Which Depression Therapies Made the Updated US Guideline for Treating MDD?

Newer therapies, such as ketamine or esketamine, or the broader use of bright light therapy, made an updated clinical practice guideline for treating major depressive disorder (MDD), but psilocybin and cannabis did not.

An updated clinical practice guideline (CPG) from the US Department of Veterans Affairs (VA) and the Department of Defense (DoD) for the management of major depressive disorder (MDD) includes recommendations for newer therapies, such as ketamine or esketamine or widening the use of bright light therapy, as well as a revamped way of describing management of MDD.

However, some therapies were considered but were not included or recommended in the update, including psilocybin and hallucinogens, MDMA, and cannabis, due to a lack of evidence about safety and efficacy.

The updates to the CPG, first published in 2016, were published Monday in Annals of Internal Medicine. The CPG was updated by a workgroup from by the VA and DoD, which conducted a literature review from which they made their recommendations. The CPG also includes 2 updated treatment algorithms.

One major update is how the management section is structured. In 2016, the section was called “treatment of uncomplicated mild to moderate MDD” and “treatment of severe, chronic, or recurrent MDD (complex).”

To align with current evidence and practice, the 2022 guideline refers to “treatment of uncomplicated MDD” and “treatment of MDD that is severe or has a partial or limited response to initial treatment.”

The update released Monday also includes therapies that did not meet inclusion criteria or had a limited recommendation in 2016. They include:

Short-term psychodynamic psychotherapy (STPP). STPP is added to the list of psychotherapy approaches to treat uncomplicated MDD. The list continues to include acceptance and commitment therapy, behavioral therapy/behavioral activation, cognitive behavioral therapy, interpersonal therapy, mindfulness-based cognitive therapy, and problem-solving therapy.

Trazodone. Trazadone was added to the list of pharmacotherapies that might be considered initially or for patients who have responded well previously to another drug.

Repetitive transcranial magnetic stimulation (rTMS). For patients with severe MDD or for those who had a partial or limited response to drug initial treatment, rTMS might be offered.

Second-generation antipsychotics. This class was added to a list of therapies (including another antidepressant and switching or augmenting psychotherapy) for severe MDD or for those who had a partial or limited response to initial treatment.

Ketamine or esketamine. These were not recommended in 2016, the authors noted. Evidence now suggests that both ketamine infusion and intranasal esketamine improve depressive symptoms when at least 2 other drug trials have failed.

Bright light therapy. The updated CPG recommends bright light therapy for persons with mild to moderate MDD, regardless of time of year; the previous guideline recommended bright light therapy only for those with a seasonal pattern.

The strength of the evidence for all of the above recommendations was weak.

Two interventions were not recommended, but were considered as part of the literature review. One is the use of psilocybin and hallucinogens and other unapproved substances to treat MDD. Both substances raise concerns, the authors said. The treatment requires heavy use of resources, with health care providers needing to help prepare and then guide the patient through the treatment, which usually lasts 8 to 12 hours. The authors said there is a “risk for psychotic events and harmful behaviors in patients who do not receive appropriate guidance throughout the treatment process.”

The work group recommends against the use of MDMA, cannabis, or other unapproved substances outside of clinical trials. The CPG considers the strength of the evidence for their recommendation to be strong.

The work group also said there was not enough evidence either for or against the use of pharmacogenomic testing as a guide for selecting antidepressants.


McQuaid JR, Buelt A, Capaldi V, et al. The management of major depressive disorder: synopsis of the 2022 U.S. Department of Veterans Affairs and U.S. Department of Defense clinical practice guideline. Ann Intern Med. Published online September 19, 2022. doi:10.7326/M22-1603

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