Can Metabolic Therapy Help People with Treatment-Resistant Depression?

Depressive disorders are associated with suicide. About 15 percent of individuals with depression do not respond to known treatments. In other words, they experience treatment resistant depression (TRD).

Many approaches have been tested to improve the outcome for those with treatment resistant depression, with minimal improvement. One area that does show promise relates to metabolites, the compounds that help the body turn nutrients into energy. Metabolites are in the cells and are acted upon by enzymes. Folate, for example, is a metabolite that relates to the development of nerves.

This study began when a 19-year-old male with treatment-resistant depression and repeated suicide attempts presented for treatment with Dr. Lisa Pan. He was identified as having a metabolic abnormality, and had a complete response to treatment with the specific metabolite identified as abnormal. Five other adolescent patients, also identified as having different metabolic abnormalities, were treated with success by addressing the specific metabolite with which they had an abnormality.

The Question
Are metabolic abnormalities more likely for people with treatment-resistant depression? Might they respond to metabolic treatment?

The Study
33 patients with treatment-resistant depression and 16 healthy comparison subjects aged 14-40 years old were evaluated. Participants were assessed prior to and after treatment, using a structured psychiatric interview; a review of records; and self-report instruments to characterize depression, suicidal ideation and behavior, the presence of other diseases or conditions, and family history. A neurologic examination was also conducted. Blood, plasma, cerebrospinal fluid, and urine were tested for central nervous system-specific metabolic abnormalities

Abnormalities were evidenced in 21 of the 33 participants in the depression group. No abnormalities were discovered in the comparison group. The most common abnormality was cerebral folate deficiency (CFD), a metabolite that affects nerve function. This deficiency was found in 12 of these participants who were then treated with 1-2 mg daily doses of folinic acid for at least six weeks while continuing previous treatment.

At follow-up, 10 of the participants with cerebral folate deficiency who had been treated with folinic acid showed reductions in symptoms related to depression or suicidal ideation. For the other two patients, one did not complete the follow up and the other did not adhere to the treatment. Eight participants with cerebral folate deficiency did not have any other biochemical comorbidities. These four participants’ depression assessment scores dropped below the threshold for depression. Three of the five participants in this subset who had originally met threshold scores for suicidal ideation prior to treatment fell below that threshold post-treatment. Depression scores dropped significantly and suicidal ideation scores dropped to a lesser extent.

An evaluation of metabolites related to nervous system functioning is important for people with depression, especially those with treatment-resistant depression. Targeted metabolic therapy for people with treatment-refractory depression shows promise. With further research it may be possible to diagnose and treat these abnormalities in this non-intrusive way, and thereby revolutionize psychiatric treatment for treatment-resistant depression.

Publication from AFSP Grant

  • Pan, L.A., Martin, P., Zimmer, T., Segreti, A.M., Kassiff, S., McKain, B.W., Baca, C.A., Rengasamy, M., Hyland, K., Walano, N., Steinfield, R., Hughes, M., Dobrowolski, S.K., Pasquino, M., Diler, R., Perel, J., Finegold, D.N., Peters, D.G., Naviaux, R.K., Brent, D.A., &Vockley, J. (2016). Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior. The American Journal of Psychiatry, 1-8.

Click here to read about Dr. Pan’s Standard Research Grant.


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