A New Direction for Treatment-Resistant Depression?
Joel Yager, MD reviewing Pan LA et al. Am J Psychiatry 2016 Aug 13.
More than a third of treatment-resistant patients had cerebral folate deficiencies, and all who were treated with folinic acid showed some improvement in depression.
About one third of patients with major depression don't respond to first-line treatments; 15% are resistant to all treatments (treatment-resistant depression [TRD]). After successfully treating TRD in a patient deficient in cerebrospinal fluid (CSF) tetrahydrobiopterin (necessary for biosynthesis of several neurotransmitters) with sapropterin (synthetic form of tetrahydrobiopterin's active isomer), investigators searched for this and other potential metabolic abnormalities in 33 TRD patients.
Patients had failed >3 medication trials (mean age, 26; 76% women; age at onset: ≤17 years, 91%; <10 years, 33%); 85% had comorbid diagnoses, primarily anxiety disorders, post-traumatic stress disorder, or both. Of their first-degree relatives, 82% had histories of depression and 24% had attempted suicide.
Metabolic abnormalities examined in CSF, blood, and urine involved tetrahydrobiopterin, 5-methyltetrahydrofolate (5-MTHF; related to vitamin B9), pyridoxal-5-phosphate (vitamin B6), amino-adipic semialdehyde (biomarker of low cerebral pyridoxine), and major neurotransmitter metabolites (homovanillic acid, 5-hydroxyinoleacetic acid). CSF metabolic abnormalities were detected in 21 patients. Twelve (36%) had cerebral folate deficiency (CFD; low CSF 5-MTHF with normal serum folate); one also had tetrahydrobiopterin deficiency. Nine patients had other abnormalities. CFD patients received 6 weeks of adjunctive folinic acid treatment. All 10 patients with follow-up data showed improved depression scores, which reached normal range in 4. Of 5 patients with elevated suicide scores, 3 showed reductions below threshold.
Comment
This first-ever metabolomics survey specific to the central nervous system in TRD patients lacking neurological symptoms reveals many actionable abnormalities. We need to identify biomarkers not requiring spinal taps and explore how abnormalities might reflect sequelae of depression or other acquired or genetic effects. Although additional study is needed before clinicians begin adopting this adjunctive approach, the authors mention that clinicians wishing to try it in select patients who have failed all other options should use folinic acid (1–2 mg/kg/day), which acts earlier in folate pathways than L-methylfolate.
Editor Disclosures at Time of Publication
- Disclosures for Joel Yager, MD at time of publication Editorial boards Bulletin of the Menninger Clinic; Eating Disorders Review (Editor-in-Chief Emeritus); International Journal of Eating Disorders; UpToDate; FOCUS: The Journal of Lifelong Learning in Psychiatry
Citation(s):
- Pan LA et al. Neurometabolic disorders: Potentially treatable abnormalities in patients with treatment-refractory depression and suicidal behavior. Am J Psychiatry 2016 Aug 13; [e-pub]. (http://dx.doi.org/10.1176/appi.ajp.2016.15111500)
