Description

• Major depressive disorder (MDD) that has been unresponsive to treatment with at least ≥2 different classes of antidepressants is considered to be “treatment resistant.”
• Individual antidepressants must be given for 6 to 8 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.

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.
• Growing evidence suggest that proinflammatory cytokine release in the brain has been linked to early uptake of serotonin, decrease dopamine release, and decrease effectiveness of SSRIs.

Risk Factors

• Suicidal thoughts and behavior, severity of disease
• Early age of onset of major depression (<18 years of age)
• Recurrent depressive episodes
• Mislabeling bipolar patients as depressed
• Comorbid medical disease and chronic pain
• Comorbid personality, anxiety, and substance use disorder
• Adverse life events (childhood trauma or abuse, marital problems)
• Genetic familial predisposition to poor response to antidepressants
• Loss of employment and low socioeconomic status

General Prevention

• Medication adherence
• Maintenance electroconvulsive therapy (ECT) may prevent relapse.
• Adhering to psychotherapy

Commonly Associated Conditions

• Suicide
• Bipolar disorder, dysthymia, anxiety
• Substance use disorders
• Eating disorders
• Somatic symptom disorders