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Psychiatry›Condition·Updated Jul 11, 2026·v1

Major Depressive Disorder

Major depressive disorder (MDD) is a common, recurrent mood disorder characterized by depressed mood and anhedonia. Diagnosis is clinical using DSM-5 criteria; the PHQ-9 is the standard screening tool. First-line treatment includes SSRIs/SNRIs and psychotherapy (CBT, BA). For treatment-resistant cases, augmentation with atypical antipsychotics or esketamine, and neuromodulation (rTMS, ECT) are effective. Suicide risk must be assessed in all patients, and maintenance therapy for at least 6-12 months reduces relapse risk by half.

High Evidence593 references·2,035 words·9 min read·v1
MDDmajor depressive disorderdepressionpsychiatrymood disorderantidepressantsSSRIpsychotherapytreatment-resistant depressionsuicide preventionketamineesketamineneuromodulation

Quick Reference

RxDrug of choiceSSRIs (escitalopram 10-20 mg/day or sertraline 50-200 mg/day) for moderate-to-severe MDD; fluoxetine 10-20 mg/day for pediatric patients.
AltAlternativesSNRIs (venlafaxine XR 75-225 mg/day, duloxetine 60-120 mg/day), bupropion SR 150-400 mg/day, mirtazapine 15-45 mg/day, vortioxetine 10-20 mg/day. For augmentation: aripiprazole 2.5-10 mg/day, lumateperone 42 mg/day, brexpiprazole 1-3 mg/day, esketamine nasal spray 56-84 mg twice weekly.
⊘AvoidAvoid antidepressants alone for mild depression (HAM-D <23). Avoid venlafaxine as first-line in adolescents. Avoid lithium in first trimester of pregnancy. Avoid non-dihydropyridine CCBs in patients with concomitant heart failure.
DxTest of choicePHQ-9 (score ≥10) for screening and severity monitoring; DSM-5-TR criteria for diagnosis; C-SSRS for suicide risk assessment.
ScKey scorePHQ-9 (severity: 5-9 mild, 10-14 moderate, 15-19 moderately severe, ≥20 severe); MADRS (≥20 cut-off for MDD); HAM-D-17 (≥15 for moderate severity); C-SSRS for suicidal ideation.
→When to referDiagnostic uncertainty (rule-out bipolar disorder), failure of ≥2 adequate antidepressant trials, presence of psychotic features or catatonia, acute suicidal risk, need for ECT/ketamine/esketamine, or patient preference for specialist care.
MDD is a common, treatable condition. First-line treatment is SSRIs or psychotherapy for mild cases. Augment with atypical antipsychotics or esketamine for resistant cases. Always screen for suicide risk and bipolarity. Maintenance therapy for ≥6-12 months reduces relapse risk by half.
Major depressive disorder (MDD) is a common, disabling psychiatric syndrome characterized by episodes of depressed mood or anhedonia with cognitive and vegetative symptoms. It is a leading cause of disability worldwide, with a lifetime prevalence of ~26% [30]. The disorder is highly heterogeneous, requiring careful diagnostic assessment and individualized treatment.

Overview and Recommendations

Background

  • •MDD is a syndrome defined by episodes of depressed mood or anhedonia lasting at least two weeks, with cognitive and vegetative symptoms causing significant distress or impairment. Lifetime prevalence is approximately 26% in some populations, making it the most common mood disorder and a leading cause of disability worldwide.
  • •The disorder is heterogeneous, with DSM-5-TR specifiers including melancholic, atypical, psychotic, catatonic, peripartum, seasonal, and anxious distress subtypes. Each subtype carries distinct treatment implications, for example, melancholic features predict better response to ECT, while atypical features are associated with higher metabolic syndrome risk.
  • •Neurobiologically, MDD involves dysfunction in large-scale brain networks: hyperconnectivity of the default mode network (DMN) drives rumination, while hypoconnectivity of the frontoparietal network (FPN) impairs cognitive control. Structural changes include hippocampal volume reduction (Cohen's d = -0.14) and cortical thinning in orbitofrontal and cingulate regions.
  • •The monoamine hypothesis (serotonin, norepinephrine, dopamine) has been the basis for most antidepressants, but newer evidence points to impaired neuroplasticity (reduced BDNF), hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and chronic low-grade inflammation (elevated IL-6, TNF-α) as key mechanisms. These findings explain the delayed onset of antidepressant action and the rationale for novel agents like ketamine.
  • •Major risk factors include female sex (OR 1.4-1.9), younger age (OR 3.0 for 18-29 vs older adults), childhood trauma (OR 1.89), and metabolic conditions such as prediabetes (HR 2.66) and insulin resistance. Genetic factors account for ~5.7% of liability for suicide attempt, and polygenic risk scores interact with social support to predict depressive symptoms.
  • •Recurrent course is the rule: ~80% of outpatients in the STAR*D trial had chronic or recurrent illness. Cumulative remission across four sequential treatment steps is 67%, but per-step success declines sharply from 36.8% after the first trial to 13.0% after the fourth, underscoring the need for early augmentation strategies.

Evaluation

  • •Suspect MDD when a patient reports persistent depressed mood, anhedonia, or both for at least two weeks, accompanied by neurovegetative symptoms (sleep/appetite changes, fatigue, psychomotor disturbance) and cognitive complaints (poor concentration, indecisiveness). Somatic pain is present in up to 65% of depressed patients and predicts non-remission.
  • •Ask about the onset, duration, and pattern of episodes; specific DSM-5 symptoms (depressed mood, anhedonia, sleep, appetite, energy, concentration, guilt, suicidal ideation); and functional impairment. Inquire about prior manic/hypomanic symptoms, nearly 40% of those with MDD have subthreshold bipolarity, which alters treatment selection.
  • •Examine for psychomotor retardation or agitation, constricted affect, and signs of medical illness (thyroid enlargement, neurological deficits). Note the presence of somatic pain, which is a marker for treatment resistance. Red flags include suicidal ideation with intent or plan, psychotic features, catatonia, and severe weight loss.
  • •Order baseline labs: complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone, vitamin B12, folate, and toxicology screen when indicated. Reserve neuroimaging for first-episode psychosis, catatonia, focal neurological signs, head trauma, or cognitive decline disproportionate to age.
  • •Diagnose using DSM-5-TR criteria: at least five of nine symptoms (including depressed mood or anhedonia) present for ≥2 weeks, causing clinically significant distress or impairment, and not attributable to a substance or another medical condition.
  • •Use the for screening and severity grading: a score ≥10 has 88% sensitivity and 88% specificity for MDD. The (score ≥3) is a rapid initial screen. For research or severe cases, use the clinician-administered (cut-off ≥20) or (cut-off ≥15).
  • •Exclude bipolar disorder by systematically asking about past manic/hypomanic episodes; use the as a screening tool. Misdiagnosis as unipolar MDD occurs in up to 40% of bipolar cases and leads to inappropriate antidepressant monotherapy that may worsen outcomes.
  • •Assess suicide risk using the . Key risk factors include prior attempts, childhood trauma, substance use disorder, borderline personality disorder, and chronic pain (Mendelian randomization OR 1.67). A score ≥4 on the Scale for Suicidal Ideation indicates clinically significant ideation requiring urgent intervention.
  • •Consider differential diagnoses: bipolar disorder (especially bipolar II with depressive onset), (dysthymia: ≥2 years of less severe symptoms), with depressed mood (within 3 months of stressor, resolves within 6 months), anxiety disorders, substance-induced depression, and medical conditions (hypothyroidism, diabetes, obstructive sleep apnea, dementia).
  • •In older adults, depression may present as cognitive decline (pseudodementia), somatic complaints, or irritability rather than sadness. Use the Two-Question Screen (sensitivity 91.8%, specificity 67.7%) or PHQ-9. In adolescents, irritability and social withdrawal are prominent; only fluoxetine is statistically superior to placebo as first-line pharmacotherapy.
  • •For peripartum women, screen for depression during pregnancy and postpartum using the PHQ-9 (USPSTF B recommendation). Brief interpersonal psychotherapy (IPT) during pregnancy reduces MDD risk by 80% and should be offered as first-line for mild-to-moderate symptoms.

Management

  • •For mild depression (HAM-D <23), initiate psychotherapy alone as first-line: , , or . Antidepressants have minimal benefit over placebo at this severity level.
  • •For moderate to severe depression (HAM-D ≥25), initiate pharmacotherapy with an SSRI or SNRI: 10 mg/day, titrate to 20 mg/day; 50 mg/day, titrate to 200 mg/day; or 37.5 mg/day, titrate to 225-375 mg/day. Titrate to target dose over 2-4 weeks and continue for at least 4-8 weeks before assessing response.
  • •For pediatric MDD (age 12-18), use as first-line: start 10 mg/day, target 20 mg/day. It is the only antidepressant statistically superior to placebo in this age group. For adolescents with SSRI-resistant depression, switch to a second SSRI plus CBT (response rate 54.8% vs medication switch alone 40.5%).
  • •For peripartum depression, offer brief IPT during pregnancy. If pharmacotherapy is needed, SSRIs (sertraline, escitalopram) are preferred. Avoid lithium in the first trimester due to increased risk of major malformations (7.4% vs 4.3% in mood disorder reference group).
  • •For older adults, is best tolerated (lowest discontinuation rates). Antidepressant benefit is most pronounced in those with illness duration >10 years and HAM-D ≥21 (NNT=4). Consider in older adults with insomnia to prevent incident depression (NNT=7).
  • •Initiate psychotherapy concurrently with pharmacotherapy for moderate/severe depression. CBT and BA are equally effective at 12 months (PHQ-9 mean difference 0.1 points). Sequential psychotherapy (adding CBT after medication response) reduces relapse risk (pooled RR 0.84).
  • •For treatment-resistant depression (failure of ≥2 adequate trials), augment with an atypical antipsychotic: 2.5-10 mg/day, 42 mg/day, or 1-3 mg/day. The VAST-D trial favored aripiprazole augmentation over bupropion switch (28.9% vs 22.3% remission at 12 weeks).
  • •Alternative augmentation strategies: (target serum level 0.6-1.2 mEq/L) or 50-300 mg/day. The lithium vs quetiapine trial found quetiapine superior for depressive symptom burden over 12 months. augmentation (mean dose 2.3 mg) reduced QIDS-SR16 by 6.4 points vs 2.4 with placebo.
  • •For treatment-resistant depression with inadequate response to oral agents, refer for nasal spray: 56 mg or 84 mg twice weekly, combined with a new oral antidepressant. Effect size is modest (0.15-0.23 at weeks 2-4), similar to atypical antipsychotics. Real-world safety data over 58 months showed no new signals; sedation and dissociation occur in 34.7% and 41.0% of sessions, respectively.
  • •For acute suicidal ideation in MDD, administer 0.5 mg/kg over 40 minutes. It reduces suicidal ideation (Scale for Suicidal Ideation) by 4.96 points more than midazolam at 24 hours (Cohen's d=0.75; NNT=4 for ≥50% reduction). 0.5-0.9 mg/kg twice weekly for 4 weeks induces remission in 19.6% vs 2.0% with midazolam (OR 12.1).
  • •For patients who fail pharmacotherapy, refer for neuromodulation: or are non-inferior to each other (HRSD-17 improvement of ~10 points in both). remains the most effective acute treatment for severe depression, with offering better cognitive safety (autobiographical memory worsening 2.7% vs 20% with ECT).
  • •Maintenance therapy: continue antidepressants for at least 6-12 months after remission to prevent relapse (NNT=6). For patients with ≥3 lifetime episodes, indefinite maintenance is recommended. Flexible-dose regimens are more protective than fixed-dose (OR 0.30 vs 0.41).
  • •What NOT to do: do not use antidepressants alone for mild depression (HAM-D <23); do not prescribe omega-3 monotherapy (low quality evidence); do not rely on probiotics or multinutrient supplements for prevention or treatment; do not use venlafaxine as first-line in adolescents (higher adverse events); do not use antidepressants without psychotherapy in SSRI-resistant adolescent depression; do not use non-dihydropyridine CCBs (diltiazem, verapamil) in heart failure patients with depression.
  • •Monitor for adverse effects: SSRIs/SNRIs can cause nausea, sexual dysfunction, insomnia, and QT prolongation (citalopram, escitalopram). Antipsychotic augmentation requires baseline and periodic metabolic monitoring: weight, fasting glucose, lipids, HbA1c at 12 weeks and annually. Perform screening at baseline and every 6-12 months for tardive dyskinesia.
  • •Refer to psychiatry when: diagnosis is uncertain (especially rule-out bipolar disorder), failure of ≥2 adequate treatment trials, presence of psychotic features, catatonia, acute suicidal risk requiring hospitalization, or patient preference for ECT, ketamine, or esketamine therapy.
  • •Discharge criteria for inpatient care: resolution of imminent suicide risk, stabilization of psychotic symptoms (if present), establishment of outpatient follow-up within 7 days, completed safety plan with means restriction, and tolerability of the medication regimen.

Board Review — High Yield

  • •STAR*D, Cumulative remission across four treatment steps is 67%, but per-step success declines from 36.8% to 13.0%; 30% of patients never remit.
  • •PHQ-9, Score ≥10 has 88% sensitivity and 88% specificity for MDD; the two-question PHQ-2 (score ≥3) is a rapid screen.
  • •Melancholic features, Anhedonia, psychomotor disturbance, diurnal mood variation (worse in morning), early morning awakening, guilt; predicts better response to ECT.
  • •Atypical features, Mood reactivity (brightens with positive events), leaden paralysis, hypersomnia, hyperphagia, rejection sensitivity; associated with higher metabolic syndrome risk.
  • •Ketamine, IV 0.5 mg/kg over 40 min reduces suicidal ideation within 24 h (NNT=4); subcutaneous 0.5-0.9 mg/kg twice weekly for 4 weeks produces remission in 19.6% of TRD.
  • •Esketamine, Nasal spray 56-84 mg twice weekly for TRD; modest effect size (0.15-0.23) similar to atypical antipsychotics; sedation and dissociation in 34-41% of sessions.
  • •Fluoxetine, Only antidepressant proven effective in pediatric MDD; NNT=10 for response, NNH=143 for suicidal ideation/attempt.
  • •Sertraline, Best tolerated in older adults (lowest discontinuation rates); antidepressant benefit limited to those with illness duration >10 years and HAM-D ≥21 (NNT=4).
  • •CBT-I, Cognitive behavioral therapy for insomnia prevents incident/recurrent depression in older adults with insomnia (HR 0.51, NNT=7).
  • •Bipolar screen, 40% of MDD patients have subthreshold hypomania; always screen with Mood Disorder Questionnaire before starting antidepressants to avoid mood destabilization.

Deep Dive — Evidence Details

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