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).
Epidemiological data refers to the US, unless otherwise specified.
- Monoamine hypothesis: Most antidepressants work by inhibiting the reuptake of monoamines (e.g., serotonin, noradrenaline, dopamine), indicating that a lack of monoamines plays a major role in the pathophysiology of depression (and other mood disorders).
- Genetic factors
- Increased production of stress hormones (e.g., dysfunction of the hypothalamic-pituitary-adrenal axis)
- Psychological factors: traumatic and stressful experiences, behavioral factors (e.g., learned helplessness)
- Comorbidities: neurodegenerative diseases (e.g., Alzheimer disease), chronic inflammatory diseases (e.g., systemic lupus erythematosus or inflammatory bowel disease), and other psychiatric disorders (e.g., panic disorder)
|Diagnostic criteria for major depressive disorder (according to DSM-5)|
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.
|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
- Leaden paralysis (legs and arms feel heavy)
- Interpersonal rejection sensitivity that leads to social and occupational impairment
Major depressive disorder with psychotic features
Major depression accompanied by psychotic symptoms
- Features of MDD (see diagnostic criteria for major depressive disorder)
- Psychotic features, such as delusions and hallucinations, which are usually mood-congruent (delusions and hallucinations are often about worthlessness, guilt, death, and hopelessness)
- Psychotic features occur only alongside a major depressive episode.
- Overactivity of the hypothalamic-pituitary-adrenal axis (increased dopamine activity) is believed to play a major role.
Persistent depressive disorder (dysthymia) 
- Depressed mood in addition to ≥ 2 of the following symptoms
- 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.
- See diagnostic criteria for major depressive disorder.
- Questionnaires can be used to help determine the features of depression:
- Beck Depression Inventory
- Assessment of suicide risk: indicated for all patients
Laboratory evaluation: indicated to rule out organic disease
- Thyroid function tests; : to rule out hypothyroidism, which can manifest with lethargy, cognitive impairment (slowed mentation, poor concentration), psychomotor retardation, social withdrawal, and depressed mood
- Urine toxicology: to screen for drug use causing depressive symptoms, such as benzodiazepine withdrawal, amphetamine use, and cocaine “crash”
- Neuroimaging: to evaluate for structural brain disease if suspected
- Polysomnography: not routinely performed; indicated in case a concurrent primary sleep disorder is suspected 
In pediatric patients, remember to first rule out organic causes, which are the most common cause of depression in this population.
|Overview of depressive disorders|
|Major depressive disorder|| |
|Persistent depressive disorder (dysthymia)|| |
|Depression with seasonal pattern|| || |
|Minor depressive disorder|| |
|Mood disorder due to another medical condition|| || |
|Substance-induced depressive disorder|| |
|Disruptive mood dysregulation disorder (DMDD)|| || |
|Adjustment disorder|| || |
- 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)
- Intense sorrow, yearning, emotional distress
- Anxiety, insomnia
- Anorexia, weight loss
- Somatic symptoms (e.g., nonspecific chest pain, epigastric discomfort, etc.)
- Simple hallucinations of deceased loved ones (e.g., hearing the voice of the deceased)
- No suicidal ideation (as opposed to persistent complex bereavement disorder); thoughts of joining the deceased loved one may be present
- Preoccupation with the deceased and circumstances surrounding their death
- No functional impairment
- Some symptoms are similar to those seen in MDD and acute stress disorder (see )
- Duration: vary significantly among different cultural groups (commonly resolves within 6 to 12 months)
Persistent complex bereavement disorder 
- Definition: a pathological grieving process
- 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
- Hallucinations of the deceased
- Somatic symptoms
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 
- Depressed mood and/or anhedonia attributable to a general medical condition
- Conditions associated with depressive disorder include the following:
Substance/medication-induced depressive disorder 
- Depressed mood and/or anhedonia attributable to the use of, or withdrawal from, substances or medications
- Substances or medications associated with depressive disorder include the following:
- 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 ; or anxiety disorders in adulthood.
The differential diagnoses listed here are not exhaustive.
- 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).
- Most drugs have comparable efficacy but different side effects.
- Most antidepressants require > 4 weeks to take effect.
- Always start with the lowest dose and increase in small steps. 
- Initial treatment: 6–12 weeks
- If the patient is in remission, continue antidepressants for at least 4–9 months (continuation phase).
- If the patient has had ≥ 3 prior major depressive episodes in total or severe episodes (e.g., including suicide attempt or psychosis) or has risk factors for recurrence , or chronic MDD, continue antidepressants for at least 1–3 years (maintenance phase).
- Tapering off medications should be done over 6–8 weeks because this can help to:
- First-line: SSRIs
- Atypical antidepressants
- TCA and MAO inhibitors: cause more side effects than SSRIs
- Augmenting agents: lithium, second-generation antipsychotics (e.g., aripiprazole), thyroid hormones 
- Cognitive-behavioral therapy (CBT)
- Interpersonal therapy
- Psychodynamic psychotherapy
- Family and couples therapy
- Lifestyle changes (aerobic exercise, nutrition, sleep hygiene, social support, stress reduction)
- Light therapy
- Repetitive (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)
- Electroconvulsive therapy: reserved for severe, refractory, and/or psychotic depression
Special patient groups
- Peripartum mood disturbances are mood disorders that commonly occur during pregnancy or within a month after delivery.
- Patients with a previous history of mood disorders are at increased risk of developing peripartum mood disorders.
|Differential diagnosis of peripartum mood disturbances|
|Features||Postpartum blues||Major depressive disorder with peripartum onset (postpartum depression)||Postpartum psychosis|
|Epidemiology|| || || |
|Timing|| || || |
|Diagnosis|| || || |
Depression in palliative patients
- Definition: depressive symptoms or thoughts of suicide in patients with a limited life expectancy
Depression in children and adolescents
- Classical symptoms of major depressive disorder (e.g., depressed mood, loss of energy)
- Symptoms may be less marked than in adults.
- MDD in pediatric patients often resembles attention deficit hyperactivity disorder (difficulties concentrating, impaired memory, restlessness, aggression). 
- Treatment 
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