Last updated May 10, 2022

Management of Major Depressive Disorder (MDD)

Screening

We suggest that all patients not currently receiving treatment for depression be screened for depression. (Weak for)
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Monitoring Outcomes

For patients with MDD, we suggest using a quantitative measure of depression severity in the initial treatment planning and to monitor treatment progress at regular intervals to guide shared treatment decision making. (Weak for)
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Treatment Setting

For patients with MDD who are being treated in the primary care setting, we recommend the use of collaborative/integrated care models. (Strong for)
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For patients with MDD, there is insufficient evidence to recommend for or against the use of a team-based model in specialty mental health care settings. (Neither for or against)
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For patients with MDD, there is insufficient evidence to conclude that interventions delivered by clinicians using telehealth are either superior or inferior to in-person treatment. (Neither for or against)
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Treatment of Uncomplicated MDD

We recommend that MDD be treated with either psychotherapy or pharmacotherapy as monotherapy, based on patient preference. Factors including treatment response, severity, and chronicity may lead to other treatment strategies such as augmentation, combination treatment, switching of treatments, or use of non-first line treatments (see Recommendations 17, 18, and 20). (Strong for)
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When choosing psychotherapy to treat MDD, we suggest offering one of the following interventions (not rank ordered):
  • Acceptance and commitment therapy
  • Behavioral therapy/behavioral activation
  • Cognitive behavioral therapy
  • Interpersonal therapy
  • Mindfulness-based cognitive therapy
  • Problem-solving therapy
  • Short-term psychodynamic psychotherapy
(Weak for)
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For patients who select psychotherapy as a treatment option, we suggest offering individual or group format based on patient preference. (Weak for)
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There is insufficient evidence to recommend for or against combining components from different psychotherapy approaches. (Neither for or against)
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For patients with mild to moderate MDD, we suggest offering clinician-guided computer/internet-based cognitive behavioral therapy either as an adjunct to pharmacotherapy or as a first-line treatment, based on patient preference. (Weak for)
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When choosing an initial pharmacotherapy, or for patients who have previously responded well to pharmacotherapy, we suggest offering one of the following (not rank ordered):
  • Bupropion
  • Mirtazapine
  • A serotonin-norepinephrine reuptake inhibitor
  • Trazodone, vilazodone, or vortioxetine
  • A selective serotonin reuptake inhibitor
(Weak for)
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When choosing an initial pharmacotherapy, we suggest against using:
  • Esketamine
  • Ketamine
  • Monoamine oxidase inhibitors
  • Nefazodone
  • Tricyclic antidepressants
(Weak against)
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There is insufficient evidence to recommend for or against pharmacogenetic testing to help guide the selection of antidepressants. (Neither for or against)
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For patients with mild to moderate MDD who decline pharmacotherapy and who decline or cannot access first-line evidence-based psychotherapies (either in-person or virtually), we suggest considering non-directive supportive therapy. (Weak for)
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Treatment of MDD that is Severe or has a Partial or Limited Response to Initial Treatment

We suggest offering a combination of pharmacotherapy and evidence-based psychotherapy for the treatment of patients with MDD characterized as:
  • Severe (e.g., PHQ-9 >20)
  • Persistent major depressive disorder (duration greater than two years)
  • Recurrent (with two or more episodes)
(Weak for)
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For patients with MDD who have demonstrated partial or no response to an adequate trial of initial pharmacotherapy, we suggest (not rank ordered):
  • Switching to another antidepressant (including TCAs, MAOIs, or those in Recommendation 12)
  • Switching to psychotherapy
  • Augmenting with a psychotherapy
  • Augmenting with a second-generation antipsychotic
(Weak for)
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For patients who have demonstrated partial or no response to two or more adequate pharmacologic treatment trials, we suggest offering repetitive transcranial magnetic stimulation for treatment. (Weak for)
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There is insufficient evidence to recommend for or against theta-burst stimulation for the treatment of MDD. (Neither for or against)
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For patients with MDD who have not responded to several adequate pharmacologic trials, we suggest ketamine or esketamine as an option for augmentation. (Weak for)
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We recommend offering electroconvulsive therapy (ECT) with or without psychotherapy in patients with severe MDD and any of the following conditions:
  • Catatonia
  • Psychotic depression
  • Severe suicidality
  • A history of a good response to ECT
  • Need for rapid, definitive treatment response on either medical or psychiatric grounds
  • The risks associated with other treatments are greater than the risks of ECT for this specific patient (i.e., co-occurring medical conditions make ECT the safest MDD treatment alternative)
  • A history of a poor response or intolerable side effects to multiple antidepressants
(Strong for)
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Relapse Prevention/Continuation Phase - All Severities and Complexities

For patients with MDD who achieve remission with antidepressant medication, we recommend continuation of antidepressants at the therapeutic dose for at least six months to decrease risk of relapse. (Strong for)
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For patients with MDD at high risk for relapse or recurrence (e.g., two or more prior episodes, unstable remission status), we suggest offering a course of cognitive behavioral therapy, interpersonal therapy, or mindfulness-based cognitive therapy during the continuation phase of treatment (i.e., after remission is achieved) to reduce the risk of subsequent relapse/recurrence. The evidence does not support recommending one of these three evidence-based psychotherapies over another. (Weak for)
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Recommendations for Specific Populations

For individuals with mild to moderate MDD who are breastfeeding or pregnant, we recommend offering an evidence-based psychotherapy as a first-line treatment (see Recommendation 7). In patients with a history of MDD prior to pregnancy who responded to antidepressant medications, and are currently stable on pharmacotherapy, weigh risk/benefit balance to both mother and fetus in treatment decisions. (Strong for)
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For older adults (≥65 years) with mild to moderate MDD, we suggest offering a first-line psychotherapy (see Recommendation 7). Patient preference and the additional safety risks of pharmacotherapy should be considered when making this decision. (Weak for)
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For patients with mild to moderate MDD and significant relationship distress, we suggest offering couples-focused therapy. (Weak for)
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For patients with mild to moderate MDD with or without a seasonal pattern (formerly seasonal affective disorder), we suggest offering light therapy. (Weak for)
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For patients with MDD, we suggest exercise (e.g., yoga, tai chi, qi gong, resistance, aerobics) as an adjunct. (Weak for)
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Self-help, Complementary, and Alternative Treatments

For patients with MDD, we suggest exercise (e.g., yoga, tai chi, qi gong, resistance, aerobics) as an adjunct. (Weak for)
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For patients with MDD, we suggest CBT-based bibliotherapy as an adjunct to pharmacotherapy or psychotherapy, or as an alternative when patients are unwilling or unable to engage in other treatments. (Weak for)
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For patients with mild MDD who are not pregnant or breastfeeding and who prefer herbal treatments to first-line psychotherapy or pharmacotherapy, we suggest standardized extract of St. John’s wort as monotherapy. (Weak for)
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For patients with MDD, there is insufficient evidence to recommend for or against acupuncture as an adjunct. (Neither for or against)
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For patients with MDD, there is insufficient evidence to recommend for or against the addition of biofeedback. (Neither for or against)
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For patients with MDD, there is insufficient evidence for or against the use of meditation as an adjunct. (Neither for or against)
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Other Treatments with a Recommendation Against Use

For patients with MDD, we suggest against using vagus nerve stimulation outside of a research setting. (Weak against)
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For patients with MDD, we recommend against using deep brain stimulation outside of a research setting. (Strong against)
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Given the limited information on the safety and efficacy of psilocybin, MDMA, cannabis, and other unapproved pharmacologic treatments, we recommend against using these agents for MDD outside of a research setting. (Strong against)
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We suggest against using omega-3 fatty acids or vitamin D for treatment of MDD. (Weak against)
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Algorithms

Module A: Initial Assessment and Treatment


Module B: Advanced Care Management


Sidebars

Sidebar 1: Risk Assessment and Work-up

  • Functional status, medical history, past treatment history, and relevant family history
  • Consider administration of PHQ-9
  • Evaluate for suicidal and homicidal ideation and history of suicide attempts, and consult the VA/DoD Assessment and Management of Patients at Risk for Suicide CPG, as appropriate
  • Rule out depression secondary to other causes (e.g., hypothyroidism, vitamin B-12 deficiency, syphilis, pain, chronic disease)
  • Incorporate MBC principles in the initial assessment

Sidebar 2: DSM-5 Criteria

  • Criterion A: Five or more of the following symptoms present during the same 2-week period; at least one of the symptoms is either (1) depressed mood or (2) loss of interest/pleasure:
    • Depressed mood most of the day, nearly every day
    • Markedly diminished interest or pleasure in almost all activities most of the day, nearly every day
    • Significant weight loss when not dieting or weight gain
    • Insomnia or hypersomnia nearly every day
    • Psychomotor agitation or retardation nearly every day
    • Fatigue or loss of energy every day
    • Feelings of worthlessness or excessive inappropriate guilt
    • Diminished ability to think, concentrate, or indecisiveness, nearly every day
    • Recurrent thought of death, recurrent suicidal ideation without a specific plan, a suicide attempt or a specific plan for committing suicide
  • Criterion B: The symptoms cause significant distress or functional impairment
  • Criterion C: The episode is not attributable to the physiological effects of a substance or another medical condition

Sidebar 3: Factors to be Considered in Treatment Choice

  • Prior treatment response
  • Severity (e.g., PHQ-9)
  • Chronicity
  • Comorbidity (e.g., substance use, medical conditions, other psychiatric conditions)
  • Suicide risk·
  • Psychosis
  • Catatonic or melancholic features
  • Functional status
  • Tolerability of prior treatments

Sidebar 4: Considerations in Treatment of Uncomplicated MDD

  • Consider collaborative/integrated care in primary care for appropriate patients
  • For initial treatment, select pharmacotherapy or psychotherapy based on SDM
  • If previous treatment was successful, consider restarting this approach
  • Based on patient preferences, consider the following as an adjunct to psychotherapy or pharmacotherapy (self-help with exercise [e.g., yoga, tai chi, qi gong, resistance, aerobics], patient education, light therapy, and bibliotherapy) or as an alternative if first-line treatments are not acceptable and/or available
  • Include patient characteristics (e.g., treatment of co-occurring conditions, cultural factors, social determinants, patients who are pregnant, geriatric patients) in SDM

Sidebar 5: Treatment Options for Patients Who Have Not Responded to Adequate Treatment Trialsa

Consider the following treatment options:
  • Consider other pharmacotherapy options (e.g., MAOIs, TCAs) (see Recommendation 16)
  • ECT (see Recommendation 20)
  • rTMS (see Recommendation 17)
  • Ketamine/esketamine (see Recommendation 19)
a: Patients who have demonstrated partial or no response to initial pharmacologic monotherapy (maximized) after a minimum of four to six weeks of treatment

Sidebar 6: Treatment Options for Switching or Augmenting

Consider the following treatment options:
  • Adding psychotherapy or an antidepressant
  • Switching to a different treatment (e.g., switch between psychotherapy or pharmacotherapy, switch to a different focus of psychotherapy or different antidepressant)
  • Augmenting with a different class of medication (e.g., adding an SGA)

Sidebar 7: Treatment Options During Remission

Consider the following treatment options:
  • For patients treated with antidepressants, consider continuation at the therapeutic dose for at least six months
  • For patients with a high risk of relapse, regardless of prior treatment received, consider offering a course of CBT

Recommendation Grading

Overview

Title

Management of Major Depressive Disorder (MDD)

Authoring Organization

Publication Month/Year

April 26, 2022

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Male, Female, Adult, Older adult

Health Care Settings

Ambulatory

Intended Users

Addiction treatment specialist, psychologist, social worker, nurse, nurse practitioner, physician, physician assistant

Scope

Counseling, Diagnosis, Assessment and screening, Treatment, Management

Diseases/Conditions (MeSH)

D003865 - Depressive Disorder, Major

Keywords

depression, major depressive disorder