Major Depressive Disorder (MDD)

1. Definition

• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 5022

2. Epidemiology

• MDD is one of the leading causes of disability worldwide
• Lifetime prevalence: approximately 15-17% in the general population; twice as common in women
• Mean age of onset: late 20s, but can occur at any age
• Without treatment, depression recurs in 50% of cases after a first episode; after three or more episodes, the odds of recurrence exceed 90%
• About 1-in-6 patients follow a chronic, unremitting course
• A milder but persistent form - dysthymia (Persistent Depressive Disorder) - affects approximately 2% of adults
• Neuroscience: Exploring the Brain, 5th Ed., p. 1968

3. DSM-5-TR Diagnostic Criteria

• Symptoms cause clinically significant distress or impairment in social, occupational, or other areas
• Not attributable to substances or another medical condition
• Not better explained by schizoaffective disorder or other psychotic disorders
• No history of manic or hypomanic episode (otherwise bipolar)
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, Table 13.3-3, p. 5023
• Rosen's Emergency Medicine, p. 5140

4. Clinical Features by Domain

Mood

Psychomotor Disturbance

• Psychomotor retardation: slowed thinking, speaking, and physical movement, with delayed responses
• Psychomotor agitation: fidgeting, pacing, hand-wringing, restlessness

Vegetative (Neurovegetative) Symptoms

• Sleep: insomnia (difficulty initiating, frequent awakening, early morning awakening) OR hypersomnia (12-14+ hours/day)
• Appetite: significant weight loss or gain
• Sexual function: loss of libido (not a formal DSM criterion but clinically common)

Cognitive Symptoms

• Impaired concentration, forgetfulness, impaired executive functioning
• Negatively biased thought content: ruminations on guilt, failure, worthlessness, self-criticism
• In severe cases: inability to perform basic activities of daily living
• Rosen's Emergency Medicine, pp. 5143-5166

5. Specifiers (Important for Prognosis and Treatment)

• Kaplan and Sadock's Synopsis of Psychiatry, pp. 1172-1173

6. Pathophysiology

A. Monoamine Hypothesis (Classical)

• Reserpine (depletes monoamines) causes depression
• All effective antidepressants enhance monoamine signaling
• Monoamine oxidase inhibitors (MAOIs), which prevent monoamine breakdown, are antidepressant

B. Neurotrophic Hypothesis (Modern)

• Stress decreases BDNF (Brain-Derived Neurotrophic Factor) in the hippocampus
• Chronic stress causes atrophy and death of CA3 hippocampal neurons in animal models
• MRI studies show small but consistent reduction in hippocampal volume in patients with depression and PTSD
• Antidepressants (SNRIs, SSRIs) upregulate BDNF and CREB (a cAMP-dependent transcription factor) over 10-20 days - a time course matching their clinical latency
• Exogenous BDNF in the hippocampus has antidepressant effects in animal models

C. HPA Axis Dysregulation

• Chronic stress activates the hypothalamic-pituitary-adrenal (HPA) axis, elevating cortisol
• Hypercortisolemia is neurotoxic to hippocampal neurons
• Blunted cortisol awakening response is seen in seasonal affective disorder

D. Anterior Cingulate Cortex Dysfunction

• The anterior cingulate cortex (ACC) is a key area regulating mood and executive function
• Functional neuroimaging shows ACC hypoactivity in depression, partly reversed by treatment
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, pp. 553-554
• Neuroscience: Exploring the Brain, 5th Ed., p. 1968

7. Differential Diagnosis

8. Comorbidities

• Anxiety disorders (most common comorbidity - up to 50-60%)
• Substance use disorders (especially alcohol)
• Chronic pain, cardiovascular disease, diabetes
• In adolescents: conduct disorder, oppositional defiant disorder
• Suicide: all depressed patients must be assessed for suicidal ideation; active suicidal ideation with a plan requires urgent intervention

9. Suicidality - Essential Assessment

• Passive: "I wish I weren't here" / life not worth living
• Active: specific plan with intent

10. Treatment

Step 1: Severity Assessment

• Less severe (mild): Prefer psychological treatments first - CBT, behavioral activation, mindfulness, interpersonal psychotherapy (IPT), exercise
• Moderate-to-severe: Antidepressants indicated, often combined with psychotherapy

Step 2: Pharmacotherapy

• Onset of action: 2-6 weeks (do not switch prematurely)
• Full trial: 4-6 weeks at therapeutic dose
• After remission: continue for at least 6 months to prevent relapse
• Recurrent episodes or high-risk: continue for ≥2 years
• Discontinue very gradually to avoid discontinuation syndrome (flu-like symptoms, electric shock sensations, anxiety)
• Network meta-analysis of 21 antidepressants found all superior to placebo; SSRIs have similar efficacy but differ in tolerability
• SSRIs show greatest benefit in severe depression; benefit over placebo is modest in mild-to-moderate illness

Step 3: Psychotherapy

• CBT (Cognitive Behavioral Therapy): Challenges negative thought patterns; as effective as medication for mild-moderate depression; combined CBT + pharmacotherapy superior to either alone for severe depression
• Interpersonal Psychotherapy (IPT): Addresses relationships and role transitions
• Behavioral Activation: Particularly effective; focuses on re-engagement with rewarding activities
• Psychodynamic therapy: Insight-oriented; evidence base growing

Step 4: Treatment-Resistant Depression (TRD)

• Maudsley Prescribing Guidelines in Psychiatry, 15th Ed., pp. 560-607
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, pp. 5151+

11. Special Populations

Children and Adolescents

• Same DSM-5 criteria, but irritability may substitute for depressed mood
• Somatic complaints, psychomotor agitation, and mood-congruent hallucinations are more prominent in prepubertal children
• Adolescents: antisocial behavior, substance use, school failure, peer rejection sensitivity
• Psychotic depression is rare prepuberty but present in ~50% of psychotically depressed adolescents
• Childhood-onset MDD tends to be most severe and runs in families with high rates of mood disorders and alcohol use disorder

Pregnancy / Peripartum

• MDD is common during pregnancy and postpartum
• Treatment decisions require careful weighing of risks to fetus/infant vs. risk of untreated depression
• SSRIs are generally preferred if pharmacotherapy is necessary
• Kaplan and Sadock's Synopsis of Psychiatry, pp. 567+

12. Course and Prognosis

• A single major depressive episode typically lasts weeks to months (rarely >2 years without treatment)
• Recurrence is the rule: 50% recur after first episode; >90% after three episodes
• Poor prognostic indicators: psychotic features, early onset, melancholic features, comorbid anxiety/substance use, chronic medical illness, poor social support, inadequate initial treatment
• Mood disorders beginning in childhood tend to be most chronic and severe

Summary Diagram

MDD OVERVIEW
├── DIAGNOSIS: ≥5/9 symptoms for ≥2 weeks (must include depressed mood OR anhedonia)
│   └── SIG E CAPS mnemonic
├── PATHOPHYSIOLOGY
│   ├── Monoamine deficiency (5-HT, NE, DA)
│   ├── BDNF/hippocampal atrophy
│   ├── HPA axis dysregulation (hypercortisolemia)
│   └── Anterior cingulate dysfunction
├── SPECIFIERS: Melancholic, Psychotic, Atypical, Seasonal, Peripartum
├── TREATMENT
│   ├── Mild: CBT, behavioral activation, exercise first
│   ├── Moderate-severe: SSRI (1st line) ± psychotherapy
│   ├── Maintenance: 6 months minimum; ≥2 years if recurrent
│   └── TRD: Augmentation, ECT, esketamine, rTMS
└── RED FLAG: Always assess suicidality

• Kaplan and Sadock's Synopsis of Psychiatry (primary psychiatry reference)
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry
• Maudsley Prescribing Guidelines in Psychiatry, 15th Ed.
• Rosen's Emergency Medicine, Concepts and Clinical Practice
• Neuroscience: Exploring the Brain, 5th Ed.
• Goldman-Cecil Medicine, International Edition