Trusted medical expertise in seconds.

Access 1,000+ clinical and preclinical articles. Find answers fast with the high-powered search feature and clinical tools.

Try free for 5 days
Evidence-based content, created and peer-reviewed by physicians. Read the disclaimer.

Major depressive disorder

Last updated: June 2, 2021

Summarytoggle arrow icon

Major depressive disorder (MDD) is an episodic mood disorder primarily characterized by depressed mood and anhedonia lasting for at least 2 weeks. Women have a higher risk of developing MDD than men. The peak age of onset is the 3rd decade. The etiology is multifactorial, including both biological and psychological factors. Reduced levels of neurotransmitters (serotonin, noradrenaline, dopamine) are believed to be the pathophysiological basis in most cases. Other symptoms of MDD include sleep disturbance, loss of appetite, and thoughts of suicide. There are various subtypes of MDD characterized by additional symptoms or occurrence in specific conditions, such as atypical depression (additionally characterized by, e.g., weight gain and increased appetite), psychotic depression (with additional psychotic features such as hallucinations and delusions), and peripartum depression (which occurs during or shortly after pregnancy). In elderly patients, MDD can also manifest with memory loss and other symptoms seen in dementia, referred to as pseudodementia. Treatment is multifaceted and often requires pharmacotherapy, psychotherapy, and lifestyle changes. First-line treatment mainly consists of SSRIs (e.g., citalopram) and SNRIs (e.g., venlafaxine).

  • Sex: >
  • Lifetime prevalence: 10–20% [1]
  • Age of onset: 3rd decade of life

References: [2]

Epidemiological data refers to the US, unless otherwise specified.


Diagnostic criteria for major depressive disorder (according to DSM-5)

Five or more of the nine symptoms listed below, for at least 2 weeks, with at least one of the symptoms being depressed mood or anhedonia

  1. Depressed mood for most of the day, almost every day (in children, can manifest with irritability)
  2. Sleep disturbance (insomnia or hypersomnia)
  3. Anhedonia
  4. Feelings of worthlessness or disproportionate guilt
  5. Fatigue or loss of energy
  6. Diminished concentration, cognition, and ability to make decisions (pseudodementia)
  7. Weight change due to appetite change
  8. Psychomotor changes (observed by others)
  9. Suicidal ideation

There is clinically significant distress or impaired functioning in important areas of life (e.g., work, school).


Symptoms are not due to the effects of psychoactive substances or organic disease.


Symptoms are not due to another psychiatric disorder.


There is no history of a manic or hypomanic episode.

A to E refer to a single depressive episode. Depressive episodes are considered recurrent when there is a gap of at least two months between episodes during which the criteria for MDD are not met.

The presence of symptoms from criteria A to C constitutes a major depressive episode. For a diagnosis of major depressive disorder, the following two criteria must also be present: the symptoms are not due to another psychiatric disorder AND there is no history of a manic or hypomanic episode.

DICES GAPS” (D or I must be present for diagnosis): Depressed mood (can present as irritability in children), Interest loss (anhedonia), Concentration (poor concentration or difficulty making decisions), Energy (low energy or fatigue), Sleep (insomnia or hypersomnia), Guilt (low self-esteem), Appetite (decreased appetite or overeating), Psychomotor agitation or retardation, and Suicidal ideation are the features of the major depressive disorder.


Major depressive disorder with seasonal pattern (seasonal affective disorder, winter depression)

  • Occurs in a yearly, season-specific pattern (commonly in fall or winter)
  • Symptoms must be present for ≥ 2 consecutive years and for the majority of years in a lifetime.
  • Patients present with typical symptoms of MDD alongside atypical ones, such as weight gain and requiring more sleep.
  • Light therapy has been shown to improve symptoms.

Major depressive disorder with atypical features

  • Most common variant of MDD
  • Mood reactivity: brightening of mood in response to positive events, which is usually not the case in classical MDD
  • Two or more of the following features are present:
    • Increased appetite or over-eating
    • Hypersomnia
    • Leaden paralysis (legs and arms feel heavy)
    • Interpersonal rejection sensitivity that leads to social and occupational impairment
  • Treatment
    • 1st line: CBT with or without SSRIs
    • MAO inhibitors can be effective although not commonly prescribed due to their side effects.

Major depressive disorder with psychotic features

Persistent depressive disorder (dysthymia) [6]

  • Depressed mood in addition to ≥ 2 of the following symptoms
    • Poor appetite or overeating
    • Insomnia or hypersomnia
    • Low energy or fatigue
    • Low self-esteem
    • Poor concentration or difficulty making decisions
    • Feelings of hopelessness
  • The symptoms are present for most of the day, and for the majority of days, for ≥ 2 years in adults.
  • In children and adolescents, symptoms present for ≥ 1 year.
  • Periods of remissions should not last more than 2 consecutive months.
  • Unlike in MDD, thoughts of suicide, loss of interest, and psychomotor agitation or retardation are not typical features of persistent depressive disorder; therefore, dysthymia is often regarded as a milder form of MDD.
  • In case all the criteria for MDD are met, the diagnosis should be changed to MDD.

HE'S 2 SAD: Hopelessness, Energy loss or fatigue, Self-esteem is low, 2 years minimum of depressed mood, Sleep is increased or decreased (insomnia or hypersomnia), Appetite is increased or decreased, Decision-making and/or concentration is impaired.


In pediatric patients, remember to first rule out organic causes, which are the most common cause of depression in this population.


Overview [6]

Overview of depressive disorders
Condition Timing Diagnostic features
Major depressive disorder
  • Symptoms are present for at least 2 weeks.
Persistent depressive disorder (dysthymia)
  • Symptoms are present for ≥ 2 years.
  • Depressed mood, in addition to the presence of ≥ 2 of the following symptoms:
    • Poor appetite or overeating
    • Insomnia or hypersomnia
    • Low energy or fatigue
    • Low self-esteem
    • Poor concentration or difficulty making decisions
    • Feelings of hopelessness
Depression with seasonal pattern
  • Typically occurs in the fall or winter
  • Symptoms are the same as those in MDD.
Minor depressive disorder
  • Symptoms are present during a 2-week period for < 2 years.
  • Variable
Mood disorder due to another medical condition
  • Variable
  • Depressive symptoms are explained by organic diseases, such as:
    • Hormonal imbalances
    • CNS disorders
    • Cancer
Substance-induced depressive disorder
  • Variable
  • Depressive symptoms in the setting of substance use, e.g., one of the following:
Disruptive mood dysregulation disorder (DMDD)
  • Symptoms are present for ≥ 12 months.
  • Severe temper outbursts (verbal or behavioral) ≥ 3 times/week
  • Irritability or anger in between outbursts
  • Diagnosis can only be established in children under 18 years of age.
Adjustment disorder
  • Symptoms last ≤ 6 months following termination of the stressor
  • Inappropriate subjective distress (not in relation to the nature of the event)
  • Impaired functioning

Grief [6][15]

  • Definition: normal reaction to the loss or death of a loved one
  • Kübler-Ross model: a model describing 5 stages of emotional changes an individual experiences in grief (denial, anger, bargaining, depression, and acceptance; can manifest in any order)
  • Features (often occurs in waves)
  • Duration: vary significantly among different cultural groups (commonly resolves within 6 to 12 months)

Persistent complex bereavement disorder [16]

  • Definition: a pathological grieving process
  • Diagnostic features
    • Persistent preoccupation with the death of someone close
    • Clinically significant yearning for the deceased that persists beyond 12 months (adults) or 6 months (children)
    • The disturbance impairs social and/or occupational functioning.
    • Suicidal ideation can be present (as opposed to grief).
    • Criteria for a major depressive episode can be met during the course of the disorder.
    • Difficulty adjusting to life without the deceased
    • Yearning that is inconsistent with cultural norms
  • Additional features

Patients who have experienced significant loss due to serious illness, disability, the death of a loved one, or a natural disaster may present with symptoms that resemble a depressive episode. These patients should be carefully assessed to see whether they fulfill the diagnostic criteria for MDD.

Depressive disorder due to another medical condition [6]

Substance/medication-induced depressive disorder [6]

Disruptive mood dysregulation disorder (DMDD)

  • A disorder characterized by persistent irritability and episodes of extreme behavioral dyscontrol; in children under 18 years of age.
  • Can manifest with severe temper outbursts (verbal or behavioral) ≥ 3 times/week, sometimes with severe, persistent irritability in between outbursts
  • Duration of symptoms: ≥ 12 months
  • Prognosis: Individuals with DMDD are at increased risk of developing major depressive disorder; or anxiety disorders in adulthood.

References: [6][16][17][18][19][20]

The differential diagnoses listed here are not exhaustive.

Approach [21]

  • For initial treatment of adult patients, pharmacotherapy and psychotherapy can be used alone or in combination.
  • For nonresponders to initial pharmacotherapy, consider one of the following:
  • Therapy should be continued until the patient is in remission.
  • Patients with ≥ 3 prior major depressive episodes or chronic MDD (≥ 2 years) should receive maintenance therapy (see below).


MAO inhibitors should not be combined with SSRIs/SNRIs or tricyclic antidepressants, because this may lead to serotonin syndrome.


Other measures

  • Lifestyle changes (aerobic exercise, nutrition, sleep hygiene, social support, stress reduction)
  • Light therapy
  • Repetitive transcranial magnetic stimulation (rTMS)
  • Sleep deprivation therapy
    • Approach: complete or partial (second half of the night) sleep deprivation
    • Effect: A short-term antidepressive effect is achieved on the same day.
    • Goal: restoration of physiological sleep architecture
    • Implementation: 3 cycles/week as follows
      • Staying awake from 7 a.m. of day 1 to 7 p.m. of day 2
      • Recovery sleep from 7 p.m. of day 2 to 7 a.m. of day 3
      • Sleep deprivation should be repeated again as explained above
      • Short sleep phases in between diminish the antidepressive effect and hence should be avoided
      • Sleep-phase-advance (follows a sleep deprivation phase)
    • Complications
  • Electroconvulsive therapy: reserved for severe, refractory, and/or psychotic depression


Peripartum mood disturbances

Differential diagnosis of peripartum mood disturbances
Features Postpartum blues Major depressive disorder with peripartum onset (postpartum depression) Postpartum psychosis
  • Typically develops within 1 week of delivery
  • Symptoms typically resolve spontaneously within 2 weeks.
  • Typically develops during pregnancy or in the 4 weeks following delivery
  • Symptoms must be present for at least 2 weeks to confirm the diagnosis.
  • Typically develops within 2 weeks of delivery
  • Onset is sudden
Clinical findings
  • Common symptoms include depressed mood, crying outbursts, lethargy
  • Somatic symptoms (e.g., changes in sleep and energy level) may overlap with physiological changes usually observed in postpartum women.
  • A minimum number of symptoms is not required to confirm the diagnosis.
  • Includes the typical symptoms seen in major depressive disorder (SIGECAPS)
  • A minimum of 5 symptoms is required to confirm the diagnosis.
  • Most commonly part of a unipolar disorder, but the presence of a bipolar disorder must be excluded in all cases

Depression in palliative patients

Depression in children and adolescents

Interested in the newest medical research, distilled down to just one minute? Sign up for the One-Minute Telegram in “Tips and links” below.

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM–5). undefined. 2013 . doi: 10.1176/appi.books.9780890425596 . | Open in Read by QxMD
  2. Duval F, Mokrani MC, Crocq MA et al.. Dopaminergic function and the cortisol response to dexamethasone in psychotic depression. Prog Neuropsychopharmacol Biol Psychiatry.. 2000; 24 (2): p.207-225.
  3. Avery D, Roy-Byrne PP, Solomon D. Seasonal Affective Disorder: Epidemiology, Clinical Features, Assessment, and Diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. updated: March 21, 2017. Accessed: May 26, 2017.
  4. Lyness J. Unipolar depression in adults: Assessment and diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. updated: September 13, 2016. Accessed: May 26, 2017.
  5. Rothschild AJ, Roy-Byrne PP, Solomon D. Unipolar Major Depression with Psychotic Features: Epidemiology, Clinical Features, Assessment, and Diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. updated: July 30, 2016. Accessed: May 26, 2017.
  6. Viguera A, Roy-Byrne PP, Lockwood CJ, Solomon D. Postpartum Unipolar Major Depression: Epidemiology, Clinical Features, Assessment, and Diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. updated: November 9, 2016. Accessed: May 26, 2017.
  7. Hasin DS, Sarvet AL, Meyers JL, et al. Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry. 2018; 75 (4): p.336. doi: 10.1001/jamapsychiatry.2017.4602 . | Open in Read by QxMD
  8. Kessler RC, Berglund P, Demler O. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62 (6): p.593-602. doi: 10.1001/archpsyc.62.6.593 . | Open in Read by QxMD
  9. Hasler G. Pathophysiology of depression: Do we have any solid evidence of interest to clinicans?. World Psychiatry. 2010; 9 (3): p.155-161.
  10. Siegel GJ, Agranoff BW, Albers RW et al.. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Lippincott-Raven ; 1999
  11. Murphy MJ, Peterson MJ. Sleep Disturbances in Depression. Sleep Medicine Clinics. 2015; 10 (1): p.17-23. doi: 10.1016/j.jsmc.2014.11.009 . | Open in Read by QxMD
  12. Giardino AP, Pataki C. Pediatric Depression. Pediatric Depression. New York, NY: WebMD. Updated: March 15, 2016. Accessed: May 26, 2017.
  13. Weeks GR. Promoting Change Through Paradoxical Therapy. Routledge ; 2013
  14. Depression and Sleep. . Accessed: May 26, 2017.
  15. Shear MK, Reynolds III CF, Simon NM, Zisook S. Grief and bereavement in adults: Clinical features. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. updated: November 13, 2017. Accessed: December 3, 2017.
  16. Jordan AH, Litz BT. Prolonged grief disorder: Diagnostic, assessment, and treatment considerations. Prof Psychol Res Pr. 2014; 45 (3): p.180-187. doi: 10.1037/a0036836 . | Open in Read by QxMD
  17. Using the DSM-5 in the Differential Diagnosis of Depression.
  18. Taylor R. Family Medicine: Principles and Practice. Springer Science & Business Media ; 2002
  19. Andrade C. Ketamine for depression, 1: clinical summary of issues related to efficacy, adverse effects, and mechanism of action.. J Clin Psychiatry. 2017; 78 (4): p.e415-e419. doi: 10.4088/JCP.17f11567 . | Open in Read by QxMD
  20. Beers MH, Passman LJ. Antihypertensive medications and depression.. Drugs. 1990; 40 (6): p.792-799.
  21. Kennedy SH, Lam RW, McIntyre RS, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder: Section 3. Pharmacological Treatments.. Can J Psychiatry. 2016; 61 (9): p.540-60. doi: 10.1177/0706743716659417 . | Open in Read by QxMD
  22. Machado-Vieira R, Baumann J, Wheeler-Castillo C, et al. The Timing of Antidepressant Effects: A Comparison of Diverse Pharmacological and Somatic Treatments. Pharmaceuticals. 2010; 3 (1): p.19-41. doi: 10.3390/ph3010019 . | Open in Read by QxMD
  23. Practice Guidelines for the Treatment of Patients With Major Depressive Disorder. Updated: October 1, 2010. Accessed: October 25, 2020.
  24. Mohamed S, Johnson GR, Chen P, et al. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment. JAMA. 2017; 318 (2): p.132. doi: 10.1001/jama.2017.8036 . | Open in Read by QxMD
  25. Connolly KR, Thase ME. If at First You Donʼt Succeed: a review of the evidence for antidepressant augmentation, combination and switching strategies. Drugs. 2011; 71 (1): p.43-64. doi: 10.2165/11587620-000000000-00000 . | Open in Read by QxMD
  26. Ganti L, Kaufman MS, Blitzstein SM. First Aid for the Psychiatry Clerkship. McGraw Hill Professional ; 2016
  27. Thase M, Connolly R, Roy-Byrne PP, Solomon D. Unipolar Depression in Adults: Treatment of Resistant Depression. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. updated: July 20, 2016. Accessed: May 27, 2017.
  28. Questions and Answers about the NIMH Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study — All Medication Levels. Updated: November 1, 2006. Accessed: May 27, 2017.
  29. Kim DR, Epperson CN, Weiss AR, Wisner KL. Pharmacotherapy of postpartum depression: an update. Expert Opin Pharmacother. 2014; 15 (9): p.1223-1234. doi: 10.1517/14656566.2014.911842 . | Open in Read by QxMD
  30. Marangoni C, De Chiara L, Faedda GL. Bipolar disorder and ADHD: comorbidity and diagnostic distinctions.. Curr Psychiatry Rep. 2015; 17 (8): p.604. doi: 10.1007/s11920-015-0604-y . | Open in Read by QxMD
  31. Clinical Practice Guideline for the Treatment of Depression Across Three Age Cohorts. Updated: February 16, 2019. Accessed: November 1, 2019.
  32. Eugene T, Briscoe D, Reddy B, Britton B. Case Files Family Medicine, Second Edition. McGraw-Hill Medical ; 2009 : p. 200-202
  33. UpToDate. DSM-5 diagnostic criteria for a major depressive episode. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. Accessed: May 26, 2017.
  34. Hasler G. Pathophysiology of depression: do we have any solid evidence of interest to clinicians?. World Psychiatry. 2010; 9 (3): p.155-61.