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