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Depression: Symptoms, Causes, Diagnosis, and Evidence-Based Treatment Options

Definition

Major Depressive Disorder (MDD) is a prevalent, serious mood disorder characterized by ≥2 weeks of pervasive low mood or anhedonia plus associated cognitive, somatic, and functional impairment. It is not transient sadness.

Diagnostic Criteria (DSM-5)

≥5 of 9 symptoms (including #1 or #2) for ≥2 weeks:

  1. Depressed mood most of the day, nearly daily.
  2. Markedly diminished interest or pleasure (anhedonia).
  3. Significant weight or appetite change (±5% in a month).
  4. Insomnia or hypersomnia.
  5. Psychomotor agitation or retardation (observable by others).
  6. Fatigue or energy loss.
  7. Feelings of worthlessness or excessive guilt.
  8. Diminished concentration or indecisiveness.
  9. Recurrent thoughts of death, suicidal ideation, plan, or attempt.

Etiology: Biopsychosocial Model

  • Genetic: Heritability ~40%; polygenic (GWAS: >100 loci identified).
  • Neurobiological: Monoamine (5-HT, NE, DA) dysregulation; glutamate/GABA imbalance; HPA axis hyperactivity; reduced BDNF and hippocampal volume; neuroinflammation.
  • Psychological: Negative cognitive schemas (Beck), learned helplessness, rumination, low self-esteem.
  • Social/Environmental: Childhood adversity (ACE score), recent loss, chronic stress, isolation, medical illness, substance use.

Treatment Hierarchy

Mild MDD

  • Watchful waiting + psychoeducation + lifestyle interventions (exercise, sleep, social rhythm).
  • Guided self-help (CBT-based), digital therapeutics (e.g., Woebot, MoodGYM).
  • Psychotherapy first-line: CBT, Behavioral Activation (BA), IPT, MBCT.

Moderate MDD

  • Psychotherapy + antidepressant (SSRI first-line: sertraline, escitalopram).
  • Or psychotherapy alone if patient prefers.

Severe MDD

  • Antidepressant + psychotherapy (combination is superior to either alone).
  • Consider ECT (gold standard for psychotic, catatonic, treatment-resistant, or high suicidality cases).
  • Ketamine/esketamine (SPRAVATO) for treatment-resistant depression.
  • TMS (transcranial magnetic stimulation) for treatment-resistant depression.

Treatment-Resistant Depression (TRD)

Defined as failure of ≥2 adequate antidepressant trials. Options include: switching class, augmentation (atypical antipsychotic, lithium, thyroid hormone, ketamine/esketamine, TMS, ECT, VNS, DBS).

Lifestyle as Adjunct

  • Exercise: 150 min/week moderate → effect size ~0.8 vs. control.
  • Mediterranean diet: SMILES RCT showed remission improvement.
  • Sleep regularity: CBT-I if insomnia is present.
  • Light therapy: 10,000 lux × 30 minutes morning (seasonal and non-seasonal).
  • Omega-3 (EPA ≥1g), vitamin D (if deficient), folate (L-methylfolate).

Suicide Risk Assessment

  • Ask directly: "Are you thinking of killing yourself?" — this does not plant the idea.
  • Assess plan, means, intent, past attempts, and protective factors.
  • Safety plan: coping strategies, contacts, crisis lines (988 in US), means restriction.

Recovery & Relapse Prevention

  • Continue effective treatment 6–12 months after remission (2 years if recurrent).
  • Maintenance psychotherapy (MBCT halves relapse risk).
  • Monitor residual symptoms (insomnia, anhedonia)—they predict relapse.

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