Allele worsens symptoms in high-risk patients.

The presence of a specific allele of a schizophrenia susceptibility gene is associated with an increase in the deterioration of neuropsychiatric symptoms and cognitive function in patients who are at very high risk for schizophrenialike disorders, reported Dr. Doron Gothelf of Stanford (Calif.) University and colleagues.

The study is the first to show the long-term effects of the gene COMT (catechol-O-methyltransferase), which breaks down dopamine, in a disorder related to schizophrenia. It also adds to previous knowledge about how COMT exerts its effects in the brain and contributes to the risk of schizophrenia.

Dr. Gothelf and associates studied patients with velocardiofacial syndrome, which also is called the 22q11.2 deletion syndrome. These patients have characteristics that include cleft palate, heart defects, and cognitive deficits. They are missing one copy of COMT because of a deletion in a tiny section of one of the two copies of chromosome 22, where COMT and other genes reside.

The 22q11.2 deletion syndrome is the most common chromosomal microdeletion in humans, affecting about 1 in 4,000 people. Up to one-third of people with the syndrome have schizophrenia or a related disorder. The syndrome is present in about 2% of people with schizophrenia overall.

"Since we know of the genes that are missing in the syndrome, it makes it an ideal setting to study the contribution of the genes in the deleted region to schizophrenia in this disease in particular but also to some degree in the general population," Dr. Andreas Meyer-Lindenberg, chief of the unit for systems neuroscience in psychiatry at the National Institute of Mental Health, said in an interview.

Both a low- and a high-activity COMT allele exist. In the study, patients with the low-activity COMT allele developed significantly greater cognitive dysfunction, psychotic symptoms, and decline in the volume of the prefrontal cortex as they progressed from childhood to adolescence and young adulthood, compared with those who had the high-activity allele (Nat. Neurosci. 2005;8:1500-2).

A variety of different studies of the effect of the low- and high-activity COMT alleles have shown that the biologic context in which each allele operates determines its ultimate effects on cognition and the risk of schizophrenia. In normal individuals in the general population, two copies of the high-activity allele produce 40% higher COMT enzyme activity than those who have two copies of the low-activity allele. Those with higher COMT activity have less extracellular dopamine available in their prefrontal cortex, and perform slower and must use more of their brain on cognitive tasks than people who have one low- and one high-activity allele, who perform at an intermediate level, and people with two low-activity alleles, who perform the best on such tasks.

Optimal performance on these tasks declines when people have either too much or too little extracellular dopamine in their prefrontal cortex, Dr. Meyer-Lindenberg said. The model for how COMT exerts its effects suggests that dopamine helps neurons in the prefrontal cortex to achieve an optimal signal-to-noise ratio, which may be especially important when the brain "prunes" its neuronal connections during brain development throughout childhood and into adolescence.

The presence of two high-activity alleles in people in the general population who have schizophrenia may lead to too little extracellular dopamine in the prefrontal cortex and too much dopamine in the midbrain so that the brain cannot compensate. But in people with 22q11.2 deletion syndrome who have only a single low-activity allele, the prefrontal cortex may be overwhelmed with too much dopamine, which worsens neuropsychiatric symptoms and cognition as individuals go into adolescence, he said.

In the current study, 7 of 24 children with the syndrome developed a psychotic disorder (schizophrenia, schizoaffective or schizophreniform disorders, or psychotic depression) in adolescence or young adulthood, compared with only one case of psychotic depression in 23 children with idiopathic developmental disabilities.

As children with the syndrome became adolescents or young adults, those who had the low-activity allele had significantly greater worsening of verbal IQ, language ability, prefrontal cortex volume, and scores on the Brief Psychiatric Rating Scale (BPRS) than did children with the syndrome who had a high-activity allele. On the other hand, children with idiopathic developmental disabilities did not have any significant changes in cognition or BPRS scores as they aged.

The study suggests that too much dopamine activity affects brain structure in the prefrontal cortex as much as too little dopamine activity does. "This is one of the points that really needs to be replicated in independent studies, because the methodology that [the investigators] have been using to look at the structure wasn't specifically geared to the abnormal brains in this population," Dr. Meyer-Lindenberg said. "In schizophrenia, the jury is definitely still out on the question of whether you have structural changes that are progressive at all."

The action of antipsychotics in blocking dopamine receptors in the prefrontal cortex in people with schizophrenia in the general population is not thought to be good, because such individuals already lack dopamine in that region. This seems to account for the lack of efficacy or the unsatisfactory response of cognitive dysfunction to treatment with antipsychotics. "Most people, given that evidence, don't think that antipsychotics do anything beneficial to prefrontal cortex dopamine," he said.

The disturbance in dopamine levels in the prefrontal cortex in individuals in the general population with schizophrenia most likely causes "downstream" problems in subcortical structures that contribute to the development of schizophrenia; this is where antipsychotics may have their efficacy, he said.

Studies of the interaction of COMT with another gene in the 22q11.2 region that is independently implicated in increased risk for schizophrenia in the general population--PRODH, which codes for proline dehydrogenase--could also prove to be fruitful, he said.

BY JEFF EVANS

Senior Writer