• Clinical science

Major depressive disorder (Unipolar depressive disorder)


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.



Clinical features

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)
    • Agitation
    • Retardation
  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.


Subtypes and variants

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.


Differential diagnoses

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.
  • 2–4 diagnostic criteria for major depressive disorder (must include depressed mood or loss of interest)
  • Variable
  • Identifiable loss or death of a loved one
  • No functional impairment
  • Symptoms typically occur in waves.
  • Hallucinations of deceased loved one
  • No suicidal ideation
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 [15][6]

  • 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

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][17][18][19][20][16]

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


Special patient groups

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
  • Antipsychotic medications
  • Hospitalization might be indicated, especially if there is a risk of infanticide.
  • ECT in severe cases

Depression in palliative patients

  • Definition: depressive symptoms or thoughts of suicide in patients with a limited life expectancy
  • Treatment
    • Psychostimulants (e.g., methylphenidate) are effective for the urgent treatment of severe depressive symptoms or thoughts of suicide in terminally ill adults with a short life expectancy.
    • SSRIs can be introduced concurrently in patients with an anticipated life expectancy of several months.

Depression in children and adolescents

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