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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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
Antidepressant class comparison — first-line vs second-line options with key trade-offs.
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
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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