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While clozapine and related drugs have helped with cognition in many patients, it is recognized that this class of drugs will not be sufficient to produce all the needed improvement. So Meltzer’s group has been investigating a series of add-on therapies to further enhance the levels of two chemicals in the brain whose activity may be less than optimal – dopamine and acetylcholine. The Meltzer team is currently recruiting patients with schizophrenia whose psychosis is being treated with atypical antipsychotic drugs for add-on cognitive enhancement therapy with the drug Nu-Vigil.

And during that study, using brain imaging and genetic markers, he and Vanderbilt colleagues Adam Anderson, Ph.D., and Stephan Heckers, M.D., chair of the Department of Psychiatry, will investigate why higher doses are more effective in these patients and why it takes longer to get a response.

Rolling in like a fog
Elyn Saks, a Vanderbilt University graduate and a successful law scholar, is taking a very high dose of clozapine. She credits the drug and intensive psychoanalytic psychotherapy in helping the clarity of her thinking and the ability to cope with the stresses of everyday life, Meltzer said.

Saks, an endowed professor at the University of Southern California Gould School of Law, and former Vanderbilt Founder’s Medalist, is the author of a bestselling book, “The Center Cannot Hold: My Journey Through Madness.” In it, she compares her childhood in the 1950s and early 1960s in Miami to a Norman Rockwell magazine cover or a 50s sitcom. She had kind and caring parents who loved each other and their children. They filled their home with music and laughter and enjoyed family activities together.

But her life was not as idyllic as it seemed. In her book, Saks says she developed “quirks” when she was 8. She would line up shoes in her closet or beside her bed. She washed her hands obsessively. She imagined things, including a man standing outside her window, every night, waiting to break in and kill her family.

Her parents dismissed many of her paranoid thoughts and odd mannerisms as typical childhood fantasies, but there were things they didn’t know – like an episode when Saks was 8 and felt like she was dissolving. “Consciousness gradually loses its coherence. One’s center gives away. The center cannot hold,” she wrote in her memoir, one of Time magazine’s top 10 nonfiction books of 2007. “The ‘me’ becomes a haze, and the solid center from which one experiences reality breaks up like a bad radio signal.”

As a college student at Vanderbilt, a Marshall Scholar at Oxford University, and then a law student at Yale, her world began to unravel. She became depressed, socially isolated and lost a lot of weight. Her thoughts become more paranoid and more delusional. Her quirkiness had progressed into full-blown schizophrenia. She spent time in and out of psychiatric facilities, and soon after she began law school at Yale, she was confined to bed for 30 hours during a hospitalization, arms and legs restrained and a net thrown over the rest of her immobilized body.

“Schizophrenia rolls in like a slow fog, becoming imperceptibly thicker as time goes on,” she writes in her book. At first the day is bright enough, the sky is clear, the sunlight warms your shoulders. But soon, you notice a haze beginning to gather around you, and the air feels not quite so warm. After awhile, the sun is a dim light bulb behind a heavy cloth. The horizon has vanished into a gray mist, and you feel a thick dampness in your lungs as you stand, cold and wet, in the afternoon dark.”

Finding new types of drugs
Historically, the treatment of schizophrenia has centered on compounds that block the receptors for dopamine pathways in the brain. That’s the way that the vast majority of antipsychotics work, by blocking dopamine activity. Antipsychotic drugs, both first-generation and second, are effective in reducing hallucinations and delusions in patients with schizophrenia, but not in attacking the entire spectrum of symptoms.

A team of Vanderbilt researchers, led by Jeffrey Conn, Ph.D., Lee E. Limbird Professor of Pharmacology and director of Vanderbilt’s Program in Drug Discovery, is working on a different approach, one that might have a dramatic effect in treating the tragic cognitive symptoms of the disease – social withdrawal, inability to experience pleasure, flawed memory and verbal function.

The target: glutamate receptors, which respond to the main “excitatory” neurotransmitter glutamate to promote the passing of messages from one neuron to the next. The new efforts involve trying to manipulate glutamate systems in the brain in a way that would have a therapeutic benefit.

“The hope is by targeting glutamate, which is a much more fundamental transmitter to these circuits that are involved in information processing and cognition (than dopamine), that we may be able to achieve efficacy not only in controlling hallucinations and delusions, but also the cognitive disturbances,” Conn said.

“Most people in the field treating patients think that cognitive disturbances and negative symptoms might be more important to treat than the positive symptoms in the overall outcome of patient care. That’s why we want to move away from these dopamine-related therapies to try to target glutamate systems where you may have a more fundamental effect.”

You can’t just dive in and manipulate a system that is involved in virtually every function of the brain – the effects would be too far-reaching, so the Vanderbilt team is looking at a more subtle way of manipulating the glutamate system.

They’re trying to increase the function of the primary glutamate receptor implicated in schizophrenia, the NMDA receptor. NMDA receptors are involved in synaptic plasticity (lasting changes in neuronal communication), particularly a type called long-term potentiation which is thought to reflect the cellular changes that underlie learning and memory.

To accomplish this, they are targeting a different type of glutamate receptor, mGluR5, as a way to subtly increase the NMDA receptor function.

The approach holds much promise, Conn said. The Vanderbilt drug discovery group is working at chemically optimizing a molecule that regulates the function of MGluR5, and are in negotiations with a company to fully fund the research and take it into clinical development.

The group is also involved in other related efforts – one, nearing the end of the drug discovery process. The effort targets glycine, another neurotransmitter that is required in addition to glutamate for NMDA receptor activation.

“Glycine is removed from the synapse by a transporter. There’s a protein that transports glycine and acts as a vacuum cleaner. It keeps glycine levels low by pumping them out of the synapse. The approach we’re working on is inhibiting that transporter.”

Conn said that schizophrenia is just one of many diseases that the drug discovery team hopes to impact.

“They’re all closely related – schizophrenia, Alzheimer’s disease, Parkinson’s disease. The mGluR5-targeted agents, for example, have the potential to increase cognition in Alzheimer’s patients. “In the work with mGluR5, we can be focused on schizophrenia first, but we hope they will be tested in other patient populations as well.” VM

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