Schizophrenia researchers seek elusive ‘quantum leap’

But glutamate-based drugs for schizophrenia remain elusive. “It is disappointing that the new antipsychotic drugs becoming available now are still all variations on the dopamine antagonist or partial agonist theme, even if they have some advantages in terms of side effects and evidence that they may have some limited effects on negative or cognitive symptoms,” Dr. Reynolds said. “Several drugs addressing glutamate systems – indirectly modulating the NMDA receptor or synaptic glutamate – have been developed that had good potential but have failed in clinical trials. Nevertheless, this strategy is still being pursued by the pharma industry.”

Dr. Reynolds points to drug development challenges on several fronts. For one, research subjects don’t necessarily represent patients who’d benefit the most from treatment.

“Drug treatments are likely to be most effective, and most important, in the early stages of the disease,” he said. “However, drug trials are almost inevitably undertaken on subjects who may have had many years of treatment prior to the trial without, perhaps, always responding very well.”

Another challenge: The tight interconnectedness of neural systems linked to schizophrenia. Tinkering with something in one part of the brain may lead to something going wrong somewhere else. “Glutamate and GABA neurons are ubiquitous throughout the brain,” Dr. Reynolds said, “and targeting systems particularly affected in schizophrenia is difficult without influencing other neuronal systems, potentially leading to further side effects.”

Targets offer hope for new medications

The challenges are significant, but the latest schizophrenia research also is opening up opportunities for new medications.

The GABA connection, for example, is a fertile field for researchers. “One interesting and novel approach that seems promising is the development of a drug that modulates ion channels in GABA/parvalbumin neurons, thereby potentially restoring their function,” Dr. Reynolds said. “We are still years away from availability of these new treatments, however.”

But what if drugs targeted specific types of schizophrenia just like antibiotics aim to treat different types of bacterial infections?

Dr. Tamminga is pushing researchers to focus on how disruptions in glutamate processing affect specific parts of the brain and specific brain functions. “Some people want to have a single glutamate defect throughout the whole brain,” she said. But she notes that “the glutamate system is prominent in every brain region,” suggesting that a global problem would entirely incapacitate schizophrenia patients.

In fact, “while people with schizophrenia do have glutamate-mediated troubles with their condition, with their memory, they don’t have glutamate problems with their motor system or sensory system,” she said. “There’s very little evidence for a generalized brain defect. We ought to be taking another tack: We need to figure out pathophysiology by region and brain function.”

Dr. Kantrowitz also is working on developing biomarkers. He said he’s collaborating with colleagues to follow directives by the National Institute on Mental Health to develop schizophrenia biomarkers in early-stage studies.

“It’s a way to assess how well a specific drug is hitting its target,” he said. “Once you’ve developed a good understanding of how well they’re hitting their target, then you can more finely tune doses before you put the drugs in thousands of people.”

The research may shed light on a question that continues to divide schizophrenia researchers: Is the disease one single condition or multiple disorders masquerading as one?

“I think that eventually, once we get better at genetics and looking at schizophrenia, we’ll realize it’s not one thing, that it’s many different things,” Dr. Kantrowitz said. “The brain is a very complex organ, and there are lots of different areas of things that can go wrong to produce similar symptoms that are grouped together as schizophrenia.”

It’s possible, he believes, that one group of schizophrenia patients, maybe 10 percent, will respond to a glutamate-based treatment. An additional 10 percent, perhaps will require something else.

“We’re not good enough to discern these things yet,” he said. “But eventually we’ll get to more targeted treatment.”

And then we’ll finally get to reset the clock marking the time – now almost 70 years – since the last major milestone in schizophrenia treatment.

Dr. Reynolds reported that over the past 3 years, he has received honoraria for lectures, advisory board membership, travel support and/or research support from Janssen, Lundbeck, Otsuka, Sunovion, and Sumitomo. Dr. Kantrowitz reported having received consulting payments within the last 24 months from Vindico Medical Education, Annenberg Center for Health Sciences at Eisenhower, Health Advances, SlingShot, Strategic Edge Communications, Havas Life, and Cowen and Company. He has conducted clinical research supported by the NIMH, the Stanley Foundation, Merck, Roche-Genentech, Forum, Sunovion, Novartis, Lundbeck, Alkermes, NeuroRx, Pfizer, and Lilly. He owns a small number of shares of common stock in GlaxoSmithKline.

Dr. Tamminga reported no relevant disclosures.