In the 2001 movie “A Beautiful Mind,” Russell Crowe plays a real-life mathematical genius named John Nash who helps the CIA break codes. Though Nash is a successful cryptographer, his paranoia and delusions amplify to the point that he is unable to fulfill his potential as a mathematician.
What Nash had is schizophrenia, a mental illness that alters the structure and function of areas in the human brain involved in its highest cognitive functions, such as quantitative reasoning. Like Nash, many others who formerly possessed incredible talents and abilities have lost certain gifts to the onset of the disease. It is this heartrending loss that inspires Dr. John Krystal, Chair of Psychiatry at Yale School of Medicine, to research the illness.
Krystal began his research on schizophrenia in 1988. At that time, medications that blocked the actions of the neurotransmitter dopamine at the dopamine D-2 receptor were the same treatments for schizophrenia that had been used since the 1950s. A new treatment developed in the 1980s, called clozapine, targeted a number of sites in addition to the D-2 receptor.
Yet “even clozapine, which remained the most effective anti-psychotic med, was an incremental advance in terms of disability associated with schizophrenia,” says Krystal, who was frustrated by the absence of more effective treatments. In particular, he saw that contemporary treatments left many of his patients with residual symptoms. As a result, he felt a strong desire to “help patients resume the lives they had before their illness.”
Ditching the Dopamine: A New Goal in Glutamate
Beginning his quest to find a better treatment, Krystal took his research in a new direction. Instead of continuing investigations on the dopamine receptor, he attempted to examine other models by which one might develop psychosis. This search led him to the glutamate system in the brain.
In studying the glutamate system, Krystal and his team compared the effects of an anesthetic medication, ketamine, to the signs and symptoms of schizophrenia. Building on research dating to the late 1950s, Krystal was struck by reports that the street drug PCP (commonly known as “angel dust”) produced symptoms that resembled schizophrenia.
Of course, Krystal could not administer angel dust to his patients due to its potent and long-lasting effects. Ketamine, however, is weaker and shorter-acting than PCP, rendering it safe for use in clinical studies. As both ketamine and PCP block NMDA (N-methyl-D-aspartic acid) glutamate receptors, studying ketamine effects allowed Krystal and his collaborators to study the role of NMDA receptors in human behavior.
For Krystal, the NMDA receptor was fascinating because it is “a little computer, a coincidence detector.” The receptor can only be activated when glutamate is released at the precise time the nerve cell in which it sits is activated. Furthermore, the NMDA receptor had been implicated in long-term potentiation, a process related to information storage or learning. Krystal and his collaborators had recently collected evidence that long-term potentiation is impaired in schizophrenia, suggesting that NMDA receptors might be impaired in this disorder.
First, Krystal and his team established that ketamine transiently produced the full spectrum of symptoms and cognitive impairments associated with schizophrenia. Ketamine effects included psychosis or feelings of “unreality,” blunting of emotional responses, and impairments in higher cognitive functions, including “judgment, planning, and problem solving.” Additionally, people were not generally disoriented, and many cognitive functions remained unaffected, just “as we see in schizophrenia.” According to Krystal, the similarity of ketamine effects to schizophrenia “suggested that a common biological mechanism, a deficit in NMDA glutamate receptor function, linked these two conditions.”
Next, the researchers tested whether medications used to treat schizophrenia could block ketamine effects in humans. The results of these studies were “surprisingly disappointing.” During these trials, Krystal says, “We tried to replicate findings emerging from the anesthesiology literature.”
For example, the researchers found that a dopamine D-2 receptor-blocking antipsychotic, haloperidol, did not reduce ketamine effects. This finding suggested that the ketamine model did not apply to typical antipsychotic medications. However, by suggesting that there were forms of psychosis that did not depend on stimulating dopamine D-2 receptors, Krystal’s research began to point to a new type of antipsychotic medication.
The next step was suggested by research studies conducted in animals by Dr. Bita Moghaddam, then at Yale and now Professor of Neuroscience and Psychiatry at the University of Pittsburgh. Her studies suggested that ketamine increases brain glutamate release by blocking the stimulation of nerve cells responsible for suppressing glutamate release. These inhibitory nerve cells release the neurotransmitter gamma-aminobutyric acid (GABA).
With the “glutamate disinhibition hypothesis” in mind, Krystal and his team then tested the capacity of glutamate release inhibiting drugs to block the psychotic symptoms produced by ketamine. “We first tested an anticonvulsant drug, lamotrigine, that suppresses seizures in part by reducing glutamate release.” This study, led by Dr. Amit Anand of the Yale School of Medicine’s Department of Psychiatry, showed the first agent tested that successfully reduced the ketamine effects. Subsequent studies suggested that it might also enhance the treatment of schizophrenia in some patients.
Krystal’s team then obtained a drug, LY354740, from Eli Lilly and Company to be tested in their model. This drug suppresses glutamate release by stimulating the metabotropic glutamate receptor type 2/3 (MGLUR 2/3), and a prior study by Moghddam suggested that the drug blocks some of the effects of PCP in rodents. Krystal’s group found that LY354740 blocks ketamine effects on “working memory,” the scratchpad-like part of memory for information that is learned and then forgotten once it is used, like a telephone number. Building on this work, Eli Lilly and Co. conducted a study that found that another drug from this class was as effective as a standard antipsychotic even though it did not block the dopamine D-2 receptor.
Although this drug is still in the experimental phase, and although there was an important negative study, Krystal’s finding propelled research on schizophrenia in the right direction. “The field of schizophrenia was stuck,” he said. “We had been testing variations of the same mechanism for 50 years. The exciting part of this story is that it is an example of how studying a basic brain mechanism across animal and human laboratory-based research may lead to treatments that work through entirely novel mechanisms.”
The next step for Krystal was to localize measurements of activity in the brain in order to determine why, at a circuit level, ketamine effects resemble schizophrenia. He recognized that behavioral research is limited in its ability reveal basic brain mechanisms.
Thus, the first advanced technology Krystal used was functional magnetic resonance imaging (fMRI). He and his team of Dr. Naomi Driesen, Dr. Greg McCarthy, and Dr. Patricia Goldman-Rakic studied humans performing cognitive tasks similar to tasks that have been performed with monkeys. They found that schizophrenia impairs the ability to sustain activity in the prefrontal cortex while people are performing tests of working memory. They also found that ketamine produces similar alterations in circuit function. In addition to studying the “electrophysiologic signature” of schizophrenia, Krystal and his team “are now using a variety of medications to reverse neural signature related to deficits in NMDA receptor function.”
Multiple Approaches Toward Future Discoveries
Krystal and collaborators are also using multiple approaches to better understand changes in the glutamate system in schizophrenia. For example, his late collaborator, Dr. Lyn Pilowsky, used single photon emission computed tomography (SPECT) to demonstrate reductions in NMDA receptors in schizophrenia. Dr. Ralph Hoffman has been suppressing auditory hallucinations in patients whose hallucinations had not responded to available treatments using transcranial magnetic stimulation (TMS). In this work, he identified brain regions that were hyperactive during hallucinations. Using an approach developed by Dr. Dennis Spencer and Dr. James Duncan in the Bioengineering Program, Hoffman was able to deliver TMS directly over the activated regions.
In TMS, a metal coil is laid on a person’s head and researchers run alternating current through this loop to induce a magnetic field. The magnetic field passes through the subject’s brain, stimulating electrical activity within the neural tissue. The low frequency TMS that is delivered over the regions associated with hallucinations was designed to reduce the hyperactivity of these regions.
In future studies, Krystal and his colleagues plan to study genetic variation that might provide insights into the molecular underpinnings of the ketamine response. Krystal has high hopes that “this work may help to guide us to new targets.”
As Krystal says, if one follows the biology of the disease, it will lead one to the right answers.