Clinical Psychobiology

Anissa Abi-Dargham, M.D., Acting Director
Larry Kegeles, M.D.
Frankle, William, M.D.
Roberto Gil, M.D.
Ilene Reeman, M.D.
Paul Rosenfield, M.D.
Smith, Thomas, M.D.

OVERVIEW
The Department of Clinical Psychobiology is responsible for the inpatient and outpatient schizophrenia programs at NYSPI. These programs provide state of the art patient care, from diagnostics to therapeutics, a structure for research, and an environment for training medical students, residents and fellows. In addition to the Schizophrenia Research Unit (SRU) a 12 bed inpatient research unit, we now have an outpatient facility, the Lieber Outpatient Clinic, supported by the Lieber Center. The two programs are thoroughly integrated. We have exceptional staffing by Drs. Gil, Frankle and Reeman, a part time social worker, a full time recruiter (Beatrix Alvarez), and one rater (Caryn Lee). We continue our collaboration with Richard Keefe for the neuropsychological ratings. The research mission of the clinic is to support: 1) longitudinal follow-up studies that periodically assess outcome and relate neurochemical parameters to outcome, 2) studies on occupancy of medications in outpatients and most importantly 3) small therapeutic trials serving as a proof of concept studies for novel therapeutic mechanisms.

CURRENT RESEARCH
We previously observed an increase in the expression of cortical D1 receptors and a relationship of this increase to working memory deficit and severity of negative symptoms. This finding constitutes indirect evidence for a deficit in cortical dopamine. As a follow-up we assessed D1 receptors in an NMDA deficiency model of schizophrenia by studying recreational ketamine users. This study showed an increase similar to that observed in schizophrenia, supporting a possible role of NMDA hypofunction in the dopaminergic alterations detected in schizophrenia (NARSAD Independent Award, PI Abi-Dargham). These data suggest and support new therapeutic interventions such as D1 agonists and NMDA agonists in schizophrenia. We are also assessing the effects of genes on behavior and phenotypic expression in schizophrenia in collaboration with Daniel Weinberger and Conrad Gilliam. In a first study we found a significant relationship between the high efficiency allele for COMT and D1 receptors levels in the cortex but not in the striatum. This supports a prominent role for COMT in regulating dopamine transmission in the cortex but not in the striatum. It also supports the idea that an increase in D1 receptors can be used as a biomarker for a deficit in synaptic dopamine.

Studies in alcoholism using PET imaging have been another major focus of the work in this department in collaboration with Marc Laruelle and Diana Martinez in the Division of Functional Brain Mapping at Psychiatric Institute, and John Krystal at Yale University. A study of mesolimbic dopamine release in chronic alcoholics was just completed and it showed decreased amphetamine induced dopamine release in alcoholics compared to controls. The decrease is selective to the ventral striatum. This represents the first study of dopamine transmission in alcoholism.

We also found decreased striatal D2 in alcoholism correlating significantly with daily consumption of alcohol. This finding replicates previous work by Volkow and others and expands upon that work by showing generalized decrease in all striatal substructures and a relationship to severity of drinking. Studies of serotonergic indices in alcoholism are on going as part of the Center for the Translational Neuroscience of Alcoholism (CTNA, Yale, PI Krystal).

Collaborations (shared with the Division of Functional Brain Mapping)

Dr. Larry Kegeles developed a PET method capable of detecting GABAergic regulation of subcortical dopamine. He completed preclinical evaluation of a PET radioligand for GABA level measurement, and continued development of MRS methods for brain GABA level measurements. He is currently completing a PET study to determine the anatomic localization within the striatum of dopamine hyperactivity in schizophrenia. Utilizing newly developed methods and the new NYSPI 3T MRI scanner, Dr. Kegeles will be measuring brain GABA in frontal cortex in schizophrenia. (Some of this work is in collaboration with Biological Psychiatry.)

We continue to collaborate with Dr. Larry Siever (Mount Sinai School of Medicine, 1 RO1 MH63875 Supplement to LS) in imaging studies of personality disorders Schizotypal PD, measuring dopamine release and cortical D1 and impulsive aggressive PD, measuring 5HT tansporters and 5HT2A receptors.

Dr. Gordon Frankle is studying tract tracings of connections between the prefrontal cortex and midbrain dopamine cells in collaboration with Suzanne Haber, PhD, University of Rochester School of Medicine.

EDUCATION AND TRAINING
This department is involved in training of medical students and residents on the inpatient SRU unit, and training of fellows in collaboration with the Division of Functional Brain Mapping (Gordon Frankle and Olivier Guillin).

CLINICAL SERVICES
The newly founded Lieber Clinic continues to enroll patients. It currently has a total of 70 patients involved in research and treatment. In addition to treatment, the Clinic also offers a range of educational, family and social services. Staff now includes a part time social worker in addition to the psychiatrists.

GRANTS

Federally Funded
1 P50 MH066171-01A1 (PI: Laruelle, co-PIs Abi-Dargham and Rayport) Title: The Neurobiology of Dopamine in Schizophrenia. 9/15/04-6/31/09 $7,500,000
The overall goal of this Center is to combine clinical imaging with PET and epigenetic and transgenic animal models in mice and rhesus monkeys to test the hypothesis that schizophrenia is associated with an imbalance of dopamine systems. Clinical Core: PI Abi-Dargham
Project 1 Prefrontal dopamine function in schizophrenia: PI Abi-Dargham

NIH K08 MH069697-01 PI Frankle. “The neuroanatomy of antipcyhotic drug action”

NIMH 1K08MH01594 PI Kegeles, "Dopamine and GABA Imaging in Schizophrenia"

NIMH K02 MH064178-01A2 PI: Abi-Dargham "Prefrontal cortical dopamine and cognition-schizophrenia"

NIAAA IP50 AA-12870-01 “Center for the Translational Neuroscience of Alcoholism" PI: PI: John Krystal, Imaging 5-HT transporters and 5-HT1A receptors in alcoholism PI: Abi-Dargham

Industry
Research agreement with Pfizer to evaluate occupancy of 5-HT1A receptors and 5HT tansporters by ziprasidone.

Research agreement with Bristol Meyers Squibb to evaluate occupancy of extrastriatal D2 receptors by aripiprazole.

Foundations
New NARSAD Young Investigator Award to Peter Talbot in collaboration with the Division of Functional Brain Mapping to assess measures of intrasynaptic serotonin by using a tryptophan depletion paradigm in conjunction with imaging the transporter as previously developed for the dopamine system by using AMPT and a D2 tracer (mentor Abi-Dargham).

BIBLIOGRAPHY
Abi-Dargham A, Kegeles LS, Martinez D, Innis RB, Laruelle M: Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naïve healthy volunteers: results from a large cohort. Eur J Neuropharmacology 2003;13:459-468

Abi-Dargham A, Moore H: Prefrontal DA Transmission at D1 receptors in schizophrenia. The Neuroscientist 2003; 9, p:404-416

Guo N, Hwang D, Lo E, Huang YH, Laruelle M, Abi-Dargham A: Dopamine depletion and in vivo binding of PET D1 radioligands: implication for imaging studies in schizophrenia. Neuropsychopharmacology 2003; 28:1703-1711

Abi-Dargham A, Kegeles L, Zea-Ponce, Mawlawi, Martinez D, Laruelle M, Siever Dopamine Transmission in Schizotypal Personality Disorder studied with SPECT [123I]IBZM, In press, Biol Psych. This paper shows excess subcortical DA release in SPD intermediate between controls and patients with schizophrenia, suggesting an a dysregulation in spectrum disorders reflective of a trait factor in addition to the state factor present in acute psychosis.

Frankle G, Hackett G, Mawlawi, Zea-Ponce, Zhu, Fairbank, Kochan, Cangiano, Slifstein M, Gorman J, Laruelle M, Abi-Dargham A: Occupancy of dopamine D2 receptors by atypical antipsychotic drugs risperidone and olanzapine: an [123I]IBZM SPECT study, In press, Psychopharmacology. This paper uses simulations based on previously acquired data regarding intrasynaptic dopamine levels to speculate on the level of D2 occupancy by antipsychotics needed to lower D2 stimulation by dopamine to a therapeutic range similar to levels in controls.