Potentially Treatable Metabolic Abnormalities in Patients with Treatment-Resistant Depression


Metabolic depression? Researchers performed a metabolomic evaluation of patients with treatment-resistant depression.


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“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, bupropion, venlafaxine, nortriptyline, lamotrigine, lithium, liothyronine, aripiprazole, and perphenazine. He also had a brief course of transcranial magnetic stimulation, with some early improvement, but was unable to continue due to insurance issues. He declined electroconvulsive therapy (ECT) due to his father having significant adverse cognitive effects from the procedure. He experienced partial response to fluoxetine 80 mg daily and amphetamine-dextroamphetamine extended-release 20 mg daily. He had genetic testing, which showed that he is heterozygous for the short/long promoter polymorphism of the serotonin transporter gene, a normal metabolizer of CYP 1A2, 2D6, and 3A4, and homozygous for the C allele of the C677T polymorphism of the MTHFR gene (normal folic acid metabolism). He was offered trials of L-methylfolate, tranylcypromine, and clozapine. Subsequently, Mr Herringbone has responded to 100 mg clozapine daily, with significant improvement in mood and anxiety.

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 treatment-resistant depression (TRD). Recently, there has been an emphasis on ketamine and neuromodulatory treatments in TRD. A novel diagnostic and therapeutic approach to TRD based on a targeted analysis of blood, urine, and CSF metabolites has been proposed. For example, Pan and colleagues reported on a 19-year-old male with TRD and repeated suicide attempts who had deficient CSF tetrahydropiopterin (BH4) intermediates and responded to replacement with the BH4 analog sapropterin.2 In a case-control study, this group found potentially treatable metabolite abnormalities in 21 of 33 patients with TRD and zero controls.3

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 psychiatric interview, including the Family Interview for Genetics Studies. TRD status was confirmed with the Antidepressant Treatment History Questionnaire. Participants were also assessed with the Beck Depression Inventory (BDI) and Suicide Ideation Questionnaire (SIQ), and continued all current medications and other treatments during the study. Participants had blood and urine testing, as well as a lumbar puncture for CSF collection, and a follow-up appointment to review results and provide additional referrals. Participants for whom a novel treatment was available were recontacted at least 6 weeks after the start of that treatment. TRD and control groups were compared with t-tests and chi-square test. Paired t-tests were performed for subjects with cerebral folate deficiency.

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 depression and suicide improved when relevant targeted treatments were available. Although they did not treat patients with abnormal serum acylcarnitine profiles, they hypothesize that treatment with riboflavin 100 mg daily might be beneficial. Study limitations included the relatively small sample of primarily Caucasian participants, and the absence of a formal treatment trial for those with identified abnormalities. Future directions include repeat metabolic testing, including after intervention, and comparing patients with TRD to treatment-responsive patients.

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.


1. Anonymous. The burden of depression. Nature. 2014;515(7526):163.

2. Pan L, Martin P, Zimmer T, et al. Neurometabolic disorders: potentially treatable abnormalities in patients with treatment refractory depression and suicidal behavior. Am J Psychiatry. 2017;174(1):42-50.

3. Pan L, McKain BW, Madan-Khetarpal S, et al. GTP-cyclohydrolase deficiency responsive to sapropterin and 5-HTP supplementation: Relief of treatment-refractory depression and suicidal behaviour. BMJ Case Rep. 2011;2011:bcr0320113927.

4. Pan LA, Segreti AM, Wrobleski, et al. Metabolomic disorders: confirmed presence of potentially treatable abnormalities in patients with treatment refractory depression andsuicidal behavior. Psychol Med. 2022;1-9.

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