Major depressive disorder

Last updated: September 5, 2022

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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. Subtypes of MDD 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.

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

References: [2]

Epidemiological data refers to the US, unless otherwise specified.

References:[3][4]

Older adults with depression may be more likely than younger adults to present with physical symptoms than a low mood. [6]

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)
  • Clinical features
  • 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
  • Clinical features
    • Increased appetite or over-eating
    • Hypersomnia
    • 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
  • 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) [7]

  • 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.
    • Poor appetite or overeating
    • Insomnia or hypersomnia
    • Low energy or fatigue
    • Low self-esteem
    • Poor concentration or difficulty making decisions
    • Feelings of hopelessness
  • Diagnostic criteria
    • 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.

References:[7][8]

Approach [9]

  • 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 [5][10]

Overview

  • Screen all adults aged ≥ 18 years and children aged ≥ 12 years.
  • Recommended screening intervals [5]
    • 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. [10][11]

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:
    • Patient Health Questionnaire-9 (PHQ-9) [12]
    • Major depression inventory
    • Beck Depression Inventory (BDI) [13]
  • Consider using specific screening scores when assessing for depression in special patient groups. [10]

Diagnostic criteria

Diagnostic criteria for major depressive disorder (according to DSM-5) [7][14]
A

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
B

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

C

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

D

Symptoms are not superimposed upon or due to schizoaffective disorder or another psychotic disorder.

E

There is no history of a manic or hypomanic episode.

  • Criteria A-C are met: major depressive episode
  • Criteria A-E are met: major depressive disorder

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 [5]

Suicide risk [15][16]

Exclusion of organic causes [5][15]

Assessment for comorbid psychiatric disease [5][15]

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. [15]

Overview [7]

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.
Grief
  • 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
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

Depressive disorder due to another medical condition [7]

Substance/medication-induced depressive disorder [7]

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.

Burnout syndrome

References: [7][25][26][27][28][29]

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.”

Approach [15][30][31]

  • Advise patients on lifestyle modifications. [30]
  • Start initial treatment based on severity.
    • Mild depression: typically psychotherapy alone [15][32]
    • Moderate and severe depression: psychotherapy and pharmacotherapy [31][32][33]
  • 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:
  • Review patients regularly; assess the efficacy of treatment at ∼ 6 weeks and consider modifications. [30]

Shared decision-making should be used to plan treatment, taking into consideration previous experience of MDD treatment. [31]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 suicide safety plan. [15][22]

Lifestyle modifications [34]

  • Sleep hygiene [35][36]
  • Reduction in substance use, e.g., alcohol, recreational drugs [37]
  • Stress reduction
  • Increasing social support
  • Regular aerobic exercise [38][39]
  • Relaxation/mindfulness [40]
  • Improved nutrition [34][41]

Lifestyle modifications are more effective when individualized to the patient.

Psychotherapy [15][30][31]

There is no evidence to support the use of one modality of psychotherapy over another for the treatment of MDD. [31]

Initial pharmacotherapy [15][30][31]

Initiation

  • Choice of initial medication
    • Most antidepressants have comparable efficacy but different adverse effects.
    • When choosing an antidepressant, consider:
      • Psychiatric and medical comorbidities
      • Current symptoms
      • Previous treatment experiences
      • Medication adverse effects
      • Interactions with other medications
  • Initial medication trial

First-line antidepressant medications

First-line medications for the treatment of major depressive disorder [15][30]

Drug class Examples Important considerations
SSRIs
  • Associated with sexual adverse effects
  • Escitalopram may have fewer general adverse effects than other SSRIs and SNRIs.
SNRIs
  • Duloxetine may be preferable for patients with concomitant neuropathic and chronic pain.
Atypical antidepressants
  • Can cause sedation and weight gain, which may be desirable for some patients (e.g., those with insomnia or poor appetite)

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. [43]

Other antidepressant medications

MAOIs should not be combined with SSRIs/SNRIs or tricyclic antidepressants, because this may lead to serotonin syndrome. [15]

Ongoing management

Monitoring treatment efficacy

  • Monitor treatment response using an objective score of symptom severity, e.g., PHQ-9. [44]
  • Determine next steps after ∼ 6 weeks of good adherence to treatment. [30]
Ongoing management of depression [15][30][31]
Treatment response Recommended actions
Minimal or no response
Partial response
Remission
  • Continue treatment; duration depends on the risk of relapse. [15][30]
    • Low risk: ≥ 6 months
    • High risk : ≥ 2 years
  • Offer/continue psychotherapy for relapse prevention.

If an antidepressant has an insufficient effect, always assess the patient's medication adherence before adjusting the treatment plan. [30]

Switching or discontinuing antidepressants [30][31]

When changing between antidepressants, monitor patients carefully for the development of serotonin syndrome. [20]

Symptoms of antidepressant discontinuation syndrome occur when treatment is FINISHed: Flu-like symptoms, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal [50]

Treatment-resistant depression [30][51]

Management

Consider ECT for patients with treatment-resistant depression, depression with psychotic features, catatonia, or a high risk of suicide. [57]

Additional therapies [30][31]

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 [30][58]
    • Used by some patients as an alternative to antidepressants and/or psychotherapy
    • Exercise monotherapy can be considered for mild depression. [30][59]
    • Herbal remedies, e.g., St. John's wort, are typically advised against because potential risks outweigh benefits. [30][58]
  • Bright-light therapy: daily exposure to a light intensity of 5000–10,000 lux [30][60]
  • Sleep deprivation therapy [61][62][63]

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

Overview

Prevention

Modifications to diagnostics of MDD

  • Screening [10][69][70]
    • 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. [64][71]

Modifications to treatment of MDD

  • Antenatal modifications
    • 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. [67]
    • Patients starting or continuing antidepressants: Educate on the risks and benefits of antidepressants and monitor carefully. [67]
    • Avoid paroxetine during pregnancy because of the potential risk of cardiac anomalies. [30]
    • Use monotherapy whenever possible.
  • Postnatal modifications

Depression has adverse effects on maternal and fetal health; the risks of pharmacotherapy should be balanced against the risks of leaving the condition untreated. [67]

ECT can be safely offered to pregnant and lactating patients who prefer to avoid pharmacotherapy. [30]

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. [64]

Differential diagnosis of postpartum low mood

Overview of postpartum low mood [30][64][68]
Features Postpartum blues Postpartum depression Postpartum psychosis [74]
Epidemiology
  • Up to 80% of childbirths [75]
  • ∼ 13% of childbirths [68][76]
  • Up to 0.2% of childbirths [75]
  • Often associated with underlying bipolar disorder [68]
Timing
  • Typically develops within the first few days of delivery [64]
  • Symptoms usually resolve spontaneously within 2 weeks. [64][68]
  • Typically develops within 4 weeks following delivery
  • Symptoms must be present for at least 2 weeks to confirm the diagnosis. [7]
  • Typically develops within 2–4 weeks of delivery [74]
  • Onset is sudden.

Clinical features [64][68][77]

  • Common symptoms
  • Symptoms and their impact on function are mild.
  • Somatic symptoms (e.g., changes in sleep) may overlap with physiological changes usually observed in postpartum women. [73]
Diagnosis
Management
  • Support and education [65]
  • Further assessment for possible development of postpartum depression [65][68]

Depression in patients receiving palliative care [78]

Overview

  • Depressive symptoms or thoughts of suicide are common in patients with a limited life expectancy. [78][79]
  • Symptoms of depression (e.g., changes in appetite, low energy, impaired sleep) may overlap with : [78][80][81]
    • Symptoms of an underlying medical condition
    • Adverse effects of treatment
    • Grief

Modifications to diagnostics of MDD [82]

Modifications to treatment of MDD [78][80]

Consider life expectancy when selecting treatment for depression in patients near the end of life; many antidepressants can take several weeks to have an effect. [78]

Depression in children and adolescents [31][85][86]

Overview

Modifications to diagnostics of MDD [86]

Modifications to treatment of MDD [11][85][86]

  • Mild depression: Consider 6–8 weeks of active support and monitoring. [85]
  • Moderate to severe depression or refractory mild depression

Monitor all children starting on SSRIs for suicidality. [85]

Depression in older adults [6][30][31]

Overview

Modifications to diagnostics of MDD

  • 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. [5]

Modifications to treatment of MDD

  • Lifestyle changes: Exercise may be particularly beneficial. [6]
  • Pharmacotherapy: Older adults have an increased risk of adverse effects from medications (see “Pharmacology for older adults”). [6][90]
    • SSRIs: preferred first-line treatment in individuals aged ≥ 60 years [6]
    • Consider using reduced frequencies and/or lower doses than in the general adult population.
    • Minimize polypharmacy whenever possible.
  • Psychotherapy: Consider modifications in patients with cognitive impairment; problem-solving therapy may be effective. [6]
  • ECT: highly effective; ; response rates are higher in adults aged > 65 years than in younger adults. [30]

Cognitive impairment should be considered as a possible underlying cause of depression in older adults. [6]

In older patients, monitor for hyponatremia after starting or adjusting the dosages of SSRIs, SNRIs, TCAs, or mirtazapine. [90]

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