Dr. Daniel Javitt displays an electrode-studded cap used to measure electrical activity generated by the brain. The device provides unique insights into how and why information processing breaks down in the brains of those with schizophrenia. (Photo by John Abbott)

Unraveling the Mysteries of Schizophrenia

$10 Million NIMH Grant Creates New Research Center

In an innovative and promising approach to understanding and treating schizophrenia, Daniel C. Javitt, MD, PhD, professor of psychiatry, and his research team are focusing on a type of brain receptor that appears to play a key role in this devastating brain disease. This receptor, known as an N-methyl-D-aspartate (NMDA) receptor, which modulates the neurotransmitter glutamate, is essential to learning, brain development, and the formation of short-term memories, all of which the brain relies on to make sense of its surroundings. When NMDA receptors fail to work, important brain processes are disrupted.

Dr. Javitt and his colleagues were recently awarded a five-year, $10 million grant from the National Institute of Mental Health (NIMH) to establish the Silvio O. Conte Center for Schizophrenia Research (named after the late U.S. congressman, a champion of mental health research). The center, to be based at NYU Langone Medical Center and its affiliate the Nathan Kline Institute for Psychiatric Research in Orangeburg, New York, will explore the link between schizophrenia and dysfunctional NMDA receptors—research that is challenging the long-held view that excess dopamine is the primary cause of schizophrenia.

“That theory,” notes Dr. Javitt, “came about because amphetamines, which increase dopamine levels, produce schizophrenia-like paranoia and auditory hallucinations, while dopamine blockers relieve these symptoms.” In fact, he adds, all drugs currently used to treat schizophrenia work by blocking dopamine. But dopamine can’t account for schizophrenia’s other symptoms, such as the breakdown in cognitive abilities and sensory processes that characterize the illness.

“Schizophrenia disconnects people from their environment,” explains Dr. Javitt, director of the Nathan Kline Institute’s Center for Schizophrenia Research. “They can’t understand sarcasm or decipher the image of a cat behind a venetian blind. People with schizophrenia are also very ambivalent: they can’t initiate activity because the disease disrupts the brain’s ability to commit to a single course of action.”

The NMDA theory—which posits that not only dopamine overproduction but also other features of the illness are a result of NMDA receptor dysfunction—began gaining attention in the 1970s, when it was observed that phencyclidine, or PCP (angel dust), which blocks NMDA receptors, caused users to exhibit the full range of schizophrenia symptoms. Similarly, drugs that increase NMDA receptor function appear to alleviate these symptoms. Dr. Javitt was the first investigator to demonstrate an effect of NMDA receptor manipulation on brain PCP binding.

“We’re focusing right now on a number of NMDA-boosting compounds,” says Dr. Javitt. “Several naturally occurring amino acids—glycine, D-serine, and sarcosine—improve symptoms significantly when administered in large doses and could potentially be given as nutritional supplements.” Also promising are glycine-transport inhibitors, which block removal of glycine from the brain, allowing glycine levels to build up without the need for supplements. Dr. Javitt is the named inventor on several patents related to the use of D-serine, along with other compounds used to treat schizophrenia.

“Current schizophrenia medications have troublesome mental and physical side effects—like weight gain—so compliance is often very poor,” says Dr. Javitt. “The hope is that these newer treatments, which already work well in animals, can control milder cases, so that current medications won’t be needed.”

Another important goal is to begin identifying presymptomatic individuals in adolescence to intervene before the disease’s permanent effects set in—most notably, atrophy of the brain’s connective white matter, which is associated with schizophrenia’s most severe symptoms. “Sixty percent of schizophrenics develop adult dyslexia,” notes Dr. Javitt. “If reading tests could spot this trend early, we could potentially use these new treatments, along with remedial cognitive exercises, to prevent or even reverse the loss of white matter.”