MAILMAN RESEARCH CENTER

WBUR (04/15/2011)
Running To Support Schizophrenia Research As Federal Funds Dry Up (pdf)

Psychology Research Laboratory

Current Research: Gene Discovery and Personalized Treatment

Dr. Deborah Levy and her colleagues are engaged in breakthrough research into the genetic causes of schizophrenia, bipolar disorder and autism. This research can furnish invaluable clues about the biological underpinnings of these severe illnesses—and, in turn, lead to individually tailored treatments to people suffering from these diseases.

Gene discovery is essential for identifying the genetic causes of schizophrenia, bipolar disorder and autism. Dr. Deborah Levy and her colleagues have discovered an unusually high rate of certain kinds of rare genetic mutations in people with schizophrenia. Mutations in these same genes are also found in people with bipolar disorder and autism. In some families, these mutations were inherited from a parent, but often, the mutations arise spontaneously as de novo events; that is, the genetic mutations are new in the patient, rather than mutations passed down by a family member. This is one reason that these illnesses can occur in the absence of a family history of psychiatric disease.

Deborah L. Levy, Ph.D.

Dr. Levy's multifaceted research involves the study the genetic mutations in families who have a high probability of carrying such mutations. She and her colleagues are also creating genetically modified mice with mutations seen in humans with psychiatric disease and studying their effects in the brains of these mice and on their behavior. Some of the mutations they have discovered have important treatment implications because these mutations reveal and identify a specific mechanism associated with disease. This knowledge makes it possible in some cases to develop individual treatment interventions that target specific genetic causes, with the hope of improving clinical responses to medications.

Dr. Levy's work is vital to discovering the causes of mental illness and finding more effective treatments. Research such as hers, which has the promise to improve symptoms and outcome, provides hope for many millions of people. At a time when the science is so exciting and promising, your support is vital to Dr. Levy's ability to sustain a robust and innovative psychiatric research program. Recent economic conditions have hindered the flow of funds for research, threatening the pace of scientific progress. Nevertheless, Dr. Levy and her colleagues are steadfast in their dedication to conducting research that can improve people's lives. She needs your support to continue her important work and is thankful to all who believe in and support her scientific mission.

To earmark your support for the research of Dr. Levy and her colleagues, please click: Your Donations Support Our Work.

Founding and History of the Psychology Research Laboratory

Founded in 1977 by Seymour S. Kety, M.D., the Psychology Research Laboratory has had a long tradition of distinguished leadership and scientific excellence under the stewardship of Philip S. Holzman, Ph.D. (1977-1982), Dr. Holzman and Steven Matthysse, Ph.D. (1982-1991), and, from 1991-2004, Dr. Holzman, Dr. Matthysse and Deborah L. Levy, Ph.D. The current director, Dr. Levy, carries on the tradition and vision of the laboratory since the retirement of Dr. Matthysse and the death of Dr. Holzman in 2004.

For many years this laboratory has been interested in the genetic contributions to major psychiatric illness. Certain traits are not only strongly associated with schizophrenia, but also have a much higher prevalence than schizophrenia in relatives of schizophrenics. We have focused intensively on characterizing these schizophrenia-related traits, because they may be pleiotropic effects (variable manifestations) of schizophrenia-related genes. Importantly, unlike schizophrenia, which is generally thought to involve a number of co-acting genes, family data on the schizophrenia-related traits are consistent with monogenic transmission models, and may therefore clarify the complex genetics of schizophrenia. Several of these schizophrenia-related traits stand out as especially probative for clarifying the neurobiological interpretation of schizophrenia susceptibility loci. These include smooth pursuit eye movements, specific kinds of formal thought disorder, spatial working memory, relational memory, and a certain kind of craniofacial dysmorphology. The qualitative and quantitative phenotypes that we have developed for these schizophrenia-related traits may both improve power to detect linkage to schizophrenia genes and clarify the neurobiological interpretation of linkages that are found. Analogous endophenotypes have been developed for bipolar disorder and are become a growing focus of work in the Psychology Research Laboratory.

Personnel

Deborah L. Levy, Ph.D. - Director
J. Alexander Bodkin, M.D. - Investigator
Lenore Boling, M.D. - Investigator
Michael Coleman, M.A. - Co-Investigator
Anne Gibbs, M.S.N. - Project Manager
Fred Johnson, Ph.D. - Investigator
Olga Krastoshevsky - Database Manager
Verena Krause - Research Assistant
Jan Lerbinger, Ph.D. - Investigator
Mei-Hua Hall, Ph.D. – Postdoctoral Fellow
Minnie Tse - Administrative Assistant

Collaborating Scientists

Francine Benes, M.D., Ph.D. (McLean Hospital)
Curtis Deutsch, Ph.D. (Shriver Center)
Howard Eichenbaum, Ph.D. (Boston University)
Karen Froud, Ph.D. (Columbia University)
Dennis Kinney, Ph.D. (McLean Hospital)
Alec Marantz, Ph.D. (New York University)
Steven Matthysse, Ph.D. (Emeritus, Harvard Medical School)
Nancy R. Mendell, Ph.D. (SUNY at Stony Brook)
Gregory F. Oxenkrug, M.D. (Tufts - New England Medical Center)
Ken Nakayama, Ph.D. (Harvard University)
Josef Parnas (Kommunehospital, Copenhagen, Denmark)
Donald Rubin, Ph.D. (Harvard University)
Debra Titone, Ph.D. (McGill University)
Jonathan Sebat, Ph.D., (Cold Spring Harbor Laboratory)
Linda Brzustowicz, M.D., (Rutgers University)
James Kennedy, (University of Toronto)
Hakon Hakonarson, (Children's Hospital of Philadelphia)

Research Funding

Selected Recent Publications

Gooding DC, Coleman MJ, Roberts SA, Shenton ME, Levy DL, Erlenmeyer-Kimling L. Thought disorder in offspring of schizophrenic parents: Findings from the New York High-Risk Project. Schiz Bull, 2012, in press, doi: 10.1093/schbul/sbq061.
Hall M-H, Taylor G, Salisbury DF, Levy DL. Sensory gating event related potentials and oscillations in schizophrenia patients and their unaffected relatives. Schizophrenia Bulletin, 2011, 37:1187-99.
Malhotra D, McCarthy S, Michaelson JJ, Vacic V, Burdick KE, Yoon S, Cichon S, Corvin A, Gary S, Gershon ES, Gill M, Karayiorgou M, Kelsoe JR, Krastoshevsky O, Krause V, Leibenluft E, Levy DL, Makarov V, Bhandari A, Malhotra AK, McMahon FJ, Nothen MM, Potash JB, Rietschel M, Schulze TG, Sebat, J. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron, 2011, 72:951-963.
Vacic V, McCarthy S, Malhotra D, Murray F, Cho H-H, Peoples A, Makarov V, Yoon S, Bhandari A, Corominas R, Iakoucheva L, Krastoshevsky O, Krause V, Larach-Walters V, Welsh DK, Craig D, Kelsoe JR, Gershon ES, Leal SM, Dell Aquila M, Morris DW, Gill M, Corvin A, Insel PA, McClellan J, King M-C, Karayiorgou M, Levy DL, DeLisi L, Sebat J. Duplications of the neuropeptide receptor VIPR2 confer significant risk for schizophrenia. Nature, 2011,471:499-503.
Levy DL, Sereno AB, Gooding DC, O'Driscoll, G. Eye tracking dysfunction in schizophrenia: Characterization and pathophysiology. Curr Top Behav Neurosci 2010;4:311-47.
Coleman M, Titone D, Krastoshevsky O, Krause V, Huang Z, Mendell NR, Eichenbaum HE, Levy DL. Reinforcement ambiguity and novelty do not account for transitive inference deficits in schizophrenia. Schizophrenia Bulletin, 2010; 36:1187–1200.
Froud K, Titone D, Marantz A, Levy DL. Brain/behavior asymmetry in schizophrenia: A preliminary MEG study of cross-modal semantic priming in schizophrenia patients. J Neurolinguistics, 2010, 23: 223–239.
Levy DL, Coleman MJ, Sung H, Ji, F, Matthysse S, Mendell NR, Titone D. The genetic basis of thought disorder and language and communication disturbances in schizophrenia. J Neurolinguistics, 2010, 23:176–192.
Krause V, Krastoshevsky O, Coleman MJ, Bodkin JA, Lerbinger J, Boling L, Johnson F, Gibbs A, Cole JO, Huang Z, Mendell NR, Levy DL. Tailoring the definition of the clinical schizophrenia phenotype in linkage studies. Schizophrenia Research, 2010, 116:133–142.
Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, Vives L, Walsh T, McCarthy SE, Baker C, Mefford HC, Kidd JM, Browning SR, Browning BL, Dickel DE, Levy DL, Ballif BC, Platky K, Farber DM, Gowans GC, Wetherbee JJ, Asamoah A, Weaver DD, Mark PR, Dickerson J, Garg BP, Ellingwood SA, Smith R, Banks VC, Smith W, McDonald MT, Hoo JJ, French BN, Hudson C, Johnson JP, Ozmore JR, Moeschler JB, Surti U, Escobar LF, El-Khechen D, Gorski JL, Kussmann J, Salbert B, Lacassie Y, Biser A, McDonald-McGinn DM, Zackai EH, Deardorff MA, Shaikh TH, Haan E, Friend KL, Fichera M, Romano C, Gécz J, Delisi LE, Sebat J, King MC, Shaffer LG, Eichler EE. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics, 2010, 42:203-209.
Sung H, Ji F, Levy DL, Matthysse S, Mendell NR. The power of linkage analysis of a disease-related endophenotype using asymmetrically ascertained sib pairs. Computational Statistics and Data Analysis 2009; 53:1829-1842.
Coleman MJ, Cestnick L, Krastoshevsky O, Krause V, Huang Z, Mendell NR, Levy DL. Schizophrenia patients show deficits in shifts of attention to different levels of global-local stimuli: Evidence for magnocellular dysfunction. Schizophrenia Bulletin, 2009, 35:1108-1116.
McCarthy S, Makarov V, Kirov G, Addington A, McClellan J, Yoon S, Perkins D, Dickel DE, Kusenda M, Krastoshevsky O, Krause V, Kumar RA, Grozeva D, Malhotra D, Walsh T, Zackai EH, Kaplan P, Ganesh J, Krantz ID, Spinner NB, Roccanova P, Bhandari A, Pavon K, Lakshmi B, Leotta A, Kendall J, Lee Y, Vacic V, Gary S, Iakoucheva L, Crow TJ, Christian SL, Lieberman J, Stroup S, Lehtimäki T, Puura K, Haldeman-Englert C, Pearl J, Goodell M, Willour VL, DeRosse P, Steele J, Kassem L, Wolff J, Chitkara N, McMahon F, Malhotra AK, Potash JB, Schulze T, Nöthen MM, Cichon S, Rietschel M, Leibenluft E, Sutcliffe JS, Skuse D, Gill M, Gallagher L, Mendell NR, Wellcome Trust Case Control Consortium, Craddock N, Owen MJ, O'Donovan MC, Shaikh TH, Susser E, DeLisi LE, Sullivan PF, Deutsch CK, Rapoport J, Levy DL, King M-C, Sebat J. Microduplications of 16p11.2 are associated with schizophrenia. Nature Genetics, 2009, 41:1223-1227.
Sebat J, Levy DL, McCarthy S. Rare structural variants in schizophrenia. Trends Genet, 2009, 25:528-535.
Levy DL, Sweeney, JA. Eye tracking and mental illness. In: Squire LR, editor-in-chief. Encyclopedia of Neuroscience (CD ROM), Academic press, Oxford, 2009, pp. 179-184.
Sung H, Ji F, Levy DL, Mendell NR. The power of linkage analysis of a disease-related endophenotype using asymmetrically ascertained sib pairs. Comput Stat Data Anal, 2009, 53(5):1829-1842.
Hall M-H, Schulze K, Sham P, Kalidindi S, McDonald C, Bramon E, Levy DL, Murray RM, Rijsdijk, F. Further Evidence for Shared Genetic Effects Between Psychotic Bipolar Illness and P50 Suppression---A Combined Twin and Family Study. Am J Med Genetics, 2008, 147:619-27.
Chen Y, Grossman ED, Bidwell LC, Yurgelun-Todd D, Gruber SA, Levy DL, Nakayama K, Holzman PS. Altered posterior and prefrontal cortical activation during visual motion processing in schizophrenia. Cognitive, Affective, and Behavioral Neuroscience, 2008, 147B(5):619-27.
Levy DL, Bowman E, Abel LA, Krastoshevsky O, Krause V, Mendell NR. Does performance on the standard antisaccade task meet the co-familiality criterion for an endophenotype? Brain & Cognition, 2008, 68: 462–475.
Titone, D, Libben, M, Niman M, Ranbom L, Levy DL. Conceptual combination in schizophrenia: Contrasting property and relational interpretations. J Neurolinguistics, 2007;20:92-110.
Chen Y, Levy DL, Sheremata S, Holzman PS. Bipolar and schizophrenic patients differ in patterns of visual motion. Schiz Res, 2006, 88:208-216.
Bidwell LC, Holzman PS, Chen Y. Aging and visual motion discrimination in normal adults and schizophrenia patients. Psychiatry Research, 2006, 145:1-8.
Chen, Y., Bidwell, C., and Holzman, P.S. Visual motion integration in schizophrenia patients, their first-degree relatives, and patients with bipolar disorder. Schizophr Res, 2005, 74, 271-281.
Brownstein J, Krastoshevsky O, McCollum C, Kundamal S, Matthysse S, Holzman PS, Mendell NR, Levy DL. Antisaccade performance is abnormal in schizophrenia patients but not in their biological relatives. Schizophrenia Research, 2003; 63:13-25.
Coleman MJ, Cook S, Matthysse S, Barnard J, Lo Y, Levy DL, Rubin DB, Holzman PS. Spatial and object working memory impairments in schizophrenia patients: A Bayesian item-response theory. Journal of Abnormal Psychology, 2002; 111:425-435.
Chen Y, Levy DL, Sheremata S, Holzman PS. Compromised late-stage motion processing in schizophrenia. Biological Psychiatry, 2004; 55:834-841.
Harte CB, Kanarek R. Effects of nicotine and sucrose on spatial memory and attention. Nutritional Neuroscience, 2004;7: 121-125.
Heckers, S., Zalesak M, Weiss AP, Ditman T, Titone D. Hippocampal activation during transitive inference in humans. Hippocampus, 2004; 14:153-162.
Holzman, P.S. Eye movements and the search for the essence of schizophrenia. Brain Research Reviews (Nobel Symposium Contribution), 2000;31: 350-356.
Holzman, P.S. and Sokoloff, L. Seymour S. Kety (1915-2000). Archives of General Psychiatry, 2001; 58:604-606.
Holzman, P.S. Less is truly more: Psychopathology research in the 21st century. In: Lenzenweger MF, Hooley J M (Eds.) Principles of Experimental Psychopathology: Essays in honor of Brendan A. Maher. Washington DC, American Psychological Association, 2003, pp. 175-194.
Holzman, P.S. The Rorschach Method: A starting point for investigating formal thought disorder. In: Auerbach, JS, Levy Kenneth J., and Schaffer, Carrie E., (eds). Relatedness, Self-Definition, and Mental Representation. Essays in Honor of Sidney J. Blatt. New York: Routledge (Taylor & Francis Group), 2005, pp. 172-187.
Holzman PS, Levy DL. Eye tracking dysfunction and mental illness. In: Adelman G, Smith B, editors. Encyclopedia of Neuroscience (CD ROM and Book), Elsevier; 2004.
Holzman, PS, Levy DL, Johnston MH. The use of the Rorschach technique for assessing formal thought disorder. In Bornstein RF, Masling JM (Eds.). Scoring the Rorschach: Seven Validated Systems. Mahwah, New Jersey, Lawrence Erlbaum Associates, 2005, pp. 35-95.
Levy DL. Obituary: Philip S. Holzman. Schizophrenia Research, 2005; 73:1-3.
Levy DL, Mendell NR, Holzman PS. The antisaccade task and neuropsychological tests of prefrontal cortical integrity in schizophrenia: Empirical findings and interpretative considerations. World Psychiatry, 2004; 2:131-139.
Levy DL, O'Driscoll G, Matthysse S, Cook, S, Holzman PS, Mendell NR. Antisaccade performance in biological relatives of schizophrenia patients: A meta-analysis. Schizophrenia Research, 2004; 71:113-125.
Lo, Y., Matthysse, S., Rubin, D.S., Holzman, P.S. Permutation tests for detecting the presence of mixtures in task performance within groups. Statistics in Medicine, 2002;21:1937-1953.
Manoach DS, White NS, Lindgren KA, Heckers S, Coleman MJ, Dubal S, Holzman PS. Hemispheric specialization of the lateral prefrontal cortex for strategic processing during spatial and shape working memory. Neuroimage, 2004; 21:894-903.
Manoach D.S., White N.S., Lindgren K.A., Heckers S., Coleman, M.J., Dubal, S., Goff, D., Holzman, P.S. Intact hemispheric specialization for spatial and shape working memory in schizophrenia. Schizophrenia Research, 2005; 78:1-12.
Matthysse S, Holzman PS, Gusella J, Levy DL, Harte C, Jørgensen A, Møller, L, Parnas. Linkage of eye movement dysfunction to chromosome 6p in schizophrenia: A confirmation. American Journal of Medical Genetics, 2004;128B:30-36.
Titone D, Holzman PS, Levy DL. Idiom processing in schizophrenia: Literal implausibility saves the day for idiom priming. Journal of Abnormal Psychology 2002;111:313-320.
Titone D, Levy DL. Lexical competition and spoken word identification in schizophrenia. Schizophrenia Research, 2004;68:75-85.
Titone D, Ditman T, Holzman PS, Eichenbaum H, Levy DL. Transitive inference in schizophrenia: Impairments in relational memory organization. Schizophrenia Research, 2004;68:235-247.