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Neurometabolic Disorders: Potentially Treatable
Abnormalities in Patients With Treatment-Refractory
Depression and Suicidal Behavior
Lisa A. Pan, M.D., Petra Martin, B.S., Thomas Zimmer, B.S., Anna Maria Segreti, B.S., Sivan Kassiff, B.S.,
Brian W. McKain, R.N., M.S.N., Cynthia A. Baca, R.N., M.S.N., Manivel Rengasamy, M.D., Keith Hyland, Ph.D.,
Nicolette Walano, M.S., Robert Steinfeld, M.D., Marion Hughes, M.D., Steven K. Dobrowolski, Ph.D., Michele Pasquino, B.S.,
Rasim Diler, M.D., James Perel, Ph.D., David N. Finegold, M.D., David G. Peters, Ph.D., Robert K. Naviaux, M.D., Ph.D.,
David A. Brent, M.D., Jerry Vockley, M.D., Ph.D.

Objective: Treatment-refractory depression is a devastating mass spectrometry and high-performance liquid chroma-
condition with significant morbidity, mortality, and societal tography electrospray ionization tandem mass spectrometry.
cost. At least 15% of cases of major depressive disorder re-
main refractory to treatment. The authors previously iden- Results: CSF metabolite abnormalities were identified in
tified a young adult with treatment-refractory depression 21 of the 33 participants with treatment-refractory de-
and multiple suicide attempts with an associated severe pression. Cerebral folate deficiency (N=12) was most
deficiency of CSF tetrahydrobiopterin, a critical cofactor common, with normal serum folate levels and low CSF
for monoamine neurotransmitter synthesis. Treatment with 5-methyltetrahydrofolate (5-MTHF) levels. All patients with
sapropterin, a tetrahydrobiopterin analogue, led to dramatic cerebral folate deficiency, including one with low CSF levels
and long-lasting remission of depression. This sentinel case of 5-MTHF and tetrahydrobiopterin intermediates, showed
led the authors to hypothesize that the incidence of met- improvement in depression symptom inventories after
abolic abnormalities contributing to treatment-refractory treatment with folinic acid; the patient with low tetrahy-
depression is underrecognized. drobiopterin also received sapropterin. None of the healthy
comparison subjects had a metabolite abnormality.
Method: The authors conducted a case-control, targeted,
metabolomic evaluation of 33 adolescent and young adult Conclusions: Examination of metabolic disorders in treatment-
patients with well-characterized histories of treatment- refractory depression identified an unexpectedly large pro-
refractory depression (at least three maximum-dose, portion of patients with potentially treatable abnormalities. The
adequate-duration medication treatments), and 16 healthy etiology of these abnormalities remains to be determined.
comparison subjects. Plasma, urine, and CSF metabolic
profiling were performed by coupled gas chromatography/ AJP in Advance (doi: 10.1176/appi.ajp.2016.15111500)

Major depressive disorder is the second leading cause of such as deep brain stimulation, which, while promising,
disability worldwide and affects an estimated 350 million requires neurosurgical intervention. We propose a novel
people (1). Although strides have been made in the treatment diagnostic and therapeutic approach to treatment-refractory
of depression, an estimated 15% of depressed individuals do depression based on a targeted analysis of metabolites in
not respond despite adequate pharmacotherapy, psycho- blood, urine, and CSF.
therapy, and even ECT (2). Current predictors of treatment Metabolomics is the study of patterns of metabolic in-
response for depression, such as severity, chronicity, and termediates to characterize dysfunctional metabolic path-
exposure to adverse life events, are nonspecific and without ways potentially related to symptomatic presentation. This
clear therapeutic implications in treatment-refractory de- approach has previously contributed to our understanding of
pression. The clinical management of treatment-refractory the pathophysiology of depression. For example, over three
depression has not advanced significantly in the past two decades ago, decreased CSF levels of 5-hydroxyindoleacetic
decades, and the suicide rate in the United States has been acid (5-HIAA) in depressed patients were shown to be as-
increasing (3). Recent emphasis on treatment-refractory sociated with a markedly elevated risk of suicide (4). This
depression has focused on neuromodulatory treatments, work helped spur the development of selective serotonin

ajp in Advance 1

psychiatryonline. study. indicating cerebral folate deficiency Questionnaire (14). Broader identification of such metabolic disorders structured psychiatric interviews. which are now widely used for the discovery of substance use disorder and suicidal behavior in treatment of depression (5.NEUROMETABOLIC DISORDERS IN TREATMENT-REFRACTORY DEPRESSION reuptake inhibitors. Targeted studies of CSF and behavior (Suicidal Ideation Questionnaire. A neurologic examination was conducted by the principal investigator. We compared this group with young adult trometry and high-performance liquid chromatography healthy comparison subjects who had no personal or first. disorders. Four participants in the also a common comorbidity in both primary (7) and sec. In addition. pyridoxal-5-phosphate. All participants completed the Beck CSF levels of 5-methyltetrahydrofolate (5-MTHF) and nor. (Atlanta). as well other metabolomic ab. a tetrahydrobiopterin analogue psychosis. Adolescent comparison subjects were not included Lumbar puncture for CSF collection was performed under because lumbar puncture confers greater than minimal ajp in Advance . are diagnosis of Asperger’s syndrome. We previously reported on the case of a 19-year-old male Participants were assessed with a structured psychiatric patient with unremitting treatment-refractory depression interview. comorbidity (anxiety. tandem mass spectrometry profiling of blood to examine degree-relative history of psychiatric disorder or suicidal groups of metabolites known to contribute to depression. and amino-adipic semialdehyde. when standard treatments are ineffective. particularly in severe symptom questionnaires. and samples were analyzed as for blood and urine the University of Pittsburgh. responded to at least three maximum-dose medication trials homovanillic acid. and anxiety. and family history (Family Interview for with depression. suicidal ideation and disorders of CNS metabolism. We testing. If a specific abnormality was suspected on the basis One comparison subject was subsequently excluded after of the initial testing. One errors of metabolism. depression group and four in the comparison group were ondary forms of mitochondrial dysfunction (8).P. course. 6). try laboratories of UPMC and Medical Neurogenetics. psychosis. Assessment consisted of a psychiatric interview. Genetic Studies and three-generation pedigree) (11). describe the systematic evaluation of 33 patients with review of records. possibly caused by metabolic abnormalities. Patients remained on their current of these patients’ difficulties. Plasma through the Clinical and Translational Science Institute’s and urine testing were performed by the clinical biochemical Research Participant Registry at the University of Pittsburgh genetics and clinical chemistry laboratories of University or by clinical referral. Analysis of at least 6 weeks each were recruited by advertisement of blood and CSF began immediately after collection. Columbia Suicide peripheral samples (blood and urine) were utilized to identify History Form [16]. and self-report instruments at intake to treatment-refractory depression for primary and secondary characterize depression course (BDI). None of the conventional clinical or research diagnostic Rating Scale–Revised (15) was completed on the basis of or therapeutic approaches would have identified the source clinical assessment. neuropsychiat.) completed subjects. placement with sapropterin. fluoroscopic guidance by the Neuroradiology Department The study was approved by the Institutional Review Board of at UPMC. METHOD Testing for CNS-specific metabolic abnormalities in- Sample Characteristics cluded 5-methyltetrahydrofolate. sion and 22 healthy comparison subjects were enrolled. and Beck Suicide Ideation Scale [17]). the patient was referred to a biochemical 2 ajp. substance use. the Child Depression (10). Treatment-refractory depression (9). of Pittsburgh Medical Center (UPMC). patients with abnormalities in the monoamine neurotrans. All adult participants provided in. and history of trauma. including gas chromatography-mass spectrometry assent for involvement in the study and parents provided of urine and liquid chromatography tandem mass spec- informed consent. and arranged for study laboratory depression. including the Family Interview for Genetics and repeated suicide attempts who had deficient CSF levels Studies (11). Inc. comorbidity. Adolescent and adult neuropsychiatric participant in the depression group was excluded because of a symptoms. attention mitter synthesis pathway. adolescent participants provided informed protocols. excluded because they declined lumbar puncture. one of the participant’s parents and another after discovery of ric symptoms are a common manifestation of many inborn self-administration of large quantities of B vitamins. per their standard formed consent. neo- Participants 14–40 years of age with depression that has not pterin. administered self-report could transform psychiatric practice. nor would they have suggested medications and other treatments during the course of the the subsequent successful treatment strategies. assessed with the DSM-5 Level 1 Cross-Cutting normalities leading to apparent isolated CNS dysfunction Symptom Measure). family history. Depression Inventory (BDI) (13) and the Suicidal Ideation mal blood levels of folate. 5-hydroxyindoleacetic acid. at the time of referral to characterize depression of tetrahydrobiopterin intermediates and responded to re. We hypothesized that the incidence of metabolic abnor- malities contributing to treatment-refractory depression Study Procedures would be significantly greater than in healthy comparison The research staff and principal investigator (L. CSF testing of five additional adolescent patients with was confirmed with the Antidepressant Treatment History treatment-refractory depression revealed that three had low Questionnaire (12). by the clinical biochemical genetics and clinical chemis- A total of 38 patients with treatment-refractory depres. behavior. and for adolescents. tetrahydrobiopterin.

57.1 episodes 15q13. suicidal ideation (Suicidal Ideation Questionnaire).2 [SD=8. Abnormalities were identified in nine additional partici- Characterization of Depression pants: five with an acylcarnitine profile abnormality. df=47.). a follow-up appointment was Treatment-Refractory Depression and Healthy Comparison Subjects Assessed for Neurometabolic Disorders scheduled for all participants in the depression group to review results and provide additional referrals if needed. 82% for tient with CFD was also treated with sapropterin (20 mg/kg depression. In patients with On neurologic examination. Participants for whom a novel Age (years) 26. Wilcoxon signed-ranks tests were performed be. sex. A chi- square goodness-of-fit test was used to compare the sex either of the two groups. cidal Ideation Questionnaire score than the comparison Eight participants with CFD who completed follow-up did group (mean=36. Cerebral folate deficiency (CFD).4 years (SD=5. Metabolic Clinical Studies tween pre.39 [SD=21.001). the mean BDI score decreased from 30. 33 participants in the depression group (Tables 3 and 4). t=13. with the exception of one adolescent distribution of each group. participants who were assessed before and after intervention (N=10). Armonk. Demographic Characteristics of Patients With testing became available.05). Of the 12 patients with CFD. t=6. N. one with a The characteristics of each of the 33 patients in the low guanidinoacetate level and a creatine/creatinine ratio treatment-refractory depression group are summarized consistent with a creatine synthesis deficit. FOLR1 gene healthy comparison subjects had no personal or first-degree. Five of the eight patients met threshold scores for one suicide attempt.40 nmol/L). and one with a ting or recurrent depression. The Treatment Outcomes mean age at onset of depressive symptoms in the de.18 not have any comorbid biochemical findings. One patient was lost to follow-up.9 weeks (SD=386. four [SD=1.51). 88% of par. the BDI. disease. p. and age. a metabolic abnormality in which the serum folate level is normal but the CSF 5-MTHF level is low (. sequencing was conducted for eight of the 12 patients. (SD=15. and no relative history of psychiatric disorders or suicidal behavior. all were treated with folinic acid pression group was 12.Y. PAN ET AL.psychiatryonline.08]. The mean BDI (1–2 mg/kg per day) for at least 6 weeks (range 6–79 weeks). Because of the small number of in the depression group who had a benign fine hand tremor.6 (SD=7. case of a patient who responded to treatment with sapropterin (9). and 24% for suicide attempts. no abnormalities were noted in CFD.60. Ten of the 12 patients showed reductions in symptom in- pared with mean=0. version Caucasian 30 91 9 56 21 (IBM.40] compared with 3 . Participants reported long-standing unremit. At Depression Group Comparison Group Characteristic (N=33) (N=16) this appointment.11 treatment was available were recontacted at least 6 weeks N % N % after start of treatment to determine outcome with repeated Female 25 76 9 56 administration of the BDI. was the most common metabolic RESULTS abnormality identified. Of these.0.and posttreatment BDI and Suicidal Ideation We identified evidence of metabolite abnormalities in 21 of the Questionnaire scores among the participants who were de. df=47.98) and a mean longest duration of episode with- out symptom remission of 453. suicidal ideation on the Suicidal Ideation Questionnaire at On the Family Interview for Genetic Studies. One pa- in at least one first-degree relative for any disorder. intake. geneticist for additional confirmatory testing. and three of these five had reductions in suicidal ticipants in the depression group had a positive family history ideation scores to below threshold after treatment. score was much higher in the depression group than in while continuing their pre-evaluation treatment regimen. The depression group also had a much higher mean Sui.1 microdeletion.4] com. the healthy comparison group (mean=29.2].3 microduplication on microarray analysis. and the DSM-5 Level 1 Cross-Cutting Symptom Mean SD Mean SD Measure were repeated. By definition. sequence abnormalities were identified. one with a 20p12. Once results of TABLE 1. Half of the participants had reductions in BDI score to below the threshold for de- in the depression group (N=17) reported a history of at least pression.6 [SD=1. with a mean of 5. Asian 0 0 4 25 Analyses were conducted in IBM SPSS Statistics. the Suicidal Ideation Question- Race naire. and ethnicity (Table 1). ventory scores at follow-up. present in 12 participants (36%). ficient in cerebral folate. and the DSM-5 Level 1 Cross-Cutting Symptom African American 1 3 2 13 Measure. and one was nonadherent with the folinic acid treatment.21 7. We employed independent t tests to Multiple races 2 6 1 6 examine the differences between the depression and healthy Hispanic 2 6 0 0 comparison groups in depression severity (BDI).63 26.12 6.0. the Suicidal Ideation Question- naire. the per day) for low CSF tetrahydrobiopterin levels. One The treatment-refractory depression group (N=33) and the participant with CFD also had low CSF levels of tetrahy- healthy comparison group (N=16) were similar with respect drobiopterin metabolites.29) to ajp in Advance ajp. p.001). as seen in our previously published to age. one with Fabry’s in Table 2.

psychosis Yes No . b Assessed from Family Interview for Genetic Studies ajp in Advance . psychosis not Yes Yes . this CNS-specific metabolomic survey with treatment-refractory depression. and energy metabolism in clinical norms for all tests reported.10 29 1 14 1.0 (SD=23. 16.100 21 104 1 Anxiety No No .0. Z=2. ADHD Yes No 9 20 2 11 208 0 Anxiety. pterin. 4.092 0 OCD.1 (SD=17. and 28. anxiety Yes Yes 6 2 1 9 468 1 Anxiety Yes No . p.352 10 PTSD.0. substance Yes Yes 9 use disorder 6 2 16 312 0 Substance use disorder Yes No 4 7 2 12 72 0 Anxiety No No 4 8 2 13 156 5 PTSD Yes No . c Only four patients had a personal history of bipolar disorder: patients 5. for whom it was rated 1 (“impaired”). except patient 29.10 18 1 17 1. 4 ajp. anxiety. Figure 1).09).10 a For all patients. although the change logic symptoms. of a young man with a severe deficiency of CSF tetrahy- drobiopterin who responded to treatment with sapropterin.13) to 23. 11. Results were determined based on established rotransmitter. OCD=obsessive-compulsive disorder.300 3 PTSD. anxiety Yes No 6 23 1 12 884 2 None Yes Yes 8 24 5 9 728 0 None Yes No 7 25 1 23 572 0 Anxiety No No 10 26 2 6 364 0 None Yes No 8 27 1 10 416 2 Anxiety Yes No 6 28 1 13 364 4 PTSD.0 (SD=11.psychiatryonline. PTSD Yes No 4 14 2 5 468 0 Anxiety Yes No 5 15 1 12 1. followed by our discovery of CFD in three of five additional DISCUSSION patients (9). d Five patients had also received ECT: patients 2. and 18. 17. OCD No No 4 21 15 8 12 2 Anxiety Yes Yes 10 No metabolic disorder 22 6 9 468 1 PTSD.10 3 2 12 468 5 PTSD. PTSD=posttraumatic stress disorder.10 19 1 13 364 1 Anxiety. 21 had metabolite is the first to systematically evaluate abnormalities of neu.10 9 1 20 28 1 None No No 3 10 1 4 1.10 otherwise specified 16 2 13 364 0 Anxiety Yes No 6 17 .03) (Wilcoxon signed ranks test. Characterization of Depression Among Patients With Treatment-Refractory Depression Assessed for Neurometabolic Disordersa Age at Duration of Onset of Longest Suicide Family History Family History b Depressed Depression Episodeb Attemptsb of Major of Bipolar Medication b Patient Episodes (N) (years) (weeks) (N) Comorbid Disorders Depression Disorderc Trialsd (N) Cerebral folate deficiency 1 2 15 600 1 PTSD. peripheral and CSF samples from patients with isolated The mean Suicidal Ideation Questionnaire score decreased psychiatric symptoms in the absence of primary neuro- from 38. vitamin. abnormalities. ADHD Yes No 8 4 1 26 208 4 PTSD No Yes 4 5 .092 0 PTSD Yes Yes .100 9 50 0 PTSD.NEUROMETABOLIC DISORDERS IN TREATMENT-REFRACTORY DEPRESSION TABLE 2. substance Yes Yes 7 use disorder 30 1 7 780 0 None Yes No 4 31 4 13 36 1 Anxiety Yes No 4 32 1 12 208 1 Anxiety No No 5 33 5 16 24 0 None Yes No . level of impairment on the Family Interview for Genetic Studies was rated 2 (“incapacitated”). 15. 11. ADHD=attention deficit hyperactivity disorder. anxiety. It was spurred by our initial identification was not statistically significant (Table 3. ADHD. anxiety Yes No 9 11 1 11 362 0 PTSD Yes Yes 3 12 90 14 12 0 Substance use disorder No Yes 3 Other metabolic disorders 13 1 5 1. In this case-control study of 33 individuals To our knowledge.022).042 0 PTSD.

baclofen. low 31 .org 5 . 13 13 15 fluoxetine 7 Low CSF 5-MTHF 14 18. 18 17 20 gabapentin. trazodone. 33 35 52 tetrahydrobiopterin escitalopram. Folate is involved in nearly 100 tional diagnostic approaches without a more comprehen. or by changes in transport across the blood-brain who completed follow-up and did not have a comorbid barrier. Kearns-Sayre syndrome folate pathways and therefore would have eluded conven. or epilepsy). amitriptyline. 58 36 11 vilazodone vilazodone 5 Low CSF 5-MTHF 36 .g. 36 25 Folinic acid. SIQ=Suicide Ideation Questionnaire. trazodone carbidopa 3 Low CSF 5-MTHF 37 . lamotrigine lamotrigine 8 Low CSF 5-MTHF 35 14. typically with other obvious The findings in this patient population are different from systemic manifestations (18).20.6 Lamotrigine. 47 40 Folinic acid. asphyxia. Secondary CFD is also score to below the threshold for depression. Findings and Treatment Results for Patients With Treatment-Refractory Depression and Cerebral Folate Deficiencya Interval From CSF Serum Initial Visit Posttreatment Visit Initial to 5-MTHF Folate Posttreatment Level Level Psychiatric SIQ BDI Psychiatric SIQ BDI Self-Report Patient Metabolic Findings (nmol/L) (ng/mL) Medications Score Score Medications Score Score (weeks) 1 Low CSF 5-MTHF 40 6. 20). injury to the CNS from infection. Twelve patients had CFD. ease. trazodone 45 29 8 4 Low CSF 5-MTHF 39 12.0 None 8 25 Folinic acid 4 21 10 abnormal acylcarnitine profile a 5-HTP=5-hydroxytryptophan. one was nonadherent with folinic acid treatment and duced in any metabolic defect that increases use of methyl the other was lost to follow-up. TABLE 3. norepinephrine. hydroxyzine lisdexamfetamine. 17 14 36 risperidone. 70 37 Folinic acid.4 Sertraline 67 43 Folinic acid. patients had normal serum metabolites associated with such as Alpers’ syndrome (21). pathway. lisdexamfetamine. carbidopa. (25. Adjunctive treatment with L-methylfolate may im- is a CNS-specific syndrome characterized by low CSF prove depressive symptoms because of its role as a cofactor ajp in Advance ajp. sertraline.20.20..0 Citalopram. metabolic reactions (24). PAN ET AL.0 Sertraline. 20 16 7 carbidopa. late receptor gene (FOLR1) but can be secondarily re- tients. amitriptyline. of the remaining two pa. seen in disorders of the mitochondrial respiratory chain. hydroxyzine 12 Low CSF 5-MTHF. BDI=Beck Depression Inventory. CFD (27–30). folinic acid clonazepam.psychiatryonline.0 Bupropion 20 20 Lost to follow-up 10 Low CSF 5-MTHF 40 17.20. lithium carbonate.20.1 None 13 22 Folinic acid 8 15 6 2 Low CSF 5-MTHF 39 . (22). carbidopa. FOLR1 gene sequencing was normal in the first identified metabolic abnormality had reductions in BDI eight patients with identified CFD.2 Zolpidem. Half of the eight patients groups. sapropterin. and in 10 of these patients BDI 5-MTHF levels and normal plasma folate levels (19. tramadol tramadol. contributing to impaired tetrahydrobiopterin. In all cases.0 Trazodone 61 29 Folinic acid. dextroamphetamine 6 Low CSF 5-MTHF 15 . trazodone 11 Low CSF 5-MTHF. It should be noted that the abnormalities identified may serotonin. 23 33 Folinic acid.3 Sertraline. and others (23). 5-MTHF=5-methyltetrahydrofolate. 41 28 Folinic acid. including the purine synthetic sive evaluation.20. 26). autoimmune dis. zolpidem.0 Baclofen. sertraline 15 0 79 9 Low CSF 5-MTHF 37 . 5-HTP. and dopamine synthesis. 36 . 53 31 Nonadherent with escitalopram. The abnormalities identified those in reports of empirical treatment with L-methylfolate could also be sequelae of unremitting depression.0 Fluoxetine 14 24 Folinic acid. and be due either to a primary genetic disorder in a metabolic thus polygenic effects due to the accumulation of muta- pathway or a secondary abnormality of indirect etiology tions in multiple genes may play a role in this population (e. It and Suicidal Ideation Questionnaire scores were reduced can be caused primarily by mutations in the cerebral fo- after treatment with folinic acid.20. 5-HTP. gabapentin.

0 Clozapine 88 49 29 53 .1 microdeletion on 67 .5 Imipramine.psychiatryonline. 59 .20. the administration of L-methylfolate will falsely bolic findings in our patients.6 None 41 22 28 59 .2 Gabapentin. This time four participants were clinically referred.20. our patients had no other overt clini- ative in the eight patients with CFD in whom we conducted cal disease. fluvoxamine 22 24 chromosome analysis 21 15q13. quetiapine 37 41 fumarate 23 46 . It is clear generation sequencing technologies (i.20.20. homogeneous patient individuals. trazodone 15 19 18 Abnormal acylcarnitine profile 92 10.20. diazepam. and the possi- frame is due to neuronal turnover and growth in the set.0 Lamotrigine. 6 ajp. hydroxyzine 17 Fabry’s disease 77 14.. other systemic conditions are unlikely.20. melatonin 53 37 14 Abnormal creatine/guanidinoacetate 55 13. lamotrigine.0 Amitriptyline.3 Lamotrigine.e. quetiapine fumarate 59 33 24 54 . This ting of availability of active folate metabolites needed for was a relatively small sample of mostly Caucasian patients. Applications of next- ologic mechanism of our biochemical findings. and thus secondary deficiencies related to gene testing.4 Aripiprazole.0 Venlafaxine. citalopram. mirtazapine 48 24 33 48 . lorazepam. olanzapine 19 Abnormal acylcarnitine profile.6 ajp in Advance . and the full effects of treatment with folinic recruited by advertisement through a research registry. 36 29 sertraline.20. lithium carbonate. trazodone. population with treatment-refractory depression will pro- bolic pathway that produces bioactive metabolites.20. Fur.6 Desvenlafaxine. L-methylfolate is most helpful whether the metabolite abnormalities are primary or sec- in those with the MTHFR polymorphism.0 Venlafaxine 11 17 30 59 18. venlafaxine. because of a deficit earlier in the folate meta. divalproex sodium. This is different from our appropriate white matter structure.0 Lisdexamfetamine. fluoxetine 33 35 16 Abnormal acylcarnitine profile 109 19. 15 38 ratio lamotrigine.3 microduplication on 45 16. vide further insight into genetic components of the meta- thermore. melatonin 22 25 27 52 17. temazepam. However.20. After further evaluation and correct the CSF test to identify these individuals. lurasidone. next step. bupropion 15 Abnormal acylcarnitine profile 60 . BDI=Beck Depression Inventory.5 Lithium carbonate. which was neg. We cannot determine findings in CFD (18).0 None 20 22 32 78 . vilazodone.NEUROMETABOLIC DISORDERS IN TREATMENT-REFRACTORY DEPRESSION TABLE 4. methylphenidate. Findings for Patients With Treatment-Refractory Depression Who Had Metabolic Disorders Other Than Cerebral Folate Deficiency or Who Had No Metabolic Disordera Initial Visit CSF 5-MTHF Level Serum Folate SIQ BDI Patient Metabolic Findings (nmol/L) Level (ng/mL) Psychiatric Medications Score Score Other metabolic disorders 13 Abnormal acylcarnitine profile 68 17. clonazepam.3 Levothyroxine sodium. While characterization of a larger population of patients. bility of an ascertainment bias cannot be excluded.0 Fluoxetine. acid in an individual with CFD occur over years. Also. levothyroxine 12 12 sodium 25 58 9. models of biochemical abnormalities will be an important this again is problematic with our current understanding. 11 19 clonazepam 26 49 10. clonazepam.0 Sertraline. sertraline 72 32 abnormal creatine/ guanidinoacetate ratio 20 20p12. 49 30 levothyroxine sodium a 5-MTHF=5-methyltetrahydrofolate. ondary.6 Clonazepam 55 39 31 51 . SIQ=Suicide Ideation Questionnaire.0 Nortriptyline. whole exome or that treatment with L-methylfolate is not sufficient in these genome sequencing) on a focused. 17 26 chromosome analysis aripiprazole No metabolic disorder 22 60 17. in monoamine metabolism (31). 32 32 lamotrigine. animal empirical treatment with folinic acid may seem appealing.8 Bupropion. We continue to work to understand the bi. definitive testing cannot Although the majority of patients in this study were be conducted. After folinic acid administration.

there were concomitant medica.09) at follow-up (Z=1. L -Methylfolate potentially low activity of dihydrofolate reductase in CFD and (5-L-methyltetrahydrofolate) is the treatment specific because of its tight binding to folate receptor alpha. A clinical response should be expected in patients tion changes in addition to folinic acid supplementa. Preliminary experience with treatment has been levels. folinic acid has therapeutic effect refractory depression.6 (SD=7. Historically. although of actionable abnormalities and some evidence of symp- there is controversy surrounding the assessment of these tom improvement with treatment strongly support the autoantibodies (33). Before and After Treatment With Folinic Acid (N=10)a Suicide Ideation Questionnaire Beck Depression Inventory 80 50 45 70 Patient 1 40 60 Patient 2 35 Patient 3 50 Patient 4 30 Patient 5 Score Score Patient 6 25 40 Patient 7 Patient 8 20 30 Patient 11 (CFD and low tetrahydrobiopterin) 15 20 Patient 12 (CFD and abnormal acylcarnitine) 10 10 5 0 0 Baseline Follow-up Baseline Follow-up a Follow-up interval ranged from 6 to 79 weeks. Review of the CSF meta. with treatment-refractory depression and low CSF 5-MTHF tion. It is important to note with L-methylfolate. The best option for patients converted to 5-. and eventually to 5-MTHF.107). meaning that administration because they correct deficient CSF 5-MTHF in three cases of CFD. metabolites in the folate pathway in individuals with CFD Our findings indicate a need for further evaluation of that is not caused by methylenetetrahydrofolate de. and the treatment component of the study was an open prescription-strength folinic acid. the role of neurometabolic abnormalities in treatment- ficiency. folinic acid or L-methylfolate will preclude testing after tion changes during the course of the study. Furthermore.3) at baseline and 19. need for larger studies. which to methylenetetrahydrofolate deficiency (32). The mean score on the Suicide Ideation Questionnaire was 38. folinic acid is preferable because of acid treatment in our patients did have some side effects its superior stability and lower costs when compared (facial flushing and initial anxiety). however.0. PAN ET AL. Dihydrofolate reductase converts that vitamin B12 acts as a cofactor in this pathway. Symptom Inventory Outcomes in Patients With Treatment-Refractory Depression and Cerebral Folate Deficiency (CFD).13) at baseline and 23. Treatment with either trial. levels. turnover in an environment in which folate metabolites are bolic profile directs the diagnosis and avoids missing other newly available.0 (SD=23. The remarkably high incidence in the setting of folate receptor autoantibodies.04) at follow-up (Z=2. metabolic disorder has been considered in the context of ages of 1–2 mg/kg per day may be administered with a family history of a known disorder or symptoms that ajp in Advance ajp.psychiatryonline. Dos. This may be related to neuronal growth and CFD and need for treatment. Folic acid is not recommended because of the metabolic disorders that may be present. take several months. a diagnosis of a Folinic acid should be given by prescription. The mean score on the Beck Depression Inventory was 30.6 (SD=11. then 5-. Folinic majority of cases. FIGURE 1.10. p=0. Folinic acid (5-formyl-tetrahydrofolate) is treatment-refractory depression. Blood folic acid to dihydrofolate and then to tetrahydrofolate folate and B12 levels should be evaluated in all patients with (Figure 2).022). 7 . Continued treatment as usual resulted in medica. with treatment-refractory depression for whom metabolic methylenetetrahydrofolate.24. long-term outcomes remain to be associated with CFD (34) indicates that the response may determined. but in the results in reduced cerebral transport of 5-MTHF.1 (SD=17.10-methenyltetrahydrofolate. but the full effect of treatment may CSF testing is required to determine the presence of take 1–3 years. Experience with more severe neurologic disorder promising. disorder is suspected is consultation with a biochemical Folinic acid therefore allows the availability of active geneticist.

The other authors report no financial re- School of Medicine.. accepted May 20. NAD=nicotinamide adenine dinucleotide. they thank Katherine Wisner. DHF=dihydrofolate.D. and Vishwajit Nimgaonkar. the identification and treatment of an underlying metabolic Children’s Hospital of Pittsburgh Foundation. sulting fees from Healthwise. Dr. University of California.D. Ph.. Finegold is founder of Diavacs and Personalized Genomics orphan drugs. Lewis. tient population. fasting. M. they suggest that the iden. Brent. 29. dTMP=deoxy-thymidine phosphate. surgeries). If these findings are replicated. M. the Department of Pittsburgh. performing duties as an UpToDate Psychiatry section editor. for their review of the manuscript. University of Pittsburgh. neither of which was present in our pa. especially with multisystem in. DHFR=dihydrofolate reductase. ary disorders of metabolism contributing to psychiatric Dr. and by the Clinical and Translational Science Institute. Ongoing research is supported by the American temic illness.10-Methenyl-THF NADP+ NADP+ NADPH Purine nucleotides NADPH 5. 2016.D. An important question is whether early Foundation for Suicide Prevention Standard Research Award.D. School of Medicine. Address correspondence to Dr.10-Methylene-THF dUMP B2 MTHFR Glycine (Methylene-THF reductase) dTMP B6 5-Methyl-THF DHF Serine Pyrimidine nucleotides THF NADPH Transport B12 across intestine and choroid plexus Homocysteine Methionine + THF a Folinic acid (5-formyl-THF) enters the pathway without the action of DHFR and contributes active metabolites. Human Genetics. 8 ajp. Pediatrics. Our findings. Laboratories.NEUROMETABOLIC DISORDERS IN TREATMENT-REFRACTORY DEPRESSION FIGURE 2. Atlanta. Pediatrics. dUMP=deoxy-uridine phosphate. THF=tetrahydrofolate. 2016. Dr. through NIH grants UL1 RR024153 and refractory psychiatric disorders even without other sys- UL1 TR000005. M. Hyland is executive vice president of Medical Neurogenetics Labo- illness may allow repurposing of currently approved ratories. Summary of the Folate Pathwaya Folate Folinic Acid DHFR (5-Formyl-THF) Formate + THF Dihydrofolate NADH NAD+ DHFR 10-Formyl-THF 5.. if replicated.. Young Investigator Award. University Medical Center Received Nov. and departmental funding abnormality early in the course of psychiatric illness could supported by David A. honoraria for From the Departments of Psychiatry. NADP=nicotinamide adenine dinucleotide phosphate. and David prevent long-term emotional and cognitive complications..D.g. and Obstetrics and Gynecology. Pan (thomasla@upmc. NADPH=nicotinamide adenine dinucleotide phosphate. Brent receives research support from NIMH. Göttingen. lationships with commercial interests. Jerry Vockley. Germany. royalties from the electronic self-rated version of the AUTHOR AND ARTICLE INFORMATION Columbia Suicide Severity Rating Scale from ERT. M.D. A. 5-Methyl-THF is a distal metabolite. reduced. and Pathology.D. 2015.. M. fever. and tification of new inborn errors of metabolism or second. suggest that Supported by the Brain and Behavior Research Foundation NARSAD neurometabolic disorders may contribute to treatment. volvement (35). are exacerbated by significant physiologic stresses (e. and con- Pathology. royalties from Guilford Press. Inc. and the Departments of Medicine. San Diego. Medical Neurogenetics Laboratory. The authors thank the participants who made this research possible. revisions received March 11 and May 8.psychiatryonline.. Ph. Göttingen. University of ajp in Advance .

Berk M: The many roads to mitochondrial dysfunction in metabolic pathways. Fava M: Diagnosis and definition of treatment-resistant depression. Papakostas GI. Papakostas GI. Psychol Med 1992. and therapeutic aspects of cerebral folate deficiency. Asberg M. Walter JH: Treatment with mefolinate 17. safety. leads scales. Souery D. 24. in The Prediction of Suicide. Nature 2014. J Clin Psychiatry 2009. Garside SL. Mischoulon D: Folate in depression: efficacy. Trefz F. Serrano M. Blau N: Cerebral folate deficiency. Vockley J: Neuropsychiatric symptoms in inborn errors of Mol Genet Metab 2014. Papakostas GI. Expert 20. but not folic acid or folinic acid. Am J 12. Edited by Beck AT. Träskman L. Heales SJ: Cerebral folate deficiency. Knowles L. Pérez-Dueñas B. Bowie. J Clin Psychiatry 16. 73:e30 14. The burden of depression. Tarnopolsky MA. 1987 L-methylfolate 15 mg among inadequate responders to SSRIs in 15. Charles Press. Ward CH. depressed patients who were stratified by biomarker levels and vised (CDRS-R). 1974. NIMH Genetics Initiative: Family Interview for Genetic Studies adjunctive therapy for SSRI-resistant major depression: results of (FIGS). 22: 7. Pan L. Martín-Hernández E. J Inherit Metab Dis 2013. 169:1267–1274 Biol Psychiatry 2003. Motzfeldt K. et al: Adult phenylketonuria 9.2011. 33:1193–1197 23. Walterfang M. PAN ET AL.psychiatryonline. 4:199–210 70:1360–1362 6. Centers for Disease Control and Prevention: Centers for Disease Follow-up of folinic acid supplementation for patients with cerebral Control and Prevention Data and Statistical Fatal Injury Report. Reynolds WM: Suicidal Ideation Questionnaire: Professional 30. 75:855–863 Algorithm of Suicide Assessment (C-CASA): classification of suicidal 31. Mocellin R. et al. Psychiatry 2012. Poznanski EO. Ardinger HH. Re. pression. Vockley J. Jackson WC: Beyond the resistance: how novel neurobio- 13. Mendelson M.03. et al: Synergistic heterozygosity: literature. Sequeira JM. Md. and therapeutic 33. Western Psychological Services. University of Washington. Psychological Assessment Resources. 17:1299–1306 for schizophrenia associated with folate receptor autoantibodies. J Clin Psychiatry 2012. Beck AT. et al: Columbia Classification 2014. in 1. JIMD Rep (Epub 18. Asberg M. Herman I: Development of suicidal intent (5-methyltetrahydrofolate). 104(suppl): deficiency responsive to sapropterin and 5-HTP supplementation: S26–S30 relief of treatment-refractory depression and suicidal behaviour. 15:793–802 Psychiatric Aspects of Inborn Errors of Metabolism. Madan-Khetarpal S. [Internet] 2. doi: 10. pp 45–56 methylenetetrahydrofolate reductase deficiency. et al: Genetic causes of ahead of print. 71:10–18 neuroimmune and neuropsychiatric disorders. parallel-sequential trials. 1996 genotype: results from a randomized clinical trial. et al: 3. to measurable 5-methyltetrahydrofolate in cerebrospinal fluid in Lettieri DJ. chiatry. Sedel F: Cerebral Folate Deficiency. Fava M. Forslund K: Biogenic amines and their impact in psy. et al: An inventory for measuring logical understandings of depression may lead to advanced treatment depression. Adam MP. Odessa. et al: The neuropsychiatry of Europe Academy. REFERENCES 21. et al: Effect of adjunctive Manual. Garcia-Cazorla A. Dev Med Child events in the FDA’s pediatric suicidal risk analysis of antidepressants. et al: L-Methylfolate as 11. biopterin. Orphan 35. Feb 23. 67(suppl 6):16–22 Seattle. Shelton RC. 73:506–512 disease resulting from multiple partial defects in one or more 8. Neurology 2008. double-blind. Beck AT. Posner K. dif- BMJ Case Rep 2011. diseases associated with cerebral folate deficiency. Bottiglieri T. 4:561–571 strategies. 9:217 biochemical suicide predictor? Arch Gen Psychiatry 1976. Jain R. 27. J Clin Psychiatry 2012. Rinaldo P. Copeland WC: POLG-related disorders. Los Angeles. 2013 inborn errors of metabolism. GeneReviews. Zajecka JM. Edited by Pagon RA.3927 ferences in formulations. Cohen BH. Morris G. 2010. Mol Genet Metab 2011. Zajecka JM. Maillot F. Anglin RE. Gould M. Nascimento A. et al: GTP-cyclohydrolase outcome and management. Presentation at Behavioural and Rev Neurother 2015. Int Rev Psychiatr 2000. McKain BW. Orphanet J Rare Dis 4. etio- into therapeutics and prevention. 36:687–702 ajp in Advance ajp. Bonnot O. 33:563–570 28. Hyland K. Molero-Luis M. Drug Discov Today 2012. et al: Mitochondrial 5. Shelton RC. Axelrod J.1136/bcr. Forslund K: Neurobiological aspects of suicidal behavior. Thöny B. Fla. and clinical issues. 1:65–70 logical. Curr Genet Med Rep 2013. Pan L. Ramaekers VT. 113:307–314 metabolism: incorporation of genomic and metabolomic analysis 34. Bennett MJ. NIMH. Md. Laundy M. Semin Psychiatry 1972. Serrano M. 12:62–74 and monoamine metabolism in depression. 164:1035–1043 32. Hyland K. Resnick HLP. J Inherit 70(suppl 5):12–17 Metab Dis 2010. 10. Quadros EV. Shoffner J. biochemical. Neurol 2004. Ramaekers VT. et al: Folate deficiency. Paris. Mokros HB: Children’s Depression Rating Scale. et al: The psychiatric 871–876 manifestations of mitochondrial disorders: a case and review of the 25. 515:163 22. Morris AA. Trivedi MH: Treatment-resistant de. 46:843–851 Am J Psychiatry 2007. Quijada-Fraile P. BMC Med 2015. Thorén P: 5-HIAA in the cerebrospinal fluid: a 2014. 2016) cerebral folate deficiency: clinical. 1992 two randomized. et al: Folinic acid treatment 9 . O’Callaghan MM. Rockville. 13:68 26. Mol Genet Metab 2000. et al: Clinical. O’Callaghan M. Chinnery PF. 2013 folate deficiency and Kearns-Sayre syndrome. Arch Gen Psychiatry 1961. 19. Montoya J. 53:649–659 29. Oquendo MA. J Clin Psychiatry 2006. Schuyler D.