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Major Depressive Disorder (MDD) - A Complete Lesson

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1. Definition

• Bipolar disorder - by the absence of any manic/hypomanic episodes
• Dysthymia (Persistent Depressive Disorder) - milder but more chronic (>2 years)
• Schizoaffective disorder - by the absence of psychotic episodes outside depressive episodes
• Grief - generally milder and time-limited

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2. Epidemiology

• Goldman-Cecil Medicine, p. 3757

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3. Diagnostic Criteria (DSM-5)

Threshold for diagnosis:

• Minimum 5 of 9 symptoms present
• At least 1 of the 5 must be either depressed mood OR anhedonia
• Present most of the day, nearly every day, for a minimum of 2 consecutive weeks
• Causing significant distress or functional impairment
• Not due to substance effects or another medical condition
• Goldman-Cecil Medicine, Table 362-3, p. 3757-3758

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4. Symptom Groupings (Conceptual)

• Depressed mood, sadness, tearfulness
• Irritability (especially in children and elderly)
• Anxiety
• Anhedonia (loss of interest or pleasure)

• Worthlessness, lowered self-esteem
• Guilt
• Hopelessness/nihilism
• Helplessness
• Thoughts of death, suicide

• Appetite and weight changes
• Sleep disturbance (often early morning awakening in melancholia)
• Anergia
• Decreased libido
• Concentration difficulty
• Diurnal variation (worst in mornings - most characteristic pattern)

• Ruminative thinking
• Somatic complaints (especially in children)
• Psychotic features (mood-congruent negativistic delusions in severe cases)

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5. Specifiers (DSM-5)

Severity

Clinical Subtypes

Course Specifiers

• In partial remission / full remission (0 symptoms for 2 months)
• Single episode vs. Recurrent (no manic episodes)
• Kaplan and Sadock's Synopsis of Psychiatry, p. 1172-1177

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6. Pathobiology

Genetic Factors

• Account for approximately 40% of risk for depression
• Polygenic: multiple gene loci involved in complex interplay with developmental and environmental influences
• A landmark 2025 trans-ancestry GWAS identified 697 genetic associations implicating specific cell types and pharmacotherapy targets (PMID 39814019)

Monoamine Hypothesis

Receptor and Neurotrophin Hypothesis

• Monoamine depletion triggers compensatory upregulation of postsynaptic receptors (e.g., increased serotonin-2 receptors in frontal cortex - found postmortem in suicide victims)
• Downstream signaling involves the cAMP-CREB pathway and upregulation of BDNF (Brain-Derived Neurotrophic Factor)
• Antidepressants upregulate BDNF and CREB in the hippocampus over 10-20 days - a timeline that matches their delayed therapeutic onset
• Chronic stress leads to atrophy and death of hippocampal neurons (especially CA3), and MRI studies show reduced hippocampal volume in depression and PTSD - possibly due to chronically elevated cortisol

HPA Axis Dysregulation

• The hypothalamic-pituitary-adrenal axis is hyperactive in depression
• Evidenced by a nonsuppressed response to the dexamethasone suppression test (DST)
• Note: DST is too insensitive and nonspecific for routine clinical diagnostic use
• Chronically elevated cortisol may directly cause hippocampal atrophy

Neuroimaging Findings

• Smaller hippocampal volumes
• Altered cerebral metabolic activity in frontal-striatal circuitry and the anterior cingulate cortex

Cognitive/Psychosocial Factors

• Dysfunctional negative thinking patterns (Beck's cognitive triad: negative views of self, world, and future)
• These cognitive distortions are both risk markers and manifest more severely during episodes
• Stressful life events, especially "exit events" (deaths, separations, loss of function), are powerfully associated with onset
• Goldman-Cecil Medicine, p. 3757; Kaplan & Sadock's Comprehensive Textbook of Psychiatry, p. 553-554

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7. Diagnosis

Screening Tools

Over the past 2 weeks, how often have you:

1. Had little interest or pleasure in doing things?
2. Felt down, depressed, or hopeless?

Differential Diagnosis

• Bipolar disorder (requires manic episode history)
• Schizoaffective disorder (psychosis outside depressive episodes)
• Major depression secondary to medical illness (hypothyroidism, Cushing's, Parkinson's, stroke)
• Delirium or dementia with depressive features
• Substance-induced depressive disorder
• Grief/bereavement (normal if time-limited)

Key Lab Tests (to rule out secondary causes)

• TSH (hypothyroidism)
• CBC, metabolic panel
• Cortisol (if Cushing's suspected)
• Toxicology screen

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8. Course and Prognosis

• Episodes can last months to years if untreated; milder community cases may remit spontaneously in a few months
• Recurrence is the rule: risk of a second episode after the first is ~50%; after two episodes, ~70%; after three, ~90%
• Childhood/adolescent onset tends to be the most severe form with higher family loading and higher rates of comorbid conduct disorder, substance use
• Mood disorders beginning early tend to be chronic and functionally impairing across all domains (school, work, relationships)

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9. Special Populations

Children and Adolescents

• Depressed mood may present as irritability rather than sadness
• Somatic complaints and psychomotor agitation are prominent
• Anhedonia, psychomotor retardation, delusions are less common than in adults but increase with age
• Adolescents: watch for oppositional behavior, substance use, academic failure, social withdrawal
• Children can report emotions but may say "mad" rather than "sad"

Elderly

• Irritability, somatic focus, cognitive complaints may dominate over classical sadness
• Depression complicating dementia requires careful management

Perinatal

• Postpartum depression is common (6-13%)
• Requires risk-benefit analysis of antidepressant use in pregnancy/breastfeeding

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10. Treatment

Step 1: Assess Severity

• Mild-moderate: psychotherapy alone or medication, guided by patient preference and psychosocial stressors
• Severe/melancholic: medication required; psychotherapy insufficient as sole treatment
• Psychotic features: antidepressant + antipsychotic (combination more effective than either alone)
• Suicidal/severely disabled: psychiatric consultation; hospitalization may be indicated

Psychotherapies

Pharmacotherapy

• Antidepressants typically take 1-2 weeks to start working, with maximal benefit at 6-8 weeks - patients need close monitoring (every 1-2 weeks initially)
• Agents targeting both NE and 5-HT (SNRIs) may be more efficacious in severe depression
• Black box warning: increased risk of suicidal behavior in adolescents and young adults (age <25) - careful benefit/risk assessment and close monitoring required. This risk is NOT increased in adults >25 and is REDUCED in older adults.

Somatic/Neuromodulation Therapies

• Goldman-Cecil Medicine, p. 3758-3759

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11. Comorbidities

• Anxiety disorders (very common co-occurrence)
• Chronic pain - a 2025 meta-analysis found high prevalence of depression in chronic pain patients (PMID 40053352)
• Substance use disorders (especially alcohol; chicken-and-egg relationship)
• Cardiovascular disease (bidirectional relationship)
• Diabetes (SSRIs used in maintenance phase significantly increase depression-free intervals)
• Personality disorders

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12. Quick Summary Table

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• Goldman-Cecil Medicine International Edition, Chapter 362, pp. 3757-3759
• Kaplan and Sadock's Synopsis of Psychiatry, pp. 567-568, 1172-1177
• Kaplan & Sadock's Comprehensive Textbook of Psychiatry, pp. 553-554
• Stahl's Essential Psychopharmacology, pp. 279-280
• PubMed: Esketamine meta-analysis (PMID 39876682), GWAS of depression (PMID 39814019), Depression in chronic pain (PMID 40053352)

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How to Write a Mental Status Examination (MSE)

"The MSE provides the clinician with a snapshot of the patient's mental status at the time of the interview and is useful for subsequent visits to compare and monitor changes over time."

• Kaplan and Sadock's Synopsis of Psychiatry

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Structure of the MSE

1. Appearance
2. Behavior / Psychomotor Activity
3. Attitude Toward Examiner
4. Speech
5. Mood
6. Affect
7. Thought Process
8. Thought Content
9. Perceptions
10. Cognition (Orientation, Memory, Attention, Fund of Knowledge, Abstraction, Calculations)
11. Insight
12. Judgment

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Domain-by-Domain Guide

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1. Appearance

• Does the patient appear their stated age, older, or younger?
• Is dress appropriate for the context and season?
• Are there tattoos, scars, body jewelry, or disfigurements?
• How is grooming and hygiene? (Can reflect level of self-care and functioning)

• "A well-groomed, appropriately dressed woman appearing her stated age of 34."
• "An unkempt male with disheveled hair, body odor, and mismatched clothing, appearing older than his stated age of 28."
• "A thin female in a hospital gown with multiple well-healed forearm scars."

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2. Behavior / Psychomotor Activity

• Normal vs. bradykinesia (slowed - seen in depression, Parkinson's) vs. hyperkinesia (agitated - seen in mania, anxiety)
• Gait, posture, freedom of movement
• Tics, tremors, restlessness, pacing, hand-wringing
• Tardive dyskinesia (lip-smacking, tongue protrusions) - adverse drug effects
• Akathisia (motor restlessness) - antipsychotic side effect
• Psychomotor agitation (wringing hands, inability to sit still) vs. retardation (visibly slowed movement and speech)

• "Psychomotor retardation noted with slowed movements and long latency before answering questions."
• "Marked psychomotor agitation - patient was unable to remain seated, pacing and wringing hands."
• "No abnormal involuntary movements observed."

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3. Attitude Toward Examiner

• "Cooperative and forthcoming throughout the interview."
• "Guarded and suspicious, reluctant to elaborate on responses."
• "Initially resistant but became progressively more cooperative as the interview progressed."

Note: If a patient was brought involuntarily, some uncooperativeness at the start is appropriate and understandable - document this context.

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4. Speech

• Word-finding difficulties / paraphasic errors
• Poverty of speech (brief, empty responses)
• Thought blocking (sudden mid-sentence stops)
• Language: Is the patient fluent in the language of the interview?

• "Speech is normal in rate, rhythm, volume, and prosody."
• "Speech is pressured, rapid, and difficult to interrupt."
• "Hypophonic with decreased rate and increased latency; monotonous tone."

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5. Mood

• Mood: "Sad" (patient's own words).
• Mood: "Fine" per patient, though behavior was inconsistent with this report.
• Mood: "I feel like I'm on top of the world" (patient's words).

Mood is reported by the patient - it is subjective. Never substitute your observation for the patient's words here.

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6. Affect

• Flat: Severely restricted range - almost no emotional expression (classic in schizophrenia)
• Blunted: Reduced but not absent emotional expression
• Restricted/Constricted: Mildly reduced range
• Labile: Rapid, abrupt shifts in affect (mania, personality disorders, TBI)
• Inappropriate: Affect mismatched with context (laughing at a funeral)
• Incongruent: Affect mismatched with described mood/thought content (describing a death with laughter)

• "Affect is dysphoric, restricted in range, appropriate to content, and congruent with stated mood of sadness."
• "Affect is flat with no emotional range observed throughout the interview."
• "Affect is labile, shifting from tearfulness to laughter without apparent trigger."
• "Affect is bright and euphoric, mood-incongruent with expressed concerns about hopelessness."

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7. Thought Process

• "Thought process is linear, logical, and goal-directed."
• "Thought process is circumstantial with frequent tangents but able to return to topic with redirection."
• "Thought process is loose with frequent derailment; associations are not logically connected."

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8. Thought Content

A. Delusions

B. Obsessions and Compulsions

• Obsessions: unwanted, ego-dystonic, repetitive intrusive thoughts the patient resists
• Compulsions: repetitive ritualized behaviors performed to neutralize anxiety

C. Phobias

D. Suicidal Ideation (SI)

• "Denies suicidal ideation, homicidal ideation, or intent to harm self or others."
• "Reports passive suicidal ideation ('I wish I were dead') without active plan or intent."
• "Endorses active suicidal ideation with a specific plan to overdose on medications; states high intent."

E. Homicidal Ideation (HI)

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9. Perceptions

• Auditory (most common in psychosis): command voices, conversing voices, commenting voice
• Visual (more common in delirium, substance intoxication)
• Tactile (delirium tremens, cocaine: formication - bugs crawling on skin)
• Olfactory / Gustatory (temporal lobe epilepsy)
• Somatic / Cenesthetic

• "Denies auditory, visual, or other hallucinations."
• "Reports auditory hallucinations - a male voice commenting on his actions approximately 3-4 times per day."
• "Reports visual hallucinations of small animals at night, suggestive of alcohol withdrawal."

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10. Cognition

A. Level of Consciousness

B. Orientation

• Person: "What is your name?"
• Place: "Where are you right now? What city are we in?"
• Time: "What is today's date? What month? What year? What day of the week?"

Time is usually the first to be lost in cognitive disorders.

C. Attention and Concentration

• Serial 7s: subtract 7 from 100 repeatedly (100, 93, 86...)
• Spell "WORLD" backwards
• Digit span (forward and backward)

D. Memory

E. Fund of Knowledge

• "Who is the current president/prime minister?"
• "Name 5 large cities."

F. Abstraction

• Similarities: "How are an apple and an orange alike?" (both are fruits - abstract; "both round" is concrete)
• Proverbs: "What does 'don't cry over spilled milk' mean?" (abstract vs. concrete/literal interpretation)

G. Calculations

• "If you have $10 and spend $3.50, how much do you have left?"
• Serial subtractions

H. Visuospatial (if clinically indicated)

• Draw a clock face, copy intersecting pentagons

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11. Insight

• "Good insight - patient recognizes he has depression and understands the need for treatment."
• "Limited insight - patient acknowledges feeling unwell but attributes all symptoms to work stress and denies a psychiatric diagnosis."
• "No insight - patient denies any psychiatric illness and believes others are fabricating his symptoms."

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12. Judgment

• "What would you do if you found a sealed, stamped envelope on the ground?" (pick it up and mail it = intact)
• "What would you do if you smelled smoke in a crowded theater?" (exit and alert others = intact)

• "Judgment is intact - patient described appropriate responses to hypothetical scenarios and demonstrated sound decision-making during the interview."
• "Judgment is impaired - patient described plans to stop all medications without medical guidance despite multiple prior hospitalizations from doing so."

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Sample MSE Write-Up (MDD patient)

Appearance: A thin, casually dressed female appearing older than her stated age of 32. Hair is unkempt; hygiene is fair.

Behavior/Psychomotor: Psychomotor retardation noted. Slowed movements, hunched posture, and long response latency throughout the interview.

Attitude: Cooperative but minimally engaged; maintained limited eye contact.

Speech: Hypophonic, decreased rate, with increased latency. Monotonous tone. No paraphasic errors.

Mood: "Empty" (patient's own words).

Affect: Flat, severely restricted in range, appropriate to context, congruent with stated mood.

Thought Process: Linear and goal-directed, though slowed.

Thought Content: No delusions or obsessions elicited. Passive suicidal ideation present ("I just want everything to stop") without plan, intent, or access to means. Denies homicidal ideation.

Perceptions: Denies auditory, visual, or other hallucinations. No illusions or dissociative experiences reported.

Cognition: Alert and fully oriented to person, place, and time. Attention intact (spells WORLD backwards correctly). Recalls 3/3 words immediately, 2/3 at 5 minutes. Fund of knowledge intact. Abstract thinking preserved (appropriate interpretation of proverbs). Calculations intact.

Insight: Partial - acknowledges feeling very low but attributes this to "just being weak."

Judgment: Mildly impaired - patient has been skipping medications for 3 weeks without consulting her physician.

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Common Pitfalls to Avoid

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• Kaplan and Sadock's Synopsis of Psychiatry, pp. 51-54 (main MSE chapter)
• Harrison's Principles of Internal Medicine 22E, pp. 3423-3424
• Goldman-Cecil Medicine, Chapter 362

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Hallucinations vs. Delusions

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Hallucinations - Deeper

"Hallucinations are perceptions in the absence of stimuli to account for them."

• Kaplan and Sadock's Synopsis of Psychiatry, p. 55

Types by sensory modality:

Subtypes of auditory hallucinations (important for MSE):

• Command hallucinations - voice telling the patient to do something (high risk if commanding self-harm)
• Commenting voices - voice narrating the patient's actions
• Conversing voices - two or more voices talking to each other (Schneider's first-rank symptom of schizophrenia)
• Second-person ("you are worthless") vs. third-person ("he is bad") voices

Not everything is a true hallucination:

• Illusion - a misperception of a real stimulus (hearing wind and thinking your name is being called - there IS a real stimulus, just misinterpreted)
• Hypnagogic/hypnopompic hallucinations - at the boundary of sleep and waking; can be normal
• Pseudohallucination - patient has insight that the perception is internally generated, not real

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Delusions - Deeper

"Delusions are false, fixed ideas that are not shared by others."

• Kaplan and Sadock's Synopsis of Psychiatry, p. 53

1. False - the content is not true
2. Fixed - cannot be changed with reasoning, evidence, or argument
3. Not culturally shared - it is not a belief held by the patient's cultural/religious group

Bizarre vs. Non-bizarre:

• Bizarre: physically impossible, completely outside the realm of reality (e.g., "Aliens removed my brain and replaced it with a radio receiver")
• Non-bizarre: false, but theoretically could happen (e.g., "My neighbor is poisoning my food") - the content is implausible but not impossible

Types of delusions:

Mood-congruent vs. mood-incongruent:

• Mood-congruent: content fits the mood (e.g., a depressed patient with a delusion of guilt - "I caused the drought because of my sins")
• Mood-incongruent: content doesn't fit the mood (a depressed patient with grandiose delusions) - suggests worse prognosis or comorbid primary psychotic disorder

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Key Distinctions Side by Side

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Can They Occur Together?

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Clinical Memory Hook

Hallucination = senses lying to you (you see/hear/feel something that isn't there) Delusion = mind lying to you (you believe something that isn't true)

• Hallucinations → Perceptions domain (what the patient experiences)
• Delusions → Thought Content domain (what the patient believes)
• Kaplan and Sadock's Synopsis of Psychiatry, pp. 53-55 (Thought Content, Perceptual Disturbances)
• Kaplan and Sadock's Synopsis of Psychiatry, pp. 1064-1066 (Delusional Disorder types)