Amino Acids; Behavior and Behavior Mechanisms; Mental Disorders; Nervous System Diseases; Drugs, Investigational
Public Health Interests
Psychiatry: Clinical Neuroscience Research Unit | Connecticut Mental Health Center | Neuroscience Research Training Program (NRTP) | Obsessive Compulsive Disorder Research Clinic | VA National Center for PTSD | Yale Depression Research Program | Yale Mood Disorders Research Program
Dr. Sanacora is a Professor of Psychiatry at Yale University and the Director of the Yale Depression Research Program. Dr. Sanacora’s work has focused largely on elucidating the pathophysiological mechanisms associated with mood and other neuropsychiatric disorders and using this information to inform the development of novel treatment strategies. His preclinical research laboratory explores the effects of stress and pharmaceutical agents on cellular biology, neurophysiology and behavior. His clinical laboratory employs novel imaging methodologies to investigate the pathophysiology of mood and other neuropsychiatric disorders. In addition, he has served as principal investigator on several large clinical trials investigating the efficacy and safety of newly developed therapeutic agents for the treatment of mood disorders. Dr. Sanacora received the Anna-Monkia Stiftung international award for the investigation of the biological substrate and functional disturbances of depression in 2009, the Joel Elkes Research Award for Outstanding contributions to Psychopharmacology from the American College of Neuropsychopharmacology (ACNP) in 2011, and is a Fellow of the ACNP.
Extensive Research Description
My research focuses on the pathophysiology and treatment of neuropsychiatric disorders. The majority of my studies investigated the contribution of the amino acid neurotransmitter systems and neuroplasticity to the pathogenesis, pathophysiology and treatment of mood and stress related disorders. My areas of interest and expertise range from use of preclinical rodent models to phase II clinical trials. A list of my publications can be found at: http://www.ncbi.nlm.nih.gov/pubmed/?term=Sanacora+G
- 1.MRS studies of amino acid neurotransmitter abnormalities associated with major depression and other neuropsychiatric disorders: In 1999 we published the first paper demonstrating significant abnormalities in cortical GABA concentrations in the brains of depressed individuals (Sanacora et al. 1999). Although there was earlier data suggesting abnormal concentrations of GABA in the CSF and plasma, this study was the first of several to follow that demonstrated clear evidence of cortical GABA abnormalities associated with a mood disorder. Later studies demonstrated that treatment with antidepressant medications and electroconvulsive therapy normalized the cortical GABA content in patients. In 2004, using recently developed 1H-MRS methods, we published a study demonstrating a relationship between abnormal GABA and glutamate concentrations in the brains of depressed individuals. This study led us to develop hypotheses on pathophysiological mechanisms that could be associated with the observations (see glial function below) and helped to bring greater attention to the rising interest in glutamate’s contributions to the pathophysiology of mood disorders. Most recently, in 2014 we used novel 13C-MRS methods to demonstrate abnormal energetic processes in glutamatergic cortical neurons of depressed patients relative to healthy comparison subjects. In sum, these studies have helped to demonstrate the existence of amino acid neurotransmitter system abnormalities and altered neuroenergetic functioning in the brains of mood disorder patients and provide information on possible pathogenic processes and targets for novel treatment development.
a.Sanacora G, Mason GF, Rothman DL, Behar KL, Hyder F, Petroff OAC, Berman RM, Charney DS, Krystal JH. Reduced cortical gamma-aminobutyric acid levels in depressed patients determined by proton magnetic resonance spectroscopy. Arch Gen Psychiatry 1999;56(11):1043-1047.
b.Sanacora G, Mason GF, Rothman DL, Hyder F, Ciarcia JJ, Ostroff R, and Krystal JH. Increased cortical GABA concentrations in depressed patients receiving electroconvulsive therapy. Am J Psychiatry 2003;160(3):577-579.
c.Sanacora G, Gueorguieva R, Epperson CN, Wu Y-T, Appel M, Rothman DL, Krystal JH, Mason GF. Subtype-specific alterations of [gamma]-aminobutyric acid and glutamate in patients with major depression Arch Gen Psychiatry. 2004;61(7):705-713. [PMID: 15237082]
d.Abdallah CG, Jiang L, De Feyter HM, Fasula M, Krystal JH, Rothman DL, Mason GF,Sanacora G. Glutamate Metabolism in Major Depressive Disorder. Am J Psychiatry. 2014 Dec 1;171(12):1320-7.
- 2.Glial function in relation to mood disorders: Based on the findings of the MRS studies cited above, and in the light of several emerging studies suggesting reduced numbers and density of glial cells associated with mood disorders, we proposed a model in which impaired glial cell function contributes to abnormal amino acid neurotransmitter metabolism and function in 2003. This led us to perform a series of preclinical studies using rodent models to specifically examine the relationship between glial function, amino acid neurotransmission, and behavior. Specifically, in 2007 we first demonstrated that cyclosporine, a beta-lactam antibiotic with unique property of increasing glial glutamate uptake, was capable of producing antidepressant-like effects in mice. This was then followed by a series of studies culminating in a paper in demonstrating glial pathology was associated with the chronic unpredictable stress model in rats and that drugs such as riluzole, that increases the expression and function of the glial glutamate transporter was capable of reversing the effects of stress on glutamate metabolism and stress-induced behaviors. More recently we have been working on models that integrate the changes in glial function with the general model of stress response.
- a.Sanacora G, Rothman DL, Mason GF and Krystal JH. Clinical studies implementing glutamate neurotransmission in mood disorders. In: Glutamate and Disorders of Cognition and Motivation. Moghaddam B, Wolf ME, Eds. Annals of the New York Academy of Sciences 2003 Nov;1003:292-308.
- b.Mineur YS, Picciotto MR, Sanacora G. Antidepressant-like effects of ceftriaxone in male C57BL/6J mice. Biol Psychiatry 2007 Jan 15;61(2):250-252 [PMID: 16860779].
- c.Banasr M, Chowdhury GM, Terwilliger R, Newton SS, Duman R, Behar KL and Sanacora G. Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. Molecular Psychiatry. 2010 May;15(5):501-511. [PMID: 18825147]
- d.Popoli M, Yan Z, McEwen BS, Sanacora G. The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci. 2011 Nov 30;13(1):22-37. [PMID: 22127301].
- 3.Experimental therapeutics and clinical trials: Following hypotheses generated through earlier work suggesting glutamate neurotransmission and glial cell function may serve as fertile targets for novel treatment development, I have conducted a series of clinical trials to determine the efficacy of these treatments in clinical settings. Early work provided initial evidence suggesting the glutamate modulating drug riluzole may have antidepressant effects, and provided a model to predict other glutamatergic drugs that could have antidepressant effects. Since that time I have been involved in a series of clinical trials examining the efficacy of a variety of drugs targeting different aspects of the glutamatergic system, including serving as the coordinating PI on several large multicenter phase II clinical trials. The results of the first of these trials, examining the effect of the NMDAR antagonist AZD6765 (Lanicemine), was recently published in 2013. Currently, my clinical research program is involved in several industry and NIMH sponsored clinical trials including being a collaborating site on both the NIMH RAPID and FAST-MAS consortia.
a.Sanacora G, Kendell S, Fenton L, Coric V, and Krystal JH. Riluzole augmentation for treatment-resistant depression. Am J Psychiatry 2004;161(11):2132. [PMID: 15514421]
b.Sanacora G, Zarate CA, Krystal JH, Manji HK. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat Rev Drug Discov. 2008 May;7(5):426-37 [PMID: 18425072].
c.Sanacora G, Smith MA, Pathak S, Su HL, Boeijinga PH, McCarthy DJ, Quirk MC. Lanicemine: a low-trapping NMDA channel blocker produces sustained antidepressant efficacy with minimal psychotomimetic adverse effects. Mol Psychiatry. 2013 Oct 15. doi: 10.1038/mp.2013.130. [Epub ahead of print]
d.Sanacora G, Schatzberg AF. Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology. 2015 Mar 13;40:1307
- 4.Biomarkers and novel assays to demonstrate target engagement: Appreciating the need to develop assays capable of detecting target engagement of novel therapeutics and clinically relevant biomarkers we have worked to identify biomarkers of neuroplasticity and glutamatergic activity. Considering the neurotrophic hypothesis of mood disorders and the role played by neurotrophins in regulating neuroplasticity we presented the first meta-analysis of serum BDNF levels in association with major depression and antidepressant treatment. Following up on a preclinical study showing a single nucleotide polymorphism in the BDNF gene was associated with a loss of ketamine’s effects on spine density and behavior, we also collaborated with colleagues at the NIMH to show preliminary evidence that the same SNP appeared to reduce the antidepressant response in patients. We have also worked to develop novel 13C-MRS methods to detect drug effects on glutamate cycling and metabolism. Initial studies demonstrated how chronic treatment with rilzuole could have effects on glutamate cycling and metabolism. More recent efforts have been directed at determining the acute effects of several glutamatergic drugs including ketamine on glutamate cycling.
a.Sen S, Duman RS, Sanacora G. Serum brain-derived neurotrophic factor, depression and anti-depressant medications: meta-analyses and implications. Biol Psychiatry. 2008 Sep 15;64(6):527-32. [PMID: 18571629]
b.Laje, G., Lally, N., Mathews, D., Brutsche, Anat Chemerinski, A., Akula, N.,Kelmendi, B., Simen, S., McMahon, F.J., Sanacora, G., Zarate, C. Brain-Derived Neurotrophic Factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biological Psychiatry. 2012 Dec 1;72(11):e27-28. [Epub 2012 Jul 6]. [PMID: 22771240].
c.Chowdhury GM, Banasr M, de Graaf RA, Rothman DL, Behar KL, Sanacora G. Chronic riluzole treatment increases glucose metabolism in rat prefrontal cortex and hippocampus. Cerebral Blood Flow and Metabolism. 2008 Dec;28(12):1892-7 [PMID: 18628780]
d.Chowdhury GM, Behar KL, Cho W, Thomas MA, Rothman DL, Sanacora G. (1)H-[(13)C]-Nuclear magnetic resonance spectroscopy measures of ketamine’s effect on amino acid neurotransmitter metabolism. Biol Psychiatry. 2012 Jun 1;71(11):1022-5. 2011. [PMID: 22169441].
e.Chowdhury GMI, Zhang J, Thomas M, Banasr M, Ma X, Pittman B, Bristow L, Schaeffer E, Duman RS, Rothman DL, Behar K*, Sanacora G*. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects. Molecular Psychiatry, In Press
- Laje, G., Lally, N., Mathews, D., Brutsche, Anat Chemerinski, A., Akula, N., Kelmendi, B., Simen, S., McMahon, F.J., Sanacora, G., Zarate, C. Brain-Derived Neurotrophic Factor Val66Met polymorphism and antidepressant efficacy of ketamine in depressed patients. Biological Psychiatry. In Press.
- Abdallah, C.G., Fasula, M., Kelmendi, B., Sanacora, G., Ostroff, R. The Rapid Antidepressant Effect of Ketamine in the Electroconvulsive Therapy Setting. The Journal of ECT. In Press.
- Chowdhury, G.M., Behar, K.L., Cho, W., Thomas, M.A., Rothman, D.L., Sanacora, G. (1)H-[(13)C]-Nuclear Magnetic Resonance Spectroscopy Measures of Ketamine's Effect on Amino Acid Neurotransmitter Metabolism. Biological Psychiatry. 2012 Jun 1;71(11):1022-1025.
- Popoli, M., Yan, Z., McEwen, B.E., Sanacora, G, The Stressed Synapse: The Impact of Stress and Glucocorticoids on Glutamate Transmission, Nature Reviews Neuroscience, 2011 Nov 30;13(1):22-37.
- Morgan PT, Pace-Schott EF, Mason GF, Forselius E, Fasula M, Valentine G.W, Sanacora G. Cortical GABA Levels in Primary Insomnia. Sleep. 2012 Jun 1;35(6):807-14.
- Valentine, G., Mason, G.F., Gomez, R., Fasula, M., Watzl, J., Pittman, B., Krystal, J.H., Sanacora, G. The antidepressant effect of ketamine is not associated with changes in occipital amino acid neurotransmitter content as measured by [1H]-MRS. Psychiatry Research: Neuroimaging 2011 Feb 28;191(2):122-127.
- Banasr, M., Chowdhury, G.M.I., Twillenger, R., Newton S., Duman, R.S., Behar K., Sanacora, G. Stress-induced glial pathology and depressive-behaviors are prevented by riluzole. Molecular Psychiatry. Mol Psychiatry. 2010 May;15(5):501-11.
- Sanacora, G., Zarate, C. Krystal, J. Manji, H. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nature Reviews Drug Discovery. 2008, 7(5):426-37