major depressive disorders

**DEFINITION / DSM-5 CRITERIA** - ≥5 of 9 symptoms during the same 2-week period, representing a change from baseline. At least one must be depressed mood or anhedonia (loss of interest/pleasure). - Mnemonic SIG E CAPS: Sleep changes (insomnia or hypersomnia), Interest loss (anhedonia), Guilt/worthlessness, Energy loss, Concentration problems, Appetite/weight change, Psychomotor retardation or agitation, Suicidal ideation. - Symptoms cause clinically significant distress or impairment, and are not attributable to a substance or medical condition (e.g., hypothyroidism). There must be no history of mania or hypomania, or the diagnosis becomes bipolar disorder. - Specifiers: with melancholic features, atypical features, psychotic features, peripartum onset, seasonal pattern, catatonia, anxious distress.

**EPIDEMIOLOGY / RISK FACTORS** - Lifetime prevalence is about 15–20%. Women are affected about 2x as often as men. Mean age of onset is in the 20s. - Risk factors: family history, prior episodes, early-life adversity, chronic medical illness (stroke, MI, cancer, Parkinson disease), substance use, postpartum state, and social stressors.

**PATHOPHYSIOLOGY** - Monoamine hypothesis: decreased serotonin (5-HT), norepinephrine (NE), and dopamine (DA) in the synapse. - Neuroendocrine: HPA axis hyperactivity (elevated cortisol, nonsuppression on the dexamethasone suppression test). - Neurotrophic hypothesis: decreased BDNF with hippocampal atrophy. Also increased inflammatory cytokines and altered amygdala and prefrontal cortex activity. - Sleep architecture changes: decreased slow-wave sleep, decreased REM latency, and increased REM duration/density early in the night.

**CLINICAL SUBTYPES (HIGH-YIELD)** - Melancholic: early-morning awakening, diurnal variation (worse in the morning), marked anhedonia, excessive guilt, weight loss. - Atypical: mood reactivity, hypersomnia, hyperphagia/weight gain, leaden paralysis, rejection sensitivity. Classically responds well to MAO inhibitors. - Psychotic: mood-congruent delusions or hallucinations. Treat with an antidepressant plus an antipsychotic, or ECT. - Seasonal pattern: winter onset. Treat with light therapy. - Peripartum: onset during pregnancy or within 4 weeks postpartum. This differs from "postpartum blues" (resolves within 2 weeks, no treatment needed) and postpartum psychosis (a psychiatric emergency).

**DIFFERENTIAL DIAGNOSIS** - Persistent depressive disorder (dysthymia): depressed mood most days for ≥2 years (≥1 year in children/adolescents), with less severe symptoms. - Bipolar disorder: any history of mania or hypomania. - Adjustment disorder: an identifiable stressor, with symptoms not meeting MDD criteria. - Normal bereavement: the DSM-5 allows an MDD diagnosis in the setting of grief if criteria are met. Prolonged grief disorder is a separate diagnosis. - Medical causes: hypothyroidism, anemia, Cushing syndrome, vitamin B12 deficiency, and medications (steroids, interferon, beta-blockers, isotretinoin, reserpine). - Substance-induced mood disorder.

**MANAGEMENT** - Mild to moderate: psychotherapy (CBT, interpersonal therapy) and/or an antidepressant. - Moderate to severe: an antidepressant, with or without psychotherapy. - First-line: SSRIs (fluoxetine, sertraline, escitalopram, citalopram, paroxetine). They are well tolerated and safe in overdose. Onset of effect is 2–6 weeks. Continue for 6–12 months after remission (longer, or indefinitely, for recurrent episodes). - SSRI adverse effects: sexual dysfunction, GI upset, insomnia/anxiety, and hyponatremia (SIADH, especially in the elderly). Serotonin syndrome (hyperthermia, clonus, hyperreflexia, diarrhea, agitation) occurs with combined serotonergic agents or MAOIs. Citalopram carries a dose-dependent QT-prolongation risk. Paroxetine has the most anticholinergic effects and the most teratogenic concern. - SNRIs (venlafaxine, duloxetine): useful with comorbid neuropathic pain or fibromyalgia. Venlafaxine can raise BP. - Bupropion (NDRI): no sexual side effects, aids smoking cessation, and causes weight loss. It lowers the seizure threshold, so avoid it in bulimia/anorexia and seizure disorders. - Mirtazapine (α2 antagonist): increases appetite and sedation. Useful in depressed patients with insomnia and weight loss. - Trazodone: used mainly for insomnia. Risk of priapism. - TCAs (amitriptyline, nortriptyline): "3 Cs" of toxicity (Convulsions, Coma, Cardiac arrhythmias), plus anticholinergic effects. Sodium channel blockade with a wide QRS is treated with sodium bicarbonate. - MAOIs (phenelzine, tranylcypromine): used for atypical depression. Risks are hypertensive crisis with tyramine-containing foods and serotonin syndrome. - Vortioxetine and vilazodone: multimodal agents with fewer sexual side effects. - ECT: most effective for severe, psychotic, catatonic, or treatment-resistant depression, and for acutely suicidal patients and pregnant patients. Adverse effects are transient retrograde amnesia and headache. There are no absolute contraindications, though raised ICP is a major relative one. - Treatment-resistant depression: augment with lithium, atypical antipsychotics (aripiprazole, quetiapine), or T3. Intranasal esketamine (an NMDA antagonist) and transcranial magnetic stimulation (TMS) are other options. Zuranolone and brexanolone (GABA-A modulators) are used for postpartum depression. - Black box warning: increased suicidal ideation in children, adolescents, and young adults (<25 years) starting antidepressants. Monitor closely.

**KEY CLINICAL POINTS** - Always screen for suicide risk. Risk factors: male sex, older age, prior attempts, a plan, access to firearms, substance use, and social isolation. Women attempt more often, but men complete more often. - Screening tools: PHQ-2 and PHQ-9. Screen for bipolar disorder (mania history) before starting an antidepressant, because monotherapy can precipitate mania. - Rule out organic causes with TSH, CBC, B12, and a metabolic panel. - Do not stop an antidepressant abruptly. SSRI discontinuation syndrome presents with flu-like symptoms, dizziness, and "brain zaps".