Depression, Treatment Resistant
Basics
Description
- 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.
Epidemiology
- 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.
Incidence
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.
Genetics
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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Citation
Domino, Frank J., et al., editors. "Depression, Treatment Resistant." 5-Minute Clinical Consult, 33rd ed., Wolters Kluwer, 2025. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117633/all/Depression_Treatment_Resistant.
Depression, Treatment Resistant. In: Domino FJF, Baldor RAR, Golding JJ, et al, eds. 5-Minute Clinical Consult. Wolters Kluwer; 2025. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117633/all/Depression_Treatment_Resistant. Accessed October 13, 2024.
Depression, Treatment Resistant. (2025). In Domino, F. J., Baldor, R. A., Golding, J., & Stephens, M. B. (Eds.), 5-Minute Clinical Consult (33rd ed.). Wolters Kluwer. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117633/all/Depression_Treatment_Resistant
Depression, Treatment Resistant [Internet]. In: Domino FJF, Baldor RAR, Golding JJ, Stephens MBM, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2025. [cited 2024 October 13]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/117633/all/Depression_Treatment_Resistant.
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