Advances In Neuropsychiatry
ASENT 4th Annual Meeting
Thursday, March 14 - Saturday, March 16, 2002
Capital Hilton Hotel Washington, DC
Speaker Abstracts: Advances In Neuropsychiatry
PREFRONTAL NEURONS AND THE GENETICS OF SCHIZOPHRENIA
Daniel R. Weinberger, MD
Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Both the physiologic abnormalities and the cognitive deficits are predicted by a cellular measure in dorsolateral prefrontal cortex (DLPFC) – low N-acetyl aspartate (NAA) signals from MR spectroscopy. In pharmacologic imaging studies, patients manifest excessive dopamine release induced by amphetamine, an abnormality also predicted by low NAA in DLPFC. These findings suggest that abnormal function of the working memory cortical system (associated with positive symptoms) represent emergent properties of specific DLPFC neuronal pathology. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the COMT gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. fMRI confirms that COMT genotype affects prefrontal physiology during working memory. Family based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing – the first plausible biologic mechanism by which a specific allele affects variation in normal human cognition and risk for mental illness. These findings have implications for the development of novel treatments aimed at the prefrontal dopamine signaling cascade.
THE NEUROBIOLOGY OF MOOD DISORDERS
Dennis S. Charney, MD
There have been major advances in our understanding of the neurobiology of depression. The role of the monoamines, serotonin and norepinephrine have remained a focus. However, given the complexity of these systems, more refined hypotheses have been developed. In addition, it has become more clear that other neurotransmitter systems, neuropeptides, and intracellular molecular mechanisms may be equally or even more important in the etiology and treatment of depression. This presentation will update the audience on recent findings pertaining to these areas. Possible new approaches to the treatment of depression based upon this work will be presented.
DEVELOPMENT OF ATYPICAL NEUROLEPTICS
Richard C. Meibach, PhD
It has been 12 years since the first atypical neuroleptic was approved for use in the U.S. Since that time four additional drugs have entered the marketplace. Several more are in late stage of clinical development and should be submitted for approval in the near future. All of these compounds have in common qualities that differentiate them from first generation neuroleptics. They all share affinity for the dopamine (d2) receptor, but they bind with much lower affinity. They are all less selective in that they also bind with high affinity to serotonin receptors. All of these new compounds were developed in schizophrenic patients but due to their effects on improving positive symptoms were approved for the broader claim of treatment of the ‘manifestations of psychotic disorders’. New rating scales such as the SANS and PANSS were employed to further elucidate the effects on the negative symptoms and product labeling includes mention of these effects in the clinical trial section. Although it has been debated whether these new drugs offer greater efficacy it is well accepted that this class has significantly less extrapyramidal side effects than typical neuroleptics. Due to this greater safety margin, atypicals are being used in much broader patient populations today resulting in a 5 billion dollar market.
This presentation will highlight the clinical development of these compounds. Strengths and weaknesses of the individual study designs will be reviewed, as well as hurdles of using new rating scales in drug trials. Discussion will also include attempts to differentiate these drugs on the basis of both efficacy and safety. Clinical results in other areas including neurological uses will be presented. Finally, pre-clinical research is already exploring the next generation of antipsychotic medications. Some thoughts on how these may be developed in the clinic order to differentiate them from our current medications will be outlined.
ADVANCES IN NEUROPSYCHIATRY
K. Ranga R. Krishnan, MD
Two problems in trials of psychotropic medications are the use of placebo and the high placebo response. This leads to both ethical concerns and a number of failed trials. The ethical issue with regard to use of placebo has been well addressed for trials in depression and panic disorders where the risk with the placebo arm is small and there is a need for placebo to demonstrate that a drug has efficacy. Another issue is the potential use of surrogate markers in designing trials. In this presentation, I will discuss use of novel trial designs to minimize placebo exposure and the use of surrogates in Alzheimer’s disease. I will discuss play the winner as an example of a design that could be used to reduce the number of subjects exposed to placebo and also its potential as a design for proof of concept. The limitations and problems with this type of design will be discussed. The use of MRI imaging and MRS as a surrogate in AD trials will be discussed. Results from clinical trials will be presented to illustrate their use.