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Major Depressive Disorder (MDD)

General Information


  • MDD is characterized by persistent low mood, lack of positive affect, and loss of interest in usually pleasurable activities (anhedonia) that is different from patient's usual self and causes significant distress or impairment for ≥ 2 weeks2,3

Also called

  • depression
  • major depression
  • major depressive affective disorder
  • melancholia
  • terms used to distinguish depression alone from depression in bipolar disorder
    • unipolar depression
    • unipolar disorder
    • unipolar mood disorder


  • Diagnostic and Statistical Manual of Mental Disorders (DSM) specifiers/modifiers (may be clinically useful for predicting outcomes and choosing treatment) of MDD include1,3,4,5
    • anxious distress
    • mixed features
    • melancholic depression (also called melancholia or endogenous features)
    • atypical features
    • psychotic features
    • catatonic features
    • seasonal affective disorder - regular temporal relationship between time of year and symptom onset/remission
    • postpartum depression
    • see Diagnosis for more information on MDD specifiers
  • double depression - major depression superimposed on underlying persistent depressive disorder3
  • see also Depression in Children and Adolescents and Depression in Older Adults


General references used

  1. Davidson JR. Major depressive disorder treatment guidelines in America and Europe. J Clin Psychiatry. 2010;71 Suppl E1:e04
  2. National Collaborating Centre for Mental Health commissioned by the National Institute for Health and Care Excellence (NICE). Depression in adults: the treatment and management of depression in adults (updated edition). NICE 2009 Oct:CG90, updated 2018PDF)
  3. Gelenberg AJ, Freeman MP, Markowitz JC, et al; American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (third edition). APA 2010 Nov PDF
  4. Thase ME. The multifactorial presentation of depression in acute care. J Clin Psychiatry. 2013;74 Suppl 2:3-8
  5. Otte C, Gold SM, Penninx BW, et al. Major depressive disorder. Nat Rev Dis Primers. 2016 Sep 15;2:16065

Recommendation grading systems used

  • American College of Physicians (ACP) guideline grading system
    • strength of recommendation
      • Strong - benefits clearly outweigh risks and burden, or risks and burden clearly outweigh benefits
      • Weak - benefits closely balanced with risks and burden or uncertainty in estimates of benefits, risks, and burdens
      • Insufficient - balance of benefits and risks cannot be determined
    • quality of evidence
      • High - randomized trials without important limitations, or overwhelming evidence from observational studies
      • Moderate - randomized trials with important limitations (inconsistent results, methodologic flaws, indirect, or imprecise), or exceptionally strong evidence from observational studies
      • Low - observational studies or case series
      • Insufficient - evidence is conflicting, poor quality, or lacking
    • Reference - ACP methods for development of clinical practice guidelines and guidance statements (20679562Ann Intern Med 2010 Aug 3;153(3):194)
  • Institute for Clinical Systems Improvement (ICSI) grading system for recommendations
    • strength of recommendation
      • Strong recommendation - benefits outweigh risks or harms, recommendation applies to most patients
      • Weak recommendation - benefits and harms are balanced or uncertainty exists about best estimates of benefits and harms; recommendation may depend on local circumstances, patient values, or preferences
    • quality of evidence
      • High-quality evidence - further research unlikely to change confidence in estimate of effect
      • Moderate-quality evidence - further research may impact recommendation and confidence in estimate of effect
      • Low-quality evidence - further research very likely to have important impact on confidence in estimate of effect and likely to change, so any estimate of effect is very uncertain
    • Reference - ICSI guideline on adult depression in primary care (ICSI Sep 2013PDF)
  • American Psychiatric Association (APA) categories of recommendation
    • Category I - recommended with substantial clinical confidence
    • Category II - recommended with moderate clinical confidence
    • Category III - may be recommended on the basis of individual circumstances
    • Reference - APA 2010 practice guideline on treatment of patients with major depressive disorder, third edition (APA 2010 Nov PDF)
  • American College of Obstetricians and Gynecologists (ACOG) levels of recommendation
    • Level A - recommendations based on good, consistent scientific evidence
    • Level B - recommendations based on limited or inconsistent scientific evidence
    • Level C - recommendations based primarily on consensus and expert opinion
    • Reference - ACOG Practice Bulletin No. 92 on use of psychiatric medications during pregnancy and lactation (18378767Obstet Gynecol 2008 Apr;111(4):1001)
  • Canadian Network for Mood and Anxiety Treatments (CANMAT) criteria for levels of evidence and lines of treatment
    • level of evidence
      • Level 1 - ≥ 2 randomized controlled trials (RCTs) with adequate sample sizes, placebo-controlled preferred, and/or meta-analysis with narrow confidence intervals
      • Level 2 - ≥ 1 RCT with adequate sample size and/or meta-analysis with wide confidence intervals
      • Level 3 - nonrandomized, controlled perspective studies or case series or high-quality retrospective studies
      • Level 4 - expert opinion/consensus
    • line of treatment
      • First-line - level 1 or level 2 evidence plus clinical support
      • Second-line - level 3 evidence or higher plus clinical support
      • Third-line - level 4 evidence or higher plus clinical support
    • Reference - CANMAT clinical guidelines for management of major depressive disorder in adults: complementary and alternative medicine treatments (19666194J Affect Disord 2009 Oct;117 Suppl 1:S54)
  • European expert consensus grading system
    • level of recommendations
      • Level A - definitely effective or definitely ineffective, based on ≥ 2 convincing Class I studies or 1 convincing Class I study and ≥ 2 consistent, convincing Class II studies
      • Level B - probably effective or probably ineffective, based on ≥ 2 convincing Class II studies or 1 convincing Class II study and ≥ 2 consistent, convincing Class III studies
      • Level C - possibly effective or possibly ineffective, based on 1 convincing Class II study or ≥ 2 convincing Class III studies
    • classification of evidence
      • Class I - adequately data-supported, prospective, randomized, placebo-controlled clinical trial with masked outcome assessment in a representative population (n ≥ 25 patients receiving active treatment) and includes
        • randomization concealment
        • clearly defined primary outcomes
        • clearly defined exclusion/inclusion criteria
        • adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
        • relevant baseline characteristics substantially equivalent among treatment groups or appropriate statistical adjustment for differences
      • Class II - a randomized, placebo-controlled trial performed with a smaller sample size (n < 25) or that lacks ≥ 1 of the above-listed criteria
      • Class III - all other controlled trials
      • Class IV - uncontrolled studies, cases series, and case reports
    • Reference - European expert consensus on therapeutic use of repetitive transcranial magnetic stimulation (rTMS) (25034472Clin Neurophysiol 2014 Nov;125(11):2150)
  • United States Preventive Services Task Force (USPSTF) grades of recommendation (June 2007 to June 2012)
    • Grade A - USPSTF recommends the service with high certainty of substantial net benefit
    • Grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate certainty of moderate-to-substantial net benefit
    • Grade C - clinicians may provide the service to select patients depending on individual circumstances; however, only small benefit is likely for most individuals without signs or symptoms
    • Grade D - USPSTF recommends against providing the service with moderate-to-high certainty of no net benefit or harms outweighing benefits
    • Grade I - insufficient evidence to assess balance of benefits and harms
    • Reference - USPSTF Grade Definitions
  • Canadian Task Force on Preventive Health Care (CTFPHC) uses Grading of Recommendations, Assessment, Development and Evaluation (GRADE) recommendation grading system
    • strengths of recommendation
      • Strong - panel confident that desirable effects of intervention outweigh its undesirable effects (or vice versa); implies most or all individuals will be best served by recommended course of action
      • Conditional - desirable effects probably outweigh undesirable effects (or vice versa), but appreciable uncertainty exists; dependent on patient values, resources available, or setting
    • quality of evidence
      • High - panel very confident that true effect lies close to estimate of effect
      • Moderate - panel moderately confident in effect estimate; true effect likely to be close to estimate of effect, but possibility that it is substantially different
      • Low - confidence in effect estimate limited; true effect may be substantially different from estimate of effect
      • Very low - very little confidence in effect estimate; true effect likely to be substantially different from estimate of effect
    • PubMed23670157CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienneCMAJ201306111859775-82775Reference - CMAJ 2013 Jun 11;185(9):775full-text, correction in CMAJ. 2013 Sep 3;185(12):1067, editorial can be found in CMAJ 2013 Jun 11;185(9):753

Synthesized Recommendation Grading System for DynaMed Content

  • The DynaMed Team systematically monitors clinical evidence to continuously provide a synthesis of the most valid relevant evidence to support clinical decision-making (see 7-Step Evidence-Based Methodology).
  • Guideline recommendations summarized in the body of a DynaMed topic are provided with the recommendation grading system used in the original guideline(s), and allow users to quickly see where guidelines agree and where guidelines differ from each other and from the current evidence.
  • In DynaMed content, we synthesize the current evidence, current guidelines from leading authorities, and clinical expertise to provide recommendations to support clinical decision-making in the Overview & Recommendations section.
  • We use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to classify synthesized recommendations as Strong or Weak.
    • Strong recommendations are used when, based on the available evidence, clinicians (without conflicts of interest) consistently have a high degree of confidence that the desirable consequences (health benefits, decreased costs and burdens) outweigh the undesirable consequences (harms, costs, burdens).
    • Weak recommendations are used when, based on the available evidence, clinicians believe that desirable and undesirable consequences are finely balanced, or appreciable uncertainty exists about the magnitude of expected consequences (benefits and harms). Weak recommendations are used when clinicians disagree in judgments of relative benefit and harm, or have limited confidence in their judgments. Weak recommendations are also used when the range of patient values and preferences suggests that informed patients are likely to make different choices.
  • DynaMed synthesized recommendations (in the Overview & Recommendations section) are determined with a systematic methodology:
    • Recommendations are initially drafted by clinical editors (including ≥ 1 with methodological expertise and ≥ 1 with content domain expertise) aware of the best current evidence for benefits and harms, and the recommendations from guidelines.
    • Recommendations are phrased to match the strength of recommendation. Strong recommendations use "should do" phrasing, or phrasing implying an expectation to perform the recommended action for most patients. Weak recommendations use "consider" or "suggested" phrasing.
    • Recommendations are explicitly labeled as Strong recommendations or Weak recommendations when a qualified group has explicitly deliberated on making such a recommendation. Group deliberation may occur during guideline development. When group deliberation occurs through DynaMed Team-initiated groups:
      • Clinical questions will be formulated using the PICO (Population, Intervention, Comparison, Outcome) framework for all outcomes of interest specific to the recommendation to be developed.
      • Systematic searches will be conducted for any clinical questions where systematic searches were not already completed through DynaMed content development.
      • Evidence will be summarized for recommendation panel review including for each outcome, the relative importance of the outcome, the estimated effects comparing intervention and comparison, the sample size, and the overall quality rating for the body of evidence.
      • Recommendation panel members will be selected to include at least 3 members that together have sufficient clinical expertise for the subject(s) pertinent to the recommendation, methodological expertise for the evidence being considered, and experience with guideline development.
      • All recommendation panel members must disclose any potential conflicts of interest (professional, intellectual, and financial), and will not be included for the specific panel if a significant conflict exists for the recommendation in question.
      • Panel members will make Strong recommendations if and only if there is consistent agreement in a high confidence in the likelihood that desirable consequences outweigh undesirable consequences across the majority of expected patient values and preferences. Panel members will make Weak recommendations if there is limited confidence (or inconsistent assessment or dissenting opinions) that desirable consequences outweigh undesirable consequences across the majority of expected patient values and preferences. No recommendation will be made if there is insufficient confidence to make a recommendation.
      • All steps in this process (including evidence summaries which were shared with the panel, and identification of panel members) will be transparent and accessible in support of the recommendation.
    • Recommendations are verified by ≥ 1 editor with methodological expertise, not involved in recommendation drafting or development, with explicit confirmation that Strong recommendations are adequately supported.
    • Recommendations are published only after consensus is established with agreement in phrasing and strength of recommendation by all editors.
    • If consensus cannot be reached then the recommendation can be published with a notation of "dissenting commentary" and the dissenting commentary is included in the topic details.
    • If recommendations are questioned during peer review or post publication by a qualified individual, or reevaluation is warranted based on new information detected through systematic literature surveillance, the recommendation is subject to additional internal review.

DynaMed Editorial Process

  • DynaMed topics are created and maintained by the DynaMed Editorial Team and Process.
  • All editorial team members and reviewers have declared that they have no financial or other competing interests related to this topic, unless otherwise indicated.
  • DynaMed content includes Practice-Changing Updates, with support from our partners, McMaster University and F1000.

Special acknowledgements

  • Choosing Wisely Canada acknowledges dissemination of their recommendations through DynaMed Plus to reach the point of clinical decision-making.
  • The American College of Physicians (Marjorie Lazoff, MD, FACP; ACP Deputy Editor, Clinical Decision Resource) provided review in a collaborative effort to ensure DynaMed provides the most valid and clinically relevant information in internal medicine.
  • DynaMed topics are written and edited through the collaborative efforts of the above individuals. Deputy Editors, Section Editors, and Topic Editors are active in clinical or academic medical practice. Recommendations Editors are actively involved in development and/or evaluation of guidelines.
  • Editorial Team role definitions
    Topic Editors define the scope and focus of each topic by formulating a set of clinical questions and suggesting important guidelines, clinical trials, and other data to be addressed within each topic. Topic Editors also serve as consultants for the internal DynaMed Editorial Team during the writing and editing process, and review the final topic drafts prior to publication.
    Section Editors have similar responsibilities to Topic Editors but have a broader role that includes the review of multiple topics, oversight of Topic Editors, and systematic surveillance of the medical literature.
    Recommendations Editors provide explicit review of Overview and Recommendations sections to ensure that all recommendations are sound, supported, and evidence-based. This process is described in "Synthesized Recommendation Grading."
    Deputy Editors oversee DynaMed internal publishing groups. Each is responsible for all content published within that group, including supervising topic development at all stages of the writing and editing process, final review of all topics prior to publication, and direction of an internal team.

How to cite

National Library of Medicine, or "Vancouver style" (International Committee of Medical Journal Editors):

  • DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T116638, Major Depressive Disorder (MDD); [updated 2018 Nov 30, cited place cited date here]. Available from Registration and login required.


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