Major depressive disorder is defined by the presence of at least one major depressive episode — a period of ≥2 weeks of depressed mood or anhedonia plus ≥4 additional symptoms causing clinically significant distress or functional impairment. [2] The following is a clinically focused summary organized for emergency medicine and primary care workflows.
The following figure from the RANZCP guidelines provides a comprehensive overview of the multifactorial nature of MDD, including symptoms, neurobiology, and illness course:
1. History
- Core symptoms (must have ≥1): Depressed mood most of the day nearly every day, or markedly diminished interest/pleasure (anhedonia) [2]
- Additional symptoms (need ≥4 more): Significant weight/appetite change, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue/loss of energy, worthlessness or excessive guilt, diminished concentration/indecisiveness, recurrent thoughts of death or suicidal ideation [2]
- Duration: Symptoms must persist ≥2 weeks, nearly every day, for most of the day [2]
- Presenting complaint may be somatic: In primary care, 45–95% of patients with MDD initially present with somatic symptoms such as pain, fatigue, or insomnia rather than depressed mood [4]
- Key HPI questions: Onset and timeline, triggers/stressors, prior episodes, prior treatment response, substance use, functional impairment (work, relationships, ADLs), diurnal variation
- Important negatives: Screen for manic/hypomanic episodes (to rule out bipolar disorder), psychotic symptoms, bereavement vs. MDD, substance use [2][5]
2. Alarm Features
- Active suicidal ideation with intent or plan, or recent suicide attempt [6]
- Active homicidal ideation [6]
- Psychotic symptoms (hallucinations, delusions — especially mood-congruent guilt/worthlessness themes) [6]
- Severe anorexia with weight loss posing health risk [6]
- Inability to maintain ADLs (grooming, eating, catatonia) [6]
- Psychomotor retardation so severe it approaches catatonia [2]
- Approximately 5% of primary care depression patients report frequent suicidal ideation on PHQ-9 item 9, carrying ~1% risk of self-harm or suicide attempt over 90 days [4]
3. Medications
Medications that can cause/worsen depressive symptoms: [7]
- Beta-blockers, barbiturates, glucocorticoids, anabolic steroids, statins, oral contraceptives, levodopa, methyldopa, opioids, fluoroquinolones, mefloquine, metronidazole
- Withdrawal from marijuana, sedatives, opiates, cocaine, or stimulants
First-line treatments: [7-8]
- SSRIs: Escitalopram (5–20 mg), sertraline (50–200 mg) — ranked highest for both efficacy and acceptability [4]
- SNRIs: Venlafaxine (75–225 mg), duloxetine (60–120 mg) — consider for comorbid pain or anxiety
- Bupropion (150–450 mg) — no sexual dysfunction; contraindicated in seizure disorder, bulimia/anorexia, alcohol/benzodiazepine withdrawal [7]
- Mirtazapine (15–45 mg) — useful for insomnia and poor appetite; causes weight gain and sedation
Key prescribing pearls
- Start at one-third to one-half the usual dose; titrate over 1–2 weeks [4]
- Optimal efficacy for SSRIs at the lower end of the licensed dose range (20–40 mg fluoxetine equivalents) [9]
- All antidepressants carry a black box warning for new-onset suicidal ideation/behavior, especially in young adults [4]
- All SGAs are contraindicated within 2 weeks of MAOI use [8]
- Avoid paroxetine and TCAs in elderly (anticholinergic burden → falls, delirium) [4]
- Serotonin syndrome risk with SSRIs/SNRIs — agitation, confusion, fever, tremors, seizures [7]
The following table from JAMA summarizes first-line pharmacotherapy options with dosing, adverse effects, and efficacy data:
4. Diet
- No specific dietary intervention is established as treatment for MDD, but Mediterranean-style diets have shown association with reduced depression risk in observational studies
- Alcohol should be minimized — it is a CNS depressant and worsens depressive symptoms; screen for problem drinking [5]
- Adequate hydration and nutrition are important, especially in patients with anorexia or significant weight loss
- Omega-3 fatty acids have been studied as complementary therapy with modest evidence [8]
- Caffeine may worsen insomnia and anxiety symptoms in MDD
5. Review of Systems
- Psychiatric: Anxiety symptoms (~40% comorbidity), panic attacks, obsessive thoughts, PTSD symptoms [4]
- Neurologic: Cognitive complaints (concentration, memory), headaches, psychomotor changes
- Sleep: Insomnia or hypersomnia, early morning awakening, sleep quality
- Endocrine: Fatigue, weight changes, cold intolerance (hypothyroidism), menstrual irregularities
- GI: Appetite changes, nausea, abdominal pain (somatic presentation)
- Pain: Chronic pain is both a risk factor and common comorbidity
- Substance use: Alcohol, cannabis, opioids, stimulants — both as cause and comorbidity
6. Collateral History and Family History
- Family history of depression confers 2–4× increased risk; heritability ~35–40% [2][10]
- Screen for family history of bipolar disorder (antidepressant monotherapy can precipitate mania) [4]
- Family history of suicide is an independent risk factor
- Collateral from family/friends is essential — patients may underreport symptoms, especially elderly patients [11]
- Assess social support, living situation, relationship quality, employment status, financial stressors
- Childhood adversity (abuse, neglect, domestic violence) is a potent risk factor [2][12]
7. Risk Factors
- Female sex (~2× prevalence vs. males) [10]
- Family history of MDD or bipolar disorder [2]
- Adverse childhood experiences — emotional, physical, sexual abuse; neglect [2][13]
- Neuroticism/negative affectivity as a temperamental trait [2]
- Comorbid psychiatric disorders: Anxiety, PTSD, substance use, eating disorders, personality disorders [2]
- Chronic medical illness: Cardiovascular disease, diabetes, cancer, chronic pain, neurologic conditions [14-15]
- Social determinants: Low income, unemployment, social isolation, food insecurity, intimate partner violence [13]
- Reproductive life stages in women: Premenstrual, postpartum, perimenopause [2]
- Insomnia and sleep disturbance [16]
- Smoking [16]
- Approximately 60% of young adult MDD cases are attributable to risk factors before age 18 [17]
8. Differential Diagnosis
- Bipolar disorder (type I or II) — at least 7% of primary care depression patients may have unrecognized bipolar disorder; screen for prior manic/hypomanic episodes [2][4]
- Adjustment disorder with depressed mood — symptoms arise within 3 months of identifiable stressor, do not meet full MDD criteria [12]
- Persistent depressive disorder (dysthymia) — depressed mood more days than not for ≥2 years [2]
- Depressive disorder due to another medical condition — hypothyroidism, Cushing's, Parkinson's, stroke, MS, B12 deficiency, pancreatic cancer [7][15]
- Substance/medication-induced depressive disorder — temporal relationship to substance use or medication [2]
- Normal bereavement/grief — if severe and persistent beyond acute grieving, consider MDD [12]
- Delirium or neurocognitive disorder — especially in elderly; cognitive screening is essential [7]
- Schizoaffective disorder, depressive type — psychotic symptoms with mood episodes [14]
- Anxiety disorders — significant symptom overlap; ~2/3 of MDD patients have clinical anxiety [12]
9. Past Medical History
- Prior depressive episodes (recurrence rate: 26% within 1 year, 76% within 10 years) [7]
- Prior treatment response and tolerability (guides medication selection) [6]
- History of suicide attempts
- History of manic or hypomanic episodes (rules out bipolar disorder)
- Chronic medical conditions: cardiovascular disease, diabetes, thyroid disease, chronic pain, cancer [14][18]
- Substance use history
- Surgical history (especially recent or disabling procedures)
- Medication list review — identify depressogenic medications [7]
10. Physical Exam
- Vital signs: Generally normal; check for tachycardia (anxiety), hypertension, weight changes
- General appearance: Psychomotor retardation or agitation, poor grooming, flat or tearful affect, poor eye contact, slowed speech
- Thyroid exam: Goiter or thyroid nodules (hypothyroidism mimic)
- Neurologic exam: Cognitive screening (especially in elderly), assess for focal deficits suggesting stroke or neurodegenerative disease
- Skin: Self-harm marks (cutting, burns), injection sites
- Mental status exam: Mood, affect, thought content (suicidal/homicidal ideation, guilt, worthlessness), thought process, cognition, insight, judgment
11. Lab Studies
Recommended initial labs: [6-7]
- CBC with differential (anemia)
- BMP (electrolytes, glucose, renal function)
- TSH (hypothyroidism — must be ruled out in all MDD patients) [5]
- Vitamin B12 and folate levels
Consider as clinically indicated: [7]
- Liver function tests
- Testosterone (in men)
- Urine drug screen / serum toxicology
- RPR (syphilis)
- HIV test
- Lyme titer (in endemic areas)
- Calcium (hyperparathyroidism)
The 2024 CANMAT guidelines note that laboratory tests should be considered only if history and physical examination suggest contributing medical conditions — there is no evidence supporting routine ECG, EEG, or neuroimaging for diagnosis. [19]
12. Imaging
- No routine imaging is recommended for the diagnosis of MDD [19]
- Consider brain MRI if focal neurologic deficits, cognitive decline disproportionate to depression, or suspicion of stroke/mass lesion
- Consider CT head in the ED for acute altered mental status or new neurologic findings
- Neuroimaging is reserved for atypical presentations or when ruling out structural pathology
13. Special Tests
Screening and severity tools
- PHQ-2 → if score ≥3, administer full PHQ-9 [4][20]
- PHQ-9 — sensitivity ~85%, specificity ~85% at cutoff ≥10 for MDD [4]
- 5–9: Mild | 10–14: Moderate | 15–19: Moderately severe | 20–27: Severe [21]
- Item 9 (suicidal ideation) should always be further assessed regardless of total score [21]
- Score ≥15 suggests need for active treatment [21]
- Columbia-Suicide Severity Rating Scale (C-SSRS) — for structured suicide risk assessment when suicidal ideation is endorsed [4]
- Geriatric Depression Scale (GDS) — useful in elderly populations [22]
- Mood Disorder Questionnaire — screen for bipolar disorder [23]
- GAD-7 — screen for comorbid anxiety [4]
14. ECG
- Not routinely indicated for MDD diagnosis [19]
- Obtain baseline ECG before starting citalopram (black box warning for QT prolongation at doses >40 mg) [4][7]
- Consider ECG before starting TCAs (risk of conduction abnormalities, QT prolongation)
- Monitor ECG if using antipsychotic augmentation (QTc prolongation risk)
- In the ED, ECG is essential if overdose is suspected (TCA overdose → wide QRS, arrhythmias)
15. Assessment
- MDD is a clinical diagnosis based on DSM-5 criteria: ≥5 of 9 symptoms for ≥2 weeks, with at least one being depressed mood or anhedonia, causing functional impairment [2]
- Severity stratification using PHQ-9 guides treatment intensity: [21]
- Mild (PHQ-9 5–9): Consider watchful waiting or CBT monotherapy
- Moderate (10–14): Pharmacotherapy or CBT monotherapy
- Moderately severe to severe (≥15): Pharmacotherapy ± psychotherapy; consider combination
- Atypical presentations include reactive mood, hypersomnia, increased appetite, weight gain, leaden paralysis [6]
- Melancholic features include marked psychomotor retardation, diurnal variation (worse in morning), early morning awakening, anorexia [6]
- Psychotic features occur in severe episodes — mood-congruent delusions of guilt, worthlessness, nihilism [6]
- Complications: Suicide (lifetime risk ~4% in MDD), substance abuse, functional disability, cardiovascular disease, chronic pain amplification [10]
16. Treatment Plan
Mild MDD: [8]
Moderate to severe MDD: [4][8]
- Monotherapy with CBT or a second-generation antidepressant (ACP strong recommendation)
- Combination CBT + antidepressant may be considered (ACP conditional recommendation)
- For severe or persistent depression, combination therapy improves outcomes over monotherapy (NNT = 3 for remission at 12 weeks) [24]
Pharmacotherapy approach: [4][7]
- Start low, titrate over 1–2 weeks to therapeutic dose
- Initial follow-up at 2 weeks, then every 4–6 weeks until remission
- If no benefit after 4 weeks at adequate dose → consider switching or augmentation
- Full symptom relief may take 8–12 weeks [7]
- After remission, continue antidepressant at therapeutic dose for ≥6 months [6]
- For high relapse risk (≥2 episodes, residual symptoms, severe/prolonged episodes) → maintenance treatment for ≥2 years [7]
Treatment-resistant depression (partial/no response after ≥2 adequate trials): [6][24]
- Augmentation with second-generation antipsychotic (aripiprazole, quetiapine) — increases remission but watch for akathisia, sedation, weight gain
- Ketamine/esketamine (Spravato) — FDA-approved for treatment-resistant depression and MDD with acute suicidal ideation [24-25]
- rTMS — NNT 5–7 for remission vs. sham [24]
- ECT — most effective intervention for severe, refractory MDD; indicated for catatonia, psychotic depression, severe suicidality, need for rapid response [6]
The following algorithm from American Family Physician outlines the stepwise approach to managing treatment-resistant depression:
17. Disposition
Criteria for inpatient psychiatric admission: [6][27]
- Active suicidal ideation with specific plan and means
- Recent suicide attempt
- Active homicidal ideation
- Psychotic symptoms
- Inability to maintain ADLs or care for self
- Severe catatonia
- When in doubt about need for admission, inpatient care is the prudent option [27]
Outpatient management appropriate when: [27]
- Suicidal ideation without intent, plan, or means
- Adequate social support
- Ability to contract for safety (though "no-harm contracts" are not evidence-based)
- Able to maintain ADLs and follow-up
Observation/partial hospitalization
Specialty consultation triggers: [4]
- Suicidal ideation with planning or intent
- Suspected bipolar disorder
- Psychotic features
- Treatment-resistant depression (≥2 failed adequate trials)
- Pregnancy with severe depression
- Need for ECT or esketamine
18. Follow Up / Return Precautions
Follow-up timing: [4][7]
- Initial contact at 2 weeks after starting treatment
- Subsequent visits every 4–6 weeks until remission
- After remission, continue monitoring every 1–3 months during maintenance phase
- Repeat PHQ-9 at each visit for measurement-based care [6]
Return precautions — instruct patients to seek immediate care for:
- New or worsening suicidal thoughts or self-harm urges
- Emergence of psychotic symptoms (hearing voices, paranoia)
- Symptoms of serotonin syndrome (agitation, confusion, rapid heart rate, fever, muscle rigidity)
- Inability to eat, drink, or care for self
- Symptoms of mania (decreased need for sleep, racing thoughts, impulsive behavior)
Patient counseling points
- Antidepressant improvement may not appear for 2–4 weeks; early side effects (nausea, headache) often subside in 1–2 weeks [4]
- Do not abruptly discontinue antidepressants — taper to avoid discontinuation syndrome (especially paroxetine, venlafaxine) [7]
- Up to 70% of patients may not achieve remission with the initial treatment attempt — this is expected and does not mean treatment has failed [8]
- Safety planning should include reducing access to lethal means (firearms, stockpiled medications) and identifying crisis resources (988 Suicide & Crisis Lifeline) [4]
- Expected recovery: Most patients improve within 8–12 weeks of adequate treatment; residual symptoms are common and should be addressed [7]
References
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