Staglin Family Professor of Psychology and Psychiatry, UCLA
If teens who are at risk for developing psychosis can be identified and treated before the onset of a full-blown illness, they have a chance to bypass years of disability. Understanding how genetic defects can lead to the symptoms of psychotic disorders may someday allow doctors to give at-risk teens an even better chance at ongoing health than they have today. At two IMHRO-funded UCLA facilities, the Center for the Assessment and Prevention of Prodromal States (“CAPPS”), and the Center for Cognitive Neuroscience ("the CCN"), Tyrone Cannon Ph.D. is leading teams of scientists to develop psychosis early detection, intervention, and prevention as a regular clinical technique. Working with the North American Prodrome Longitudinal Study (NAPLS), a consortium of 8 clinical research centers across the U.S. and Canada, CAPPS and the CCN have made significant strides toward being able to predict whether a clinically high-risk teen will convert to psychosis within a 15-month time span, and to better treat the illness early on. It actually looks as though, with continued funding, NAPLS, CAPPS and the CCN will in a few years be able to consistently find, and proactively treat, people biologically fated for psychosis before their first episode–and offer them a much healthier outcome.
CAPPS and Psychosis Prediction
Two years ago, Dr. Cannon's CAPPS team used an MRI study to find that a group of patients who developed psychosis showed a significantly lower average gray matter density in their brain's prefrontal cortex about a year before their first episode. The excitement of finding this predictive biomarker for psychosis helped the NAPLS to receive a $23 million grant from the NIMH to investigate further. Last year, another pioneering study at CAPPS revealed another significant discovery: when clinical high-risk subjects showed certain defects in the structure of their brain's white matter in their youth, it indicated that their social skills would deteriorate, as was determined at a follow-up 15 months later. Combining this finding with the fact that healthy study subjects did not show similar biological or social deficiencies suggests something important: the integrity of a youth's brain's white matter may indicate whether he or she will develop psychosis.
This year, CAPPS has worked with NAPLS to complete a 2-1/2 year study which has uncovered an additional tool in the predictive kit: When 304 clinically high-risk (“CHR” on the chart) people were compared on indices of neuropsychological performance with 52 non-CHR people with a family history (FH) of psychosis and 193 “normal” subjects, their scores stacked in a revealing order:
- The “normal” subjects performed best,
- Clinically high-risk people who did not progress to psychosis during the study period scored next-best,
- Subjects with a family history scored third-best,
- CHR people who did convert to psychosis during the study period had the lowest scores.
Usefully, tests of verbal memory revealed the greatest disparities, enough so that they provide the ability to predict whether a clinically high-risk person will develop psychosis sooner rather than later.
The CCN: Understanding How Dysbindin Deficiency Might Cause Thought Disorder Symptoms
Meanwhile, at the Center for Cognitive Neuroscience, Dr. Cannon’s team has discovered how a defect in a schizophrenia candidate risk gene, DTNBP1, might cause some of the thought disorder inherent in the disease. The CCN team had found in 2009 that mice with a mutation in this gene (and thus a reduction in its associated protein, dysbindin) would more easily forget the locations of places and objects around them, reflective of the spatial working memory deficits inherent in schizophrenia. Although it was already known that dysbindin mediates how neurons in the brain release the neurotransmitter glutamate in synaptic interactions with other neurons, the team has now found that it also affects how neurons on the receiving end of the synapse process the glutamate. When they decreased dysbindin expression in mice, they found two telling results: (1) the mice’s post-synaptic neurons showed less electrical response to stimulation of glutamatergic NMDA receptors, and, at the same time, (2) the mice’s performance in spatial working memory tests suffered. As Dr. Cannon states, these discoveries indicate a possible biological reason why reduced expression of this gene can lead to schizophrenia-like symptoms.
Furthermore, the CCN team found that mice with this genetic defect showed reduced ability to form new neural pathways, as a specific long-term synaptic connection formed less readily. Fortunately for the mice, Dr. Cannon’s team was able to discover an effective therapy: a glycine bath. Mice treated with this allosteric protein, known to help post-synaptic neurons receive glutamate, showed substantially better synaptic plasticity. As Dr. Cannon states, “These findings also help to place disruptions of the dysbindin gene in the context of a major neurochemical theory of schizophrenia – the glutamate hypofunction model and suggest a pharmacological therapeutic strategy based on allosteric modulation of the NMDA receptor complex.” Based on this understanding, if people who have (or who are at risk to develop) schizophrenia can someday be given an allosteric therapy like glycine, it may improve their neural health, and help to remedy, or prevent, their symptoms.
If you'd like to meet Dr. Cannon and ask him about his research, please come to the Staglin Music Festival for Mental Health on September 11, 2010. He will be there and will be available to answer your questions after the free scientific symposium.
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