Major Depressive Disorder (MDD)
Persistent depressed mood or anhedonia >=2 weeks with neurovegetative and cognitive symptoms causing functional impairment.
Also known as: MDD, depression, unipolar depression, clinical depression, major depression
Overview
A mood disorder defined by one or more major depressive episodes — >=2 weeks of depressed mood or anhedonia plus additional neurovegetative, cognitive, and psychomotor symptoms causing significant distress or functional impairment, without a history of mania or hypomania.
Epidemiology
Lifetime prevalence ~20% in US adults; 12-month prevalence ~8%. Female-to-male ratio ~2:1. Peak onset in 20s-30s but can occur at any age. Higher rates with chronic medical illness, perinatal period, and substance use.
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Risk factors
- Personal or family history of mood disorder; first-degree relative confers 2-3x risk
- Female sex, perinatal period, perimenopause
- Chronic medical illness (CAD, stroke, diabetes, cancer, chronic pain, hypothyroidism)
- Adverse childhood experiences, recent loss or psychosocial stressor
- Substance use disorders; comorbid anxiety disorders
- Medications: interferon, corticosteroids, isotretinoin, beta-blockers (modest signal)
Pathophysiology
Multifactorial. Dysregulation of monoaminergic neurotransmission (serotonin, norepinephrine, dopamine), HPA-axis hyperactivity with elevated cortisol, reduced hippocampal neurogenesis and BDNF, neuroinflammatory changes, and altered limbic-prefrontal connectivity. Genetic heritability ~40%.
Clinical presentation
Symptoms
- Depressed mood most of the day, nearly every day (self-reported or observed)
- Markedly diminished interest or pleasure in nearly all activities (anhedonia)
- Significant weight change or appetite disturbance
- Insomnia (especially early-morning awakening) or hypersomnia
- Psychomotor agitation or retardation observable by others
- Fatigue or loss of energy
- Feelings of worthlessness or excessive/inappropriate guilt
- Diminished concentration or indecisiveness
- Recurrent thoughts of death, suicidal ideation, plan, or attempt
Signs / physical exam
- Flat or constricted affect, slowed speech, poor eye contact
- Tearfulness; psychomotor retardation or agitation
- Poor grooming in severe cases
- Cognitive testing may reveal pseudodementia in older adults (reversible with treatment)
Classic findings
SIG E CAPS mnemonic — Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicidality. Five of nine including depressed mood or anhedonia x 2 weeks.
Differential diagnosis
- Bipolar depression — Screen for past hypomania/mania (elevated energy + decreased need for sleep + goal-directed activity); antidepressant monotherapy can precipitate mania
- Persistent depressive disorder (dysthymia) — Chronic low-grade depressed mood >=2 years without meeting full MDE criteria; may co-exist as 'double depression'
- Adjustment disorder with depressed mood — Identifiable stressor within 3 months, symptoms insufficient for MDD, resolves within 6 months of stressor end
- Grief / bereavement — Waves of yearning, preserved self-esteem, ability to experience positive emotion; consider MDD if symptoms persist, involve worthlessness, or include active SI
- Hypothyroidism — Fatigue, weight gain, cold intolerance, constipation; check TSH in every new presentation
- Substance-induced mood disorder — Symptoms emerge in context of intoxication or withdrawal (alcohol, sedatives, stimulants, opioids); resolves with abstinence
- Premenstrual dysphoric disorder — Mood symptoms confined to luteal phase, remitting with menses; prospective daily ratings confirm
- Seasonal affective pattern — MDEs with onset in fall/winter and remission in spring; consider light therapy
Diagnostic workup
Diagnostic criteria
DSM-5-TR: >=5 of 9 symptoms present for >=2 weeks, with at least one being depressed mood OR anhedonia. Symptoms must cause clinically significant distress/impairment, not be attributable to a substance or medical condition, and not be better explained by a psychotic or bipolar disorder. PHQ-9 >=10 supports diagnosis and tracks severity (5-9 mild, 10-14 moderate, 15-19 moderately severe, >=20 severe).
Labs
- TSH to exclude hypothyroidism
- CBC, BMP, vitamin B12, vitamin D
- Urine drug screen if substance use suspected
- HIV, RPR in select populations
Imaging
- Neuroimaging not routine; consider MRI brain if new focal neurologic findings, atypical features, or first episode after age 50
Diagnostic algorithm
| Class | Examples | Strengths | Cautions |
|---|---|---|---|
| SSRI | sertraline, escitalopram, fluoxetine | First-line; broad efficacy; safe in overdose | GI upset, sexual dysfunction, hyponatremia, QT (citalopram) |
| SNRI | venlafaxine, duloxetine, desvenlafaxine | Comorbid pain, fatigue | BP elevation, discontinuation syndrome |
| Atypical (NDRI) | bupropion | No sexual side effects, activating | Lowers seizure threshold; avoid in eating disorders |
| Atypical (NaSSA) | mirtazapine | Sedation, appetite, weight gain | Sedation, weight gain |
| TCA | nortriptyline, amitriptyline | Refractory cases, neuropathic pain | Anticholinergic, cardiotoxic in overdose |
| MAOI | phenelzine, tranylcypromine | Atypical depression | Tyramine crisis, serotonin syndrome |
Treatment
First-line
- Psychotherapy — cognitive behavioral therapy (CBT) or interpersonal therapy (IPT); comparable to medication for mild-moderate episodes
- SSRI — sertraline, escitalopram, fluoxetine (first-line pharmacotherapy; start low, titrate after 2-4 weeks; full effect at 6-8 weeks)
- SNRI — venlafaxine, duloxetine, desvenlafaxine (consider with comorbid pain or fatigue)
- Combine medication + psychotherapy for moderate-to-severe MDD
- Lifestyle: aerobic exercise >=150 min/week, sleep hygiene, reduce alcohol, social engagement
Severe / psychotic / catatonic
- Antidepressant + atypical antipsychotic (olanzapine, quetiapine, aripiprazole) for psychotic features
- Electroconvulsive therapy (ECT) for severe, treatment-resistant, psychotic, catatonic, or pregnancy cases — rapid onset, highly effective
- Inpatient admission if active suicidality, inability to care for self, or psychosis
Treatment-resistant (>=2 adequate trials)
- Augment with bupropion, mirtazapine, lithium, or atypical antipsychotic (aripiprazole, quetiapine XR, brexpiprazole)
- Esketamine intranasal (Spravato) under REMS for treatment-resistant MDD
- Repetitive transcranial magnetic stimulation (rTMS)
- ECT remains gold standard for severe refractory disease
Perinatal
- Sertraline preferred during pregnancy and lactation
- Avoid paroxetine in first trimester (cardiac malformation signal)
- Brexanolone or zuranolone for postpartum depression
- Screen with Edinburgh Postnatal Depression Scale
Second-line / adjunct
- Bupropion (avoid in seizure disorder, eating disorder, active alcohol withdrawal) — useful when sexual side effects or sedation are limiting
- Mirtazapine for prominent insomnia or weight loss
- Tricyclics (nortriptyline, amitriptyline) reserved for refractory cases — overdose lethality limits use
- MAOIs (phenelzine, tranylcypromine) — atypical depression; dietary tyramine restrictions
Complications
- Suicide — lifetime risk ~5-8% in treated MDD; highest early in treatment and in first weeks after hospital discharge
- Functional decline: occupational disability, relationship disruption
- Comorbid substance use disorders
- Worsened outcomes in CAD, diabetes, and post-stroke recovery
- Chronic course — 50% recurrence after first episode, 70% after second, 90% after third
PANCE pearls
- Always screen for past hypomania/mania before starting an antidepressant — unopposed antidepressants in bipolar disorder can precipitate mania or rapid cycling.
- FDA black box warning: increased suicidal ideation in patients <25 during initial weeks of antidepressant treatment. Monitor closely.
- Allow 4-6 weeks at therapeutic dose before declaring treatment failure. Partial response by week 4 predicts remission.
- After full remission, continue antidepressant for >=6-12 months (first episode) or indefinitely (>=3 episodes or severe episode) to prevent relapse.
- Discontinuation syndrome: dizziness, flu-like symptoms, paresthesias ('brain zaps'), insomnia — worst with paroxetine and venlafaxine; taper slowly.
- USPSTF recommends screening all adults including pregnant/postpartum for depression with adequate systems for diagnosis and follow-up.
References
- APA 2010 — American Psychiatric Association Practice Guideline for the Treatment of Patients with Major Depressive Disorder, 3rd ed. (2010)
- USPSTF 2023 — Screening for Depression and Suicide Risk in Adults: USPSTF Recommendation Statement, JAMA 2023
- DSM-5-TR — American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed, Text Revision (2022)
- STAR*D — Rush AJ et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: A STAR*D report. Am J Psychiatry 2006
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