March 12, 2020

Metabolic differences provide biological clues and treatment potential for suicide

We often speak of mental health concerns in the context of ‘chemical imbalances’ and many of us are aware that levels of neurotransmitters, such as serotonin and dopamine, have been found to be altered in those with mental health conditions. We don’t yet know why or how, and rarely does someone go looking for the answer in an individual patient. But sometimes, a single inquiry sparks a finding that offers clues and opens up an entirely new territory for investigation.  This is exactly what happened for our physician-scientist featured here.

In treating a suicidal patient who did not respond to many traditional approaches for her severe depression, psychiatrist and researcher Lisa Pan, M.D., sought out advice on additional testing for her patient. When a colleague recommended a neurological work-up and metabolic testing of cerebral spinal fluid, a deficiency was revealed that, when treated, surprisingly and steadily improved the patient’s depression.

Curious as to whether metabolic issues were present in other treatment-refractory suicidal and depressed patients, Dr. Pan repeated these tests in others. Abnormalities were assessed by measuring various substances produced during metabolism.  These metabolic abnormalities provide indications of the function of various chemical processes such as neurotransmitters and cellular energy production. Dr. Pan’s findings addressed critical questions about why these patients were depressed
and suicidal, as well as not responding to the usual interventions. Furthermore, she learned that providing vitamins and supplements, which supply missing metabolic components, could dramatically change outcomes in these patients. By thinking outside the box, such biological evaluations revealed that some patients may not be entirely ‘treatment-resistant.’ They just need the right treatments…proving, once again, we can’t know what we don’t look for.  This transformative study illustrates why JKBF advocates for additional research into the biological basis of suicide.

Below Dr. Pan summarized her study for JKBF.  We wish her well in her continued innovative exploration of the biological risk factors and potential treatment opportunities involved in suicidal behavior.

From the Scientist: 

Summary of Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior

by Lisa Pan, M.D.

I recently tested the hypothesis that treatment-refractory depression may be associated with metabolic and neuro-metabolite signatures through a case-control pilot study. I identified Central Nervous System (CNS)-specific metabolomic disorders, not present in controls, through cerebrospinal fluid testing in patients with treatment-refractory depression. These deficiencies were treated accordingly. These included: 1) cerebral folate deficiency (CFD), responsive to treatment with folinic acid 2) CSF tetrahydrobiopterin deficiency, responsive to replacement with biopterin (sapropterin), 3) acylcarnitine profile abnormalities, responsive to treatment with riboflavin, and 4) patients with genetic microarray abnormalities who were referred to medical genetics for treatment. 

After at least three failed interventions, for these patients it was unlikely that current tools (Cognitive Behavior Therapy and antidepressant medications) would be successful in treating their depression. Assessment tools used to develop strategies for the treatment of depression (e.g., functional neuroimaging or pharmacogenetics) would not have identified the source of these patients’ difficulties, nor would they have led to the recommendation of the treatments subsequently found to be successful. I employed both precision and personalized medicine to find the molecular abnormalities in the patients’ systems, and for those with deficiencies, directed treatments providing the essential metabolites needed. This provided these patients with normally functioning neurometabolic systems, and resulted in improved mood and quality of life.  

My team believes that 20-40% of treatment-refractory depressed patients have a primary or secondary metabolomic disorder, meaning that this approach could help more than 400,000 patients per year, and potentially result in millions more depression-free days for these individuals, with improved quality of life, decreasing disability, and increasing productivity.  Given the specific biochemical anomalies identified during these preliminary investigations, and the fact that affected individuals frequently have first-degree relatives with treatment-refractory depression, I further hypothesize that these metabolic anomalies have a multifactorial genetic basis. 

My goals are to expand upon this published work by further identifying and characterizing primary and secondary disorders of CNS metabolism that lead to treatment-refractory depression, and to develop a national and international center for the treatment of treatment-refractory depression in children, adolescents and adults. Notably, such metabolic treatment is non-invasive, whereas the other current treatments for treatment-refractory depression are invasive (including brain surgery) and controversial.