Major depressive disorder (MDD) is an episodic mood disorder primarily characterized by depressed mood and anhedonia lasting for at least two weeks. Women have a higher risk of developing MDD than men. The peak age of onset is the third 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. are characterized by additional symptoms. MDD with atypical features is additionally characterized by weight gain and increased appetite, while MDD with psychotic features is characterized by hallucinations and delusions. Presentations may also vary in special patient groups, e.g., pregnant patients, older patients, children and adolescents, and patients receiving palliative care. Treatment of all forms of MDD is multifaceted and often requires psychotherapy, pharmacotherapy (most commonly SSRIs), and lifestyle changes.
- 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)
- Depressed mood
- Feelings of guilt, worthlessness, or hopelessness
- Low energy levels
- Difficulty concentrating
- Changes in appetite and weight (increased or decreased)
- Sleep disorders (insomnia or hypersomnia)
- Psychomotor agitation or retardation
- Suicidal thoughts
- May additionally manifest with:
Older adults with depression may be more likely than younger adults to present with physical symptoms than a low mood. 
Depression screening with “SIGECAPS”: 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.
Major depressive disorder with seasonal pattern (seasonal affective disorder, winter depression)
- Definition: a subtype of major depressive disorder characterized by ≥ 2 depressive episodes associated with a seasonal pattern (e.g., the winter season) over ≥ 2 years
- Epidemiology: occurs in a yearly, season-specific pattern (commonly in fall or winter)
- Patients present with typical symptoms of MDD alongside atypical ones, such as weight gain and requiring more sleep.
- See “ ” for details.
- Diagnostic criteria: Symptoms must be present for ≥ 2 consecutive years and for the majority of years in a lifetime.
- Treatment: Bright light therapy has been shown to improve symptoms.
Major depressive disorder with atypical features
- Epidemiology: most common variant of MDD
- Increased appetite or over-eating
- Leaden paralysis (legs and arms feel heavy)
- Interpersonal rejection sensitivity that leads to social and occupational impairment
- Mood reactivity: brightening of mood in response to positive events, which is usually not the case in classical MDD
- Diagnostic criteria: two or more of the clinical features are present
Major depressive disorder with psychotic features
- Definition: major depression accompanied by psychotic symptoms
- Etiology: overactivity of the hypothalamic-pituitary-adrenal axis (increased dopamine activity) is believed to play a major role.
- Clinical features: See “ ” and “ ” for details.
- 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.
Persistent depressive disorder (dysthymia) 
- Clinical features: 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.
- Depressed mood in addition to ≥ 2 of the clinical features mentioned above
- 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.
- 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.
- Screen all adults using a brief screening tool, e.g., Patient Health Questionnaire-2.
- If screening is positive, perform a full clinical assessment, including:
- Confirmation of diagnosis using DSM-5 criteria for MDD
- Determination of severity: Combined tools for screening and severity assessment can be used, e.g., Patient Health Questionnaire-9.
- Assessment of suicide risk
- Diagnostic studies for common differential diagnoses
- Identification of psychiatric and medical comorbidities
Screening for depression 
- Screen all adults aged ≥ 18 years and children aged ≥ 12 years.
- Recommended screening intervals 
- Adults: Optimum intervals are unclear; screen at least once and consider repeating either when risk factors arise or at routine health checks.
- Children aged ≥ 12 years: Screen annually until 18–21 years of age. 
Brief screening tool
- Use the Patient Health Questionnaire-2 (PHQ-2).
- A 2-item survey for assessing depressed mood and loss of interest or pleasure in activities over the last 2 weeks
- A score ≥ 3 is considered positive; follow up with a full clinical assessment.
Further screening tools
- Scores that also assess severity:
- Consider using specific screening scores when assessing for . 
|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.
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.
Further assessment 
Suicide risk 
- Screen all patients with MDD for suicidality. 
- Screening tools include the ask suicide-screening questionnaire and the Columbia-Suicide Severity Rating Scale.
- A comprehensive assessment includes consideration of and protective factors.
- See also “Diagnostics” in “Suicide.”
Exclusion of organic causes 
- Comprehensive history and physical examination
- Laboratory studies 
- Neuroimaging: Consider evaluating for structural brain disease based on clinical presentation. 
- Additional testing
Assessment for comorbid psychiatric disease 
- Consider alternative diagnoses.
- Bipolar disorder: Assess for prior episodes of mania and/or hypomania using a screening tool, e.g., .
- Schizophrenia: Negative symptoms of schizophrenia may be mistaken for depression.
- Other depressive disorders, e.g., adjustment disorder or persistent depressive disorder (see “Differential diagnoses of MDD”) 
- Identify potential psychiatric comorbidities, e.g.:
Assess all patients presenting with depression for past episodes of mania and/or hypomania to rule out bipolar disorder. Patients with bipolar disorder who are treated with antidepressants without a mood stabilizer are at increased risk of manic symptoms. 
|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|| || |
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.
- See “Burnout syndrome” for more information.
The differential diagnoses listed here are not exhaustive.
The treatment advice in this section applies to the general adult population. For depression in older adults, pregnant individuals, patients receiving end of life care, and children and adolescents, see “Special patient groups.”
- Advise patients on lifestyle modifications. 
- Start initial treatment based on severity.
- Urgently refer patients with severe/complex depression or suicidality to psychiatry; admission may be required.
- Provide the patient and their family with information on depression.
- Ensure patients receive treatment for:
- Psychiatric comorbidities, e.g., alcohol use disorder
- Contributing physical conditions 
- Review patients regularly; assess the efficacy of treatment at ∼ 6 weeks and consider modifications. 
Shared decision-making should be used to plan treatment, taking into consideration previous experience of MDD treatment. Patients with symptoms of psychosis or suicidal ideation should be urgently referred to a psychiatrist or evaluated in the emergency department; if patients at risk of suicide are deemed safe for outpatient management they should be given details of a suicide crisis line as part of a comprehensive . 
Lifestyle modifications 
- Sleep hygiene 
- Reduction in substance use, e.g., alcohol, recreational drugs 
- Stress reduction
- Increasing social support
- Regular aerobic exercise 
- Relaxation/mindfulness 
- Improved nutrition 
Lifestyle modifications are more effective when individualized to the patient.
- May be used alone or in combination with pharmacotherapy
- Options include:
Initial pharmacotherapy 
- Choice of initial medication
- Initial medication trial
First-line antidepressant medications
- Options include SSRIs (often trialed first), SNRIs, and the atypical antidepressants bupropion and mirtazapine.
- For further information on adverse effects and contraindications, see “Antidepressants.”
First-line medications for the treatment of major depressive disorder 
|Drug class||Examples||Important considerations|
SSRIs and venlafaxine have been associated with an increased risk of suicidality in adults aged < 24 years. Monitor patients starting antidepressants carefully for side effects and worsening of depressive symptoms. 
Other antidepressant medications
- These medications cause more adverse effects than first-line therapies (e.g., SSRIs). 
- Options include:
Monitoring treatment efficacy
- Monitor treatment response using an objective score of symptom severity, e.g., PHQ-9. 
- Determine next steps after ∼ 6 weeks of good adherence to treatment. 
|Ongoing management of depression |
|Treatment response||Recommended actions|
|Minimal or no response|
|Partial response|| |
Switching or discontinuing antidepressants 
- When switching between antidepressants, consider medication class and the risk of serotonin syndrome. 
- When discontinuing medications:
- Consider tapering over 6–8 weeks to : 
- Decrease the risk of relapse
- Offer psychotherapy to prevent relapse.
- Consider tapering over 6–8 weeks to : 
Symptoms of occur when treatment is FINISHed: Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal 
Treatment-resistant depression 
- Definition: MDD that persists despite trials of ≥ 2 antidepressants at optimal doses 
- Should not be diagnosed without assessing patients for:
- Refer all patients to a psychiatrist to determine further treatment.
- Augmenting agents for depression 
- Neurostimulation therapy 
Electroconvulsive therapy (ECT)
- Highly effective treatment for treatment-resistant MDD and severe MDD 
- Accessibility and patient acceptance have limited its use. 
- Requires regular attendance for intensive therapy followed by a gradual taper 
- Vagal nerve stimulation
- Transcranial magnetic stimulation
- Electroconvulsive therapy (ECT)
Additional therapies 
The following therapies are not recommended as first-line, have variable evidence to support their use, and should be performed under specialist guidance.
- Complementary and alternative therapy 
- Bright-light therapy: daily exposure to a light intensity of 5000–10,000 lux 
- Sleep deprivation therapy 
The diagnosis and treatment of depression in special patient groups is broadly the same as for the general adult population, with some modifications.
Depression in the peripartum period
- Peripartum depression: MDD that occurs during pregnancy or within a month after delivery 
- Affects up to 14% of pregnancies 
- Untreated peripartum depression can have adverse consequences. 
- Patients with a previous history of depression are at increased risk of developing peripartum depression. 
- For patients at increased risk considering pregnancy:
- Screening 
- Screen at least once in the peripartum period.
- Consider using a modified screening tool, e.g., the Edinburgh postnatal depression scale.
- Screen for infanticidal thoughts as well as suicidality. 
- Offer psychotherapy as an alternative to pharmacotherapy in mild to moderate depression.
- Discontinuation of pharmacotherapy can be considered in stable patients with a known diagnosis of MDD. 
- Patients starting or continuing antidepressants: Educate on the risks and benefits of antidepressants and monitor carefully. 
- Avoid paroxetine during pregnancy because of the potential risk of cardiac anomalies. 
- Use monotherapy whenever possible.
- Patients already on SSRIs, SNRIs, TCAs, and mirtazapine can continue treatment while breastfeeding. 
- In patients starting antidepressants, begin with a medication that has few side effects and minimal transfer to breastmilk, e.g., sertraline. 
- Mother and baby units are preferred for patients requiring hospitalization. 
Depression has adverse effects on maternal and fetal health; the risks of pharmacotherapy should be balanced against the risks of leaving the condition untreated. 
ECT can be safely offered to pregnant and lactating patients who prefer to avoid pharmacotherapy. 
While SSRIs are generally compatible with breastfeeding, infants of breastfeeding mothers taking SSRIs should be monitored for signs of medication toxicity, such as excessive tiredness, irritability, and poor feeding. 
Differential diagnosis of postpartum low mood
|Overview of postpartum low mood |
|Features||Postpartum blues||Postpartum depression||Postpartum psychosis |
|Epidemiology|| || || |
|Timing|| || || |
Clinical features 
|Diagnosis|| || |
|Management|| || || |
Depression in patients receiving palliative care 
- Depressive symptoms or thoughts of suicide are common in patients with a limited life expectancy. 
- Symptoms of depression (e.g., changes in appetite, low energy, impaired sleep) may overlap with : 
- Symptoms of an underlying medical condition
- Adverse effects of treatment
- Screen for depression at diagnosis of a life-limiting illness and periodically thereafter. 
- Identify physical symptoms that may contribute to low mood (see “Principles of cancer care”).
- Psychotherapy is first-line treatment for mild to moderate depression.
- The choice of antidepressant is based on symptoms and comorbidities.
- SSRIs are typically used first-line because they have the lowest risk of adverse effects and interactions. 
- Antidepressants may be selected because they have a dual function. 
- Psychostimulants (e.g., methylphenidate) are sometimes used for patients with limited life expectancy. 
Depression in children and adolescents 
- ∼ 15% of adolescents (12–17 years of age) report major depression in the past 12 months. 
The presentation of depression in children may differ from adults. 
- Classical may be less marked.
Some symptoms may resemble those of attention deficit hyperactivity disorder, e.g.: 
- Difficulty concentrating or worsening performance at school
- Psychiatric comorbidities are common, e.g.: 
- Consider using the PHQ-9 modified for adolescents to .
are the same as for adults, with two exceptions: 
- Irritability can be noted in the assessment of mood.
- Failure to gain weight can be noted in the assessment of appetite.
- Mild depression: Consider 6–8 weeks of active support and monitoring. 
- Moderate to severe depression or refractory mild depression
- Initiate psychotherapy and/or pharmacotherapy.  with
- For psychotherapy, CBT and interpersonal therapy for adolescents are preferred.
- Patients requiring pharmacotherapy
Depression in older adults 
- MDD in older adults (late-life depression) is common. 
- Risk factors include: 
- Older patients may present atypically with irritability, anxiety, or physical symptoms as opposed to low mood. 
- Consider using an adapted screening score, e.g., the Geriatric Depression Scale-15.
- Neurological disease and coexisting medical conditions are more common in this patient group; work up thoroughly to exclude physical causes.
- Older adults have an elevated suicide risk; screen carefully for suicidality. 
- Lifestyle changes: Exercise may be particularly beneficial. 
- Pharmacotherapy: Older adults have an increased risk of adverse effects from medications (see “Pharmacology for older adults”). 
- Psychotherapy: Consider modifications in patients with cognitive impairment; problem-solving therapy may be effective. 
- ECT: highly effective; ; response rates are higher in adults aged > 65 years than in younger adults. 
Cognitive impairment should be considered as a possible underlying cause of depression in older adults.