SHERVERT H. FRAZIER RESEARCH INSTITUTE
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The Shervert H. Frazier Research Institute at McLean Hospital supports a multidisciplinary team of basic and clinical scientists devoted to understanding the causes and developing new treatments for major psychiatric disorders, especially mood, psychotic, anxiety, and neurodegenerative disorders. Techniques and discoveries arise from clinical, laboratory and brain imaging components.
Principal Researchers
Director
Bruce M. Cohen, M.D., Ph.D.
Research Coordinator
Suzann M. Babb, MS
Executive Administrator
Fontini Savvides
Clinical Collaborators:
Brian Brennan, M.D.
Laura Flynn, B.A.
Brent Forester, M.D.
Jean Frazier, M.D.
Peter Harris, M.D., Ph.D.
Michael Henry, M.D.
Jennifer Kahn, B.A.
Jeanne Lothrop, B.S.
Beth Murphy, M.D., Ph.D.
Sarah Young, B.A.
Imaging Collaborators:
Xiaoying Fan, M.D.
Marc Kaufman, Ph.D.
Döst Öngur, M.D., Ph.D.
Elizabeth Quattrocki Knight, M.D., Ph.D.
Michael Rohan, Ph.D.
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Preclinical Collaborators:
Cécile Béguin, Ph.D.
Anita Bechtholt-Gompf, Ph.D.
Sabina Berretta, Ph.D.
Edgar (Ned) Buttner, M.D., Ph.D.
William Carlezon, Ph.D.
Anne Cataldo, Ph.D.
Elena Chartoff, Ph.D.
Sarah Elmiligy, B.S.
Rakesh Karmacharya, M.D., Ph.D.
Yenarae Lee, B.A.
Noah McKenna, B.A.
Donna McPhie, Ph.D.
Edward Meloni, Ph.D.
Thomas Munro, Ph.D.
Angelica Ortiz
David Potter, M.A.
Laura Sargent, B.S.
Jordan W. Smoller, M.D., Sc.D.
Kai Sonntag, M.D., Ph.D.
Jonathan Wong, M.S.
Nancy Ye, M.S.
Biostatisticians:
Nicholas Lange, Ph.D.
Clinical Trials
An overview of our Clinical Trials effort is presented in Table I. Trials of kappa modulators have moved from the laboratory to the clinical arena for the first time. Ongoing or follow-up trials of promising early studies include the pursuit of low field magnetic stimulation (LFMS, which originally came from observations in our Brain Imaging Center), the combination of omega-3 fatty acids and cytidine (which may have synergistic effects on mood as suggested in our preclinical studies) and the glutamatergic agents riluzole and memantine (which showed success in early clinical trials). We have begun several pilot studies that could represent significant new directions for therapeutics, including the treatment of bipolar disorder with mitochondrial supplements and bipolar depression with SAMe, and have begun a collaboration testing intranasal insulin as a treatment for chronic psychosis (schizophrenia). We have initiated studies to evaluate whether rtfMRI neurofeedback can be used in the treatment of mood and anxiety disorders.
Mania Acute Changes Scale (MACS)
In the past, rating scales for mania have been designed to assess symptoms over many hours or days. Clinical researchers supported by the Frazier Institute are interested in looking at more rapid changes in manic symptoms. To do this, they have developed a novel rating scale called the Mania Acute Rating Scale, or the MACS for short. The MACS is being used at McLean in clinical trials of new agents for treating mania and bipolar disorder.
Genetics
With the sequencing of the human genome and the increasing power of genetic analysis, the pace of discovery of risk genes for human illness, including psychiatric disorders, has accelerated. We are collaborating with the Broad Institute at MIT and Harvard and its affiliated hospitals to identify genes that determine
- the risk for developing psychiatric illness, and
- response to treatment
At present, over 250 patients are volunteering for these studies yearly.
Preclinical Research
Studies performed in our preclinical component are summarized in Table II. Animal studies at our center on the effects of current antidepressant and antimanic drugs point to an important role for the peptide neurotransmitter dynorphin, acting through kappa receptors, in the determination of mood state and psychosis. Based on this information, we are working to synthesize and test agents that act at kappa receptors to produce mood stabilizing effects. We are studying whether agents that modulate trace amines may help regulate mood and cognition. We have promising leads on new ways to treat neuropsychiatric disorders, including depression, bipolar disorder, schizophrenia and Alzheimer’s disease, through nerve and glial cell growth in the brain and through remodeling or replacement of dysfunctional cell elements. We have new evidence on the circuits underlying the stress response, which may trigger episodes of PTSD and other psychiatric disorders. We have initiated a new model system using C. elegans to study current drugs and have evidence on new targets for novel treatments of bipolar disorder and schizophrenia.
Brain Imaging
Brain imaging remains an important component of our work. It is focused on techniques and projects directly relevant to treatment development and testing. The work specifically emphasizes spectroscopic imaging of brain chemistry and functional imaging of brain activity related to psychiatric illness and treatment response. Imaging studies have not only suggested the value of LFMS, but helped suggest the use of uridine derivatives, glutamatergic agents and mitochondrial supplements to correct abnormal metabolic findings in bipolar disorder and schizophrenia.
Some Recent Publications of Investigators in the Frazier Institute
Recently Published Articles:
- Brennan BP, Hudson JI, Jensen JE, McCarthy J, Roberts JL, Prescot AP, Cohen BM, Pope HG, Renshaw PF, Öngür D. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology 35(3): 834-846, 2010.
- Öngür D, Prescot AP, Jensen JE, Rouse ED, Cohen BM, Renshaw PF, Olson DP. T2 relaxation time abnormalities in bipolar disorder and schizophrenia. Magn Reson Med 63(1): 1-8, 2010.
- Brennan BP, Hudson JI, Jensen JE, McCarthy J, Roberts JL, Prescot AP, Cohen BM, Pope HG, Renshaw PF, Öngür D. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Neuropsychopharmacology 35(3): 834-846, 2010.
- Forester BP, Berlow YA, Harper DG, Jensen JE, Lange N, Froimowitz MP, Iosifescu DV, Ravichandran C, Lukas SE, Renshaw PF, Cohen BM. Age-related changes in brain energetics and phospholipid metabolism. NMR Biomed, Epub ahead of print, Nov 11, 2009.
- Karmacharya R, Sliwoski GR, Lundy MY, Cohen BM, Buttner EA. Clozapine interaction with phosphatidyl inositol 3-kinase (PI3K)/insulin-signaling pathway in Caenorhabditis elegans. Neuropsychopharmacology 34(8): 1968-78, 2009.
- Béguin C. Duncan KK, Munro TA, Ho DM, Xu W, Liu-Chen LY, Carlezon WA Jr, Cohen BM. Modification of the furan ring of salvinorin A: Identification of a selective partial agonist at the kappa opioid receptor. Bioorg Med Chem 17(3): 1370-1380, 2009.
- Öngür D, Lin L, Cohen BM. Clinical characteristics influencing age at onset in psychotic disorders. Comprehensive Psychiatry 50(1): 13-19, 2009.
- Forester BP, Harper DG, Jensen JE, Ravichandran C, Jordan B, Renshaw PF, Cohen BM. 31Phosphorus magnetic resonance spectroscopy study of tissue specific changes in high energy phosphates before and after sertraline treatment of geriatric depression. Int J Geriatr Psychiatry 24(8): 788-797, 2009.
- Yoon SJ, Lyoo IK, Haws C, Kim TS, Cohen BM, Renshaw PF. Decreased glutamate/ glutamine levels may mediate cytidine’s efficacy in treating bipolar depression: A longitudinal proton magnetic resonance spectroscopy study. Neuropsychopharmacology 34(7): 1810-1818, 2009.
- Carlezon WA Jr, Béguin C, Knoll AT, Cohen BM. Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther 123(3): 334-43, 2009.
- Lewandowski KE, DePaola J, Camsari GB, Cohen BM, Öngür D. Tactile, olfactory, and gustatory hallucinations in psychotic disorders: A descriptive study. Ann Acad Med Singapore 38(5): 383-5, 2009.
- Öngür D, Prescot AP, Jensen JE, Cohen BM, Renshaw PF. Creatine abnormalities in schizophrenia and bipolar disorder. Psychiatry Res 172(1): 44-8, 2009.
- Hooker JM, Munro TA, Béguin C, Alexoff D, Shea C, Xu Y, Cohen BM. Salvinorin A and derivatives: protection from metabolism does not prolong short term whole brain residence. Neuropharmacology 57(4): 386-91, 2009.
- Tomasiewicz HC, Todtenkopf MS, Chartoff EH, Cohen BM, Carlezon WA Jr. The kappa-opioid agonist U69,593 blocks cocaine-induced enhancement of brain stimulation reward. Biol Psychiatry 64(11): 982-988, 2008.
- Chartoff EH, Potter D, Damez-Werno D, Cohen BM, Carlezon WA Jr. Exposure to the selective kappa opioid salvinorin A modulates the behavioral and molecular effects of cocaine in rats. Neuropsychopharmacology 33(11): 2676-2687, 2008.
- Jensen JE, Daniels M, Haws C, Bolo NR, Lyoo IK, Yoon SJ, Cohen BM, Stoll AL, Rusche J, Renshaw PF. Triacetyluridine (TAU) decreases depressive symptoms and increases brain pH in bipolar patients. Exp Clin Psychopharm 16(3): 199-206, 2008.
- Öngür D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM, Renshaw PF. Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry 64(8): 718-726, 2008.
- Cohen BM, Murphy B. The effects of pentazocine, a kappa agonist, in patients with mania. Int J Neuropsychopharmacol: 11(2): 243-7, 2008.
- Béguin C, Potter DN, DiNieri JA, Munro TA, Richards MR, Paine TA, Berry L, Zhao Z, Roth BL, Xu W, Liu-Chen L-Y, Carlezon WA Jr, Cohen BM. N-methylacetamide analogue of salvinorin A: a highly potent and selective kappa opioid receptor agonist with oral efficacy. J Pharmacology Exp Ther: 324(1): 188-95, 2008.
- Meloni EG, Reedy CL, Cohen BM, Carlezon WA, Jr. Activation of raphe efferents to the medial prefrontal cortex by CRF; correlation with anxiety-like behavior. Biol Psychiatry 63(9): 832-839, 2008.
- Öngür D, Pohlman J, Dow AL, Eisch AJ, Edwin F, Heckers S, Cohen BM, Patel TB, Carlezon WA, Jr. Electroconvulsive seizures stimulate glial proliferation and reduce expression of Sprouty2 within the prefrontal cortex of rats. Biol Psychiatry 62(5): 505-512, 2007.
- Ma J, Ye N, Cohen BM. Expression of noradrenergic a1, serotoninergic 5HT2a and dopaminergic D2 receptors on neurons activated by typical and atypical antipsychotic drugs. Prog Neuropsychopharmacol. Biol. Psychiatry 30(4): 647-657, 2006.
- Ma J, Ye N, Cohen BM. Typical and atypical antipsychotic drugs target DARPP-32 and neurotensin-containing neurons, but not GABAergic interneurons and substance P-containing neurons in the shell of nucleus accumbens of ventral striatum. Neuroscience 141(3): 1469-1480, 2006.
- Béguin C, Richards MR, Li JG, Wang Y, Xu W, Liu-Chen LY, Carlezon WA Jr, Cohen BM. Synthesis and in vitro evaluation of salvinorin A analogues: Effect of configuration at C(2) and substitution at C(18). Bioorg Med Chem Lett 16(17): 4679-4685, 2006.
- Carlezon WA Jr, Mague SD, Parow AM, Stoll AL, Cohen BM, Renshaw PF. Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats. Biol Psychiatry 57(4): 343-350, 2005.
- Carlezon WA Jr, Rohan ML, Mague SD, Meloni EG, Cayetano K, Tomasiewicz HC, Rouse ED, Cohen BM, Renshaw PF. Antidepressant-like effects of cranial stimulation within a low energy magnetic field in rats. Biol Psychiatry 57(6): 571-576, 2005.
- Yurgelun-Todd DA, Coyle JT, Gruber SA, Renshaw PF, Silveri MM, Amico E, Cohen B, Goff DC. Functional magnetic resonance imaging studies of schizophrenic patients during word production: Effects of D-cycloserine. Psychiatry Res: 138(1): 23-31, 2005.
- Frazier JA, Chiu S, Breeze JL, Makris N, Lange N, Kennedy DN, Herbert MR, Bent EK, Koneru VK, Dieterich ME, Hodge SM, Rauch SL, Grant PE, Cohen BM, Seidman LJ, Caviness VS, Biederman J. Structural brain magnetic resonance imaging of limbic and thalamic volumes in pediatric bipolar disorder. Am J Psychiatry 162(7): 1256-1265, 2005.
- Gören JL, Stoll AL, Damico KE, Sarmiento IA, Cohen BM. Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans. Pharmacotherapy 24(11): 1501-1507, 2004.
- Hirashima F, Parow AM, Stoll AL, Demopulos CM, Damico KE, Rohan ML, Eskesen JG, Zuo CS, Cohen BM, Renshaw PF. Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder. Am J Psychiatry 161(10): 1922-1924, 2004.
- Rohan M, Parow A, Stoll AL, Demopulos C, Friedman S, Dager S, Hennen J, Cohen BM, Renshaw PF. Low field magnetic stimulation in bipolar depression using a MRI based stimulator. Am J Psychiatry 161(1): 93-98, 2004.
- Friedman SD, Dager SR, Parow A, Hirashima F, Demopulos C, Stoll AL, Lyoo IK, Dunner DL, Renshaw PF. Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biol Psychiatry 56(5):340-8, 2004.
- Forester BP, Berlow YA, Harper DG, Jensen JE, Lange N, Froimowitz MP, Iosifescu DV, Ravichandran C, Lukas SE, Renshaw PF, Cohen BM. Age-related changes in brain energetics and phospholipid metabolism. NMR Biomed, Epub ahead of print, Nov 11, 2009.
Recently Published Abstracts:
- Cohen BM, McPhie D, Cataldo AM, Lange NT, Ye NZ, Froimowitz MP, Hassinger LC, Menesale EB, Punzell S. Abnormalities in mitochondrial structure in cells from patients with bipolar disorder. American College of Neuropsychopharmacology Annual Meeting, December 2008.
- Baker JT, Buckner RL, Cohen BM, Öngür D. Toward a genomics of brain activity in acute psychosis and mania. Harvard Psychiatry/Mysell, February 2009.
- Shinn AK, Cohen B, Öngür D. Functional magnetic resonance imaging of the primary auditory cortex in current- vs. never- hallucinators with schizophrenia or schizoaffective disorder. Harvard Psychiatry/Mysell, February 2009.
- Chartoff EH, Damez-Werno D, Peterson J, Hassinger L, Potter D, Peev V, Cataldo AM, Cohen BM. Morphological characterization of adult bone marrow stem cells after intranasal delivery to mice with striatal lesions: a cautionary tale. Society for Neuroscience Annual Meeting, 2009.
- Bechtholt AJ, Walther HV, Adams MA, Carlezon WA, Öngür D, Cohen BM. Dysregulation of glial glutamate transmission induces anhedonia, but not dysphoria. Society for Neuroscience Annual Meeting, 2009.
- Dow AL, Lee KN, Lin T, Van’t Veer AV, Knoll AT, Neve RL, Patel TB, Öngür D, Cohen BM, Carlezon WA. Disruption of SPRY2 function in the dorsal hippocampus enhances neurogenesis and resilience to the behavioral consequences of stress. Society for Neuroscience Annual Meeting, 2009.
- Lynn SK, Lynch L, Buttner EA, Cohen BM, Miller GM. Mouse trace amine associated receptor 1 may mediate clozapine-induced sensory-motor gating improvement in vivo. Society for Neuroscience Annual Meeting, 2009.
- Olson DP, Jensen JE, Prescot AP, Rouse ED, Cohen BM, Renshaw PF, Öngür D. Metabolite T2 relaxation abnormalities in bipolar disorder and schizophrenia. Biol Psychiatry 2009; 64:IS-244S, #12.
- Karmacharya R, Haggarty SJ, Cohen BM, Schreiber SL. HDAC regulation of β-Catenin signaling as a target in the treatment of bipolar disorder. Biol Psychiatry 2009; 64:IS-244S, #257.
- Béguin C, Munro TA, Duncan KK, Nu W, Liu-Chen LY, Carlezon WA, Cohen BM. Design and synthesis of selective kappa opioid receptor agents. Tenth Tetrahedron Symposium, 2009.
- Bechtholt-Gompf A, Walther H, Adams M, Carlezon W, Öngür D, Cohen BM. Blockade of glial glutamate uptake induces anhedonia without dysphoria and activates prefrontal cortex and hippocampus in rats. Poster, American College of Neuropsychopharmacology Annual Meeting, December 2009.
- Öngür D, Prescot A, McCarthy J, Cohen B, Renshaw P. Elevated gamma-aminobutyric acid levels in chronic schizophrenia. Poster, American College of Neuropsychopharmacology Annual Meeting, December 2009.
- Forester B, Zuo C, Kim S, Ravichandran C, Renshaw P, Cohen B. 31P MR Spectroscopy magnetization transfer study of coEnzyme Q10 in geriatric bipolar depression. Poster, American College of Neuropsychopharmacology Annual Meeting, December 2009.
- Shinn AK, Rauch S, Cohen BM, Öngür D. Resting state correlation of activity in the primary auditory cortex to other brain regions in current- vs. never-hallucinators with schizophrenia or schizoaffective disorder. Poster, American College of Neuropsychopharmacology Annual Meeting, December 2009.
- Brennan B, Hudson J, Jensen JE, McCarthy J, Roberts J, Prescot A, Cohen B, Pope H Jr., Renshaw P, Öngür D. Rapid enhancement of glutamatergic neurotransmission in bipolar depression following treatment with riluzole. Poster, American College of Neuropsychopharmacology Annual Meeting, December 2009.
- Bechtholt-Gompf AJ, Walther HV, Fidler TL, Cohen BM, Öngür D, Cunningham CL. Ethanol exposure differentially affects glial and neuron populations in the prefrontal cortex of C57BL/6J and DBA/2J mice. Research Society on Alcoholism, 2010 Annual Meeting.
This work is supported by federal grants, foundation awards and private gifts
