
Potentially Treatable Metabolic Abnormalities in Patients with Treatment-Resistant Depression
Metabolic depression? Researchers performed a metabolomic evaluation of patients with treatment-resistant depression.
RESEARCH UPDATE
CASE VIGNETTE
“Mr Herringbone” is a 29-year-old Caucasian male with a history of major depressive disorder (MDD), recurrent, severe, without psychosis. The onset of his depression was around age 12. He has some features of atypical depression, including hypersomnia, weight gain, and anxiety. Mr Herringbone previously failed trials of sertraline, escitalopram,
Approximately 15% of patients with MDD do not respond to adequate pharmacotherapy, psychotherapy, and neurostimulation.1 Unfortunately, in recent decades there have been limited advances in the clinical management of
The Current Study
Pan and colleagues performed a systematic evaluation of 141 patients with TRD and controls for primary and secondary disorders of CNS metabolism.4 They recruited n=141 participants aged 14 to 70 with depression unresponsive to at least 3 maximum dose medication trials of at least 6 weeks. These participants were compared to n=36 healthy controls with no personal or first-degree relative history of psychiatric disorder or suicidal behavior. Participants were assessed with a structured
Mean participant age was 27.5, 39% were male, and 86% were Caucasian. Almost half of the TRD participants reported a history of at least 1 suicide attempt. Sixty seven of 141 participants with TRD (48%) had evidence of metabolomic abnormalities. Cerebral folate deficiency (CFD), in which serum folate is normal but CSF 5-MTHF is low, was present in 20 participants (14%). Low (n=11) and borderline low (n=20) CSF BH4 intermediates were also common. Abnormal serum acylcarnitine profiles (n=12) and serum amino acids (n=20) were also found. Eighteen participants (13%) had 2 or more metabolic findings.
Twenty participants with low CSF 5-MTHF were offered folinic acid, of whom 16 were treated for at least 6 weeks. All 16 of these participants with CFD showed reduction in SIQ scores (40 to 23) and 15 showed reduction in BDI scores (31 to 18.5). Eleven participants with low CSF BH4 intermediates were offered sapropterin, of whom 7 were treated for at least 6 weeks. All 7 showed reduction in SIQ scores (60 to 38) and BDI scores (43 to 28). Twenty participants with borderline low CSF BH4 intermediates were offered sapropterin, of whom 5 were treated for at least 6 weeks. All 5 showed reduction in SIQ scores (41 to 20) and BDI scores (30 to 16).
Study Conclusions
The authors systematically evaluated abnormalities of neurotransmitter, vitamin, pterin, and energy metabolism in peripheral and CSF samples in subjects with TRD. They found that almost half (48%) of these participants had metabolic abnormalities, and symptoms of
The Bottom Line
Neurometabolic abnormalities are common, and often actionable and clinically relevant in patients with TRD. Identification of genetic and secondary metabolic disorders contributing to psychiatric illness may allow orphan drug repurposing for TRD.
Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
References
1. Anonymous.
2. Pan L, Martin P, Zimmer T, et al.
3. Pan L, McKain BW, Madan-Khetarpal S, et al.
4. Pan LA, Segreti AM, Wrobleski, et al.
Newsletter
Receive trusted psychiatric news, expert analysis, and clinical insights — subscribe today to support your practice and your patients.