Treating Metabolic Conditions May Resolve Some Depressive Symptoms

New research suggests that treatable metabolic abnormalities underlie some treatment-resistant cases of depression—and treating the metabolic condition has the possibility of dramatically reducing depressive symptoms


A new study, published online ahead of print in the American Journal of Psychiatry, suggests that a particular subtype of treatment-resistant depression includes treatable metabolic abnormalities. Almost two-thirds of the patients in the study with treatment-resistant depression had at least one identifiable metabolic condition, while none of the healthy controls had metabolic problems. When the metabolic condition was treated, at least four patients exhibited dramatic improvements in their depressive symptoms.

The researchers, led by Lisa A. Pan, MD, at the University of Pittsburgh, compared 33 people with treatment-resistant depression with 16 healthy individuals. The participants in the healthy control group were required to have had no immediate family history of mental illness as well. Treatment-resistant depression was defined by the researchers as “depression that has not responded to at least three maximum-dose medication trials of at least 6 weeks each.”

The researchers found that 21 of the 33 patients with treatment-resistant depression had identifiable metabolic abnormalities. The most common, cerebral folate deficiency, was found in 12 of the patients. All 12 of these patients received treatment for this deficiency (folinic acid treatment), although 1 patient was lost to follow-up and another patient did not adhere to the folinic acid treatment. After treatment, most patients showed improvement in depressive symptoms. Four of the patients improved enough to no longer meet the threshold for depression on the measure used (the Beck Depression Inventory).
Dr. Pan writes,

“None of the conventional clinical or research diagnostic or therapeutic approaches would have identified the source of these patients’ difficulties, nor would they have suggested the subsequent successful treatment strategies.”

"Depression USA“ by McInerney, John. Photo Credit: Flickr
“Depression USA“ by McInerney, John. Photo Credit: Flickr

This research adds to the literature suggesting that the construct of depression is not a homogenous disease. Instead, the term “depression” may encompass all manner of causes and prognoses. For instance, “depression” may indicate a normal response to significant stressors; it may indicate a melancholy personality; it may indicate an unusually dramatic mood change in the absence of obvious stressors; or it may indicate changes in mood and energy level due to metabolic abnormalities. Each of these forms of depression may require significantly different treatment regimens. Indeed, researchers have found that most people with common mental health concerns actually improve without any formal treatment. However, if an identifiable subtype of depression is associated with treatable metabolic abnormalities, the treatment of at least some individuals suffering with depression may be improved.

Unfortunately, current American guidelines for the treatment of depression do not acknowledge this heterogeneity. Instead, they call for antidepressant medications for all cases of depression—medications which have limited effectiveness and a multitude of dangerous side effects. In fact, researchers have claimed that “There are now plenty of data and evidence that, in the long term, the drugs do not work.”

The current study suggests that the medications currently prescribed, such as SSRIs, affect brain chemistry that is mostly unrelated to depression for at least some of those whose depressed symptoms are at their worst.

There were numerous limitations to the current study. Significantly, the researchers did not find any metabolic explanation for the symptoms of 12 of the patients with treatment-resistant depression. Also, the researchers do not explain the appropriate treatment for the other metabolic abnormalities besides cerebral folate deficiency. The other detected metabolic conditions may not be indicative of a clear disorder, nor may they have a specific treatment.

Importantly, the researchers could not tell whether the metabolic abnormalities were the cause of depression, or whether they were the result of long-term depressive symptoms or long-term psychopharmaceutical use. However, that the treatment of the metabolic condition improved depressive symptoms so dramatically makes a striking case for causality.

The small sample size of the study means that studies with more people need to be done before we can assume that these results will hold true across the population. For instance, people without depressive symptoms and people with other mental health diagnoses will need to be tested to determine if these metabolic problems can occur in the absence of depression. If so, then even detection of these conditions may still not serve as an adequate marker for this subtype of depression.

Additionally, the current study did not include individuals diagnosed with mild or moderate depression or those diagnosed with severe depression who responded to medication or other treatment. Because of this, we do not know if people experiencing milder symptoms or those whose symptoms respond to treatment also have similar metabolic markers.

The examination for metabolic abnormalities requires a lumbar puncture, also known as a spinal tap, to obtain cerebrospinal fluid. This procedure is usually considered safe but does entail some risks and in rare cases can result in paraplegia. It would be costly and risky to suggest this procedure for every individual diagnosed with depression. Thus, more research needs to be conducted to determine what observable traits are associated with these particular metabolic subtypes of depression.

The researchers found that a percentage of patients with treatment-resistant depression also have metabolic conditions. This suggests that we may have a possible treatment for some of those whose depression is long-lasting and severe. However, more research is needed before we can say for sure. Moreover, this study suggests that the causes of depressive symptoms may be as varied as the symptoms themselves—indicating that the universal prescription of “antidepressant” medications may be an inherently flawed recommendation that results in more harm than good.



Pan, L. A., Martin, P., Zimmer, T., Segreti, A. M., Kassiff, S., McKain, B. W. . . . Vockley, J. (2017). Neurometabolic disorders: Potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior. Am J Psychiatry, 174(1). (Abstract)


    • Great point Randall. They also cause diabetes which will cause most physicians to direct patients to certified diabetic educators who advise patients to go on a high carb diet that the American Diabetes Association supports because meds will cover it. Since diabetes is an issue of carbohydrate intolerance, it is like telling people with a gluten intolerance to eat alot of gluten.

      My guess is that people try to diligently follow this advice only to see themselves getting worse which can be quite depressing. And the extreme highs and lows this diet causes can also result in depression.

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    • No, it presents more like reality than an excursion into Diagnostic Wonderland, the reality being that depression is just a syndrome with a variety of origins. I hate to bring this up, but Hoffer was treating depressions with folate decades ago- the work isn’t that original. These subsets that respond to various treatments other than psych drugs aren’t ever going to have psychiatric diagnoses, because they’re physical conditions, anathema to psychiatric “diagnosis” and treatment.

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  1. I would suggest we consider what is the chicken and what the egg? If we consider emotional distress states such as depression, anxiety, insomnia etc. as our natural ‘alarm systems’ – alerting us that something is not working, either in our emotional lives or in our physical systems functioning, then treating ‘depression’ with medication is akin to overriding these alarms … and has consequences.
    I write about this in my recent MIA blog

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