Growing evidence from both animal and human clinical studies supports the hypothesis that the underlying pathophysiology of depression implicates dysfunction in wide array of systems, including immune, monoaminergic and glutamatergic system. One potential intersection point for these three systems is the kynurenine(KYN) pathway of tryptophan metabolism.

Treatment-resistant bipolar depressed patients exhibit heightened inflammatory state (cytokines, NF-κB), increased markers of microglial activation and disruption of astrocytic function. (Raison et al., 2013; Psychiatric Times).

Activation of inflammation and stress conditions within the brain contribute to a confluence of decreased neurotrophic support, altered glutamate release/reuptake and oxidative stress. (Miller et al., 2009; Biol Psychiatry).

KADRIU B, FARMER C, DENG ZD, YUAN P, MACHADO-VIEIRA R, ZARATE CA JR.

EXPERIMENTAL THERAPEUTICS AND PATHOPHYSIOLOGY BRANCH, INTRAMURAL RESEARCH PROGRAM,NATIONAL INSTITUTE OF MENTAL HEALTH, NATIONAL INSTITUTES OF HEALTH

We found that single ketamine infusion induced significant decrease in brain IDO of patient with bipolar disorder, while increased the levels of Kyn and KynA.

Ketamine-induced increase in hepatic kynurenine production is expected to counter the substantial peripheral pro-inflammatory state of depressive illness. On the other hand, increased hepatic kynurenine production presents a greater kynurenine load to the brain.

While this might ordinarily increase the rise of the production of toxic metabolites, ketamine-induced suppression of IDO would protect against this potential eventuality.

This work highlights the significant salutatory effect of ketamine not only in core components of depressive symptoms but also in the interplay of inflammatory, monoaminergic and glutamate pathways in patients with bipolar depression.

Only studies of larger scales that aim on addressing neuroinflammatory pathway both centrally and peripherally are needed to confirm these preliminary finding.

In the future, we aim on adding findings from the placebo arm.

1. Reus, G. Z., Jansen, K., Titus, S., Carvalho, A. F., Gabbay, V., & Quevedo, J. (2015). Kynurenine pathway dysfunction in the pathophysiology and treatment of depression: Evidences from animal and human studies. J Psychiatr Res, 68, 316-328.

2. Myint, A. M. (2012). Kynurenines: from the perspective of major psychiatric disorders. Febs j, 279(8), 1375-13853. Parrott, J. M., & O'Connor, J. C. (2015). Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology. Front Psych, 6, 116. 4. Diazgranados, N., Ibrahim, L., Brutsche, N. E., Newberg, A., Kronstein, P., Khalife, S., … Zarate, C. A.: A Randomized Add-on Trial of

an N-methyl-d-aspartate Antagonist in Treatment-Resistant Bipolar Depression. Archives of General Psychiatry. 2010; 67(8): 793–802. 5. Haroon, E., Raison, C. L. & Miller, A. H. Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the

impact of inflammation on behavior. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 37, 137-162, doi:10.1038/npp.2011.205 (2012).

6. Miller, A. H., Haroon, E., Raison, C. L. & Felger, J. C. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 30, 297-306, doi:10.1002/da.22084 (2013).

7. Raison CL,Felger CJ, Miller AH; Inflammation and Treatment Resistance in Major Depression: The Perfect Storm; Psych Times 2013

INTRODUCTION

METHODS

CONCLUSIONS

REFERENCES

THE KYNURENINE PATHWAY AND BIPOLAR DISORDER: THE INTERSECTION OF THE MONOAMINERGIC, GLUTAMATERGIC SYSTEMS AND IMMUNE RESPONSE

ACKNOWLEDGEMENTS AND DISCLOSURESThe authors gratefully acknowledge the support of the Intramural Research Program at the National Institute ofMental Health, National Institutes of Health (IRP-NIMH-NIH).A patent application for the use of ketamine indepression has been submitted listing Dr. Zarate among the inventors; he has assigned his rights on the patent tothe U.S. government but will share a percentage of any royalties that may be received.

Contact:Email: bashkim.Kadriu@nih.gov

We sought to examine whether a single infusion (0.5 mg/kg over 40 minutes) of theglutamatergic modulator ketamine could alter the potential proinflammatory and excitotoxiceffects associated with downstream activation of KYN metabolites.

Examined the impact of baseline proinflammatory cytokines (TNF-α, sTNFR1, IFN-γ, IL-1, IL-5, IL-6, IL-8) and anti-inflammatory markers (Il-2, IL-8 (negative loading) , and IL-10) onkynurenine pathway

Assessed whether baseline kynurenine pathway analytes predicted changes in depressivesymptoms post-ketamine infusion

STUDY AIMS

CHANGE IN KYNURENINE PATHWAY ANALYTES AND INDEX-RATIO POST-KETAMINE INFUSION IN BIPOLAR DEPRESSION

RESULTS

IMPACT OF KETAMINE ON KYNURENINE PATHWAY

IMPACT OF DEPRESSION ON KYNURENINE PATHWAY ANALYTES

Demographics N (%) Mean ± SDAge 39 (100) 45.92 ± 10.52

Sex

Male 16 (41)

Female 23 (59)

BMI 29.84 ± 5.83

Age of illness onset 17.51 ± 6.88

MADRS Total 33.00 ± 4.39

Generalized Anxiety 6 (15%)

Mood stabilizer

Lithium (0.6 mEq/L - 1.2 mEq/L) 26 (67)

Valproic Acid (50-125 µg/mL) 13 (33)

BASELINE INFLAMMATORY MARKERS AS MODERATORS OF CHANGE IN KYNURENINE PATHWAY (PANEL A) ANDBASELINE KYNURENINE PATHWAY AS MODERATORS OF CHANGE IN DEPRESSION SYMPTOM RATINGS (PANEL B)

THE METHODOLOGICAL QUESTIONS BEING ADDRESSED: Alterations in glutamate metabolism have been implicated in pathophysiology of

depression and treatment resistance. Multiple lines of evidence indicate that abnormal activation of kynurenine (KYN) pathway may trigger production of microglial byproducts that alter glutamate release/reuptake and ultimately leading to decreased neurotrophic support and excitotoxicity.

This study aimed on assessing the impact of ketamine on kynurenine pathway in patient with treatment-resistant bipolar disorder, as well as assessing its interrelation with behavioral and peripheral inflammatory markers related to depression.

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