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 and anxiety 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
Cathie Bowen
Clinical Collaborators:
Brian Brennan, M.D.
Brent Forester, M.D.
Jean Frazier, M.D.
Peter Harris, M.D., Ph.D.
Michael Henry, M.D.
Hyojin Kim
Elizabeth Quattrocki Knight, M.D., Ph.D.
Beth Murphy, M.D., Ph.D.
Jennifer O'Brien
Imaging Collaborators:
Marc Kaufman, Ph.D.
Dost Ongur, M.D., Ph.D.
Michael Rohan, S.M.
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Preclinical Collaborators:
Cecile Beguin, Ph.D.
Edgar (Ned) Buttner, M.D., Ph.D.
William Carlezon, Ph.D.
Anne Cataldo, Ph.D.
Elena Chartoff, Ph.D.
Antonia Dow, Ph.D.
Diane Damez-Werno, M.S.
Sarah Demarco
Sarah Elmiligy
Jennifer Kahn
Rakesh Karmacharya, M.D., Ph.D.
Hyojin Kim
Jeanne Lothrop
Donna McPhie, Ph.D.
Edward Meloni, Ph.D.
Thomas Munro, Ph.D.
Angelica Ortiz
David Potter, M.A.
Steven Punzell
Gregory Sliwoski
Jordan W. Smoller, M.D., Sc.D.
Nancy Ye, M.S.
Clinical Trials
An overview of our Clinical Trials effort is presented in Table I. Trials of kappa modulators are moving 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 taurine (which showed success in early clinical trials). We are beginning 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. We have initiated studies to evaluate whether rtfMRI neurofeedback can be used in the treatment of mood and anxiety disroders.
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 bipolar disorder through nerve and glial cell growth in the brain and through 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 discover 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 (Table III). 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 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:
- Karmacharya R, Lundy MY, Silowski GR, Cohen BM, Buttner EA. (2008) Identification of clozapine effects on the insulin-signaling pathway in Caenorhabditis elegans. Submitted.
- Forester B, Harper D, Jensen E, Ravichandran C, Renshaw P, Cohen BM. (2008) 31Phosphorus Magnetic Resonance Spectroscopy Study of Tissue Specific Changes in High Energy Phosphates Before and After Sertraline Treatment of Geriatric Depression. In Press, International Journal of Geriatric Psychiatry.
- Chartoff EH, Potter D, Damez-Werno D, Cohen BM, Carlezon WA Jr. (2008) Exposure to the selective kappa-opioid receptor agonist salvinorin A modulates the behavioral and molecular effects of cocaine in rats. Neuropsychopharmacology. 33(11):2676-87.
- Tomasiewicz HC, Todtenkopf MS, Chartoff EH, Cohen BM, Carlezon WA Jr. (2008) The kappa-opioid agonist U69,593 blocks cocaine-induced enhancement of brain stimulation reward. Biol Psychiatry. 64(11):982-8.
- Ongür D, Jensen JE, Prescot AP, Stork C, Lundy M, Cohen BM, Renshaw PF. (2008) Abnormal glutamatergic neurotransmission and neuronal-glial interactions in acute mania. Biol Psychiatry. 64(8):718-26.
- Jensen JE, Daniels M, Haws C, Bolo NR, Lyoo IK, Yoon SJ, Cohen BM, Stoll AL, Rusche JR, Renshaw PF. (2008) Links Triacetyluridine (TAU) decreases depressive symptoms and increases brain pH in bipolar patients. Exp Clin Psychopharmacol. 16(3):199-206.
- Meloni EG, Reedy CL, Cohen BM, Carlezon WA Jr. (2008) Activation of raphe efferents to the medial prefrontal cortex by corticotropin-releasing factor: correlation with anxiety-like behavior. 63(9):832-9.
- Cohen BM, Murphy B. (2008) The effects of pentazocine, a kappa agonist, in patients with mania. Int J Neuropsychopharmacol. 11(2):243-7.
- Béguin C, Potter DN, Dinieri JA, Munro TA, Richards MR, Paine TA, Berry L, Zhao Z, Roth BL, Xu W, Liu-Chen LY, Carlezon WA Jr, Cohen BM. (2008) N-methylacetamide analog of salvinorin A: a highly potent and selective kappa-opioid receptor agonist with oral efficacy. J Pharmacol Exp Ther. 324(1):188-95.
- Ongür D Pohlman J, Dow AL, Eisch AJ, Edwin F, Heckers S, Cohen BM, Patel TB, Carlezon WA Jr (2007) Electroconvulsive seizures stimulate glial proliferation and reduce expression of Sprouty2 within the prefrontal cortex of rats. Biol Psychiatry. 2007 Sep 1;62(5):505-12.
- Ma J, Ye N, Cohen BM (2006) Expression of noradrenergic alpha1, serotoninergic 5HT2a and dopaminergic D2 receptors on neurons activated by typical and atypical antipsychotic drugs. Prog Neuropsychopharmacol Biol Psychiatry. 30(4):647-57.
- Beguin C, Richards MR, Chen Y, Wang Y, Liu-Chen L-Y, Ma Z, Lee DYW, Carlezon WA, Cohen BM. (2005) Synthesis and in vitro pharmacological evaluation of salvinorin A analogues modified at C(2). BMCL 15(11):2761-5.
- Carlezon WA Jr, Mague SD, Parow AM, Stoll AL, Cohen BM, Renshaw PF (2005). Antidepressant-like effects of uridine and omega-3 fatty acids potentiated by coadministration in rats. Biol Psychiatry 57(4): 343-50.
- Carlezon WA Jr, Rohan ML, Mague SD, Meloni EG, Parsegian A, Cayetano K, Tomasiewicz HC, Rouse ED, Cohen BM, Renshaw PF (2005). Antidepressant-like effects of cranial stimulation within a low-energy magnetic field in rats. Biol Psychiatry 57(6): 571-6.
- Damico KE, Stoll AL, Marangell LB, Cohen BM (2005) How blind is double-blind? A study of fish oil versus placebo. Prostaglandins Leukot Essent Fatty Acids 66:393-5.
- Frazier JA, Breeze JL, Makris N, Giuliano A, Herbert MR, Seidman L, Biederman J, Hodge SM, Dieterich ME, Gerstein E, Kennedy DN, Rauch SL, Cohen B, Caviness VS. (2005) Cortical gray matter differences identified by structural magnetic resonance imaging in pediatric BPD. Bipolar Disord. 7(6):555-69.
- Friedman SD, Dager SR, Parow A, Hirashima F, Demopulos C, Stoll AL, Lyoo IK, Dunner DL, Renshaw PF (2004). Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biol Psychiatry 56(5):340-8.
- Goren JL. Stoll AL. Damico KE. Sarmiento IA. Cohen BM (2004). Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans. Pharmacotherapy 24(11):1501-7.
- Hirashima F, Parow AM, Stoll AL, Demopulos CM, Damico KE, Rohan ML, Eskesen JG, Zuo CS, Cohen BM, Renshaw PF (2004). Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder. Am J Psychiatry 161(10):1922-4.
- Rohan M, Parow A, Stoll AL, Demopulos C, Friedman S, Dager S, Hennen J, Cohen BM, Renshaw PF (2004) Low-field magnetic stimulation in bipolar depression using an MRI-based stimulator. Am J Psychiatry 161(1):93-8.
- Yurgelun-Todd DA. Coyle JT. Gruber SA. Renshaw PF. Silveri MM. Amico E. Cohen B. Goff DC (2005). Functional magnetic resonance imaging studies of schizophrenic patients during word production: effects of D-cycloserine.. Psychiatry Research 138(1):23-31.
Recently Published Abstracts:
- Cohen BM (2004) Overview and discussion of the potential applications of MR based imaging techniques in drug development. Internatl J Neuropsychopharm 7; 853. CINP Annual Meeting.
- Cohen BM, Rohan ML, Renshaw PF, Carlezon WA (2004) Low field magnetic stimulation: Mood effects in bipolar humans and in rodents. American College of Neuropsychopharmacology Annual Meeting #78, Hot Topic Session.
- Ke Y, Babb SM, Henry ME, Kaufman M, Renshaw PF, Cohen BM (2004) Increased brain choline level observed by proton MRS measurement after IV choline infusion. ISMRM Annual Meeting.
- Beguin C, Richards MR, Wang Y, Chen L-Y, Ma Z, Lee DYW, Carlezon WA, Cohen BM (2005) Synthesis and evaluation of salvinorin A analogues as k-opioid receptor ligands for the treatment of mood disorders. American Chemical Society 229th Annual Meeting.
- DiNieri J, Todtenkopf MS, Beguin C, Zhongze M, Karnati M, Lee DYW, Cohen BM, Carlezon WA Jr (2004) The kappa receptor agonist Salvinorin A elevates intracranial self-stimulation thresholds in rats. Society for Neuroscience Abstracts 30.
- He M, Lee DYW, Liu-Chen, L-Y, Ma Z, Wang Y, Chen WA, Carlezon WA, Beguin C, Cohen BM (2005) Syntheses of kappa-opioid receptor ligands: Salvinorin A analog with modification at C-4 position. MEDI Division of Medicinal Chemistry Annual Meeting.
- Todtenkopf MS, DiNieri JA, Beguin C, Portoghese PS, Lee DY, Cohen BM, Carlezon WA. (2005) Regulation of mood in rats by kappa opioid receptor ligands. American College of Neuropsychopharmacology Annual Meeting #85.
- Tomasiewicz HC, Meloni EG, Todtenkopf MS, Carlezon WA Jr (2004) Depressive- and anxiogenic-like effects of a kappa-opioid receptor agonist as measured by intracranial self-stimulation and fear conditioning in rats. Society for Neuroscience Abstracts 30 (This was with the "U" drugs, not salvinorin).
- Yurgelun-Todd DA, Tohen MF, Risser R, Wei H, Gruber SA (2004). Improved cognitive outcome with olanzapine treatment in bipolar patients. 157th Annual Meeting of the American Psychiatric Association.
- Yurgelun-Todd DA, Rusche J, Juaregui K, Rioux P, Rogowska J, Gruber SA (2004). Increased brain activity after secretin administration: An fMRI study. 157th Annual Meeting of the American Psychiatric Association.
This work is supported by federal grants, foundation awards and private gifts