What depression treatments have provided the updated American guideline for treating major depressive depression?

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

Updated Clinical Practice Guidelines (CPG) from the US Department of Veterans Affairs (VA) and Department of Defense (DoD) for managing severe depressive disorder The (MDD) includes recommendations for newer treatments, such as ketamine or esketamine, or expanded use of bright light therapy, as well as an innovative way to describe the management of major depressive disorder.

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

The Consumer Protection Handbook updates, first published in 2016, were published Monday at Annals of internal medicine. The Policy Manual was updated by a working group from the Department of Veterans Affairs and the Department of Defense, which conducted the literature review through which it made its recommendations. CPG also includes updated processing algorithms.

One of the major updates is how the management department is structured. In 2016, the department was named “Treatment of mild to moderate uncomplicated MDD” and “Treatment of severe, chronic or recurrent (combined) MDD.”

For consistency with current evidence and practice, the 2022 guidelines refer to “treatment of uncomplicated MDD” and “treatment of MDD that is severe or has a partial or limited response to initial therapy.”

The update released Monday also includes treatments that don’t meet the inclusion criteria or have a limited recommendation in 2016. They include:

Short Term Psychodynamic Therapy (STPP). STPP has been added to the list of psychotherapeutic approaches to treat uncomplicated MDD. The list continues to include acceptance and commitment therapy, behavioral/activation therapy, cognitive behavioral therapy, interpersonal therapy, mindfulness-based cognitive therapy, and problem-solving therapy.

trazodone. Trazadone has been added to the list of drug treatments that may be considered initially or for patients who previously responded well to another drug.

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

second generation antipsychotics. This chapter has been added to the list of treatments (including another antidepressant and switch-enhanced psychotherapy) for severe mental disorders or for those with a partial or limited response to initial treatment.

Ketamine or esketamine. The authors note that these were not recommended in 2016. Evidence now indicates that both intranasal injections of ketamine and esketamine improve symptoms of depression when at least two other trials have failed.

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

The strength of 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, hallucinogens, and other substances not approved for the treatment of MDD. Both articles raise concerns, the authors said. Treatment requires a heavy use of resources, as health care providers need to help prepare and then guide the patient through treatment, which usually lasts 8 to 12 hours. The authors said there is a “risk of psychotic events and adverse behaviors in patients who do not receive appropriate guidance throughout the treatment process.”

The working group recommends not using MDMA, cannabis, or other unapproved substances outside of clinical trials. CPG considers the strength of evidence to recommend it to be strong.

The working group also said that there was insufficient evidence either to support or oppose the use of pharmacogenomics testing as a guide for selecting antidepressants.


McQuaid JR, Buelt A, Capaldi V, et al. Managing Major Depressive Disorder: The 2022 US Department of Veterans Affairs Summary and US Department of Defense Clinical Practice Guidelines. Ann med trainee. Published online September 19, 2022. doi: 10.7326/M22-1603