Everything You Need to Know About Major depressive disorder for Step 1

Major depressive disorder (MDD) is one of those Step 1 diagnoses that seems “obvious” until a question stem starts mixing in sleep changes, guilt, poor concentration, vague somatic complaints, and the occasional psychotic feature. The key is to build a clean framework: what it is, why it happens, how it presents, how to diagnose, and how to treat—with the classic USMLE pitfalls (bipolar mislabeling, bereavement vs MDD, medication side effects, serotonin syndrome, and suicidality).

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What Is Major Depressive Disorder (MDD)?

Major depressive disorder is defined by $\ge 5$ depressive symptoms lasting $\ge 2$ weeks, representing a change from baseline, with at least one of:

• Depressed mood, or
• Anhedonia (loss of interest/pleasure)

Plus clinically significant distress/impairment, and not due to substances/medical conditions, and no history of mania/hypomania (that would suggest bipolar disorder).

The “SIGECAPS” Symptom List (High-Yield)

USMLE loves this mnemonic; think $\ge 5$ total:

• Sleep changes (insomnia or hypersomnia)
• Interest decreased (anhedonia)
• Guilt/worthlessness
• Energy decreased
• Concentration decreased
• Appetite/weight changes
• Psychomotor agitation or retardation
• Suicidal ideation

Step trap: Symptoms must be present most of the day, nearly every day, for at least 2 weeks.

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First Aid Cross-References (Where This Lives)

In First Aid for the USMLE Step 1 (Psychiatry):

• Mood disorders: MDD vs bipolar disorders (diagnostic differences; SIGECAPS)
• Antidepressants: SSRIs/SNRIs/TCAs/MAOIs, adverse effects, washout periods
• Neurotransmitters: serotonin, norepinephrine, dopamine associations
• Serotonin syndrome and hypertensive crisis (classic pharm stems)

(Edition/page numbers vary—use your book’s Psychiatry chapter headings above.)

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Epidemiology & Risk Factors (What They Like to Test)

Big-picture

• More common in women than men (roughly 2:1 in many cohorts)
• Peaks in early adulthood, but can occur at any age
• Often recurrent (prior episode is a strong predictor of future episodes)

High-yield risk factors

• Family history (genetic vulnerability)
• Female sex
• Chronic medical illness (e.g., CAD, stroke, diabetes, hypothyroidism)
• Substance use disorders
• Psychosocial stressors, trauma
• Postpartum period
• Certain medications (Step 1 classic: think mood symptoms after starting/using certain drugs)

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Pathophysiology (Step 1–Friendly Mechanisms)

Monoamine hypothesis (core testable concept)

MDD is associated with decreased monoamine neurotransmission, especially:

• Serotonin (5-HT)
• Norepinephrine (NE)
• (Sometimes emphasized) Dopamine (DA)

Antidepressants generally increase synaptic monoamines, but clinical improvement takes time due to downstream effects (receptor regulation and neuroplasticity).

Neuroendocrine & circuit-level changes (high-yield add-ons)

• HPA axis dysregulation → elevated cortisol patterns in some patients
• Sleep architecture changes:
  • Decreased REM latency (enter REM sooner)
  • Increased total REM
  • Decreased slow-wave sleep (often taught)
• Neurotrophic hypothesis: decreased BDNF and impaired neuroplasticity may contribute; antidepressants can increase BDNF over time

Inflammation association (increasingly tested conceptually)

Inflammatory cytokines may be elevated in subsets of depression and correlate with sickness behavior-like symptoms (fatigue, anhedonia).

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Clinical Presentation: How MDD Shows Up in Question Stems

Classic clues

• Persistent low mood, tearfulness
• Loss of interest in hobbies
• Trouble sleeping (often early morning awakening)
• Low energy, slowed movement/speech (psychomotor retardation)
• Poor concentration (“can’t focus at work/school”)
• Guilt, worthlessness

Somatic and “masked” depression

On exams, depression may present as:

• Headaches, abdominal pain
• Diffuse fatigue
• Multiple medical visits with minimal findings
  Especially common in patients who primarily report physical symptoms.

Melancholic vs atypical features (worth recognizing)

• Melancholic features: anhedonia, worse in the morning, early morning awakening, psychomotor changes, excessive guilt
• Atypical features: mood reactivity + hypersomnia, hyperphagia, leaden paralysis, rejection sensitivity
  These descriptors can guide stems but don’t change the basic diagnosis.

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MDD With Psychotic Features (High Yield)

Severe depression can include psychosis (delusions or hallucinations). Key test point: determine whether psychotic content is mood-congruent.

• Mood-congruent psychosis: themes of guilt, deserved punishment, nihilism, poverty, illness
  • Example: “I have committed unforgivable sins; I deserve to die.”
• Mood-incongruent psychosis: bizarre or not aligned with depressive themes (raises concern for schizoaffective disorder, schizophrenia, bipolar with psychosis depending on time course)

Treatment pearl: MDD with psychotic features often requires:

• Antidepressant + antipsychotic, or
• ECT (especially if severe, suicidal, catatonic, or refractory)

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Diagnosis: Criteria + Must-Not-Miss Differentials

Diagnostic criteria (tight summary)

MDD = $\ge 5$ SIGECAPS symptoms for $\ge 2$ weeks, including depressed mood or anhedonia, causing impairment, not substances/medical, and no mania/hypomania history.

Differential diagnosis table (USMLE-style)

What to screen for in vignettes (high-yield)

• Suicide risk: plan, intent, means, prior attempts, substance use
• Bipolar history: prior episodes of decreased need for sleep, grandiosity, pressured speech, risky behavior
• Medical mimics: hypothyroidism, anemia, medication side effects

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Treatment of MDD (Step 1 + Step 2 Relevant)

Core management approach

1. Psychotherapy (CBT, interpersonal therapy) for mild/moderate depression
2. Pharmacotherapy for moderate/severe depression or persistent symptoms
3. ECT for severe, refractory, catatonia, psychotic depression, or urgent suicidality

First-line medications (high-yield)

SSRIs are classic first-line.

• Examples: sertraline, escitalopram, fluoxetine, paroxetine, citalopram

SNRIs are also first-line.

• Examples: venlafaxine, duloxetine

Bupropion (NDRI) is a frequent board favorite.

• Useful when avoiding sexual side effects or when targeting low energy
• Avoid in seizures and eating disorders (lowers seizure threshold)

Mirtazapine (NaSSA)

• Sedating, increases appetite/weight gain
• Useful in depression with insomnia and low appetite

Second-line / special cases

TCAs (amitriptyline, nortriptyline, imipramine, clomipramine)

• Effective but more side effects, dangerous in overdose

MAOIs (phenelzine, tranylcypromine, selegiline)

• Reserved for atypical or treatment-resistant cases; dietary interactions

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Antidepressant Adverse Effects: What Step 1 Loves

SSRIs

• Sexual dysfunction
• GI upset
• Insomnia or activation (varies)
• Serotonin syndrome risk (especially with other serotonergic drugs)
• Discontinuation syndrome (notably paroxetine): flu-like symptoms, insomnia, irritability, “brain zaps”

SNRIs

• SSRI-like effects plus increased BP (especially venlafaxine)

Bupropion

• Activating, can worsen anxiety in some
• Seizures (dose-related); contraindicated in bulimia/anorexia nervosa

Mirtazapine

• Sedation
• Weight gain / increased appetite

TCAs (high yield overdose toxidrome)

• Antimuscarinic: dry mouth, urinary retention, constipation
• Antihistamine: sedation
• Alpha-1 block: orthostatic hypotension
• Cardiotoxicity: QRS widening, ventricular arrhythmias
  Treatment of TCA overdose: sodium bicarbonate

MAOIs (diet and drug interactions)

• Hypertensive crisis with tyramine (aged cheeses, cured meats, draft beer)
• Serotonin syndrome with serotonergic agents
  Washout: typically 2 weeks before switching to/from many serotonergic meds; 5 weeks for fluoxetine due to long half-life.

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Serotonin Syndrome vs Neuroleptic Malignant Syndrome (Classic Comparison)

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High-Yield Clinical Associations & Exam “Gotchas”

1) Always rule out bipolar disorder before starting antidepressants

A history of mania/hypomania shifts diagnosis to bipolar → antidepressant monotherapy can precipitate mania/rapid cycling.

2) Depression and medical illness: check the basics

Common testable labs/considerations:

• TSH (hypothyroidism mimic)
• CBC (anemia)
• Substance use (alcohol is a huge confounder)

3) Suicide risk: know the most predictive factors

• Prior attempt is one of the strongest predictors
• Substance use, access to lethal means, older age (men), severe hopelessness, psychosis

4) Psychotic depression is still a mood disorder

If psychosis occurs only during depressive episodes, think MDD with psychotic features—not schizophrenia.

5) Timing matters for schizoaffective disorder

Psychosis for $\ge 2$ weeks without mood symptoms → schizoaffective disorder (timeline is the whole question).

6) Sleep architecture clue

Depression: decreased REM latency + increased REM is a classic Step 1 association.

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Rapid-Fire USMLE Review (What to Remember Under Time Pressure)

• MDD = $\ge 5$ SIGECAPS, $\ge 2$ weeks, impaired functioning, no mania history
• Decreased monoamines (5-HT, NE ± DA); antidepressants increase monoamines but take time
• Decreased REM latency, increased REM
• First-line meds: SSRIs/SNRIs; also bupropion, mirtazapine
• MDD + psychosis: antidepressant + antipsychotic or ECT
• TCA overdose: wide QRS → sodium bicarb
• MAOI + tyramine: hypertensive crisis; serotonergic combos → serotonin syndrome
• Rule out bipolar before antidepressant monotherapy