MDD

**Definition (DSM-5):** ≥5 of 9 symptoms for ≥2 weeks, representing a change from baseline, and including at least one of: (1) depressed mood or (2) anhedonia. Symptoms must cause clinically significant distress or impairment. They must not be attributable to a substance or medical condition (e.g., hypothyroidism). There must be no history of manic or hypomanic episodes (which would indicate bipolar disorder).

**Mnemonic: SIG E CAPS** - Sleep changes (insomnia or hypersomnia) - Interest loss (anhedonia) - Guilt/worthlessness - Energy loss - Concentration problems - Appetite/weight changes - Psychomotor agitation or retardation - Suicidal ideation

**Epidemiology:** Lifetime prevalence is about 15–20%. Women are affected about 2× as often as men. The median age at onset is in the 20s. Risk factors include family history, prior episodes, chronic illness, stressful life events, postpartum state, and substance use.

**Pathophysiology:** - The monoamine hypothesis proposes decreased serotonin (5-HT), norepinephrine (NE), and dopamine (DA) in the CNS. - Other findings: HPA-axis hyperactivity (elevated cortisol, nonsuppression on the dexamethasone suppression test), decreased hippocampal volume, and reduced BDNF. - Sleep architecture changes: decreased slow-wave sleep, **decreased REM latency**, and increased REM duration and density early in the night.

**Specifiers:** - Atypical features: mood reactivity, hypersomnia, hyperphagia, leaden paralysis, and interpersonal rejection sensitivity. MAOIs are particularly effective. - Melancholic features - Psychotic features: treat with an antidepressant plus an antipsychotic, or with ECT. - Catatonia - Peripartum onset (postpartum onset within 4 weeks per DSM-5) - Seasonal pattern

**Related disorders (high-yield differentials):** - Persistent depressive disorder (dysthymia): depressed mood ≥2 years, with fewer or milder symptoms. - Bipolar disorder: at least one manic or hypomanic episode. Always screen before starting an antidepressant. - Adjustment disorder: depressive symptoms within 3 months of an identifiable stressor, not meeting MDD criteria. - Normal bereavement: symptoms are tied to the loss, and self-esteem is usually preserved. - Medical mimics: hypothyroidism, anemia, vitamin B12 deficiency, and Cushing syndrome. - Medications: corticosteroids, interferon-α, and beta-blockers (controversial).

**Treatment:** - **First line:** SSRIs (fluoxetine, sertraline, escitalopram) and/or psychotherapy (CBT). SSRIs take about 4–6 weeks for full effect. Adverse effects include sexual dysfunction, GI upset, insomnia, and hyponatremia (SIADH). The main toxicity is serotonin syndrome (especially with MAOIs). - **SNRIs** (venlafaxine, duloxetine): useful with comorbid neuropathic pain. They may raise blood pressure. - **Mirtazapine:** helps with insomnia and poor appetite. It causes weight gain and sedation. - **Bupropion:** no sexual side effects and aids smoking cessation. It lowers the seizure threshold and is contraindicated in bulimia and seizure disorders. - **TCAs:** anticholinergic effects, cardiotoxicity (QRS widening), and overdose risk. Treat overdose with sodium bicarbonate. - **MAOIs:** used for atypical depression. Risks are hypertensive crisis with tyramine and serotonin syndrome. - **ECT:** most effective for severe, psychotic, catatonic, or treatment-resistant depression, and for acutely suicidal or pregnant patients. Adverse effects are anterograde and retrograde amnesia. No absolute contraindications exist, but raised intracranial pressure is a major concern. - **Esketamine** (intranasal) is used for treatment-resistant depression. **Brexanolone/zuranolone** (GABA-A modulators) are used for postpartum depression. - Rule out bipolar disorder before starting an antidepressant. Antidepressants carry an FDA boxed warning for increased suicidality in patients under 25.

**Clinical pearls:** - The highest suicide risk is in older white men and in patients with a plan, access to means, and hopelessness. Always ask directly about suicidal ideation. - Screening tools are PHQ-2 and PHQ-9. - Continue antidepressants for ≥6–12 months after remission. Patients with recurrent episodes may need long-term maintenance. - Treatment resistance means failure of ≥2 adequate antidepressant trials. Next steps include augmentation (e.g., lithium, atypical antipsychotics) or ECT. - Other uses of the abbreviation: "MDD" can also mean "Medical Device Directive" in a regulatory context, but on USMLE it nearly always means major depressive disorder.