associated with worse outcomes for depressed patients (7), the available clinical trial literature does not provide evidence of a greater benefit with any one SGA compared with any other (5). With the advent of less expensive generic SGAs for all compounds except Duloxetine and Escitalopram, some of which are as inexpensive as $4 for a month's supply (8), selection from a wider variety of SGAs is becoming more feasible for a larger proportion of the population. Given the potentially greater variability in the bioavailability of the active agent in generic antidepressants (9), physicians need to remember that milligram doses may not be therapeutically identical (e.g., 20 mg of a trade name preparation may not equal 20 mg of the generic), so if clinicians are switching their patients from a brand name to a generic, they need to monitor closely whether the antidepressant effect changes.
Recommendation 2: The American College of Physicians recommends that clinicians assess patient status, therapeutic response, and adverse effects of antidepressant therapy on a regular basis beginning within 1 to 2 weeks of initiation of therapy (Grade: strong recommendation; moderate-quality evidence).
In 2007, available evidence led the U.S. Food and Drug Administration (FDA) to introduce a product labeling change concerning the use of all antidepressants in adults (10). This FDA advisory suggests that during the "initial few months" of a course of antidepressant therapy or at times of dose changes, "patients should be observed for worsening suicidality and unusual changes in behavior, including anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania and mania." The FDA statement advises that monitoring should begin 1 to 2 weeks after treatment begins.
This ACP recommendation is in agreement with the FDA statement, is supported by a great deal of evidence on good clinical management of depression, and is consistent with numerous other guideline recommendations for managing patients during the acute phase of major depression (11-13). Clinicians caring for depressed patients need always to assess them for suicidality as part of standard care, but the evidence base suggests that only those in the 15 to 24-year age range are at increased risk of suicidality following initiation of antidepressants. By contrast, patients who are 25 to 64 seem not to be at increased risk of suicidality, and those who are 55 and older appear to have a decrease in suicidality after antidepressant treatment (14, 15).
Recommendation 3: The American College of Physicians recommends that clinicians modify treatment if the patient does not have an adequate response to pharmacotherapy within 6 to 8 weeks of the initiation of therapy for major depressive disorder (Grade: strong recommendation; moderate-quality evidence).
This ACP recommendation is consistent with providing measurement-based care (16). This successful and feasible evidence-based strategy, used in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (17), monitors depressive severity and side effects and advises modifying antidepressant treatment (by increasing antidepressant doses or, if a patient cannot tolerate such an increase, switching to a different medication) if patients do not recover within a specific time frame (approximately 4 weeks at a particular dose) (18, 19).
A key point is that the treatment goal for antidepressant treatment is remission, i.e., full recovery from the depressive episode as indicated by resolution of depressive symptoms and functional impairment. Clinicians should modify their patients' antidepressant treatment until this outcome is reached. Typically, they would increase their patient's antidepressant dose until the patient either recovers or cannot tolerate the side effects.
Should a patient fail to recover with the initial antidepressant treatment, treatment considerations include augmenting with a second medication agent, switching to a different antidepressant, adding an evidence-based psychotherapy such as cognitive behavioral therapy (CBT), or switching to CBT alone (20). Current available evidence does not lead to any conclusive advice about switching vs. augmenting or about making any particular choice of a next antidepressant following failure to respond to the initial antidepressant trial.
Recommendation 4: The American College of Physicians recommends that clinicians continue treatment for 4 to 9 months after a satisfactory response in patients with a first episode of major depressive disorder. For patients who have had 2 or more episodes of depression, an even longer duration of therapy may be beneficial (Grade: strong recommendation; moderate-quality evidence).
The first three recommendations address acute phase treatment, i.e., treatment of the acute depressive episode until remission is reached. By contrast, this final recommendation addresses continuation treatment (4 to 9 months), after which a patient has fully recovered from the discrete episode, and maintenance treatment, which addresses how long to treat someone after complete recovery. The goal of maintenance treatment is to decrease the likelihood of the recurrence of a subsequent depressive episode, as with each subsequent depressive episode the likelihood of a next episode increases. Patients with two prior episodes of depression have about a 75% chance of having a third depressive episode, and those with three or more depressive episodes have a greater than 90% chance of having another depressive episode (11). The existing evidence base for the optimal length and dose of treatment to maintain remission is unfortunately quite thin.
The above recommendations are based on a large collection of clinical trial information from more than 20 years of research on second-generation antidepressants; such investigators have focused primarily on treating patients in the acute phase of depression. Despite much research to develop other pharmacologic approaches to treating depression, no revolutionary antidepressants are apparent on the horizon. Further, as more of these second-generation antidepressants become available in generic formulations, their use is more likely to increase. Accordingly, the first three recommendations are likely to remain relevant for a long period of time. By contrast, the evidence base for the fourth recommendation, which addresses continuation and maintenance phase treatments, is much more limited. New evidence, although not likely to change the recommendation to continue treatment, may better specify the proper dose and duration of antidepressants.
Consequently, the ACP recommendations are likely to be clinically relevant for the foreseeable future. Given that the majority of depression is identified and treated in primary care settings, and that primary care physicians can manage a presenting episode as effectively as psychiatrists (21), these guidelines merit dissemination to those clinicians, including internists, family medicine physicians, pediatricians (to the extent they treat young adults older than 18 years), geriatricians, and obstetricians/gynecologists.
Bradley N. Gaynes, MD, MPH
Chapel Hill, NC
Gerald Gartlehner, MD, MPH
The views and opinions expressed are those of the authors and do not necessarily state or reflect those of the National Guideline Clearinghouse™ (NGC), the Agency for Healthcare Research and Quality (AHRQ), or its contractor, ECRI Institute.
Potential Conflicts of Interest
Within the last 12 months, Dr. Gaynes has received grants and research support from the National Institute of Mental Health; Agency for Healthcare Research and Quality; M-3 Information; Bristol-Myers Squibb Company; and Novartis. He has performed as an advisor for Bristol-Myers Squibb Company.
Dr. Gartlehner declares no potential conflicts of interest with respect to this expert commentary.
Both Dr. Gaynes and Dr. Gartlehner are listed as authors for companion documents used to support the recommendations in the American College of Physicians guideline on "Using second-generation antidepressants to treat depressive disorders."
- Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095-105.
- Greenberg PE, Kessler RC, Birnbaum HG, et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J Clin Psychiatry. 2003;64:1465-75.
- Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS. Efficacy and safety of second-generation antidepressants in the treatment of major depressive disorder. Ann Intern Med. 2005 Sep 20;143(6):415-26.
- Williams JW Jr., Mulrow CD, Chiquette E, Noel PH, Aguilar C, Cornell J. A systematic review of newer pharmacotherapies for depression in adults: evidence report summary. Ann Intern Med. 2000;132(9):743-56.
- Gartlehner G, Gaynes BN, Hansen RA, et al. The comparative benefits and harms of second-generation antidepressants for depressive disorders: a systematic review and meta-analysis. Ann Intern Med. 2008;149:734-50.
- Qaseem A, Snow V, Denberg TD, Forciea MA, Owens DK, for the Clinical Efficacy Assessment Subcommittee of the American College of P. Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008 Nov 18;149(10):725-33.
- Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in outpatients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008 Mar 1;165(3):342-51.
- Herrick D. Shopping for drugs: 2007. Dallas, Tx: National Center for Policy Analysis; 2006.
- Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Therapeutics. 2003;25(6):1578-92.
- Food and Drug Administration. Class suicidality labeling language for antidepressants; May 2, 2007.
- American Psychiatric Association. Practice guideline for the treatment of patients with major depression (revision). Am J Psychiatry. 2000;157(suppl 4):1-45.
- Depression guideline panel. Depression in primary care: Volume 2, Treatment of major depression. Vol AHCPR publication No. 93-0550. Rockville, MD: U.S. Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research; 1993.
- National Institute for Clinical Excellence. Depression: management of depression in primary and secondary care (amended) 2007 Apr. Clinical Guideline 23. http://www.nice.org.uk/nicemedia/pdf/CG23quickrefguideamended.pdf (PDF Help). Accessed June 13, 2009.
- Food and Drug Administration. Antidepressant use in children, adolescents, and adults. May 2007. Accessed June 13, 2009.
- Friedman RA, Leon AC. Expanding the black box -- depression, antidepressants, and the risk of suicide. N Engl J Med. 2007 Jun 7;356(23):2343-6.
- Trivedi MH, Rush AJ, Gaynes BN, et al. Maximizing the adequacy of medication treatment in controlled trials and clinical practice: STAR*D measurement-based care. Neuropsychopharmacology. 2007;32:2479-89.
- Gaynes BN, Rush AJ, Trivedi MH, Wisniewski SR, Spencer D, Fava M. The STAR*D study: treating depression in the real world. Cleveland Clinic J Med. 2008;75(1):57-66.
- Landis SE, Gaynes BN, Morrissey JP, Vinson N, Ellis AR, Domino ME. Generalist care managers for the treatment of depressed Medicaid patients in North Carolina: a pilot study. BMC Fam Pract. 2007 Mar 5;8(1):7.
- Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006 Jan 1;163(1):28-40.
- Rush AJ. STAR*D: what have we learned? Am J Psychiatry. 2007 Feb;164(2):201-4.
- Gaynes BN, Rush AJ, Trivedi MH, et al. Primary versus specialty care outcomes for depressed outpatients managed with measurement-based care: results from STAR*D. J Gen Intern Med. 2008 May;23(5):551-60.
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