Major depressive disorder (MDD) is the most prevalent mood disorder encountered in psychiatric and primary care, defined in DSM-5-TR by at least one major depressive episode of two or more weeks featuring depressed mood or anhedonia plus a constellation of neurovegetative, cognitive, and psychomotor symptoms. Lifetime prevalence in high-income countries approaches 15-20%, and MDD remains a leading global contributor to years lived with disability. The diagnosis hinges on careful exclusion of bipolarity, substance effects, and medical mimics; missing a hypomanic history is the single most consequential error and reshapes treatment entirely. First-line management combines an SSRI or SNRI with an evidence-based psychotherapy such as CBT or IPT, with neuromodulation reserved for treatment-resistant or severe presentations. Suicide risk is elevated across the course of illness and must be reassessed at every visit. The bottom line: MDD is heterogeneous, often recurrent, and most patients improve with structured, measurement-based care.

This article synthesizes current major guidelines (APA Practice Guideline for the Treatment of Patients with Major Depressive Disorder, NICE NG222, CANMAT 2016 with subsequent updates, BAP), Cochrane systematic reviews, landmark RCTs widely used in board preparation (STAR*D, EMBARC, the network meta-analysis of antidepressants by Cipriani and colleagues), and standard reference texts (DSM-5-TR, Stahl's Essential Psychopharmacology, Kaplan and Sadock's Synopsis of Psychiatry, the Maudsley Prescribing Guidelines). Search terms included "major depressive disorder," "antidepressant efficacy," "treatment-resistant depression," "ECT," "rTMS," "esketamine," "CBT depression," and "suicide risk depression." Inclusion was weighted toward guideline statements, meta-analyses, and trials cited in current ABPN and PRITE study materials. Date of literature pass: 2026-05-10.

MDD is common, female-predominant, and frequently begins in late adolescence or early adulthood. Comorbidity is the rule rather than the exception, and substance use and anxiety disorders sharply elevate suicide risk.

Prevalence

• 12-month prevalence in U.S. adults is approximately 8-10%; lifetime prevalence approximates 15-20%.^1-2
• Global point prevalence rose during the COVID-19 pandemic, with the largest increases among young adults and women.³

Demographics

• Female-to-male ratio is approximately 2:1, emerging in adolescence and persisting through midlife.¹
• Median age of onset is in the mid-20s, though first episodes occur across the lifespan.
• Prevalence is higher in separated, divorced, or widowed individuals and in those with lower socioeconomic status.

Comorbidity

• Anxiety disorders co-occur in roughly 50-60% of patients with MDD; the combination predicts greater chronicity and suicide risk.¹
• Alcohol and other substance use disorders co-occur in 20-30% of patients.
• Cardiovascular disease, diabetes, chronic pain, and stroke are bidirectionally linked with depression and worsen each other's prognosis.⁴

Risk factors

• Family history of mood disorder (heritability approximately 35-40%).⁵
• Early adversity, particularly childhood maltreatment.
• Female sex, postpartum period, and perimenopause.
• Chronic medical illness, especially neurologic disease and inflammatory conditions.
• Stressful life events in the prior six months, particularly losses and humiliations.

No single neurobiological lesion explains MDD; the disorder is best understood as the convergence of genetic vulnerability, neurodevelopmental trajectory, and environmental stress on overlapping monoaminergic, glutamatergic, neurotrophic, and circuit-level systems. The classic monoamine hypothesis remains a useful pharmacological scaffold but is insufficient on its own.

Neurotransmitter systems

• Monoamine hypothesis: deficient serotonin, norepinephrine, and dopamine signaling underpins symptoms; supported by efficacy of agents that enhance these systems but undermined by the delay between synaptic effects and clinical response.⁶
• Glutamatergic dysregulation: the rapid antidepressant action of NMDA antagonists such as ketamine implicates glutamate, AMPA-mediated synaptic potentiation, and downstream BDNF-mTOR signaling.⁷
• HPA-axis dysregulation: hypercortisolemia, dexamethasone non-suppression, and reduced hippocampal volume are observed in subsets of patients.⁸

Neurocircuitry

• Hyperactivity of the subgenual anterior cingulate (Brodmann area 25) and amygdala, with hypoactivity of dorsolateral prefrontal cortex.⁹
• Dysregulation of the default mode network with excessive self-referential rumination.
• Reduced hippocampal volume on structural MRI, partially reversible with treatment.

Genetics

• Twin heritability approximates 35-40%, lower than for bipolar I or schizophrenia.⁵
• GWAS have identified more than 100 loci of small effect; no single gene is diagnostic.¹⁰
• Gene-environment interactions, classically the serotonin-transporter (5-HTTLPR) by life-stress interaction, remain debated after replication failures.

Environmental and psychosocial factors

• Childhood abuse and neglect roughly double adult depression risk.
• Inflammatory states (post-MI, post-stroke, autoimmune disease) elevate risk and may attenuate antidepressant response.⁴
• Sleep disruption, social isolation, and unemployment are reciprocally linked with depressive episodes.

Integrative model

• Vulnerability (genetic and developmental) interacts with stressors to produce HPA-axis activation, monoaminergic and glutamatergic dysregulation, neuroinflammation, and circuit-level changes that manifest as the depressive syndrome.

DSM-5-TR requires at least five of nine symptoms during the same two-week period, representing a change from prior functioning, with at least one of the symptoms being depressed mood or loss of interest or pleasure. Symptoms must cause clinically significant distress or impairment and not be better explained by another condition or substance.¹¹

Core and associated symptoms (paraphrased)

• Depressed mood most of the day, nearly every day.
• Markedly diminished interest or pleasure (anhedonia).
• Significant weight or appetite change.
• Insomnia or hypersomnia.
• Psychomotor agitation or retardation observable by others.
• Fatigue or loss of energy.
• Feelings of worthlessness or excessive guilt.
• Diminished concentration or indecisiveness.
• Recurrent thoughts of death, suicidal ideation, plan, or attempt.

Required exclusions

• Episode is not attributable to a substance or another medical condition.
• No history of a manic or hypomanic episode (which would reclassify the patient as bipolar I or II).
• Symptoms are not better explained by a psychotic disorder.

DSM-5-TR specifiers

• With anxious distress, mixed features, melancholic features, atypical features, mood-congruent or mood-incongruent psychotic features, catatonia, peripartum onset, seasonal pattern.
• Severity: mild, moderate, severe.
• Course: single episode versus recurrent; in partial or full remission.

ICD-11 differences

• ICD-11 classifies single episode and recurrent depressive disorder separately and uses a slightly different symptom count, but core construct is concordant.¹²
• ICD-11 retains a "mixed depressive and anxiety disorder" category that has no DSM-5-TR equivalent.

The depressive syndrome shows considerable phenotypic variation, and recognizing prototypes accelerates both diagnosis and matched treatment selection. Course is often recurrent: roughly half of patients with a first episode have a second within five to ten years.

Symptom clusters

• Affective: pervasive sadness, tearfulness, irritability (especially in adolescents), anhedonia.
• Cognitive: rumination, guilt, hopelessness, impaired concentration, perceived cognitive slowing.
• Neurovegetative: insomnia (typically early-morning awakening) or hypersomnia, anorexia or hyperphagia, low energy.
• Psychomotor: retardation (slowed speech, latency, reduced movement) or agitation (pacing, hand-wringing).
• Somatic: nonspecific pain, gastrointestinal complaints, fatigue.

Prodrome and course

• Prodromal weeks to months of subsyndromal mood, sleep, and energy disturbance commonly precede a full episode.
• Untreated episodes typically last six to twelve months; treatment shortens duration and reduces symptom burden.
• Episodes recur in roughly 50% after one, 70% after two, and 90% after three lifetime episodes.¹³

Prototypical presentations

• Melancholic: profound anhedonia, terminal insomnia, marked psychomotor change, diurnal mood worsening (worse in the morning), excessive guilt, anorexia. Often responds preferentially to TCAs or ECT.
• Atypical: mood reactivity, leaden paralysis, hypersomnia, hyperphagia, rejection sensitivity. Historically associated with MAOI responsiveness.
• Anxious distress: prominent tension, restlessness, fear of losing control. Predicts poorer response and higher suicide risk.
• Psychotic depression: mood-congruent delusions of guilt, poverty, illness, or nihilism; requires antipsychotic plus antidepressant or ECT.¹⁴
• Peripartum onset: episode beginning during pregnancy or within four weeks postpartum (DSM-5-TR), though clinically relevant onset extends through the first postpartum year.
• Seasonal pattern: regular winter onset and spring-summer remission.

Atypical or under-recognized presentations

• Geriatric depression with prominent cognitive complaints ("pseudodementia").
• Pediatric depression with irritability rather than sadness.
• Masked depression presenting as somatic pain or unexplained fatigue.

Red flags

• Suicidal ideation with plan, intent, access to means, or rehearsal.
• Psychotic features.
• Catatonia.
• Recent precipitous functional decline.
• New-onset depression in older adults (rule out medical and neurologic causes).

The differential is broad because depressive symptoms are nonspecific. The two most consequential errors are missing bipolar disorder and missing a medical or substance-induced cause.

Mood disorder differential

• Bipolar I or II disorder: any prior manic or hypomanic episode reclassifies the diagnosis. Screen with a careful history and consider validated tools such as the MDQ.¹⁵
• Persistent depressive disorder (dysthymia): chronic depressed mood for two or more years with fewer required symptoms.
• Cyclothymic disorder: chronic mood instability not meeting MDE or hypomanic threshold.
• Premenstrual dysphoric disorder: symptoms confined to the luteal phase.
• Disruptive mood dysregulation disorder: chronic irritability with severe outbursts in children 6-18.
• Adjustment disorder with depressed mood: stressor-linked, subsyndromal, time-limited.

Other psychiatric conditions

• Generalized anxiety disorder, PTSD, OCD: overlapping cognitive and sleep symptoms; depression frequently comorbid.
• Schizoaffective disorder: psychotic symptoms in absence of mood symptoms for two or more weeks.
• Substance/medication-induced depressive disorder: alcohol, sedatives, stimulant withdrawal, interferon, corticosteroids, isotretinoin, propranolol, oral contraceptives in susceptible patients.
• Bereavement and prolonged grief disorder: identity around the deceased rather than pervasive worthlessness; yearning predominates over anhedonia.

Medical mimics to exclude

• Endocrine: hypothyroidism, hyperthyroidism (paradoxically presenting with depression in elderly), Cushing syndrome, Addison disease, hyperparathyroidism.
• Neurologic: Parkinson disease, stroke (especially left frontal), multiple sclerosis, dementia (Alzheimer, frontotemporal, vascular), traumatic brain injury, normal pressure hydrocephalus.
• Metabolic and nutritional: vitamin B12, folate, vitamin D deficiency; uremia; hyponatremia.
• Infectious and inflammatory: HIV, neurosyphilis, mononucleosis, lupus, post-COVID.
• Oncologic: pancreatic cancer (classic teaching), brain tumors, paraneoplastic syndromes.
• Obstructive sleep apnea: easily missed driver of treatment-resistant depression.

A structured interview augmented by a brief validated rating scale and targeted laboratory workup is sufficient for most patients. Imaging and extensive panels are reserved for atypical or red-flag presentations.

History essentials

• Full mood history including any past hypomanic or manic episodes; ask explicitly about decreased need for sleep, periods of unusual productivity, and impulsive behavior.
• Suicide assessment at every visit: ideation, intent, plan, means, prior attempts, family history, recent losses.
• Substance use, including alcohol, cannabis, and prescription stimulants and sedatives.
• Trauma and adverse childhood experiences.
• Medication review for depressogenic agents (corticosteroids, interferon, varenicline, isotretinoin, propranolol).
• Sleep history with attention to apnea symptoms.

Physical and mental status

• General exam targeting thyroid, cardiovascular, and neurologic findings.
• Mental status documentation of psychomotor state, speech, mood and affect, thought content (guilt, worthlessness, hopelessness, suicidality), thought process, perception, cognition, insight, and judgment.

Validated rating scales

• PHQ-9: nine-item self-report aligned to DSM symptom criteria; scores ≥10 suggest probable MDD; useful for screening and measurement-based care.¹⁶
• Hamilton Depression Rating Scale (HAM-D): clinician-administered, the standard outcome measure in trials.
• Montgomery-Åsberg Depression Rating Scale (MADRS): more sensitive to change than HAM-D for moderate-severe depression.
• Beck Depression Inventory (BDI-II): self-report emphasizing cognitive symptoms.
• Columbia Suicide Severity Rating Scale (C-SSRS): structured suicide risk assessment.
• MDQ: bipolar screen used when bipolarity is plausible.

Laboratory and imaging

• Routine: TSH, CBC, comprehensive metabolic panel, vitamin B12, vitamin D.
• Targeted: pregnancy test in reproductive-age women before pharmacotherapy, urine toxicology when substance use is suspected, HIV and RPR if risk factors, sleep study when apnea is suspected, ANA when autoimmune disease suggested.
• Neuroimaging only for new-onset late-life depression, focal neurologic findings, atypical course, or treatment resistance.

What not to order

• Routine MRI or PET.
• Genetic pharmacokinetic testing (CYP) for everyone — modest evidence; consider only after multiple antidepressant failures or unusual sensitivity patterns.¹⁷

Treatment selection follows severity, prior response, comorbidity, and patient preference. Most patients with mild-to-moderate MDD respond to either evidence-based psychotherapy or pharmacotherapy; combination is preferred for moderate-to-severe disease and is the standard for chronic or recurrent illness.^18-19 Measurement-based care, with repeated administration of a scale such as the PHQ-9, improves outcomes.²⁰

Pharmacotherapy

• First-line: SSRIs (sertraline, escitalopram, fluoxetine, citalopram, paroxetine) or SNRIs (venlafaxine, duloxetine). Strong evidence supports efficacy over placebo; comparative effectiveness among first-line agents is modest.^18,21
• Other first-line options: bupropion (no sexual dysfunction or weight gain; lowers seizure threshold), mirtazapine (sedating, appetite-stimulating, useful for insomnia and weight loss).
• Second-line and alternatives: vortioxetine, vilazodone, tricyclic antidepressants (nortriptyline, desipramine; cardiotoxic in overdose), MAOIs (phenelzine, tranylcypromine; dietary tyramine restrictions, drug interactions, washouts).
• Augmentation strategies for partial response: aripiprazole, quetiapine XR, brexpiprazole, olanzapine plus fluoxetine; lithium; thyroid hormone (T3); bupropion or mirtazapine added to an SSRI.²²
• Treatment-resistant depression (failure of two adequate trials): augmentation as above; intranasal esketamine with an oral antidepressant (FDA-approved for TRD); IV racemic ketamine (off-label, evidence growing); ECT.^23-24
• Adequate trial: target dose for at least 4-6 weeks before declaring failure; titrate by tolerability.
• STAR*D summary for residents: cumulative remission across four sequential steps reached approximately 67% in the original report, but each successive step had progressively lower remission and higher relapse, underscoring that early remission matters.²⁵

Psychotherapy

• First-line: cognitive behavioral therapy (CBT), interpersonal therapy (IPT), and behavioral activation. Strong evidence supports efficacy comparable to pharmacotherapy for mild-to-moderate depression.²⁶
• Other evidence-based options: mindfulness-based cognitive therapy (MBCT) particularly for relapse prevention; problem-solving therapy; short-term psychodynamic psychotherapy; cognitive behavioral analysis system of psychotherapy (CBASP) for chronic depression.
• Internet-delivered and guided self-help CBT have moderate evidence and expand access.

Neuromodulation

• Electroconvulsive therapy (ECT): highest acute efficacy of any antidepressant intervention; first-line for severe depression with psychotic features, catatonia, urgent suicidality, or pregnancy when medications are not preferred.²⁷
• Repetitive transcranial magnetic stimulation (rTMS): FDA-cleared for treatment-resistant depression; left dorsolateral prefrontal cortex high-frequency or theta-burst protocols; better tolerated than ECT but lower acute efficacy.²⁸
• Vagus nerve stimulation (VNS): FDA-approved for chronic or recurrent treatment-resistant depression; slow onset, modest sustained benefit.
• Deep brain stimulation (DBS): investigational; targets include subgenual cingulate and ventral capsule/ventral striatum.

Adjunctive

• Aerobic exercise: moderate evidence as adjunct; comparable effect size to some pharmacologic options for mild-to-moderate depression.²⁹
• Sleep regulation, light therapy (especially for seasonal pattern; expert opinion supports use in non-seasonal MDD as adjunct).
• Bright light therapy: evidence supports use for seasonal pattern depression; growing evidence for non-seasonal.
• Nutritional adjuncts (omega-3, methylfolate, SAMe): limited evidence; consider when conventional options are exhausted or contraindicated.
• Cannabidiol and psilocybin: emerging investigational, not currently recommended outside trials.

Antidepressants are generally well tolerated relative to older agents, but class-specific harms shape selection and adherence. The evidence base is large but skewed by short trial duration, exclusion of complex patients, and publication bias.

Common adverse effects

• SSRIs and SNRIs: nausea, headache, insomnia or somnolence, sexual dysfunction (often persistent), weight changes, sweating.
• Bupropion: insomnia, agitation, dry mouth, tremor.
• Mirtazapine: sedation, weight gain, dry mouth.
• TCAs: anticholinergic burden, orthostasis, weight gain.

Serious or rare adverse effects

• Hyponatremia (SIADH), particularly in elderly on SSRIs or SNRIs.
• Increased bleeding risk, magnified by NSAID or anticoagulant co-prescription.
• Serotonin syndrome with serotonergic combinations or MAOI overlap.
• Cardiac conduction effects: QT prolongation with citalopram (dose limits in older adults) and TCAs; arrhythmias and death in TCA overdose.
• Suicidality risk in patients under 25 (boxed warning).
• Bone density reduction with long-term SSRI use, magnitude debated.³⁰
• Esketamine and ketamine: dissociation, blood pressure spikes, bladder toxicity with chronic use.
• ECT: anesthesia-related risk, transient anterograde and retrograde amnesia, rare cardiovascular events.

Monitoring and discontinuation

• Reassess at 2 and 4 weeks after initiation; titrate toward target dose.
• Continue effective treatment for at least 6-12 months after remission for first episodes; longer or indefinite for recurrent or severe disease.¹⁸
• Discontinuation syndrome (flu-like symptoms, dizziness, "brain zaps," irritability) is common with short half-life agents (paroxetine, venlafaxine); taper slowly.

Limitations of the evidence base

• Most efficacy trials are 8-12 weeks, providing limited data on long-term outcomes.
• Trial populations exclude active substance use, suicidal ideation with intent, and significant medical comorbidity, limiting generalizability.
• Publication bias inflates apparent effect sizes; FDA reanalyses suggest smaller true effects than journal literature implies.³¹
• Comparative-effectiveness data among first-line antidepressants are modest; differences are typically smaller than within-patient response variability.

Several populations warrant tailored assessment and treatment, often centered on safety, dosing, and developmental stage.

Pediatric

• Fluoxetine and escitalopram are the only SSRIs with FDA approval for adolescent MDD; fluoxetine is approved down to age 8.³²
• TADS demonstrated superiority of combined fluoxetine plus CBT over either alone in adolescents.³³
• Boxed warning for increased suicidal ideation in patients under 25 mandates close monitoring.
• Irritability may dominate the presentation; collateral history from parents and school is essential.

Geriatric

• Late-life depression often features cognitive complaints, somatic preoccupation, and apathy; differentiate from major neurocognitive disorder, recognizing both can coexist.
• Start low and go slow; favor agents with low anticholinergic burden (sertraline, escitalopram, mirtazapine).
• Citalopram dose limited to 20 mg in patients over 60 due to QT concerns.
• Vascular depression (white matter hyperintensities, executive dysfunction) shows poorer response to standard agents and may benefit from rTMS or ECT.

Perinatal

• Untreated depression in pregnancy carries risks (prematurity, low birth weight, postpartum depression, impaired bonding) that must be weighed against medication exposure.³⁴
• Sertraline is commonly preferred during pregnancy and lactation due to extensive safety data.
• Paroxetine is generally avoided in the first trimester (cardiac malformation signal).
• Postpartum depression: brexanolone IV and zuranolone oral are FDA-approved; SSRIs and psychotherapy remain first-line for most patients.³⁵
• Screen all postpartum patients with the Edinburgh Postnatal Depression Scale (EPDS).

Comorbid medical illness

• Post-MI depression worsens cardiac outcomes; sertraline has favorable cardiac safety data (SADHART).³⁶
• Post-stroke depression: SSRIs are commonly used, with attention to bleeding risk.
• Chronic pain: duloxetine treats both depression and several pain conditions; TCAs at low doses help neuropathic pain.
• Cancer: depression is under-recognized; treat aggressively as it worsens adherence and outcomes.

Comorbid substance use

• Treat both disorders concurrently; depression in active substance use is common and often improves with sustained sobriety alone.
• Avoid bupropion in active alcohol withdrawal (seizure risk).
• Naltrexone, acamprosate, or buprenorphine for addiction co-management when indicated.

Cultural considerations

• Somatic complaints (fatigue, pain, GI symptoms) may predominate over reported mood in many cultural contexts.
• Idioms of distress (e.g., "nervios," "ataque de nervios") require culturally informed inquiry.
• Stigma may delay presentation and reduce adherence.

MDD is typically episodic and recurrent, with high response rates to first-line treatment but considerable residual and relapse burden across the lifetime.

Response and remission

• Response (≥50% symptom reduction) occurs in roughly 50-60% of patients with first-line treatment within 8 weeks.¹⁸
• Remission (PHQ-9 <5 or HAM-D ≤7) is achieved by approximately 30-40% with the first agent, with successive trials yielding diminishing returns.²⁵
• Residual symptoms predict relapse and warrant additional intervention.

Relapse

• Without continuation treatment, relapse rates exceed 50% within one year of acute response.
• Maintenance pharmacotherapy reduces relapse approximately 50%.³⁷
• CBT and MBCT show durable benefit on relapse prevention after acute response.

Suicide risk over the course

• Lifetime suicide death risk in MDD is estimated at 2-7%; higher in severe, psychotic, treatment-resistant, and substance-comorbid disease.³⁸
• Risk peaks in the early weeks of an episode, around treatment initiation, and during the post-discharge period.
• Hopelessness and prior attempts are the strongest individual predictors.

Functional outcome

• Even after symptom remission, many patients show residual cognitive, occupational, and interpersonal impairment.
• Workplace impairment from depression is a leading driver of disability worldwide.

Mortality

• All-cause mortality is elevated approximately 1.5-2 fold, driven by suicide and cardiovascular disease.³⁹

Depression-related emergencies center on suicide, severe psychomotor or psychotic decompensation, and treatment-emergent agitation. Disposition is a clinical judgment integrating risk, protective factors, and available supports.

Hospitalization criteria

• Active suicidal ideation with plan, intent, or means.
• Recent serious attempt.
• Severe psychotic or catatonic features.
• Inability to care for self.
• Substance intoxication or withdrawal complicating presentation.
• Failure of outpatient stabilization.

Suicide risk markers

• Static: prior attempts, family history of suicide, male sex (completed suicide), older age, chronic illness.
• Dynamic: hopelessness, agitation, recent loss, command hallucinations, intoxication, insomnia, recent psychiatric discharge, access to firearms.
• Protective: strong social ties, religious or moral objections, parental responsibilities, treatment engagement.

Acute agitation management

• Verbal de-escalation first.
• Pharmacologic options: oral or IM lorazepam; oral olanzapine, risperidone, or haloperidol when needed; combine antipsychotic with benzodiazepine when severe.
• Continuous observation and medical clearance.

Safety-relevant comorbid presentations

• Catatonia: treat with lorazepam challenge; ECT for refractory cases.
• Serotonin syndrome (autonomic instability, neuromuscular hyperactivity, mental status change): discontinue serotonergic agents, supportive care, cyproheptadine for severe cases.
• Lithium or TCA overdose: medical emergency; TCA overdose can be fatal at modest multiples of therapeutic dose.

Several areas of MDD care remain actively debated, and current guidelines diverge on important questions.

Key debates

• Magnitude of antidepressant efficacy: meta-analyses including unpublished trial data (Cipriani 2018; Kirsch reanalyses) show statistically significant but clinically modest benefit over placebo, particularly for mild depression. Whether this reflects publication bias, expectancy effects, or true small effects continues to be argued.^21,31
• Antidepressants in mild depression: NICE recommends psychotherapy or watchful waiting first for mild MDD, while APA permits medication; the divergence reflects evidence-base interpretation.
• Discontinuation symptoms versus relapse: distinguishing protracted withdrawal from emerging relapse is clinically difficult and shapes long-term prescribing.
• Pharmacogenomic testing: commercial CYP-based panels are widely marketed but show inconsistent benefit in RCTs; current consensus is selective rather than universal use.¹⁷
• Esketamine and ketamine: rapid-acting and approved for TRD, but durability beyond weeks, abuse potential, and cost remain concerns. Off-label IV ketamine clinics have proliferated ahead of robust long-term safety data.
• Psychedelic-assisted therapy: psilocybin trials show promising short-term efficacy in TRD, but trials are small, blinding is imperfect, and regulatory status varies; not currently a guideline-recommended treatment outside research settings.
• Inflammation hypothesis: anti-inflammatory adjuncts (celecoxib, minocycline, omega-3) show signal in subsets but have not entered routine care.
• Antidepressants and pediatric suicidality: the boxed warning, derived from pooled trial data, continues to influence prescribing patterns; subsequent epidemiologic data complicate the original signal.
• Duration of maintenance treatment: optimal duration after recurrent episodes is unsettled; many guidelines recommend indefinite treatment after three or more lifetime episodes, but individualized risk-benefit reassessment is needed.

• DSM-5-TR MDD requires five of nine symptoms over two weeks, including depressed mood or anhedonia, with functional impairment and exclusion of bipolarity and substance or medical cause.
• The bereavement exclusion was removed in DSM-5; clinicians must distinguish grief from a superimposed MDE on phenomenologic grounds.
• SIG E CAPS captures the depressive symptom checklist alongside depressed mood.
• Lifetime prevalence of MDD is approximately 15-20%; female-to-male ratio is approximately 2:1.
• Heritability is approximately 35-40%, lower than for bipolar disorder or schizophrenia.
• Brodmann area 25 (subgenual cingulate) hyperactivity is implicated in depression and is a target for deep brain stimulation research.
• First-line pharmacotherapy is an SSRI or SNRI; an adequate trial requires 4-6 weeks at therapeutic dose.
• STAR*D demonstrated cumulative remission of approximately 67% across four sequential treatment steps, with diminishing returns at each step.
• ECT is the most efficacious acute treatment for severe MDD and is first-line for psychotic, catatonic, or imminently suicidal depression.
• Esketamine intranasal is FDA-approved for treatment-resistant depression and for MDD with acute suicidal ideation, administered under REMS.
• TADS supports combined fluoxetine plus CBT in adolescent MDD.
• SADHART supports sertraline safety after acute MI.
• Citalopram dose is limited to 20 mg in patients over 60 due to QT prolongation.
• Paroxetine is generally avoided in pregnancy due to cardiac malformation signal; sertraline is the commonly preferred SSRI in pregnancy and lactation.
• Brexanolone (IV) and zuranolone (oral) are FDA-approved for postpartum depression.
• Continuation treatment for at least 6-12 months after first-episode remission reduces relapse; maintenance treatment reduces relapse approximately 50% in recurrent disease.
• Lifetime suicide death risk in MDD is approximately 2-7%, higher in psychotic, treatment-resistant, and substance-comorbid presentations.

No external funding. No conflicts of interest declared. Peer-review status: pending.