Targeted Metabolomic Investigations as Potential Biomarkers in Mood and Anxiety Disorders:
Phenotypic Profiling to Clinical Trial Design
Steven T. Szabo, MD PhD*, **; Jason D. Kilts, PhD*, **; Jennifer C. Naylor, PhD*, **; Jennifer L.
Strauss, PhD*, **; Rajendra A. Morey, MD MS*, **; Mira Brancu, PhD*, **; Robert M. Hamer,
PhD***; Daniel W. Bradford, MD MPH*, **; VA Mid-Atlantic MIRECC Work Group*; Christine E.
Marx, MD MA*, **
*Durham Veterans Affairs Medical Center and VA Mid-Atlantic MIRECC
508 Fulton Street, Mental Health Service Line (116A) Durham, NC 27705
**Duke University Medical Center
Psychiatry and Behavioral Sciences
DUMC Box 3309
Durham, NC, 27710
***University of North Carolina School of Medicine
Departments of Psychiatry and Biostatistics
CB#7160, 336 Medical School Wing B
Chapel Hill, NC, 27599
Methodological Question: Can metabolomic profiles be incorporated into clinical trial design?
Introduction: Neurosteroids formed in the adrenal gland and de novo in the brain (i.e.,
dehydroepiandosterone) are altered in individuals with mood and anxiety disorders. While the
relevance of serum constituents to neurobiologic function in psychiatric illness continues to be explored,
the ability to characterize serum profiles linked to phenotypic characteristics in individuals with mood
and anxiety disorders may aid clinical trial design. Methods: Serum samples were obtained from a large
cohort registry of 662 male Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans
while capturing demographic and psychiatric symptom profiles. Samples were analyzed for levels of
various neurosteroids in this cohort and metabolomic amino acid profiles (a smaller Veteran fraction of
this cohort; n=90) with covariate analysis carried out for variables of relevance to mood and anxiety
disorders. Results: Resilience scores on the Connor-Davidson Resilience Scale (CD-RISC) positively
correlated with dehydroepiandosterone sulfate (DHEAS) levels (r=0.15, p=0.0002), while global severity
of symptoms (r=0.14, p=0.0001), anxiety (r=0.13, p=0.001), depression (r=0.13, p=0.001), and
somatization (r=0.16, p=0.0001), assessed by the Symptom Checklist-90-R (SCL-90-R), were inversely
correlated with DHEAS levels. DHEAS levels were significantly lower in Veterans with Davidson Trauma
Scale (DTS) total scores ≥40 (consistent with PTSD; n=213) compared to Veterans with DTS total scores
<10 (no/minimal PTSD symptoms; n=291), p=0.033. DHEAS levels were also significantly lower in
Veterans with Beck Depression Inventory-II (BDI-II) total scores ≥20 (consistent with moderate
depression; n=149) compared to Veterans with BDI-II total scores <10 (no/minimal depressive
symptoms; n=359, p=0.026). Glycine, an excitatory amino acid and N-methyl-D-aspartate (NMDA)
receptor modulator was significantly elevated in serum samples from Veterans reporting suicidal
ideation (Beck Scale for Suicidal Ideation [BSS] score>0; n=19; p=0.043) as compared to Veterans
reporting no suicidal ideation (BSS score=0, n=71). Aspartate/asparagine and serine, also excitatory
neurotransmitters, were non-significantly increased in Veterans reporting suicidal ideation (p=0.097 and
p=0.082, respectively). In contrast, arginine (nitric oxide [NO] precursor) and citrulline (byproduct of NO
formation), were non-significantly decreased in Veterans reporting suicidal ideation (p=0.097 and
p=0.093, respectively). Discussion: DHEAS is a neurosteroid that is stable in serum that can potentially
serve as a biomarker of resilience in Veterans with likely relevance in predisposition of developing
depression and PTSD. As suicide is prevalent in these disorders, serum amino acid profiles in Veterans
consistent with enhanced signaling and compromised NO formation may be a marker of risk. While
understanding the impact of DHEA modulation of NMDA receptor and NO function in the brain may lead
to pathophysiologic insights, serum levels of neurosteroids and amino acids may currently serve to
function as fingerprints of disease. When applied to clinical trial design the potential for characterizing
homogenous subject populations and treatment impact (i.e., benefits and side-effects) may lead to
greater and early insights during clinical investigations of investigational compounds. Disclosures: This
work was funded by the VA Mid-Atlantic MIRECC (JAF), VA Mid-Level Career Development Transition
Award (CEM). CEM is an applicant/co-applicant on pending patent applications for the use of
neurosteroids in CNS disorders.