Residency · Residency · Psychiatry
Major Depressive Disorder: Diagnosis and Evidence-Based Treatment
Diagnostic Criteria and Assessment
DSM-5-TR Criteria
Five or more of the following symptoms present during the same 2-week period, representing a change from previous functioning; at least one must be (1) or (2): Depressed mood most of the day, nearly every day. Markedly diminished interest or pleasure (anhedonia) Significant weight change (>5% in a month) or appetite change. Insomnia 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, or suicide attempt. Symptoms cause clinically significant distress or functional impairment. Not attributable to substance use or another medical condition. Not better explained by a psychotic disorder. No history of manic or hypomanic episodes (which would indicate bipolar disorder)
Severity Specifiers
Mild: few symptoms beyond criteria threshold; minor functional impairment. Moderate: symptoms and functional impairment between mild and severe. Severe: many symptoms beyond threshold; marked functional impairment. With psychotic features: mood-congruent (themes of guilt, worthlessness, disease, death) or mood-incongruent delusions/hallucinations. With anxious distress: tension, restlessness, worry, fear of losing control; associated with poorer prognosis and treatment response. With melancholic features: anhedonia, worse in the morning, early morning awakening, psychomotor changes, anorexia/weight loss, excessive guilt; may preferentially respond to TCAs/SNRIs and ECT. With atypical features: mood reactivity, increased appetite/weight gain, hypersomnia, leaden paralysis, rejection sensitivity; historically responsive to MAOIs. With peripartum onset: onset during pregnancy or within 4 weeks postpartum. With seasonal pattern: recurrent episodes with consistent seasonal onset/remission.
Validated Rating Scales
| Scale | Type | Items | Scoring | Clinical Utility |
|---|---|---|---|---|
| PHQ-9 | Self-report | 9 | 0-27 (>=10 moderate, >=20 severe) | Measurement-based care; free; 2 minutes |
| HAM-D | Clinician-rated | 17 | >=17 moderate, >=24 severe | Gold standard in clinical trials |
| MADRS | Clinician-rated | 10 | 0-60 (>=20 moderate, >=35 severe) | More sensitive to change than HAM-D |
| PHQ-2 | Self-report | 2 | 0-6 (>=3 positive screen) | Ultra-brief screener; sensitivity ~80% |
| C-SSRS | Clinician-administered | Variable | Categorical (ideation, plan, behavior) | Suicide risk quantification |
PHQ-9 (Patient Health Questionnaire-9): self-report; 9 items mapping to DSM criteria; scores 0-27; >=10 suggests moderate depression; widely used in primary care and measurement-based care. HAM-D (Hamilton Depression Rating Scale): clinician-rated; 17-item version most common; >=17 moderate, >=24 severe; gold standard in clinical trials. MADRS (Montgomery-Asberg Depression Rating Scale): clinician-rated; 10 items; more sensitive to change than HAM-D; preferred in many clinical trials. PHQ-2: ultra-brief 2-item screener (depressed mood + anhedonia); sensitivity ~80%; useful for initial screening. Columbia Suicide Severity Rating Scale (C-SSRS): should accompany depression assessment to quantify suicidal ideation and behavior.
Differential Diagnosis
Psychiatric Differentials
Bipolar depression: screen for prior manic/hypomanic episodes in every patient presenting with depression; use Mood Disorder Questionnaire (MDQ) if suspected. Persistent depressive disorder (dysthymia): chronic (>=2 years) depressed mood; may have superimposed MDD episodes ("double depression") Adjustment disorder with depressed mood: symptoms in response to identifiable stressor; does not meet full MDD criteria. Bereavement/prolonged grief disorder: new DSM-5-TR entity; differentiate from MDD.
Medical Differentials
Hypothyroidism, Cushing syndrome, hyperparathyroidism. Anemia, vitamin B12/folate deficiency. Obstructive sleep apnea. Chronic infections (hepatitis C, HIV) Neurological: Parkinson disease (can precede motor symptoms), multiple sclerosis, stroke. Medications: beta-blockers, corticosteroids, interferon-alpha, isotretinoin. Substance-induced: alcohol, benzodiazepines, opioids.
Baseline Workup for New-Onset Depression
TSH, CBC, CMP, vitamin B12, folate. Consider: testosterone (males with fatigue/low libido), cortisol (if Cushing suspected), RPR, HIV. Urine drug screen if substance use suspected.
Evidence-Based Treatment
First-Line Treatment Selection
Mild depression: psychotherapy alone (CBT or IPT) is appropriate; pharmacotherapy optional. Moderate-severe depression: pharmacotherapy, psychotherapy, or combination; combination is superior to either alone. Severe with psychotic features: antidepressant + antipsychotic combination, or ECT. All severities: exercise, sleep hygiene, behavioral activation as adjuncts.
Measurement-Based Care
Systematic use of validated rating scales at every visit to guide treatment decisions. Target: >=50% reduction in PHQ-9 or HAM-D score = response; remission = PHQ-9 <5 or HAM-D <=7. If <50% improvement at 4-6 weeks at adequate dose, consider dose optimization, augmentation, or switch. STAR*D framework: sequential treatment steps with measurement at each stage.
The STAR*D Trial
Largest effectiveness trial in MDD (4,041 patients, 4 sequential treatment levels) Level 1: citalopram monotherapy -- 33% remission rate. Level 2: switch or augment -- remission rates 25-30% regardless of strategy. Level 3: further switch or augment -- diminishing returns (~12-20% remission) Level 4: tranylcypromine vs. combination venlafaxine + mirtazapine -- ~10-15% remission. Cumulative remission: ~67% after all 4 levels, but with significant dropout. Key lessons: remission is the goal, not just response; most patients require more than one treatment trial; measurement-based care improves outcomes.
Psychotherapy
CBT: most robust evidence base; addresses cognitive distortions and behavioral inactivation. IPT (Interpersonal Therapy): focuses on grief, role transitions, interpersonal disputes, interpersonal deficits. Behavioral Activation: component of CBT that is effective as standalone; may be easier to disseminate. Psychodynamic therapy: evidence for mild-moderate depression; addresses underlying conflicts and relational patterns. Combination pharmacotherapy + psychotherapy: most effective approach for moderate-severe depression (Keller et al. 2000; Cuijpers et al. meta-analyses)
<image> A measurement-based care flowchart for MDD treatment. Start with "MDD diagnosed, PHQ-9 baseline." Show the treatment algorithm: first-line SSRI/SNRI initiation, PHQ-9 assessment at 4-week intervals. Branch based on response (>=50% reduction), partial response (25-49%), or non-response (<25%). For each branch, show next steps: dose optimization, augmentation strategies, or switch. Include remission target (PHQ-9 <5) and the STAR*D sequential levels as a parallel reference. Clean clinical algorithm format with color-coded decision nodes. </image>
<image> A Venn diagram showing the overlap and distinction between MDD subtypes: melancholic features, atypical features, anxious distress, and psychotic features. In each section, list the key symptoms, preferred treatment approaches, and prognosis. Show the overlapping regions where features may co-occur. Include a sidebar listing the DSM-5-TR specifiers with brief definitions. Medical education style with clear labeling. </image>
<image> A bar graph showing cumulative remission rates from the STAR*D trial across the four treatment levels. Level 1 shows ~33%, Level 2 adds ~25%, Level 3 adds ~15%, Level 4 adds ~10%, with cumulative total ~67%. Include dropout rates at each level and the time to remission. Annotate with the treatments used at each level. Include a clinical implication callout: "Most patients need more than one treatment trial." Clean data visualization style. </image>
Clinical Pearls
Always screen for bipolar disorder before starting an antidepressant -- antidepressant monotherapy in bipolar depression can trigger mania or rapid cycling. The PHQ-9 is free, validated, takes 2 minutes, and should be used at every visit -- measurement-based care improves outcomes compared to clinical judgment alone. Melancholic depression may respond preferentially to TCAs, SNRIs, or ECT rather than SSRIs -- consider the subtype when selecting treatment. The "adequate trial" standard is 4-6 weeks at the maximum tolerated therapeutic dose -- anything less is not a fair test of the medication. Residual symptoms after treatment (especially insomnia, fatigue, and cognitive dysfunction) predict relapse -- push for full remission, not just response. After a first depressive episode, maintenance treatment for at least 6-12 months after remission; after 2+ episodes or severe episode, consider indefinite maintenance. STAR*D showed that the specific medication matters less than systematic measurement-based care and willingness to adjust treatment.
References
- Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STARD report. Am J Psychiatry*. 2006;163(11):1905-1917.
- Cipriani A, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder. Lancet. 2018;391(10128):1357-1366.
- APA Practice Guidelines for the Treatment of Major Depressive Disorder. 3rd ed. American Psychiatric Association; 2010.
- Cuijpers P, et al. A meta-analysis of cognitive-behavioural therapy for adult depression, alone and in comparison with other treatments. Can J Psychiatry. 2013;58(7):376-385.
- Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-613.
- Trivedi MH, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STARD. Am J Psychiatry*. 2006;163(1):28-40.
