Major Depressive Disorder

Major Depressive Disorder (MDD) is the prototypical mood (affective) disorder, characterised by discrete episodes of pervasive low mood and/or anhedonia lasting at least two weeks, with associated neurovegetative and cognitive symptoms. It is one of the highest-yield Psychiatry topics for NEET PG — examiners love the DSM-5 criteria, the magic "2-week" cut-off, somatic/biological symptoms, and the crucial split from bipolar depression and persistent depressive disorder.

Definition & Core Concept

MDD is defined by the presence of one or more Major Depressive Episodes (MDE) without any history of a manic or hypomanic episode (the latter would reclassify the patient as bipolar). A single episode qualifies for the diagnosis; recurrence is common, with each successive episode increasing the risk of the next (the "kindling" phenomenon).

The two cardinal (core) symptoms are:

1. Depressed mood — most of the day, nearly every day.
2. Anhedonia — markedly diminished interest or pleasure in nearly all activities.

High-yield: At least one of the two cardinal symptoms (depressed mood OR anhedonia) MUST be present to diagnose an MDE. A patient with only neurovegetative symptoms but neither low mood nor anhedonia does not qualify.

DSM-5 Diagnostic Criteria (the SIG-E-CAPS approach)

To diagnose a Major Depressive Episode, ≥5 of 9 symptoms must be present during the same 2-week period, representing a change from previous functioning, and at least one symptom must be depressed mood or anhedonia.

The classic mnemonic is SIG E CAPS (a prescription "write S.I.G., energy capsules"):

Letter	Symptom	Notes
S	Sleep disturbance	Insomnia (esp. early-morning awakening / terminal insomnia) or hypersomnia
I	Interest loss (anhedonia)	Core symptom
G	Guilt / worthlessness	Excessive, inappropriate; may be delusional
E	Energy loss / fatigue	Even small tasks feel effortful
C	Concentration impaired	Indecisiveness, "pseudodementia" in elderly
A	Appetite / weight change	>5% body weight change in a month
P	Psychomotor agitation or retardation	Must be observable by others
S	Suicidality	Recurrent thoughts of death, ideation, plan, or attempt

Add the cardinal depressed mood, and you have all nine criteria (5 needed). Symptoms must cause clinically significant distress or functional impairment and not be attributable to a substance or another medical condition.

High-yield: The minimum duration is 2 weeks (most tested fact). Contrast with persistent depressive disorder/dysthymia = 2 years in adults (1 year in children/adolescents), and mania = 1 week, hypomania = 4 days.

Bereavement note: DSM-5 removed the bereavement exclusion. Grief after loss can coexist with — and should be distinguished from — an MDE. Grief comes in waves and centres on the deceased; MDE is pervasive and self-critical with persistent anhedonia.

Severity Grading (DSM-5)

Severity is graded by symptom count, intensity, and functional impairment:

Severity	Features
Mild	Few symptoms beyond the required 5; minor functional impairment
Moderate	Symptoms/impairment between mild and severe
Severe	Most symptoms present, markedly distressing, serious functional impairment; ± psychotic features

The PHQ-9 is the standard screening/severity tool (score 0–27): 5–9 mild, 10–14 moderate, 15–19 moderately severe, ≥20 severe. A PHQ-9 ≥10 has good sensitivity/specificity for MDD.

Clinical Subtypes / Specifiers

NEET PG repeatedly tests the melancholic vs atypical distinction and the existence of psychotic depression.

Specifier	Key Features
Melancholic	Anhedonia + non-reactive mood; diurnal variation (worse in morning), early morning awakening, marked psychomotor retardation, anorexia/weight loss, excessive guilt. Most "biological" subtype
Atypical	Mood reactivity preserved + ≥2 of: hyperphagia/weight gain, hypersomnia, leaden paralysis, long-standing interpersonal rejection sensitivity. Responds well to MAOIs
Psychotic	Delusions (often mood-congruent: guilt, nihilism, poverty) ± hallucinations. Nihilistic delusion = Cotard syndrome (belief that one is dead/organs rotting)
Catatonic	Stupor, mutism, posturing, waxy flexibility; responds to ECT/benzodiazepines
Peripartum onset	Onset in pregnancy or within 4 weeks postpartum
Seasonal pattern	Recurrent episodes in a particular season (usually winter); responds to bright light therapy
With anxious distress / mixed features	Mixed = subthreshold manic symptoms; raises bipolar suspicion

High-yield: Melancholic = worse in morning, early-morning waking, weight LOSS, anorexia. Atypical = mood reactivity, weight GAIN, hypersomnia, leaden paralysis, rejection sensitivity. A classic NEET PG one-liner pair.

High-yield: Cotard's syndrome (nihilistic delusion of being dead/non-existent) is associated with severe psychotic depression. Capgras (familiar person replaced by an imposter) is associated with schizophrenia/organic states — do not confuse.

Etiology & Pathophysiology

MDD is multifactorial — a biopsychosocial interplay.

Neurochemical (monoamine hypothesis): Deficiency of serotonin (5-HT), noradrenaline, and dopamine in synaptic clefts. This underpins SSRIs/SNRIs. However, the delayed (2–4 week) clinical response despite rapid monoamine rise suggests downstream neuroplastic changes (BDNF upregulation, hippocampal neurogenesis).

Neuroendocrine: HPA-axis hyperactivity is the most consistent finding — elevated cortisol, non-suppression on the dexamethasone suppression test (DST), and hippocampal atrophy with chronic cortisol exposure. Hypothyroidism is a key reversible mimic.

Genetic: Heritability ~40%; first-degree relatives have a 2–3× risk. Concordance higher in monozygotic twins.

Sleep architecture: Reduced REM latency, increased REM density, decreased slow-wave (deep) sleep — characteristic neurophysiological markers.

Psychosocial: Early adverse childhood experiences, recent loss/stressors, learned helplessness (Seligman), Beck's cognitive triad (negative view of self, world, and future).

High-yield: In depression, REM latency is decreased (REM comes sooner after sleep onset) and slow-wave sleep is reduced. The DST shows cortisol non-suppression.

Clinical Features

• Psychological: Persistent sadness, anhedonia, hopelessness, helplessness, worthlessness, guilt, suicidal ideation, poor concentration/indecisiveness.
• Biological/somatic: Sleep disturbance, appetite/weight change, fatigue, psychomotor change, loss of libido, diurnal mood variation, constipation.
• Elderly: May present as pseudodementia (reversible cognitive impairment) — important reversible cause of memory complaints; patients say "I don't know" rather than confabulate, and have preserved orientation with poor effort.
• Children/adolescents: Mood may be irritable rather than sad; somatic complaints, declining grades.
• Masked depression: Predominant physical complaints (headache, GI symptoms) hiding the mood disorder.

Diagnosis & Investigation of Choice

MDD is a clinical diagnosis based on DSM-5 criteria and history — there is no confirmatory lab test. Investigations are to exclude organic mimics, not to diagnose MDD.

Investigations to rule out secondary causes:

• Thyroid function tests (TSH) — hypothyroidism is the classic reversible mimic.
• CBC (anaemia), fasting glucose, renal/liver function, vitamin B12 and D, calcium.
• ECG before TCAs (QT prolongation risk).
• Toxicology/substance screen if indicated; neuroimaging only if focal signs or atypical/late-onset presentation.

Screening tools: PHQ-9 (most used), Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HAM-D) for clinician-rated severity, Montgomery–Åsberg (MADRS).

High-yield: The single most important "rule-out" investigation before labelling MDD is TSH (hypothyroidism). For severity tracking in research/exams, HAM-D; for primary-care screening, PHQ-9.

Management

A stepwise, severity-based approach is favoured:

Mild MDD → psychotherapy (CBT/IPT) first-line, ± watchful waiting. Moderate–severe MDD → antidepressant + psychotherapy (combination superior to either alone). Severe/psychotic/suicidal/catatonic → consider ECT (most effective acute treatment); add antipsychotic if psychotic.

Pharmacotherapy — Drug of Choice

High-yield: SSRIs are the first-line drug of choice for MDD (favourable safety in overdose, tolerability). Escitalopram and sertraline are often cited as best balance of efficacy and tolerability.

Class	Examples	Key Points / Side Effects
SSRI (first-line)	Fluoxetine, sertraline, escitalopram, paroxetine, fluvoxamine	Nausea, sexual dysfunction, initial anxiety; fluoxetine = longest half-life (safe to stop abruptly); paroxetine = most anticholinergic + worst discontinuation; citalopram/escitalopram = QT prolongation
SNRI	Venlafaxine, duloxetine	Useful with comorbid pain; venlafaxine raises BP at high dose
Atypical	Bupropion (no sexual dysfunction, helps smoking cessation; lowers seizure threshold — avoid in eating disorders/epilepsy); Mirtazapine (sedation, weight gain — good for insomnia + poor appetite); Trazodone	Tailored to symptom profile
TCA	Amitriptyline, imipramine, nortriptyline, clomipramine	Effective but lethal in overdose (cardiotoxic — 3 C's: Coma, Convulsions, Cardiotoxicity/arrhythmia); anticholinergic
MAOI	Phenelzine, tranylcypromine, moclobemide	Reserved for atypical/treatment-resistant; tyramine "cheese reaction" → hypertensive crisis; serotonin syndrome risk

Stepwise pharmacotherapy flow: Start SSRI at therapeutic dose → wait 4–6 weeks for full response (lag period) → if partial response, optimise/increase dose → if no response, switch to another agent (different class) → if still inadequate, augment (lithium, atypical antipsychotic e.g. aripiprazole, T3/liothyronine) or combine → consider ECT for resistance/emergency.

Duration of treatment:

• First episode: continue antidepressant for 6–9 months (up to 1 year) after remission (continuation phase) to prevent relapse.
• Recurrent (≥2–3 episodes) or chronic: maintenance therapy for years to lifelong.

High-yield: Antidepressants take 2–4 weeks to begin working and 4–6 weeks for full effect. Energy/psychomotor activity may improve before mood — paradoxically increasing suicide risk early in treatment. Monitor closely, especially in young adults (<25 yrs, black-box warning).

Treatment-Resistant Depression (TRD)

Failure of ≥2 adequate antidepressant trials. Options: augmentation (lithium, antipsychotic, T3), ECT, esketamine (intranasal NMDA antagonist — rapid antidepressant/anti-suicidal effect), rTMS, vagus nerve stimulation.

ECT — most tested non-drug fact

High-yield: ECT is the most effective treatment for severe MDD, and the treatment of choice when: active suicidality, severe psychotic depression, catatonia, refusal to eat/drink, pregnancy (safe), or treatment resistance. The only absolute contraindication classically cited is raised intracranial pressure (e.g., space-occupying lesion); recent MI is relative. Main side effect = transient anterograde + retrograde amnesia.

Complications

• Suicide — the gravest complication; lifetime suicide risk in mood disorders is significant. Assess SAD PERSONS / intent, plan, means.
• Chronicity and recurrence; functional/occupational decline.
• Comorbid substance use ("self-medication").
• Increased cardiovascular morbidity/mortality.
• Treatment-emergent serotonin syndrome (with serotonergic combinations) and discontinuation syndrome (abrupt SSRI/SNRI stop — flu-like, dizziness, "brain zaps").
• Switch to mania on antidepressants → reveals underlying bipolar disorder.

Key Differentials

Condition	Distinguishing Feature
Persistent depressive disorder (dysthymia)	Chronic, low-grade depression ≥2 years; never symptom-free >2 months; less severe than MDE
Bipolar depression	Past manic/hypomanic episode; earlier onset, atypical features, family history, postpartum onset, psychosis, antidepressant-induced switch
Adjustment disorder with depressed mood	Clear stressor, onset within 3 months, does not meet full MDE criteria
Bereavement / grief	Loss-centred, comes in waves, self-esteem usually preserved
Hypothyroidism	Fatigue, weight gain, cold intolerance; TSH raised — reversible
Dementia (vs pseudodementia)	Dementia: insidious, confabulates, conceals deficits; pseudodementia: acute, "don't know" answers, prior psychiatric history
Premenstrual dysphoric disorder (PMDD)	Symptoms confined to luteal phase, resolve with menses
Substance/medication-induced	Steroids, beta-blockers, interferon, alcohol, reserpine

High-yield: The single most important differential to actively exclude in any depressed patient is bipolar disorder — always screen for a past manic/hypomanic episode, because giving an antidepressant alone to a bipolar patient can precipitate a manic switch or rapid cycling.

Recently asked / exam angle

• Minimum duration for MDE = 2 weeks (perennial favourite; contrast with dysthymia 2 yr, mania 1 wk, hypomania 4 d).
• Number of symptoms needed = 5 of 9, with at least one core symptom (depressed mood/anhedonia).
• SIG E CAPS mnemonic asked directly.
• Melancholic vs atypical feature matching (diurnal variation/early-morning awakening/weight loss vs mood reactivity/hypersomnia/weight gain/leaden paralysis).
• First-line drug = SSRI; DOC for severe/psychotic/suicidal depression / pregnancy = ECT.
• Cotard's syndrome (nihilistic delusion) ↔ psychotic depression.
• REM latency decreased + DST cortisol non-suppression as biological markers.
• TCA overdose triad (Coma, Convulsions, Cardiotoxicity) and MAOI + tyramine = hypertensive crisis.
• Pseudodementia as a reversible cause of cognitive decline in the elderly.
• Antidepressant lag period (2–4 weeks) and early increased suicide risk.
• Fluoxetine = longest half-life; paroxetine = worst discontinuation/most anticholinergic; bupropion = least sexual dysfunction; mirtazapine = weight gain + sedation.

Rapid revision

1. MDE = ≥5/9 symptoms × ≥2 weeks, with ≥1 being depressed mood or anhedonia.
2. Two cardinal symptoms: depressed mood and anhedonia — at least one mandatory.
3. Mnemonic SIG E CAPS: Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor, Suicidality (+ mood).
4. Melancholic = worse in morning, early-morning waking, weight loss, guilt; most biological.
5. Atypical = mood reactivity, weight gain, hypersomnia, leaden paralysis, rejection sensitivity → responds to MAOIs.
6. Cotard = nihilistic delusion of being dead → psychotic depression.
7. Biological markers: ↓REM latency, ↓slow-wave sleep, DST non-suppression (↑cortisol).
8. First-line drug = SSRI (escitalopram/sertraline); response lag 4–6 weeks.
9. ECT = most effective; DOC for suicidality, psychotic/catatonic, pregnancy, refusal to eat, resistance; CI = raised ICP.
10. Always exclude bipolar disorder (past mania/hypomania) before antidepressant monotherapy — risk of manic switch.
11. TCA overdose = Coma, Convulsions, Cardiotoxicity; MAOI + tyramine = hypertensive (cheese) crisis.
12. First episode: treat 6–9 months after remission; recurrent episodes → long-term maintenance. Always rule out hypothyroidism (TSH).