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Depression, Treatment Resistant

Basics

  • Defined as MDD failing to respond to ≥2 adequate antidepressant trials (each ≥6 weeks at standard doses).
  • Affects ~1/3 of patients with major depression.
  • Average adult lifetime risk of MDD is 16%.

Etiology and Pathophysiology

  • Low levels of serotonin, norepinephrine, dopamine, and GABA implicated.
  • Serotonin linked to irritability and suicidal ideation; norepinephrine with low energy; dopamine with motivation and psychotic features.
  • Environmental stressors, inflammation, and oxidative stress contribute.
  • Genetic abnormality in serotonin transporter gene (5-HTTLPR) may increase risk.

Risk Factors

  • Early onset, recurrent episodes, suicidality.
  • Misdiagnosed bipolar disorder.
  • Medical comorbidities (chronic pain), personality/anxiety/substance use disorders.
  • Genetic familial predisposition.
  • Socioeconomic challenges.

Diagnosis

  • Clinical symptoms of MDD persist despite adequate treatment.
  • Screen carefully for suicidality.
  • Use SIGECAPS mnemonic: Sleep, Interest, Guilt, Energy, Concentration, Appetite, Psychomotor changes, Suicidality.
  • Mental status exam: poor hygiene, restricted affect, psychomotor changes.

Differential Diagnosis

  • Bipolar disorder
  • Persistent depressive disorder
  • PTSD
  • Dementia, early Parkinson disease
  • Personality disorders
  • Medical illness (malignancy, thyroid, HIV, anemia)
  • Substance use

Diagnostic Tests

  • Rule out medical contributors: CBC, CMP, urine drug screen, TSH, vitamins D/B12/folate.
  • Hormonal panels (FSH, LH, testosterone) if relevant.
  • Neuroimaging (CT/MRI) if neurological or dementia concerns.
  • Depression rating scales: Beck Depression Inventory, Hamilton Depression Rating Scale, PHQ-9, Edinburgh Postnatal Depression Scale (if applicable).

Treatment

Medication

  • Combination and augmentation after failure of initial antidepressants.

Antidepressant combinations:

  • Citalopram + bupropion
  • SSRI + TCA (citalopram + nortriptyline) with caution for serotonin syndrome
  • SNRI + NaSSA (venlafaxine XR + mirtazapine)

Antidepressants + antipsychotics:

  • Citalopram + aripiprazole, risperidone, or quetiapine
  • Olanzapine/fluoxetine combination

Antidepressants + lithium:

  • Nortriptyline + lithium

  • Citalopram + lithium

  • Maximum doses may be higher than in non-resistant cases.

Second Line

  • Citalopram + triiodothyronine (T3)
  • Citalopram + buspirone
  • Citalopram + lisdexamfetamine
  • Antidepressant + cognitive-behavioral therapy (CBT)

Monoamine Oxidase Inhibitors (MAOIs)

  • Tranylcypromine, Selegiline transdermal patch
  • Risk of hypertensive crisis and drug interactions; requires washout periods.

Additional Therapies

  • First line: Electroconvulsive therapy (ECT)
  • 66.6% response rate
  • Rapid relief of suicidality, psychotic depression, catatonia

  • Cognitive side effects more common with bilateral lead placement

  • Second line / experimental:

  • Deep brain stimulation (DBS)
  • Transcranial magnetic stimulation (TMS)
  • Vagus nerve stimulation (VNS)
  • Ketamine infusion and intranasal esketamine (rapid, temporary improvement)
  • Stanford neuromodulation therapy (investigational)
  • Psilocybin (investigational psychedelic therapy)

Admission Criteria

  • Severe depression with psychosis, suicidality, catatonia.

Ongoing Care

  • Frequent follow-up (monthly) to monitor medication effectiveness, side effects, and need for advanced therapies.
  • Maintenance ECT or ketamine/esketamine may be needed to prevent relapse.
  • Combination lithium/nortriptyline after ECT may reduce relapse risk.

Diet

  • MAOI patients must avoid tyramine-rich foods to prevent hypertensive crisis.

Patient Education

  • Depression is a medical illness, not a character flaw.
  • Importance of medication adherence and follow-up.
  • Safety plan for suicidal thoughts.

Prognosis

  • Improved with adherence, social support, psychotherapy.
  • Suicide risk and disability remain significant concerns.

Complications

  • Suicide
  • Disability
  • Poor quality of life

ICD10 Codes:
- F32.9 Major depressive disorder, single episode, unspecified
- F33.9 Major depressive disorder, recurrent, unspecified

Clinical Pearls:
- TRD affects about 1/3 of patients with MDD.
- Combination and augmentation strategies improve outcomes.
- ECT and ketamine/esketamine effective in severe, life-threatening cases.
- DBS, TMS, and psilocybin show promise but remain experimental.