Depression, Treatment Resistant



  • Major depressive disorder (MDD) that has failed to respond to ≥2 adequate trials of antidepressant therapy in ≥2 different classes is considered to be “treatment resistant.”
  • Individual antidepressants must be given for 6 weeks at standard doses before being considered a failure.


  • Depression affects >16 million people in the United States and >350 million people worldwide.
  • The average adult has a 16% lifetime risk of MDD, with majority experiencing onset before the age of 30 years.
  • Approximately 1/3 of patients with MDD will develop treatment-resistant depression.

Among patients with unipolar major depression who receive initial treatment, the estimated incidence for treatment resistance ranges from 45% to 46%.

Etiology and Pathophysiology

  • Unclear. Low levels of neurotransmitters (serotonin, norepinephrine, dopamine, and Γ-aminobutyric acid [GABA]) have been indicated.
  • Serotonin has been linked to irritability, hostility, and suicidal ideation.
  • Norepinephrine has been linked to low energy.
  • Dopamine may play a role in low motivation and depression with psychotic features.
  • GABA can help with feelings of anxiety, stress, and fear.
  • Environmental stressors such as abuse and neglect may affect both the function and levels of neurotransmitters.
  • Inflammation and oxidative stress in the brain can contribute to treatment-resistant depression.

A genetic abnormality in the serotonin transporter gene (5-HTTLPR) may increase risk for treatment-resistant depression.

Risk Factors

  • Suicidal thoughts and behavior, severity of disease
  • Early age of onset of major depression
  • Recurrent depressive episodes
  • Mislabeling bipolar patients as depressed
  • Comorbid medical disease (including chronic pain)
  • Comorbid personality disorder
  • Comorbid anxiety disorder
  • Comorbid substance use disorder
  • Genetic familial predisposition to poor response to antidepressants
  • Loss of employment and low socioeconomic status

General Prevention

  • Medication adherence in combination with psychotherapy
  • Maintenance electroconvulsive therapy (ECT) may prevent relapse.

Commonly Associated Conditions

  • Suicide
  • Bipolar disorder
  • Substance use disorders
  • Anxiety disorders
  • Dysthymia
  • Eating disorders
  • Somatic symptom disorders

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