By David N. Leff

The U.S. Census Bureau has just released its year 2000 decennial count of the U.S. population ¿ now totaling 281 million men, women and children. One percent of that body count ¿ 2,810,000 ¿ approximates the number of Americans afflicted with schizophrenia.

¿One percent of the population,¿ observed clinical and research psychiatrist Michael Egan, ¿[is afflicted] in their early 20s with schizophrenia, and it¿s a profound tragedy to have their lives snatched away from them like that ¿ to become so dysfunctional.¿

Egan treats, and tests, such patients at the Clinical Brain Disorders Branch of NIMH ¿ the National Institute of Mental Health, in Bethesda, Md. ¿The schizophrenics that we study,¿ he told BioWorld Today, ¿are all clinically stable, though still very troubled by symptoms of their illness. The hallmark of schizophrenia is terrible hallucinations or delusions: They hear voices, or have paranoid delusions that people are after them. Those symptoms can be controlled to a very significant extent with anti-psychotic medications, and patients can be stabilized. But they still have tremendous problems with negative side effects ¿ just motivating themselves to do things.¿

A cohort of 181 such patients, plus 219 of their unaffected sisters and brothers, and 79 normal individuals as controls, volunteered to undergo memory testing at NIMH, designed to correlate their cognitive performance with functioning of a key brain region, the prefrontal cortex. These participants first had a gene in their genome called COMT analyzed for one of two amino-acid mutations, inherited from their parents. One mutated a polymorphic variant sequence, met, that encodes methionine; the other val, for valine.

Egan is lead author of a paper in today¿s Proceedings of the National Academy of Sciences (PNAS), dated June 5, 2001, and titled: ¿Effect of COMT Val^108/158 met genotype on frontal lobe function and risk for schizophrenia.¿ The article¿s senior author is Daniel Weinberger, who heads the NIMH branch.

All those volunteers taking the exam ¿ the Wisconsin Card-Sorting Test of executive cognition ¿ were shown selected playing cards dealt from a constantly changing deck, and asked to match them from short-term memory by number, suite or color. ¿It just involves keeping in mind what you did in the previous example, and keeping track of where you are in the scene,¿ Egan explained.

Mutations Set Good, Better, Best

The co-authors found that participants who had inherited two copies of val, performed worse than those with only one copy. Those with two sets of met did best. COMT accounted for 4.1 percent of the variance among patients and controls, suggesting that it influences prefrontal cortex functioning.

When well siblings of affected patients performed a similar memory task while their brains were scanned by magnetic resonance imaging, the prefrontal cognitive activity of those with doubled val was least efficient. ¿It¿s as if they get poorer gas mileage out of their prefrontal cortex,¿ said Weinberger. Brain activity of those with a single copy of each variant turned in better performances, while siblings who inherited two copies of met scored highest of all.

¿Our paper reports two main findings,¿ Egan noted. ¿One, that not only does the gene affect ability to perform these cognitive tasks, but it also impacts the underlying brain physiology. And two, we show that the variant, or polymorphism, of the gene, associated with poor performance and poor prefrontal physiology, slightly increases risk for schizophrenia ¿ by 1.5-fold. The COMT gene in particular seems to affect prefrontal dopamine, a neurotransmitter that¿s critical in getting the prefrontal cortex to do a working memory task.

¿That gene produces an enzyme ¿ catechol-O-methyltransferase ¿ which is important for breaking down dopamine,¿ Egan explained. ¿People with a methionine variant have a reduced enzyme activity, and can¿t metabolize dopamine. The neurotransmitter presumably hangs around a lot longer in the prefrontal cortex¿s neuronal synapses. People with the met allele don¿t break dopamine down as much. They have more of it to stimulate these prefrontal neurons, and they¿re able to keep memory information on line more. This is what helps cognition.

¿People with the valine variant, in contrast,¿ he said, ¿have more enzyme activity, break down dopamine more rapidly, and then are hypodopaminergic in their prefrontal cortex, which is why people who receive dopamine agonists, for example, perform better on certain cognitive tasks like working memory.

¿There¿s another interesting factor,¿ Egan continued. ¿If the only thing this gene did was to improve cognition, then presumably over the course of evolution, given a selective advantage, everyone would harbor the methione variant, because the cognition¿s a little bit better. The fact that a lot of the valine is still hanging around makes one wonder. Reports from cancer literature suggest that valine may confer a slightly reduced risk for estrogenic cancer. So the valine allele has slightly reduced cognition, but slightly improved cancer risk. So, you more rapidly metabolize estrogenic agents and reduce getting breast or ovarian cancer.¿

Name Of The Game: COMT Inhibition

¿As a matter of fact,¿ Egan said, ¿COMT inhibitors that convert people to a functional met allele are already used for treating Parkinson¿s disease ¿ to restore those people¿s dopamine deficits. An important implication of our study is that if one used COMT inhibitors with schizophrenic patients, their cognition might be somewhat enhanced. That will be another study that we¿re beginning soon ¿ to use this novel drug therapy for schizophrenia.

¿We¿re going to test to see if these inhibitors are useful for treating the disease,¿ Egan said, ¿and if they improve cognition. That could be one potential for a commercial application, but it would depend on what genotype the patient is. Those who have two val alleles, we¿d predict, would respond much better to such medication than those with met. There¿s evidence that current anti-psychotic drugs work by blocking dopamine receptors in lower brain circuits. We propose that the COMT inhibitor would enhance dopamine circuits specific to the prefrontal cortex. It¿s a real gene-drug interaction.

¿We suspect that COMT¿s effect, while modest, may be amplified through interaction with other susceptibility genes and environmental factors. For example, we¿re studying a gene in the brain¿s hippocampus that, together with COMT, could boost schizophrenia risk threefold ¿ an attractive target for inhibition.¿