Comprehensive Notes – Major Depressive Disorder

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• Recurrence of major depressive episodes: approximately $50\char37$–$75\char37$ of patients experience a new episode within $5\text{ yr}$.
• Protective factors against relapse: ongoing prophylactic psychopharmacology and a history of only $1$–$2$ prior episodes.
• Kindling pattern: more episodes → shorter inter-episode interval and greater symptom severity.
• Treatment philosophy:
  • Mood disorders are chronic but each acute episode has an excellent prognosis with proper care.
  • Education of patients/families about long-term management is mandatory.
• Dysthymia: contemporary evidence supports treating it with the same modalities used in major depressive disorder (MDD).
• Universal treatment goals:
  1. Ensure patient safety (suicide, homicide, self-neglect).
  2. Perform complete diagnostic assessment (rule out bipolar spectrum, comorbidity, medical causes).
  3. Design a plan that targets acute symptoms and future wellness—including stress-reduction strategies.
• Phases of treatment (Table 7-10 reference): Acute/Continuation (≈$8$–$12\text{ wk}$) and Maintenance (≥$6$–$24\text{ mo}$).

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• Prognostic indicators (Table 7-9):
  • Positive clinical factors: mild episode, absence of psychosis, short hospitalization, no comorbidities, ≤$1$ previous hospitalization, late onset.
  • Positive psychosocial factors: solid adolescent friendships, stable family, good functioning over previous $5\text{ yr}$.
  • Negative clinical factors: comorbid dysthymia + MDD, substance use disorder, prominent anxiety, >$1$ prior episode, male sex.
• Hospitalization criteria:
  • Absolute: suicidal/homicidal risk, inability to secure food/shelter, need for complex diagnostics.
  • Relative: rapid symptom escalation, collapse of natural supports, marked judgment impairment, significant insomnia/weight loss.
• Mild depressions (incl. dysthymia) can be managed outpatient with frequent visits when support systems are reliable.

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• Any deterioration in patient status or support reliability mandates reconsideration of inpatient care—often involuntary owing to hopelessness-driven decisional incapacity.
• Optimal results typically arise from combining pharmacotherapy + psychotherapy.
  • Evidence: higher response/remission rates in chronic depression when treatments are combined.
  • Counter-argument: monotherapy may suffice for many and combination increases cost/adverse-risk.
• Somatic therapies overview: pharmacotherapy remains first-line; efficacy documented in >$500$ RCTs showing all antidepressants modestly outperform placebo.

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• Treatment objective = symptomatic remission (not merely improvement); residual symptoms predict relapse/functional impairment.
• Antidepressants approximately double one-month recovery probability.
• Onset: clinically meaningful change often by $3$–$4\text{ wk}$ (sometimes earlier).
• Drug choice guided by side-effect tolerability, patient comorbidities, lifestyle.
• Historical agents: MAOIs & TCAs; newer classes are better tolerated (“clinician/patient-friendly”).
• Table 7-10 Acute/Continuation tasks: dose-optimize, alliance building, psychoeducation, measurement-based care.

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• Maintenance phase (≈$6$–≥$24\text{ mo}$): goals—full functional recovery and recurrence prevention; continue psychoeducation and comorbidity management.
• Table 7-11 (SSRIs/SNRIs): representative doses & ≥$10\char37$ side-effect frequencies. Highlights:
  • SSRI class: citalopram $20$–$40\text{ mg/d}$ (nausea, dry mouth), escitalopram $10$–$20\text{ mg/d}$ (sexual dysfunction), fluoxetine $20$–$60\text{ mg/d}$ (insomnia, tremor).
  • SNRI class: venlafaxine $75$–$375\text{ mg/d}$ (headache, sweating); duloxetine $30$–$120\text{ mg/d}$ (nausea, constipation).

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• Additional SSRIs: fluvoxamine $100$–$300\text{ mg/d}$ (somnolence, agitation); paroxetine $20$–$60\text{ mg/d}$ (diarrhea, sexual dysfunction); sertraline $50$–$200\text{ mg/d}$ (fatigue, tremor).

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• Remaining SNRIs: desvenlafaxine $50$–$100\text{ mg/d}$; levomilnacipran $20$–$80\text{ mg/d}$.
• Novel/second-generation agents:
  • Bupropion $150$–$450\text{ mg/d}$ (activating, insomnia).
  • Mirtazapine $15$–$60\text{ mg/d}$ (weight gain, somnolence).
  • Vilazodone $10$–$40\text{ mg/d}$ (GI upset).
  • Vortioxetine $10$–$20\text{ mg/d}$ (nausea).
  • Agomelatine & moclobemide—non-US routine availability.

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• Clinical-use guideline pitfalls: trials fail most often from under-dosing or premature discontinuation (<$4$–$5\text{ wk}$). Push to maximal tolerated dose unless early improvement is ongoing.
• Plasma level checks (where available) help detect non-adherence or unusual pharmacokinetics after $2$–$3\text{ wk}$ without response.
• No class shows superior efficacy overall; selection depends on comorbidity, prior-family response, drug-interaction profile, chronicity.
• Response benchmarks (outpatients, uncomplicated): $45$–$60\char37$ respond (≥$50\char37$ symptom drop) but only $35$–$50\char37$ achieve remission.

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• Continuation: maintain meds ≥$6\text{ mo}$ or as long as prior episode length; taper gradually over $1$–$2\text{ wk}$ on discontinuation.
• Prophylaxis indicated when episode spacing <$2.5\text{ yr}$ or past episodes were severe (e.g., high suicidality).
• Maintenance reserved for recurrent/chronic depressions; shown safe/effective long term.
• Differential drug choices:
  • Melancholic → dual-action agents (SNRIs, TCAs).
  • Seasonal pattern → bright-light therapy.
  • Psychotic features → antidepressant + atypical antipsychotic or ECT.
  • Atypical features → MAOIs (strong evidence), also SSRIs, bupropion.
• Comorbidity rule: treat the non-mood disorder if it drives the depression (e.g., OCD, panic). Evaluate for substance-induced mood syndromes via enforced abstinence.
• Side-effect strategizing: sedating agents (mirtazapine, paroxetine) may relieve early insomnia/anxiety but risk long-term sedation; adjunct hypnotics/anxiolytics often preferred.

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• Prior treatment history: past success predicts future success; first-degree relative response can guide class choice.
• Acute treatment failure: defined after $4$–$6\text{ wk}$ at adequate dose if <$25\char37$ improvement.
• $\approx50\char37$ of patients need a second trial.
• Switching preferred over augmentation if first drug ineffective; augment if partial benefit.
  • Evidence: STAR*D—within-class vs cross-class switch equally effective.
  • Valid augmenters: atypical antipsychotics (quetiapine, aripiprazole), lithium, thyroid hormone (T$_3$).

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• NMDA-modulating agents:
  • Ketamine IV: rapid (<$24\text{ h}$) but transient ($2$–$7\text{ d}$) antidepressant effect; dissociative adverse events; abuse potential.
  • Esketamine nasal spray: FDA-approved for treatment-resistant depression; REMS-restricted distribution.
• Brexanolone (IV allopregnanolone): $60\text{ h}$ infusion for postpartum depression; rapid benefit; somnolence, LOC reported; available only under REMS.

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• Neurostimulation:
  • Vagal Nerve Stimulation (VNS): implanted pacemaker-like device; mechanism unclear; some remission in chronic MDD.
  • Transcranial Magnetic Stimulation (rTMS): focal cortical stimulation; indicated after ≥$1$ failed antidepressant; outpatient $40\text{ min}$ sessions daily × $4$–$6\text{ wk}$; scalp discomfort most common AE; contraindicated with cranial metal.
  • Phototherapy: $1,500$–$10,000\text{ lux}$ exposure $1$–$2\text{ h}$ pre-dawn; treats Seasonal Affective Disorder (SAD), shift-work insomnia, jet lag; rare mania induction.
  • Sleep-deprivation techniques (total, partial, phase-delay): $\approx60\char37$ obtain acute relief but relapse after next sleep; combining with antidepressant/lithium sustains benefit.

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• Evidence-based psychotherapies (Table 7-12):
  • Behavioral Therapy (pleasant-event scheduling, goal setting).
  • Cognitive-Behavioral Therapy (CBT): identify automatic thoughts, cognitive restructuring, behavioral experiments.
  • Interpersonal Psychotherapy (IPT): address grief, role disputes, transitions, interpersonal deficits.
  • Behavioral Marital Therapy: communication skills, increasing positive exchanges.
• NIMH Collaborative predictors (Table 7-13):
  • IPT best when baseline social dysfunction high & depression severe.
  • CBT best with low cognitive dysfunction.
  • Pharmacotherapy favored with high work dysfunction & severe depression.

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• CBT vignette demonstrates identifying maladaptive thought (“therapist will be angry”) → behavioral test → cognitive re-evaluation → affect relief.
• Meta-analyses: CBT ≈ medications for acute efficacy; combination often superior; CBT shows better relapse prevention.
• IPT: $12$–$16$ sessions; targets current interpersonal stress rooted in early attachments; effective for severe non-psychotic MDD.
• Behavior therapy: aims to raise reinforcement density; data limited but positive.

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• Psychodynamic therapy: aims at character change (improve intimacy, coping); emerging RCTs show parity with CBT.
• Family therapy: indicated when marital/family strain maintains depression; mood disorders linked to high divorce rates—$\approx50\char37$ spouses report they would not have wed if forewarned.

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• Epidemiology highlights:
  • Meta-analysis of $90$ studies (>$1$ million participants, $1994$–$2014$):
  ◦ Point prevalence $12.9\char37$, $1\text{-yr}$ prevalence $7.2\char37$, lifetime $10.8\char37$.
  • U.S. NSDUH $2019$: $1\text{-yr}$ MDE prevalence $7.1\char37$.
  • Female : male ratio ≈$2:1$ (women $8.7\char37$ vs men $5.3\char37$).
  • Highest prevalence in adolescents—female teens $\approx20\char37$.
  • Risk elevated in divorced/separated and those lacking close ties.

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• No consistent SES correlation; rural vs urban gap diminishing; U.S. highest prevalence in White and Native American respondents.

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• Neurobiology—HPA axis: hypercortisolemia in $20$–$40\char37$ outpatients and $40$–$60\char37$ inpatients; abnormal DST (non-suppression).
• Elevated CRH neurons in hypothalamus (post-mortem).
• Thyroid: $5$–$10\char37$ have functional hypothyroidism (↑TSH); $20$–$30\char37$ display blunted TSH response (relapse predictor).
• GH ↓, prolactin responses blunted, BDNF ↓ in PFC/hippocampus (suicide studies)—serum BDNF increases with successful treatment.
• Circadian findings: reduced slow-wave sleep, shortened REM latency, ↑REM density, ↑core temperature; ~$40\char37$ outpatients & $80\char37$ inpatients show pattern.

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• Neurotransmitters:
  • NE: antidepressant response ↔ β-receptor down-regulation; presynaptic β$_{2}$ modulate both NE & 5-HT release.
  • 5-HT: CSF 5-HIAA ↓ in suicidal patients; depletion paradigms induce relapse in remitted MDD.
  • DA: decreased in depression; diseases/drugs depleting DA induce depressive states; DA-enhancers (bupropion, psychostimulants) ameliorate.
  • ACh: cholinergic agonists evoke depressive-like physiology; trait hypersensitivity found in remitted patients/relatives.
  • GABA: plasma/CSF levels ↓; antidepressants up-regulate GABA receptors.
  • Glutamate: NMDA overactivity neurotoxic; NMDA antagonists (ketamine) antidepressant.
• Second-messenger cascades: targets for mood stabilizers.
• Immune changes: ↓lymphocyte proliferation; cytokine dysregulation (IL-1 induces cortisol synthesis).

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• Imaging:
  • Structural—↑white-matter hyperintensities (subcortical), ventricular enlargement, ↓hippocampal/PFC volume proportional to episode number & cortisol.
  • Functional PET—left anterior hypometabolism; limbic hyper-metabolism (rumination); fMRI meta-analysis: hyper-reactive amygdala/insula/ACC to negative stimuli, under-active DLPFC/striatal reward circuits.
  • Figure 7-2 nodes: orbitofrontal & ventromedial PFC, DLPFC, hippocampus, amygdala, ACC.

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• Genetics:
  • Twin heritability ≈$37\char37$ (higher in women).
  • First-degree relatives OR ≈$2.8$.
  • GWAS: no large-effect common variants; polygenic risk likely involves thousands of small-effect alleles.
  • Candidate genes (e.g., 5HTTLPR, HTR1A, DRD4) findings inconsistent and small effect sizes.

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• Psychological & social risk: loss of parent <$11\text{ yr}$, spousal bereavement, unemployment (×$3$ risk).
• Personality links: higher prevalence in OCPD, histrionic, borderline; antisocial/paranoid less susceptible due to externalizing defenses.

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• Etiologic theories:
  • Classic monoamine deficit—insufficient to explain delayed therapeutic onset.
  • Brain circuit models: limbic (amygdala, hippocampus)–PFC dys-connectivity; ACC fails to modulate emotion.
  • Neurogenesis hypothesis: chronic stress → ↑glucocorticoids → ↓hippocampal neurogenesis → faulty HPA feedback → depression.
  • Neuroplasticity hypothesis: stress & ↓BDNF cause atrophy of mature neurons (esp. hippocampus).
  • Psychosocial: learned helplessness, cognitive triad (negative self-world-future), interpersonal loss models, evolutionary “risk-avoidance” framing.

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• Case vignette (Ms. C): survivor guilt and sibling dynamics precipitate episode after graduate-school acceptance—illustrates role of internalized object relations.
• Psychodynamic “classical” formulation (Freud/Abraham): early oral-phase loss → introjection → self-directed anger.
• CBT cognitive triad & distortions (Table 7-14): arbitrary inference, over-generalization, dichotomous thinking, etc.
• Learned helplessness animal model (inescapable shock) parallels motivational & affective deficits.
• Evolutionary frame: depressive withdrawal may have past adaptive value (risk minimization, social defeat signaling).

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• Integrative concept: genetic vulnerability → stress exposure → epigenetic modulation (e.g., ↓BDNF transcription) → neuronal loss in key mood circuits → neuroendocrine & neurotransmitter dysregulation → clinical syndrome.

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• Key numeric/clinical pearls for exam review:
  • Recurrence risk without prophylaxis: up to $75\char37$ within $5\text{ yr}$.
  • Adequate antidepressant trial: ≥$4$–$6\text{ wk}$ at maximal tolerated dose.
  • Maintenance treatment: ≥$3$ prior episodes or episode interval <$2.5\text{ yr}$.
  • Response threshold: ≥$50\char37$ symptom drop; partial = $20$–$25\char37$.
  • Light therapy: $10,000\text{ lux}$ × $30$–$120\text{ min}$ pre-dawn.
  • rTMS: $5$ sessions/wk for $4$–$6\text{ wk}$; each $40\text{ min}$.
  • Esketamine: administered under REMS, typically $2$ sessions/wk × $4\text{ wk}$ induction.

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• Ethical/Practical implications:
  • Weigh cost/benefit of combination therapy vs monotherapy.
  • Monitor for treatment-emergent mania with antidepressants or light therapy.
  • Informed consent for novel agents (ketamine/esketamine/brexanolone) includes addiction, monitoring, REMS.
  • Family psychoeducation reduces relapse, mitigates marital stress, and addresses caregiver burden.