Metabolic Disorders Linked to Severe, Refractory Depression

Nancy A. Melville

January 12, 2017

A large proportion of patients with severe, refractory depression have metabolic disorders that, once treated, appear to alleviate depressive symptoms over the long term.

"Our findings, if replicated, suggest that neurometabolic disorders may contribute to treatment-refractory psychiatric disorders even without other systemic illness," the authors, led by Lisa A. Pan, MD, University of Pittsburgh School of Medicine in Pennsylvania, write.

"An important question is whether early identification and treatment of an underlying metabolic abnormality early in the course of psychiatric illness could prevent long-term emotional and cognitive complications," they add.

The study was published in the January issue of the American Journal of Psychiatry.

Dramatic, Durable Remission

The impetus for the current study was a previous case reported by the same investigators and published in the BMJ. It involved a 19-year-old man with treatment-refractory depression who had attempted suicide multiple times. The researchers found that the man had a severe deficiency of cerebrospinal fluid (CSF) tetrahydrobiopterin, a critical cofactor for monoamine neurotransmitter synthesis.

Upon undergoing replacement therapy with the tetrahydrobiopterin analogue sapropterin, the patient experienced dramatic and long-lasting remission of his depression.

To investigate further, the researchers conducted a case-control study that included 33 adolescent and young adult patients with refractory depression and 16 healthy control persons. Refractory depression was defined as depression for which at least three courses of medication administered at a maximum dose for an adequate duration failed.

The patients with treatment-refractory depression were aged 14 to 40 years. For these patients, the depression was of relatively early onset (mean age of onset, 12.4 years). Half the patients reported at least one suicide attempt. Severity of depression at the time of study screening was moderate to severe.

A metabolomic analysis that included testing of central nervous system–specific metabolites showed CSF metabolite abnormalities among 21 of 33 of the patients with treatment-refractory depression, compared to none of the healthy control patients.

The most common abnormality, present in 12 (36%) participants, was cerebral folate deficiency (CFD), in which serum folate levels were normal but levels of CSF 5-MTHF were low (<40 nmol/L). CFD can be caused by mutations in the cerebral folate receptor gene (FOLR1), although genetic testing of eight patients with CFD indicated that none had the mutation.

Importantly, none of the patients had primary neurologic symptoms or other overt clinical disease, suggesting previously reported causes of the abnormalities were unlikely, the authors note.

Of the 12 patients with CFD, 10 showed improvement after referral for treatment with folinic acid (1-2 mg/kg/day) for at least 6 weeks (range, 6-79 weeks) while continuing their preevaluation treatment regimens.

Mean Beck Depression Inventory (BDI) scores decreased in those patients from 30.6 to 11.0 (P < .02). The BDI responses ranged from marginal to a dramatic decline in BDI score from 43 to 0 over 79 weeks, seen in one patient.

Of the remaining two patients, one was nonadherent with the folinic acid regimen, and the other was lost to follow-up.

Patients' mean scores on the Suicidal Ideation Questionnaire decreased from 38.0 to 23.1, although the change was not statistically significant.

Broad Testing Warranted?

As in the initial case that led to the study, one patient in the new study showed low levels of tetrahydrobiopterin intermediates. That patient was additionally treated with sapropterin (20 mg/kg/day).

Other abnormalities identified in nine participants with refractory depression included an abnormal acylcarnitine profile (five patients), a low guanidinoacetate level (one patient), and a creatine/creatinine ratio that was consistent with a creatine synthesis deficit (one patient with Fabry's disease, one with a 20p12.1 microdeletion, and one with a 15q13.3 microduplication on microarray analysis).

The authors note that neither these abnormalities nor the treatments would have been identified through current standard diagnostic practices.

"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," they write.

"Applications of next-generation sequencing technologies (ie, whole exome or genome sequencing) on a focused, homogeneous patient population with treatment-refractory depression will provide further insight into genetic components of the metabolic findings in our patients," the investigators add.

They note that CSF testing is necessary to diagnose CFD. If results are positive, folinic acid can be prescribed and administered in dosages of 1-2 mg/kg/day.

Treatment effects seen with more severe neurologic disorders associated with CFD indicate that a response may take several months, and a full effect could take from 1 to 3 years.

"This may be related to neuronal growth and turnover in an environment in which folate metabolites are newly available," they write.

Treatment with folic acid is not recommended, owing to the potentially low activity of dihydrofolate reductase in CFD and to the fact that it binds tightly to folate receptor alpha, which results in reduced cerebral transport of 5-MTHF.

Side effects associated with folinic acid treatment included facial flushing and initial anxiety.

"Although the study is clearly preliminary because of its small sample size and several limitations, the findings raise issues with immediate relevance to clinical practice," the authors note.

A key caveat of analyzing CSF in the real-world psychiatric setting is the need to perform a lumbar puncture, but the findings nevertheless suggest such abnormalities may be lurking.

"The two-thirds prevalence of at least one type of metabolic abnormality suggests that these diagnoses may be more common in psychiatric settings than is generally appreciated, providing a reasonable argument in favor of broader testing of metabolic function in treatment-resistant cases," the authors conclude.

Feasible Hypothesis

In an accompanying editorial, Marijn Liffijt, PhD, of the Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, notes that the findings, although preliminary, are intriguing.

Previous research has also linked changes in folate pathway regulation with depression, and it has been speculated that such changes play a role in treatment response, Dr Liffijt told Medscape Medical News.

"It is known that folate deficiency could impair metabolism of monoamines, including serotonin, norepinephrine, and dopamine, one characteristic of depression. It is not inconceivable that standard antidepressants may not be effective in patients with an underlying metabolic syndrome," he said.

In pursuing the analysis of biomarkers in blood, urine, and CSF, it is first important to determine what metabolites need to be assessed, Dr Liffijt added.

"It is not unlikely that refractory depression, and depression per se, could be the result of various metabolic syndromes," he said.

"Before considering collecting CSF, patients have the option of electroconvulsive therapy, transcranial stimulation, ketamine, over-the-counter options, such as fish oil, and exercise as additions to existing treatments," he added.

The study received support from the Brain and Behavior Research Foundation NARSAD Young Investigator Award and grants from the National Institutes of Health. Coauthor Keith Hyland, PhD, is executive vice president of Medical Neurogenetics Laboratories, a provider of neurogenetic testing. Coauthor David N. Finegold, MD, is founder of Diavacs and Personalized Genomics Laboratories. Dr Liffijt has disclosed no relevant financial relationships.

Am J Psychiatry. Published online January 1, 2017. Abstract, Editorial

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