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This website is made possible by third party financial support from Sage Therapeutics, Inc. and Biogen Inc.

Evidence-Based Management of Major Depressive Disorder: The Importance of Guideline Updates

Evidence-Based Management of Major Depressive Disorder: The Importance of Guideline Updates

September 30, 2022

Guidelines for managing major depressive disorder need to keep pace with clinical research.

evidence based medicine

What is evidence-based medicine?

Evidence-based medicine has been defined as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research.”1

To that end, treatment guidelines for major depressive disorder (MDD) are developed to assemble and codify the best available evidence for clinicians to draw upon and to help standardize treatment.   

Guidelines for the Management of MDD are Updated Infrequently

Guidelines for the management of MDD are updated at best every several years,2 often even less frequently; for example, the American Psychiatric Association (APA)3 and British Association for Psychopharmacology (BAP)4 guidelines were last updated in 2010 and 2015, respectively. In contrast, the National Comprehensive Cancer Network® (NCCN®) guidelines for B-cell lymphomas have been updated 5 times in 2022 alone.5 Research in MDD may not be proceeding as rapidly as cancer research, but the 7- to 12-year period since the publication of the latest BAP and APA guidelines has left numerous developments unaddressed in their latest iterations.

More frequent guideline updates would be an invaluable resource for clinicians who want to stay current and offer their patients the best available care.

Recent Developments in Precision Prescribing are Not Addressed in Recent Guidelines

The 2010 APA and 2015 BAP MDD guidelines state that the efficacy of antidepressants is generally similar between and within drug classes, meaning that drug selection is based on tolerability, drug properties such as interaction potential, and patient preference and history of drug response.3,4 Finding an effective agent may require sequential 6- to 8-week trials to gauge response.3,4 In the APA guidelines, combination antidepressant regimens are typically reserved for after first-line treatment fails.3 In the BAP update, combination therapies may be considered, but added efficacy of a combination is attributed to worse MDD severity rather than to other patient characteristics that would match individual patients with the best combination.4

Recent findings of differential response to antidepressant regimens that supports the potential use of first-line combination regimens in carefully selected patients are not included in either guideline update. The 2015 BAP guidelines update does reference the 2011 Combining Medications to Enhance Depression Outcomes (CO-MED) study,6 which reported low and nearly identical 12-week remission rates (37.7% to 38.9%) in patients treated with selective serotonin reuptake inhibitor (SSRI) monotherapy, bupropion plus an SSRI, or a serotonin-norepinephrine reuptake inhibitor (SNRI) plus a tetracyclic.6

However, in the 7 years since the BAP guidelines update, subsequent CO-MED analyses have shown differential response to study regimens based on patient profile. For example, remission rates were highest with bupropion-SSRI vs an SSRI alone in patients with higher baseline levels of interleukin-13 (67% vs 24%)7 and C-reactive protein (51.4% vs 29.7%)8; conversely, SSRI monotherapy was most effective in patients with low levels of interleukin-13 (IL-13) or C-reactive protein (CRP).7,8 Other CO-MED sub-analyses found differential response between regimens based on body mass index (BMI) and the presence of subthreshold hypomanic symptoms.9,10

In light of these developments, future guideline update committees will have an opportunity to capture exciting improvements in our ability to predict treatment response in specific MDD subpopulations, which have evolved more rapidly than treatment guidelines are being updated.

Recent Data on Novel Therapies are Not Captured in Treatment Guidelines

Drug development efforts in MDD have also yielded some exciting results. For example, therapies directed at glutamate and gamma-aminobutyric acid (GABA) have shown rapid efficacy (glutamate modulator, within 2 hours; GABA, within 2 weeks) in patients with MDD, including treatment-resistant and suicidal patients.11-14 These rapid response times would represent a meaningful improvement over the 4- to 6-week onset of efficacy expected for monoamine-based medications. The APA and BAP guideline updates focus primarily on monoamine-based medications, without the most recent drug data on developmental agents.3,4 The BAP update does reference studies of glutamate receptor modulators, but raises questions about long-term efficacy, serious adverse events, and the potential of oral or intranasal formulations.4 However, an intranasal glutamate receptor modulator has since demonstrated impressive efficacy in treatment-resistant MDD15 and was approved by the FDA in 2019.16

The practice of evidence-based medicine is essential to standardizing and ensuring the quality of care for patients with MDD, but clinicians need to have access to the best available evidence to adhere to it. Considering the rapid pace of MDD research, professional societies might consider expiration dates on published guidelines and issue more frequent updates that capture the most recent evidence-based best practices in a timely manner.

1.    Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn't. BMJ. 1996;312(7023):71-72. doi:10.1136/bmj.312.7023.71
2.    Luo Y, Chaimani A, Kataoka Y, et al. Evidence synthesis, practice guidelines and real-world prescriptions of new generation antidepressants in the treatment of depression: a protocol for cumulative network meta-analyses and meta-epidemiological study. BMJ Open. 2018;8(12):e023222. doi:10.1136/bmjopen-2018-023222
3.    Work Group on Major Depressive Disorder. Practice Guideline for the Treatment of Patients With Major Depressive Disorder. 3rd ed. American Psychiatric Association; 2010. Accessed August 14, 2022.
4.    Cleare A, Pariante CM, Young AH, et al. Evidence-based guidelines for treating depressive disorders with antidepressants: A revision of the 2008 British Association for Psychopharmacology guidelines. J Psychopharmacol. 2015;29(5):459-525. doi:10.1177/0269881115581093
5.    NCCN clinical practice guidelines in oncology (NCCN Guidelines®): Version 5.2022. National Cancer Care Network®. July 12, 2022. Accessed September 15, 2022.
6.    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(7):689-701. doi:10.1176/appi.ajp.2011.10111645
7.    Czysz AH, Mason BL, Li Q, et al. Comparison of inflammatory markers as moderators of depression outcomes: a CO-MED Study. J Affect Disord. 2021;295:1066-1071. doi:10.1016/j.jad.2021.08.116
8.    Jha MK, Minhajuddin A, Gadad BS, et al. Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology. 2017;78:105-113. doi:10.1016/j.psyneuen.2017.01.023
9.    Jha MK, Wakhlu S, Dronamraju N, Minhajuddin A, Greer TL, Trivedi MH. Validating pre-treatment body mass index as moderator of antidepressant treatment outcomes: Findings from CO-MED trial. J Affect Disord. 2018;234:34-37. doi:10.1016/j.jad.2018.02.089
10.    Jha MK, Malchow AL, Grannemann BD, Rush JA, Trivedi MH. Do baseline sub-threshold hypomanic symptoms affect acute-phase antidepressant outcome in outpatients with major depressive disorder? Preliminary findings from the randomized CO-MED trial. Neuropsychopharmacology. 2018;43(11):2197-2203. doi:10.1038/s41386-018-0180-z
11.    Duman RS, Sanacora, Krystal JH. Altered connectivity in depression: GABA and glutamate neurotransmitter deficits and reversal by novel treatments. Neuron. 2019;102(1):75-90. doi:10.1016/j.neuron.2019.03.013
12.    Preskorn S, Macaluso M, Mehra DOV, Zammit G, Moskal JR, Burch RM. Randomized proof of concept trial of GLYX-13, an N-methyl-D-aspartate receptor glycine site partial agonist, in major depressive disorder nonresponsive to a previous antidepressant agent. J Psychiatr Pract. 2015;21(2):140-149. doi:10.1097/01.pra.0000462606.17725.93
13.    Singh JB, Fedgchin M, Daly E, et al. Intravenous esketamine in adult treatment-resistant depression: a double-blind, double-randomization, placebo-controlled study. Biol Psychiatry. 2016;80(6):424-431. doi:10.1016/j.biopsych.2015.10.018
14.    Suthoff E, Kosinski M, Arnaud A, et al. Patient-reported health-related quality of life from a randomized, placebo-controlled phase 2 trial of zuronalone in adults with major depressive disorder. J Affect Disord. 2022;308:19-26. doi:10.1016/j.jad.2022.03.068
15.    Papakostas GI, Salloum NC, Hock RS, et al. Efficacy of esketamine augmentation in major depressive disorder: a meta-analysis. J Clin Psychiatry. 2020;81(4):19r12889. doi:10.4088/JCP.19r12889
16.    FDA Approves New Nasal Spray Medication for Treatment-Resistant Depression; Available Only at a Certified Doctor’s Office or Clinic. US Food and Drug Administration. March 5, 2019. Accessed September 15, 2022.