Major Depressive Disorder

Traci Speed, M.D., Ph.D., J. Raymond DePaulo, Jr., M.D.


  • A common, chronic, treatable mood disorder that typically follows a remitting and relapsing course of depressive episodes.
  • Depressive episodes are characterized by:
    • Persistent low mood
    • Decreased self-attitude—a distinctly lower sense of self-esteem and self-confidence compared to usual for the individual
      • In the most severe cases, these manifest as guilt and hopelessness.
    • Decreased mental and physical energy (vital sense), which reduces one’s daily functioning


  • Lifetime prevalence for women, 10-25%; men, 5-12%[1]
    • The wide variation in prevalences is of concern.
      • Higher prevalence estimates with questionnaire- or criterion-based interviews (such as the SCID) administered either in person or by phone (especially in recent years)
      • Lower prevalence estimates with clinician evaluations (usually following a symptomatic screening procedure)
      • There is no widely accepted method to divide cases meeting screening criteria into groups of major depressive disorder (MDD) and non-MDD depression (recurrence, number of symptoms, duration of episodes, and treatment-seeking are often cited to indicate robustness of the diagnosis of MDD).
  • Rates are equal for pre-pubescent boys and girls; rates in women following menarche are twice that of men.
  • Age of onset is typically in early twenties, but earlier and later onset occur.
  • Common psychiatric comorbidities include substance abuse, anxiety disorders, panic disorders, and personality disorders.
  • Increased risk if female; Native American; middle-aged; widowed, separated, or divorced; or low-income[1]
  • Decreased risk if Asian, Hispanic, or black[1]
  • High comorbidity with anxiety disorder, substance use disorders, general medical conditions
  • Major depression has a familial component; individuals with a first-degree relative with major depression have increased risk of developing bipolar disorder and major depression.


Clinical Presentation

  • Major depressive episodes are characterized by the triad of low mood, self-attitude, and vital sense.[2]
    • Low mood may manifest as persistent sadness, anxiety, apathy, irritability, or emotional numbness.
      • Most often a combination of these plus anhedonia
    • Low self-attitude may manifest as self-blame, self-deprecation, guilt, lack of self-confidence about the future, or hopelessness.
    • Low vital sense may manifest as decreased attentiveness to work tasks, decreased energy and/or concentration, indecisiveness, or physical slowing.
  • Helpful but less consistent signs include changes in sleep patterns (especially early a.m. awakening) or appetite (overeating or undereating), reduced libido, and diurnal variation in symptoms (with early a.m. worsening), recurrent thoughts of death, suicidality.
  • To qualify as a major depressive episode the symptoms must cause distress or impairment in functioning and not be due to alcohol, another substance, or a general medical condition.
  • Presence of psychotic features (e.g. hallucinations or delusions) with major depressive episodes reflects severe disease and is a poor prognostic indicator.
    • Mood-congruent psychotic symptoms: delusions of guilt, worthlessness, bodily disease, or impending disaster; or condemnatory auditory hallucinations
    • Mood-incongruent psychotic symptoms: persecutory or self-referential delusions, or hallucinations without affective content
  • Most patients return to normal mood between episodes, although around 20% of people have residual mood symptoms or chronic depression.
  • Episodes can be triggered by stress, loss (e.g. death of loved one, separation by divorce, unemployment), sleep deprivation, drug and alcohol use.

Tests and Procedures

  • Depression is a clinical syndromal diagnosis based on history and mental status examination. To date, there is no valid diagnostic laboratory test.
  • Tests to assess etiologic factors include CBC, BMP, LFTs, TSH, B12, folate, Vitamin D, RPR, blood alcohol level, urinalysis, and urine toxicology.
  • The US Preventive Services Task Force recommends screening adults for depression at general medical visits when staff-assisted depression care supports are in place for better diagnosis and treatment.
    • Screening for suicide potential has been shown to be of little or no value.[3]
  • Screening is useful to increase detection but is neither highly sensitive nor specific.

Differential Diagnosis



  • A combination of medication and individual psychotherapy is usually best.
  • Psychoeducation and supportive therapy can be administered in the acute phase of severe MDD. The focus is support and education. Extremely severe depression makes any formal psychotherapy very difficult, until some improvement in concentration and hopefulness develops.
  • Family involvement and supervision can be very helpful at times (to prevent a suicide attempt, non-suicidal self injury, substance use, and disordered eating behavior). Family participation can be very helpful to provide critical history, as well as to help patients remember and interpret what clinicians have told them or instructed them to do.
  • Phases of depressive illness:
    • Acute: inform the patient of the diagnosis; educate, support, and assure safety
      • Hospitalization is needed if there are life-threatening medical problems, psychosis, or moderate-to-high risk of suicide.
      • In more severe cases, medications are usually required.
      • For the most severe cases, ECT has a high probability of success.
      • Education for the family should emphasize that the patient’s mood symptoms are due to a treatable illness, that the patient must continue taking his/her medication and come to appointments, and that suicide is not acceptable.
    • Improvement: serial mental status assessments, support, identification of stressors and relationship issues (important in all stages of illness)
      • Maintain effective medical treatment.
      • Carefully reduce purely symptomatic medications (e.g., benzodiazepines).
    • Recovery: long-term medication management (at least 6-12 months)
      • More intensive psychotherapies are more effective.
      • Preventive strategies to reduce the likelihood and severity of future episodes.


  • Remission rates are low (~30%), but ~60% of moderate and severe cases of MDD will improve significantly with antidepressant treatment.
  • Antidepressant choice depends on history of response, family history of response, tolerability, adverse effects, and likelihood of adherence.
    • Clinical trials show little difference in efficacy or tolerability among SSRIs and other classes of antidepressants.
    • SSRIs are first-line choice due to minimal side effect profile.
      • In order to "fail" an anti-depressant trial, a patient must remain on a therapeutic dose of anti-depressant for 6-8 weeks.
      • Failure of one SSRI, does not mean failure of all SSRIs, so patient should trial another SSRI.
      • If a patient fails two SSRIs, the next choice can be an SNRI, TCA, or adjunct anti-depressant (e.g. buproprion or SNRI) or augmenting agent.
      • Combination therapy with a reuptake inhibitor and an antagonist of presynaptic α2-autoreceptors may be superior to monotherapy, and may be beneficial as first-line therapy for severe depression or treatment nonresponders.[6]
    • Fluoxetine may be safer in children and adolescents, and is the only SSRI consistently show to be effective in this population.
    • Mood symptoms should be carefully monitored as anti-depressants can trigger manic episodes.
    • Mood stabilizers can augment the effects of antidepressants and help prevent a switch to mania.
    • Antipsychotics are combined with antidepressants to treat psychotic depression and treatment-resistant depression. One should be cautious about long-term use and dose should be decreased as permitted.
    • Benzodiazepines can be used during the acute phase for anxiety and insomnia. Avoid in elderly due to risk of delirium.
  • To improve medication compliance with an outpatient, have a follow-up visit one week after starting, ask about side effects, and re-educate about the time required for a valid therapeutic trial (8 weeks).
  • Over 70% of patients who stop taking anti-depressant in 5 weeks or fewer after they become symptom-free will relapse, so careful monitoring of medication compliance is important.


  • Supportive therapy is important and well-received in severe, acute phases of illness.
  • CBT, interpersonal therapy, and problem-solving therapy are all helpful and delay relapse for mild and moderate depression.
  • Psychotherapy alone is not first-line treatment for severe depression, or in psychotic or bipolar forms.


  • Remission rates with ECT are 60-80% in severe MDD.
  • ECT can be first-line treatment for severe MDD with psychosis, psychomotor retardation, or catatonic features; medication resistance; or pregnancy.
  • Supplemental treatments include regular sleep, bright light therapy, physical activity, healthy eating habits, no alcohol or drugs, distracting activities, and a regular schedule.


  • PCPs manage the majority of patients with MDD.
    • A UK study showed that PCPs identified depression in almost half of cases.
    • 35% to 50% of MDD cases go unrecognized; in addition, MDD is often untreated when diagnosed.[7]
    • MDD overdiagnosis and overtreatment are also common in community settings.[8]
  • Referral to a psychiatrist is indicated if patient requires adjunct anti-depressant treatment, has co-morbid psychiatric diagnoses including substance abuse, anxiety, panic attacks, or psychotic features such as hallucinations or delusions, or has thoughts of death or harming others.
  • A person who is actively suicidal should be referred to the closest emergency department for hospitalization.


  • Individual psychotherapy needs will change as the patient improves.
  • There is an increased risk of suicide in first 30 days, and also in first year following hospitalization for MDD.


  • MDD is associated with other specific psychiatric disorders, notably substance dependence, panic and generalized anxiety disorders, and several personality disorders. If present, these will need to be addressed during treatment.
  • 90% of completed suicides have a diagnosed psychiatric disorder; 70-80% meet criteria for MDD; and comorbid alcohol use disorder is common (15-30%).
    • If the patient has long-term overuse of addictive substances, specific treatment is usually required.
  • Elderly patients often manifest depression as somatic symptoms (e.g. fatigue, abdominal pain, headache, confusion, memory loss).
  • Increased prevalence estimates of MDD (28% increase) and anxiety disorders (26% increase) during the early phase of the COVID-19 pandemic may be inflated. Robust trauma research has shown that resilience or recovery typically follow negative life events (e.g., bereavement or disaster exposure).[9]


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  2. DePaulo, Jr., J.R, & and Ablow, K. (1989). In McGraw-Hill (Ed.), How to cope with depression. A complete guide for you and your family. Ballantine Books.
  3. Gilbody S, Sheldon T, House A. Screening and case-finding instruments for depression: a meta-analysis. CMAJ. 2008;178(8):997-1003.  [PMID:18390942]
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  6. Henssler J, Alexander D, Schwarzer G, et al. Combining Antidepressants vs Antidepressant Monotherapy for Treatment of Patients With Acute Depression: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2022.  [PMID:35171215]
  7. Mitchell AJ, Vaze A, Rao S. Clinical diagnosis of depression in primary care: a meta-analysis. Lancet. 2009;374(9690):609-19.  [PMID:19640579]
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  9. Daly M, Robinson E. Depression and anxiety during COVID-19. Lancet. 2022;399(10324):518.  [PMID:35123689]
  10. DePaulo JR and Horowitz L, Understanding Depression, Wiley Press, 2002.
  11. DeRubeis RJ, Zajecka J, Shelton RC, et al. Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral Therapy: Phase 2 of a 2-Phase Randomized Clinical Trial. JAMA Psychiatry. 2020;77(3):237-245.  [PMID:31799993]
  12. Delgadillo J, Ali S, Fleck K, et al. Stratified Care vs Stepped Care for Depression: A Cluster Randomized Clinical Trial. JAMA Psychiatry. 2022;79(2):101-108.  [PMID:34878526]
  13. Folstein MF, Romanoski AJ, Nestadt G, et al. Brief report on the clinical reappraisal of the Diagnostic Interview Schedule carried out at the Johns Hopkins site of the Epidemiological Catchment Area Program of the NIMH. Psychol Med. 1985;15(4):809-14.  [PMID:4080884]
  14. Mondimore FJ, Depression: The Mood Disease, 4th Edition, Johns Hopkins Press, 2013
  15. O'Connor EA, Whitlock EP, Beil TL, et al. Screening for depression in adult patients in primary care settings: a systematic evidence review. Ann Intern Med. 2009;151(11):793-803.  [PMID:19949145]
Last updated: May 8, 2022