Major Depressive Disorder

• Monoamine Hypothesis and Synaptic Transmission Deficits: The classical monoamine hypothesis posits that MDD results from insufficient synaptic availability of serotonin (5-HT), norepinephrine (NE), and dopamine (DA)—the three primary monoamines regulating mood, motivation, and reward. Reduced presynaptic release of these neurotransmitters, combined with dysregulation of postsynaptic receptor sensitivity (particularly 5-HT1A, 5-HT1B, and β-adrenergic receptors), produces the anhedonia, psychomotor changes, and mood dysregulation characteristic of depression. While this model is oversimplified, it explains the mechanism of action of all FDA-approved antidepressants: SSRIs inhibit serotonin reuptake via the serotonin transporter (SERT), SNRIs inhibit both serotonin and norepinephrine reuptake, and tricyclic antidepressants (TCAs) block all three monoamine transporters. The time lag between drug initiation and clinical response (typically 2-4 weeks) reflects the need for downstream receptor sensitization and adaptive changes in intracellular signaling cascades (including cAMP and protein kinase A pathways), not merely acute neurotransmitter elevation.

• Glutamatergic Dysfunction and Excitotoxicity: Emerging evidence emphasizes excessive glutamatergic neurotransmission and dysregulation of the N-methyl-D-aspartate (NMDA) receptor system as central to depression pathophysiology. Chronic stress and repeated depressive episodes increase glutamate release from presynaptic terminals and reduce glutamate reuptake via the excitatory amino acid transporter (EAAT2), leading to excessive NMDA receptor activation, increased intracellular calcium, and neuronal stress. This mechanism is particularly relevant to treatment-resistant depression (TRD), where NMDA antagonists like ketamine have demonstrated rapid (hours to days) antidepressant effects through blocking excessive NMDA signaling and promoting synaptic plasticity via AMPA receptor potentiation—a mechanism distinct from monoamine modulation.

• Hypothalamic-Pituitary-Adrenal (HPA) Axis Hyperactivation: Chronic stress exposure dysregulates the HPA axis, leading to elevated corticotropin-releasing hormone (CRH) in the hypothalamus, increased ACTH from the anterior pituitary, and sustained elevation of cortisol. Rather than appropriate negative feedback inhibition of the axis, depressed patients show impaired glucocorticoid receptor (GR) sensitivity and suppression resistance on the dexamethasone suppression test (DST). Chronic hypercortisolism causes hippocampal atrophy, impaired negative feedback, and further perpetuation of HPA axis dysregulation. This pathophysiology explains neurovegetative symptoms (sleep disturbance, appetite changes) and cognitive dysfunction (memory impairment, executive dysfunction) observed in depression, and provides a mechanistic link between stress exposure and depression vulnerability.

• Neurotrophic Factor Deficiency: Brain-derived neurotrophic factor (BDNF) and other neurotrophic factors (NGF, FGF) are critical for neuronal survival, synaptic plasticity, and hippocampal neurogenesis. Depression is associated with reduced BDNF signaling via the tropomyosin receptor kinase B (TrkB) pathway, particularly in the hippocampus and prefrontal cortex, contributing to cognitive impairment and structural brain changes. Antidepressant treatment increases BDNF expression and restores synaptic plasticity; this mechanism explains the importance of environmental enrichment and exercise (which directly increase BDNF) as adjunctive treatments.

• Neuroinflammation and Cytokine Dysregulation: Emerging research demonstrates that depression—particularly severe, recurrent, and treatment-resistant forms—involves elevated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, CRP) and neuroinflammation mediated by activated microglia and astrocytes. Inflammatory markers predict poor treatment response and antidepressant resistance; this has led to investigation of anti-inflammatory augmentation strategies. The neuroinflammatory model may explain the high prevalence of depression in patients with autoimmune and chronic inflammatory conditions and the increased suicide risk in depression (microglia activation increases glutamate excitotoxicity).

• Genetic and Epigenetic Factors: MDD shows moderate heritability (approximately 35-40%), with multiple genes of small effect contributing to risk rather than a single monogenic inheritance pattern. Polymorphisms in genes encoding the serotonin transporter (5-HTTLPR), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (Val66Met) influence depression susceptibility and antidepressant response. Epigenetic mechanisms—including DNA methylation and histone modifications—regulate these genes in response to early life stress, trauma, and chronic adversity, explaining the environmental modulation of genetic risk. The differential susceptibility hypothesis proposes that certain genetic variants (including 5-HTTLPR short allele, BDNF Met allele) confer both vulnerability to depression under stress AND enhanced responsiveness to environmental support and treatment, explaining variable stress resilience.

• Structural and Functional Brain Changes: Neuroimaging studies reveal that MDD involves volumetric reductions in the hippocampus (particularly with chronic/recurrent depression), prefrontal cortex (especially dorsolateral and anterior cingulate regions), and amygdala enlargement. These structural changes reflect impaired neurogenesis, dendritic atrophy, and synaptic loss. Functionally, depressed patients show hyperactivity in limbic regions (amygdala, insula) processing negative emotions and hypoactivity in prefrontal regulatory regions, combined with altered connectivity within the default mode network (DMN) and salience network, producing characteristic rumination, impaired emotional regulation, and anhedonia.

• Genetic Predisposition: Family history is the single strongest risk factor, with first-degree relatives of affected individuals showing 2-3 fold increased risk. Twin studies indicate heritability of 35-40%, with multiple susceptibility genes of small individual effect (polygenic inheritance). This genetic risk is non-specific—relatives may develop MDD or related conditions (anxiety disorders, bipolar disorder). Certain genetic polymorphisms (e.g., serotonin transporter gene 5-HTTLPR short allele) interact with environmental stressors in determining depression risk.

• Stressful Life Events and Chronic Adversity: Early childhood trauma, abuse, neglect, and parental loss are among the strongest environmental risk factors, particularly when combined with genetic susceptibility (gene-environment interaction). Recent major stressors (loss, medical illness, financial hardship, interpersonal conflict) commonly precipitate depressive episodes in vulnerable individuals. The stress-diathesis model explains how constitutional vulnerability (genetic, temperamental, neurobiological) combined with environmental precipitants produces depression.

• Medical Illnesses and Medications: Numerous medical conditions cause secondary depression through various mechanisms: hypothyroidism (reduced monoamine signaling and metabolic effects), Cushing's syndrome (HPA axis hyperactivation and hypercortisolism), Parkinson's disease (dopamine depletion), stroke (particularly left hemisphere, basal ganglia, or prefrontal lesions), multiple sclerosis, HIV/AIDS, chronic pain conditions, diabetes, and cardiac disease. Medications causing depression include corticosteroids (particularly systemic glucocorticoids), beta-blockers, reserpine, interferon, isotretinoin, and certain antiretrovirals. These secondary depressions occur in 10-15% of medically ill patients and require identification and treatment of underlying causes.

• Neurobiological Vulnerabilities: Temperamental traits associated with increased MDD risk include neuroticism (negative emotionality), behavioral inhibition, and harm avoidance—personality dimensions reflecting underlying differences in limbic reactivity and prefrontal regulation. Individuals with anxiety disorders, substance use disorders, and impulse control disorders show elevated depression risk, suggesting shared neurobiological vulnerabilities.

• Psychosocial Factors: Chronic interpersonal difficulties, social isolation, lack of social support, low socioeconomic status, and unemployment are significant risk factors. Rumination (repetitive, passive focus on depressed mood and its causes) and cognitive distortions (catastrophizing, personalization, overgeneralization) perpetuate depression once initiated and predict poor prognosis.

• Reproductive-Related Factors in Women: Premenstrual dysphoric disorder, peripartum depression, and perimenopause are periods of elevated depression risk in women, reflecting hormonal influences on monoamine systems. Oral contraceptive use and estrogen therapy may increase or decrease depression risk depending on estrogen formulation and individual vulnerability.

• Substance Use and Alcohol: Chronic alcohol use, stimulant intoxication, and withdrawal syndromes (particularly from alcohol, benzodiazepines, and opioids) produce depression. Substance use disorders and depression show bidirectional relationships, with each increasing risk for the other.

• Depressed Mood and Anhedonia: The cardinal symptoms are persistent depressed mood (subjectively described as sadness, emptiness, hopelessness, or numbness) and anhedonia (loss of interest or pleasure in previously enjoyed activities). Unlike normal sadness, which is proportionate to circumstances and fluctuates, depressed mood in MDD is often unresponsive to positive events and shows diurnal variation (typically worse in early morning in melancholic depression). Anhedonia represents a core deficit in reward processing (dopaminergic dysfunction) and is often more clinically disabling than mood disturbance itself. At least one of these two symptoms must be present and predominant for most days over at least 2 weeks to meet diagnostic criteria.

• Cognitive Symptoms: Depressed patients characteristically exhibit negative automatic thoughts (persistent self-critical, hopeless thoughts), concentration and attention deficits (impaired ability to focus or make decisions), psychomotor retardation (slowed thinking and speech, poverty of speech), and memory impairment (particularly evident on tasks requiring effort and executive function). The cognitive slowing reflects reduced dopamine and norepinephrine signaling in prefrontal and striatal regions. Suicidal ideation ranges from passive death wishes to specific plans and intent; active inquiry about suicidality is essential given that suicide is completed in approximately 4-15% of individuals with MDD, making it a leading preventable cause of death.

• Neurovegetative Symptoms: Sleep disturbance is nearly universal, manifesting as insomnia (early morning awakening at 3-4 AM is characteristic of melancholic depression), hypersomnia, or irregular sleep architecture. Appetite change occurs in either direction (typically decreased appetite and weight loss in melancholic type, increased appetite and weight gain in atypical type). Fatigue and low energy reflect dopamine/norepinephrine deficiency and are among the most disabling symptoms, persisting even after mood improves. Decreased libido reflects both neurobiological changes and secondary effects of depression on relationships and self-perception.

• Physical Symptoms and Pain: Depressed patients frequently report multiple somatic complaints: headache, joint/muscle pain, gastrointestinal symptoms, and chest discomfort. In some cultures ("masked depression" or "depression without sadness"), somatic complaints predominate over mood symptoms. This reflects bidirectional pain-mood interaction: depression amplifies pain perception through altered descending pain inhibition (mediated by serotonergic and noradrenergic systems), while chronic pain produces depression through reward system dysfunction and HPA axis hyperactivation.

• Psychomotor Changes: Two patterns exist—psychomotor retardation (slowed movement, speech, and thought) and psychomotor agitation (restlessness, inability to sit still, pacing). Retardation predominates in melancholic depression and reflects reduced dopaminergic and noradrenergic tone. Agitation occurs in anxious depression and may be mistaken for anxiety disorders alone.

• Anxiety Symptoms: Comorbid anxiety occurs in 60-70% of MDD cases, manifesting as generalized anxiety, panic attacks, social anxiety, or specific phobias. Anxiety in depression likely reflects amygdala hyperactivity with impaired prefrontal regulation, distinguishing it from primary anxiety disorders (though both can coexist).

• Depressive Episodes with Psychotic Features: In severe MDD, patients may develop psychotic symptoms completely congruent with depressed mood: delusions of guilt (false belief that one deserves punishment), delusions of poverty (false belief of financial ruin), delusions of illness (hypochondriacal delusions), or auditory hallucinations (often voices criticizing or accusing the patient). These psychotic features indicate greater severity, higher suicide risk, and need for antipsychotic augmentation. Psychotic symptoms completely resolve with treatment of depression and remit without requiring standalone antipsychotic therapy.

• Atypical Depression: This specifier applies to patients with mood reactivity (mood brightens in response to positive events), reversed neurovegetative symptoms (hypersomnia, increased appetite/weight gain), leaden paralysis (heavy, leaden sensation in limbs), and interpersonal rejection sensitivity (heightened sensitivity to perceived rejection). Atypical depression shows better response to monoamine oxidase inhibitors (MAOIs) and some response to SSRIs; stimulating antidepressants are preferred over sedating ones.

• Melancholic Depression: Features include anhedonia (complete loss of pleasure), psychomotor retardation or agitation, early morning awakening (with 2+ hour early offset from baseline), diurnal mood variation (worst mood in early morning), significant appetite/weight loss, and excessive guilt. Melancholic depression shows better response to tricyclic antidepressants and ECT than SSRIs alone.

• Physical Examination Findings: Most depressed patients appear behaviorally normal on examination, but astute clinicians may observe depressed/sad facial expression, reduced eye contact, slowed speech or poverty of speech, decreased gestural animation, poor hygiene (in severe cases), psychomotor retardation (slowness of movement), or conversely restlessness and agitation. Vital signs typically remain normal, though some patients show mild tachycardia (related to anxiety or reduced vagal tone). Cognitive examination may reveal slowed processing, difficulty with attention/concentration tasks, and negative bias on cognitive screening.

• DSM-5 Diagnostic Criteria (Gold Standard): MDD diagnosis requires ≥5 symptoms present during a 2-week period, representing a change from baseline functioning, with at least one symptom being depressed mood OR anhedonia. The nine criterion symptoms are: (1) depressed mood most days, (2) markedly diminished interest/pleasure (anhedonia), (3) significant weight loss/gain or appetite decrease/increase, (4) insomnia or hypersomnia, (5) psychomotor agitation or retardation (observable by others), (6) fatigue or loss of energy, (7) feelings of worthlessness or excessive/inappropriate guilt, (8) diminished ability to concentrate or indecisiveness

Immediate stabilisation

• Suicide risk assessment first: every visit requires direct questioning about ideation, plan, intent, access to lethal means, and prior attempts. Imminent risk, psychotic depression, catatonia, or inability to maintain oral intake warrants inpatient psychiatric admission — voluntary if possible, involuntary if the patient lacks capacity and is at risk. Means restriction (firearms, stockpiled pills) is counselled at every level of care.

First-line therapy (APA Practice Guideline for the Treatment of Patients with Major Depressive Disorder; VA/DoD MDD Guideline)

• SSRIs: sertraline or escitalopram are typical first choices — equal efficacy across the class, so selection is driven by side-effect profile, interactions, and prior response. Start low, titrate, and reassess with a measurement-based tool (PHQ-9); an adequate trial is a therapeutic dose sustained for several weeks, since receptor downregulation — not acute reuptake blockade — drives response.
• Psychotherapy: cognitive behavioural therapy or interpersonal therapy is equally first-line for mild–moderate disease; combination with medication is preferred for moderate–severe or recurrent illness.

Escalation

• Optimise, then switch or augment: raise to maximum tolerated dose; if no response, switch within class or to an SNRI (venlafaxine, duloxetine), NDRI (bupropion — useful when sexual dysfunction or fatigue predominates), or mirtazapine (helpful with insomnia and weight loss).
• Augmentation: atypical antipsychotics (aripiprazole, quetiapine XR), lithium, or triiodothyronine. MAOIs and TCAs remain effective but are later-line because of toxicity; MAOIs retain a niche in atypical depression.

Treatment-resistant and definitive options

• Esketamine intranasal with an oral antidepressant is FDA-approved for treatment-resistant depression under a REMS because of dissociation and sedation.
• Electroconvulsive therapy is the most effective treatment and is first-line — not last resort — for psychotic depression, catatonia, refusal of food/fluids, and imminent suicidality. Repetitive TMS is an option in medication-refractory non-emergent cases.

Contraindicated

• MAOI plus any serotonergic agent (washout required; longer for fluoxetine), bupropion with seizure disorder, bulimia, or anorexia, and antidepressant monotherapy in bipolar depression. ACOG advises avoiding paroxetine in pregnancy.

Emergencies

• Completed suicide: the principal cause of excess mortality. Risk paradoxically rises early in treatment as psychomotor retardation lifts before mood improves, giving the patient energy to act. Signals: new plan, giving away possessions, sudden calm after profound hopelessness. Emergency — requires immediate safety evaluation.
• Serotonin syndrome: excess 5-HT from SSRI/SNRI combined with MAOI, linezolid, triptans, or tramadol. Triad of mental status change, autonomic instability, and neuromuscular hyperactivity with clonus and hyperreflexia greater in the lower extremities. Treat by stopping serotonergic agents, cooling, benzodiazepines, and cyproheptadine. Emergency.
• MAOI hypertensive crisis: tyramine-rich food or a sympathomimetic with an MAOI causes a surge of displaced norepinephrine — occipital headache, severe hypertension. Treat with a short-acting vasodilator or phentolamine. Emergency.
• TCA overdose: sodium-channel and anticholinergic toxicity — QRS widening, seizures, hypotension, arrhythmia. Give sodium bicarbonate. Emergency; explains why TCAs are avoided in high-risk patients.
• Catatonia / refusal of intake: dehydration, aspiration, venous thromboembolism. Lorazepam challenge, then ECT. Emergency.
• Antidepressant-induced mania: unmasks bipolar disorder; signals are decreased need for sleep, grandiosity, and rapid mood elevation. Stop the antidepressant and start a mood stabiliser.

Non-emergent but exam-tested

• SIADH/hyponatremia: SSRIs in older adults; presents as confusion, falls, or seizure with low serum sodium and inappropriately concentrated urine.
• Bleeding risk: platelet serotonin depletion; additive with NSAIDs and anticoagulants — GI bleeding.
• QT prolongation: citalopram carries an FDA dose ceiling, lowered further in the elderly and in hepatic impairment.
• Sexual dysfunction and weight change: leading causes of nonadherence; switch to bupropion or mirtazapine.
• Discontinuation syndrome: abrupt stop of a short half-life agent (paroxetine, venlafaxine) causes flu-like symptoms, dizziness, and electric-shock sensations; taper instead.
• Priapism with trazodone — urologic emergency.
• ECT: transient anterograde and retrograde amnesia; no absolute contraindication.
• Chronic disease burden: worse adherence and outcomes in coronary disease and diabetes.

• Two weeks, five symptoms, one must be depressed mood or anhedonia — the SIG E CAPS mnemonic. Fewer than five symptoms with impairment for 2 years is persistent depressive disorder, not MDD.
• Single best next step in almost every stem: ask about suicidal ideation, plan, intent, and access to means. It precedes ordering labs, starting a drug, or referring. The other reflex next step is TSH and basic labs to exclude hypothyroidism, anemia, and substance effects.
• The one association examiners test: any history of a manic or hypomanic episode converts the diagnosis to bipolar I/II, and starting an SSRI alone can precipitate mania. Screen for mania before prescribing.
• SSRIs are first-line for essentially every subtype (APA), but the classic exceptions are worth memorising: atypical depression (mood reactivity, hypersomnia, hyperphagia, leaden paralysis, rejection sensitivity) responds notably to MAOIs; melancholic, psychotic, or catatonic depression and imminent suicidality point to ECT.
• Common distractor to avoid: switching antidepressants at 1–2 weeks because the patient "isn't better." Response requires several weeks of a therapeutic dose — the delay reflects downstream receptor and BDNF adaptation, not slow reuptake blockade. Optimise the dose before switching.
• Second distractor: attributing hyperreflexia and clonus to neuroleptic malignant syndrome. Serotonin syndrome is hyperreflexic with clonus and onset within hours; NMS is lead-pipe rigid, hyporeflexic, and evolves over days.
• Boxed warning: antidepressants increase suicidal ideation in patients under 25 — this mandates close early follow-up, not withholding treatment. Fluoxetine and escitalopram are the agents with pediatric FDA approval in depression.
• Bereavement is not an exclusion in DSM-5; grief with preserved self-esteem and wave-like sadness differs from the pervasive worthlessness and anhedonia of MDD.
• Elderly patient with new "dementia" that improves with antidepressant treatment: pseudodementia — poor effort and "I don't know" answers rather than confabulation.