Treatment-resistant depression (TRD) is often defined as major depressive disorder in which an affected person does not respond adequately to at least two different antidepressant medications at an adequate dose and for an adequate duration. Electroconvulsive therapy, ketamine, esketamine, and psilocybin are the most effective and safe first-line treatments for treatment-resistant depression.

Inadequate response has most commonly been defined as less than 25% reduction in depressive symptoms following treatment with an antidepressant. Many clinicians and researchers question the construct validity and clinical utility of treatment-resistant depression as currently conceptualized. There is ongoing debate as to whether inadequate response to other treatment modalities, such as psychotherapy, should be included in defining TRD.

Treatment resistance is becoming more prominent with nearly 30% of individuals with major depressive disorder being termed treatment-resistant as defined above. There are many factors that may contribute to inadequate treatment, such as: a history of repeated or severe adverse childhood experiences, early discontinuation of treatment, failure to consider psychotherapy and other psychosocial interventions, patient noncompliance, misdiagnosis, cognitive impairment, low income and other social determinants, and concurrent medical conditions, including comorbid psychiatric disorders. Cases of treatment-resistant depression may also be referred to by which medications people are resistant to (e.g., SSRI-resistant). They may also be staged based on how many treatments they have tried. Despite being called treatment-resistant, there are many treatment options available which are described in the treatment section below.

Comorbid psychiatric disorders commonly go undetected in the treatment of depression. If left untreated, the symptoms of these disorders can interfere with both evaluation and treatment. Anxiety disorders are one of the most common disorder types associated with treatment-resistant depression. The two disorders commonly co-exist, and have some similar symptoms. Some studies have shown that patients with both major depressive disorder and panic disorder are the most likely to be nonresponsive to treatment. Substance abuse may also be a predictor of treatment-resistant depression. It may cause depressed patients to be noncompliant in their treatment, and the effects of certain substances can worsen the effects of depression. Other psychiatric disorders that may predict treatment-resistant depression include attention deficit hyperactivity disorder, personality disorders, obsessive compulsive disorder, and eating disorders.

Some people who are diagnosed with treatment-resistant depression may have an underlying undiagnosed health condition that is causing or contributing to their depression. Endocrine disorders like hypothyroidism, Cushing's disease, and Addison's disease are among the most commonly identified as contributing to depression. Others include diabetes, coronary artery disease, cancer, HIV, and Parkinson's disease. Another factor is that medications used to treat comorbid medical disorders may lessen the effectiveness of antidepressants or cause depression symptoms.

People with depression who also display psychotic symptoms such as delusions or hallucinations are more likely to be treatment resistant. Another depressive feature that has been associated with poor response to treatment is longer duration of depressive episodes. Individuals with depression who struggle with insomnia or develop depression at a younger age are also more likely to resistant to treatment. Finally, people with more severe depression and those who are suicidal are more likely to be nonresponsive to antidepressant treatment.

Multiple populations have been identified as being more at risk for treatment resistance. Individuals who are not married or identify as single are one of these groups that may be more at risk. Another population who seems to have poor response to treatment are individuals who are unemployed. Finally, while both male and female gender have been identified as risk factors, it appears that females are more prone to struggle with resistance to treatment.

Electroconvulsive therapy, ketamine, esketamine, and psilocybin are the most effective and safe first-line treatments for treatment-resistant depression, with esketamine and psilocybin showing slightly lower tolerability.