Treatment-resistant major depression in adults and young people

Treatment-resistant major depression (also known as treatment-resistant depression) is defined as depressive symptoms that persist despite using an effective dose of at least 2 antidepressants as sequential monotherapy, each for a minimum of 4 weeks. Consider if any of the reasons for antidepressant nonresponse listed in Key questions to assess nonresponse to an antidepressant for major depression could account for response; if not, refer patients with treatment-resistant major depression to a psychiatrist.

It is rarely appropriate to increase the antidepressant dose above the recommended maximum dose to try to overcome treatment resistance. Dosing above the recommended range is associated with increased adverse effects but may not improve symptoms because of the relatively flat dose-response curve of most antidepressants. However, rates of drug metabolism can vary depending on patient genetics (eg cytochrome p450 genotype) and drug interactions. In some cases, a psychiatrist may exceed the recommended dose rangeMahli 2015.

The choice of therapy for treatment-resistant major depression is influenced by patient-specific factors (eg severity of depression, comorbidities) and the availability of treatments. One of the following approaches may be considered by a psychiatrist:

• antidepressant augmentation
• irreversible monoamine oxidase inhibitors
• mianserin
• physical therapies
• tricyclic antidepressants.

At the time of writing, there are insufficient data to recommend routine use of esketamine, ketamine or psilocybin-assisted therapy for treatment-resistant major depression.