• Clinical science

Major depressive disorder (Unipolar depressive disorder)


Major depressive disorder (MDD) is an episodic mood disorder primarily characterized by depressed mood and anhedonia that lasts for at least 2 weeks. Females are diagnosed more often than men. The peak age of onset is in the 20s. 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. Additional symptoms of MDD include sleep disturbances, loss of appetite, and suicidal thoughts. Various subtypes include atypical depression (e.g., weight gain, and increased appetite), psychotic depression (e.g., hallucinations and delusions), and peripartum depression (occurring during or shortly after pregnancy). In elderly patients, it may also present with memory loss and resemble dementia, which is 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
    • General population: 15–25%
    • 1st-degree relatives of patients: 24–30%
  • The peak age of onset is in the 20s.


Epidemiological data refers to the US, unless otherwise specified.


The consensus today is that depression is influenced by genetic, neurobiological, socio-psychological, and environmental factors. The most clinically relevant contributing factor appears to be a decrease in monoamine levels.

  • Biological factors
    • Monoamine hypothesis: Most antidepressants work by inhibiting the reuptake of monoamines (e.g., serotonin, noradrenaline, dopamine). This indicates that a lack of these substances plays a major role in the pathophysiology of depression (and other mood disorders).
    • Genetic vulnerability
    • Increased levels of stress hormones (and dysfunction of the hypothalamus-pituitary axis)
  • Psychological factors: traumatic and stressful experiences, personality factors (e.g., learned helplessness)
  • Comorbidities: MDD is associated with a wide range of comorbidities, such as neurodegenerative diseases (e.g., Alzheimer disaese), chronic inflammatory diseases (e.g., systemic lupus erythematosus or inflammatory bowel disease) or other psychiatric disorders (e.g., panic disorder).


Clinical features

Diagnostic criteria for major depressive disorder (DSM-V)
  • ≥ 5 symptoms, for at least 2 weeks, with at least one of the symptoms being depressed mood or anhedonia
    • Depressed mood present most of the day, almost every day
    • Sleep disturbance (insomnia or hypersomnia)
    • Loss of interest or anhedonia
    • Feelings of worthlessness or guilt
    • Fatigue or loss of energy
    • Diminished concentration, ability to think, or make decisions (→ Pseudodementia)
    • Weight change due to appetite change
    • Psychomotor changes
    • Suicidal ideation
  • Clinically significant distress or impaired functioning in important areas of life (e.g., work, school)
  • Not due to the effects of psychoactive substances or organic disease
  • Not due to another psychiatric disorder

The criteria A to C constitute a major depressive episode. Major depressive disorder also includes the following two criteria: the symptoms are not better explained by another psychiatric disorder AND no history of a manic or hypomanic episode.

SIG E CAPS: Sleep (insomnia or hypersomnia), Interest loss (anhedonia), Guilt (low self-esteem), Energy (low energy or fatigue), Concentration (poor concentration or difficulty making decisions), Appetite (decreased appetite or overeating), Psychomotor agitation or retardation, and Suicidality.


Subtypes and variants

Depression with seasonal pattern (seasonal affective disorder, winter depression)

  • Occurs yearly in fall and winter
  • Patients suffer from the usual symptoms of MDD along with atypical ones, such as weight gain and requiring more sleep.
  • Light therapy has been shown to improve symptoms.

Atypical depression

  • Mood reactivity: brightening of mood in response to positive events, which is usually not the case in classical MDD
  • ≥ 2 of the following features
    • Increased appetite or weight gain
    • Increased sleep
    • Leaden paralysis (weighing down of arms and legs)

Psychotic depression

Major depressive disorder with peripartum onset




Differential diagnoses

Dysthymia (persistent depressive disorder)

Persistent depressive disorder Major depressive disorder
  • Symptoms are present most of the day, for the majority of days, for ≥ 2 years
  • Not asymptomatic for > 2 consecutive months
  • Symptoms have to be present for at least 2 weeks
Diagnostic features
  • 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
  • ≥ 5 SIGECAP symptoms (of which at least one is depressed mood or loss of interest)

Bereavement [14] (normal grief)

  • Bereavement is a situation involving the loss or death of someone close to an individual.
  • It can precipitate or worsen psychiatric disorders (e.g., major depressive disorder).
  • Shares some symptoms with major depressive disorder.
  • For differences see table below.
Bereavement Major depressive disorder
Identifiable loss is present Identifiable loss may or may not be present
Major complaint is feeling of loss Major complaint is depressed mood
Normal self-esteem Feeling of worthlessness
Negative feelings of pain and grief are mixed with positive memories/feelings of loved one

Feelings are predominantly negative

Guilt over specific aspects of the loss Generalized feeling of guilt
Closeness of others can be comforting Social isolation is preferred
Generally, no suicidal ideation Often suicidal ideation
Daily functioning maintained Daily functioning often impaired

Persistent complex bereavement disorder [15]

  • Refers to a pathological grieving process.
  • Diagnostic features
    • Death of a close other
    • Clinical significant yearning for the deceased persist for at least 6-12 months
    • Difficulty adjusting to a life without the deceased
    • Disturbance impairs daily life (socially, occupational)
    • Yearning is inconsistent with cultural norms
  • Additional features

Depressive disorder due to another medical condition

Certain medical conditions affect mood and may resemble major depressive disorder:


The differential diagnoses listed here are not exhaustive.



  • Therapeutic principles
    • Most drugs have comparable efficacy but differ in regards to their side effects.
    • Take > 4 weeks to take effect
    • Always start with the lowest dose and increase in small steps.
      • Single episode: continue medication for ≥ 6 months
      • Multiple episodes: continue medication for ≥ 2 years
      • If the patient is in remission: continue antidepressants for at least 4–9 months.
    • Tapering of medication over 6–8 weeks
  • First-line: SSRIs
  • Other options
  • Treatment-resistant depression: Switch to a different drug from the same class or to a different drug from a different class.
  • Suicidal patients: Lithium should be combined with an antidepressant as prophylaxis to prevent recurrence.
  • Palliative patients: Psychostimulants (e.g., methylphenidate) are effective for the urgent treatment of depressive symptoms in terminally ill adults with a short life expectancy or severe symptoms.
    • SSRIs can be introduced concurrently in patients with an anticipated life expectancy of several months.

MAO inhibitors should not be combined with SSRIs/SNRIs or tricyclic antidepressants, as this may cause serotonin syndrome.


Other measures