Major depressive disorder

Overview

• Definition: major depressive disorder (MDD) is a mood disorder characterized by one or more major depressive episodes, each defined by depressed mood or anhedonia plus at least 5 of 9 symptom criteria present nearly every day for at least 2 weeks and causing significant functional impairment; first-line care combines cognitive behavioral therapy (CBT) with a selective serotonin reuptake inhibitor (SSRI).
• More than a mood change: transient sadness alone is not an illness; MDD carries cognitive, psychomotor, and neurovegetative disturbance.
• Specifiers change management, not the threshold: psychotic features, peripartum onset, seasonal pattern, and atypical features share the same criteria.
• Distinct from the bipolar spectrum: episodes occur in unipolar MDD or in bipolar I disorder or bipolar II disorder; screen for prior mania or hypomania first.

Epidemiology

• Prevalence and sex distribution: lifetime prevalence is 15% to 25%, roughly twice as common in women; onset is usually in the mid-20s, and prevalence is higher among older adults.
• Disability burden: MDD is a leading cause of disability among individuals aged 15 to 44 years in the United States.
• Suicide mortality: approximately 2% to 9% of patients with MDD die by suicide.
• Peripartum onset: within 4 weeks of delivery; see postpartum depression.

Risk factors

• Female sex: lifetime risk is roughly double that of men.
• Chronic medical illness: depression commonly accompanies thyroid disease, cancer, Parkinson disease, heart failure, HIV infection, inflammatory bowel disease, and diabetes mellitus.
• Depressogenic medications: corticosteroids, interferon, beta-blockers, antipsychotics (especially in older adults), and reserpine can trigger or mimic depressive symptoms.
• Substance use disorder: causes secondary mood symptoms and is a listed suicide risk factor.
• Prior depressive episode: a severe index episode or 2 or more prior episodes carries high recurrence risk.
• Older age with social isolation: chronic illness, grief, and social isolation add risk; depression is itself a risk factor for cognitive dysfunction in older adults.
• Peripartum psychosocial stressors: history of depression, low income, single parenthood, unplanned pregnancy, intimate partner violence, elevated anxiety, and gestational diabetes.

Pathophysiology

• Monoaminergic drug targets: a selective serotonin reuptake inhibitor (SSRI) blocks presynaptic serotonin reuptake, leaving more serotonin available in the synaptic cleft; a serotonin-norepinephrine reuptake inhibitor (SNRI) or tricyclic antidepressant (TCA) extends this blockade to norepinephrine, and a monoamine oxidase inhibitor (MAOI) limits monoamine breakdown.
• Secondary or organic depression: endocrinopathies (Cushing or Addison disease, thyroid or parathyroid disease), malignancy (lymphoma, pancreatic carcinoma), neurologic disease (Parkinson, Huntington, or Alzheimer disease), autoimmune disease (systemic lupus erythematosus), and infection (chronic hepatitis C, HIV) can produce depressive symptoms directly; see secondary medical causes of depression.
• Substance and medication induction: corticosteroids, interferon, reserpine, stimulants, sedative-hypnotics, benzodiazepines, narcotics, and long-term alcohol use can induce mood disturbance during use or withdrawal.
• Psychotic features stay tethered to the mood episode: hallucinations or delusions are typically mood-congruent (guilt, worthlessness, punishment, nihilism, disease, death) and occur only during the episode, separating MDD with psychotic features from schizoaffective disorder.

Clinical features

• Core diagnostic criteria: 5 or more of 9 symptoms nearly every day for at least 2 weeks, with at least one being depressed mood or anhedonia: depressed mood, diminished interest or pleasure, notable weight loss or gain (more than 5% of body weight in 1 month) or appetite change, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or low energy, worthlessness or excessive guilt, diminished concentration or indecisiveness, and recurrent thoughts of death or suicidal ideation.
• Functional impairment requirement: symptoms must cause significant functional impairment and cannot be attributable to a substance, medication, or another medical condition.
• Neurovegetative and psychomotor signs: sleep, appetite, and energy disturbance are often the presenting complaint.
• Psychotic features: mood-congruent delusions or hallucinations can accompany severe episodes, occurring only during the mood episode.
• Atypical features: the most common subtype; mood reactivity, hypersomnia, hyperphagia, leaden paralysis, and interpersonal rejection sensitivity.
• Seasonal pattern: episodes confined to autumn or winter for at least 2 consecutive years; see seasonal affective disorder.

Differential diagnosis

• Bipolar I disorder or bipolar II disorder: a history of mania (bipolar I) or hypomania (bipolar II) is present, which unipolar MDD lacks; an SSRI given for unrecognized bipolar disorder can precipitate mania.
• Persistent depressive disorder (dysthymia): chronic depressed mood most days for at least 2 years with only 2 associated symptoms required, milder than MDD, without a symptom-free interval longer than 2 months.
• Adjustment disorder with depressed mood: follows an identifiable stressor and resolves within 6 months of its resolution, without meeting full episode criteria.
• Uncomplicated grief: waves of grief tied to reminders after a loss, no severe impairment or suicidality, adaptation within about a year, unlike the persistent course of MDD.
• Prolonged grief disorder: grief that stays intense beyond 6 to 12 months and impairs functioning, but does not meet criteria for another disorder such as MDD.
• Seasonal affective disorder: episodes confined to autumn or winter for at least 2 consecutive years that remit by spring, unlike MDD.
• Premenstrual dysphoric disorder: symptoms are confined to the week before menses and remit within a week after onset, unlike MDD.
• Secondary medical causes of depression: hypothyroidism, Parkinson disease, a CNS neoplasm, and stroke can produce a depressive syndrome, but treating the underlying condition is the first step, unlike primary MDD.
• Substance-induced mood disorder: symptoms track use of, or withdrawal from, a substance or medication and remit once it is stopped, unlike MDD.

Diagnosis

• Diagnostic basis: the diagnosis is clinical, confirmed by Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria: 5 or more of 9 major depressive episode symptoms nearly every day for at least 2 weeks, including depressed mood or anhedonia, causing significant functional impairment not attributable to a substance, medication, or another medical condition.
• Initial screening: screen adults with the two-question Patient Health Questionnaire (PHQ)-2 ("felt down, depressed, or hopeless" and "little interest or pleasure"); a positive response prompts the full nine-item PHQ-9 to grade severity, or the Geriatric Depression Scale in older adults.
• Suicide risk assessment: ask directly about ideation, means, intent, and a plan; risk is highest with chronic ideation, major mental illness, a prior attempt, substance use disorder, and limited social support.
• Rule out bipolar disorder first: ask about prior mania or hypomania, since treating unrecognized bipolar disorder as MDD can precipitate mania.
• Exclude secondary causes next: check thyroid-stimulating hormone, review for corticosteroids, beta-blockers, or reserpine, and screen for substance use, since these change the first step (treat the thyroid, switch the drug, or start detoxification); then, if new focal neurologic findings are present, obtain brain imaging for a CNS neoplasm or stroke.
• Then track response once treatment starts: a PHQ-9 decrease of at least 50% marks response, and a score below 5 marks remission.

Clinical pearl. Always ask about a personal history of mania or hypomania before starting an SSRI for a first depressive episode: giving an SSRI alone to a patient with unrecognized bipolar disorder can precipitate a manic episode, so a positive history changes both the diagnosis and the treatment plan.

Management

• Assess safety first: screen for suicidal or homicidal ideation, refusal to eat or drink, catatonia, and psychotic features; hospitalize, voluntarily or involuntarily, any patient with active suicidal or homicidal ideation.
• Start treatment for non-emergent MDD: begin CBT, an SSRI, or both; combining both is reasonable in moderate to severe disease and outperforms either alone.
• First-line SSRI options:
  • Sertraline: start 50 mg PO once daily, titrated weekly in 50 mg increments to 50 to 200 mg/day (max 200 mg/day).
  • Fluoxetine (drug of choice): start 20 mg PO once daily, may increase after several weeks to 20 to 60 mg/day (max 80 mg/day).
• Allow an adequate trial: continue the agent 4 to 6 weeks before judging response, and reassess adequacy by 6 to 12 weeks.
• Escalate stepwise on inadequate response: for a partial response, titrate upward or add psychotherapy; for no response, switch to another SSRI or a second-line agent.
  • Venlafaxine extended-release: start 37.5 to 75 mg PO once daily, titrated by up to 75 mg/day every 4 days to 75 to 225 mg/day.
  • Bupropion sustained-release: start 150 mg PO once daily, titrated to 150 mg twice daily after 3 days (max 400 mg/day); avoid in seizure disorder or an eating disorder.
• If 2 adequate trials fail, augment rather than switch again:
  • Add bupropion at the dose above, or add aripiprazole 10 to 15 mg PO once daily (usual range 10 to 30 mg/day, max 30 mg/day), to the SSRI.
  • Or use an FDA-approved combination: olanzapine 5 to 20 mg/day PO plus fluoxetine, or quetiapine extended-release 300 mg PO once daily added to the SSRI.
• If psychotic features are present: combine the SSRI with an atypical antipsychotic, which outperforms either drug alone in unipolar psychotic depression.
• If actively suicidal, psychotic, or needing rapid stabilization: use electroconvulsive therapy (ECT), 2 to 3 treatments per week for 6 to 12 treatments total; a recent myocardial infarction, an intracranial mass, or high anesthetic risk are relative contraindications only.
• For treatment-resistant depression or acute suicidal ideation: add esketamine nasal spray, 56 mg intranasally on day 1, then 56 or 84 mg twice weekly through week 4, then weekly, with the oral SSRI in a monitored setting.
• Continue and taper appropriately: maintain the effective dose 6 months after remission of a first episode, 1 to 3 years after 2 or more episodes, and indefinitely after 3 or more; taper rather than stop abruptly.

Complications

• Suicide: the most serious complication; approximately 2% to 9% of patients with MDD die by suicide, with risk highest for a prior attempt, active substance use, psychosis, and poor social support.
• Relapse and recurrence: about half of initial responders develop recurrent depression within 1 year without continued treatment.
• Treatment resistance: psychotic features resist standard treatment but predict a better ECT response.
• Medication toxicity: TCA overdose can cause seizures, coma, and cardiac arrhythmia (sodium bicarbonate for a QRS beyond 100 msec); an MAOI with tyramine-rich foods can precipitate hypertensive crisis; an SSRI or SNRI with an MAOI or illicit drugs can cause serotonin syndrome (fever, myoclonus, hyperreflexia, cardiovascular collapse).
• Functional and cognitive impairment: MDD is a leading cause of disability, and is itself a risk factor for cognitive dysfunction in older adults.

Prognosis

• Response and remission are trackable: a PHQ-9 decrease of 50% or more marks response, and a score below 5 marks remission.
• Relapse risk is substantial without continued treatment: roughly half of initial responders relapse within 1 year of stopping treatment.
• Psychotic features cut both ways: more treatment resistance but a stronger ECT response.
• ECT works faster than medication: a safe, effective option for severe or refractory disease; the amnesia it can cause typically resolves within 6 months.

Prevention

• Universal screening: screen all adults with the PHQ-2, followed by the PHQ-9 if positive; screen perinatal patients at least once with the PHQ-9 or the Edinburgh Postnatal Depression Scale.
• Suicide risk screening: perform a risk assessment on every patient with depression, and stabilize and hospitalize any patient who is actively suicidal.
• Relapse-prevention treatment duration: continue the effective dose 6 months after remission of a first episode, 1 to 3 years after 2 or more episodes, and indefinitely after 3 or more or in persistent depressive disorder.
• Perinatal prevention: offer CBT or interpersonal therapy to at-risk pregnant or postpartum patients (history of depression, low income, unplanned pregnancy, intimate partner violence, or gestational diabetes).
• Medication stewardship: avoid or switch medications known to trigger depressive symptoms (corticosteroids, interferon, beta-blockers, certain antipsychotics, reserpine) in at-risk patients.

Key points

• Diagnosis: 5 or more of 9 DSM-5 symptoms, including depressed mood or anhedonia, for at least 2 weeks, with functional impairment.
• Screen, then confirm: PHQ-2 then PHQ-9 if positive; always ask about suicidal ideation and prior mania or hypomania.
• First-line treatment: CBT, an SSRI such as sertraline 50 to 200 mg/day or fluoxetine 20 to 60 mg/day, or both; allow 4 to 6 weeks per trial.
• Escalation pathway: switch within class, then augment or change class, before ECT or esketamine.
• Emergency indications for ECT: active suicidality, psychotic features, catatonia, or refusal to eat or drink.
• Relapse prevention: continue treatment 6 months after episode 1, 1 to 3 years after episode 2 or more, indefinitely after episode 3 or more.