Focusing on Cognition: New Treatments for Schizophrenia

Philip D. Harvey, PhD

Dr. Harvey is Professor of Psychiatry, Mt. Sinai School of Medicine, New York

Dr. Philip Harvey is convinced, as are an increasing majority of clinicians, that cognition is the key to many aspects of schizophrenia. Dr. Harvey and colleagues have recently published a host of papers on the topic, including pieces in the American Journal of Psychiatry on cognitive rating scales http://ajp.psychiatryonline.org/cgi/content/abstract/163/3/426 and the correlation between cognition and real-world outcomes in schizophrenics http://ajp.psychiatryonline.org/cgi/content/abstract/163/3/418.

“There is huge interest in this right now,” says Dr. Harvey. “Every pharmaceutical company is racing to find compounds that effectively target molecular targets involved in cognition without interfering with antipsychotic targets.” The government is getting involved too, launching MATRICS and TURNS, both devised to provide support and funding for research that the pharmaceutical companies either can’t or won’t get involved in—Dr. Harvey notes that while MATRICS is completed TURNS has yet to get fully off the ground.

The interest is largely due to the fact that the functional outcomes of schizophrenics have been shown to strongly correspond to measures of cognition. Some preliminary (and quite large) pharmacologic cognitive enhancement studies already been carried out, but with no success, and there is reason to believe that targeting cognition in schizophrenics may be more complicated than targeting cognition in patients with other conditions. Tests of both atomoxetine, which successfully improves cognition in children with ADHD, and cholinesterase inhibitors, which have been shown to improve cognition in those suffering from dementia, have turned up negative results. “People are just beginning to realize the complexity of all this,” Dr. Harvey says. He cites a number of possible reasons why attempts to target cognition in schizophrenics have, so far, come up short.

Cognition may not be malleable. It’s possible, Dr. Harvey suggests, that cognitive deficits in schizophrenics are due to general, irreversible factors.

Cognitive impairment measures may not be sensitive to change. As Dr. Harvey explains, “these metrics are all strongly correlated with a subject’s level of education and general IQ; it’s going to be a while before any drug can affect those.” It’s further possible that only certain aspects of cognition can be positively altered, and the tests are too multi-factorial to focus in on these.

The drugs tested so far may not be the right sort of drug. One substance that has been shown affective in improving cognition in schizophrenia is amphetamine. Of course, it’s not safe for any kind of long-term use. “Amphetamine is like a sledge-hammer,” Dr. Harvey says. “It has multiple mechanisms of action in both cortical and sub-cortical regions, and that may be why it works. A drug like atomoxetine works quite well for ADHD, but maybe the deficits in schizophrenia are just too pervasive.”

It’s also possible that interactions between antipsychotics and drugs for cognition may be reducing our ability to either induce or detect improvement. These have all been plausible explanations for the failure to find drugs that effectively enhance cognition in schizophrenics, but the results of two recent studies suggest that the real problem lies in finding the right drugs.

Dr. Harvey cites two recent publications in the Schizophrenia Bulletin. Both looked at patients in supported employment situations, and both groups were randomized to receive computer-based behavioral cognitive remediation. In both studies, those patients randomized to cognitive remediation demonstrated significantly better functional outcomes (as evidenced by the amount of time they spent working in the following year) and improvements in some neuropsychological outcomes measures. “This shows three things,” Dr. Harvey says. “First, cognition is malleable. Second, neuropsychological tests can be sensitive to cognitive improvement in schizophrenic patients. Third, cognitive enhancements make a real-world difference.”

The problem then, possibly lies in drug-drug interactions between the substances believed to target cognition and various antipsychotics. One of the most successful set of drugs that have been targeting cognition in animal models act on D 1 receptors. D 1 receptors, which are mostly in the cortex, have been implicated in cognition, and manipulation of these receptors reliably results in changes in certain aspects of cognitive functioning. D 2 receptors, which lie mostly in the striatum, have also been implicated, specifically in schizophrenia, where considerable data suggest that schizophrenic patients have too much activity in the striatum, and not enough in the cortex. And therein lies the rub. All successful antipsychotics antagonize D 2 receptors; however, the majority of substances that can both target D 1 receptors and pass the blood-brain barrier excite D 2 receptors. Examples include amphetamine and l-dopa.

There are multiple other possible targets. Nicotinic acetylcholinergic activity is impaired in schizophrenia, but the extremely short half-life of the currently available drugs limits their therapeutic use. The glutamate system is also clearly involved in schizophrenia, as evidenced by the results of studies examining PCP and ketamine, but previous therapeutic efforts have been disappointing.

“We may have to move away from drugs with a single specific target,” suggests Dr. Harvey. “Sometimes, you can’t treat the cause of an illness, and you’ve got to treat the consequences instead.” This approach could explain the success of amphetamine, which has a widespread excitatory effect on the brain. Since most of the individual targets for cognitive enhancement in schizophrenia interact with each other, altering the functioning of one system may lead to a compensatory reaction on the part of other systems. This compensatory reaction may also be related to the effects of antipsychotic medications as well.

There may be other issues; some studies of people with schizophrenia suggest that there may be certain cognitive abnormalities that influence a wide array of other aspects of cognition. “The problem with schizophrenic patients may just be that their brains process things too slowly,” Dr. Harvey says. “Processing speed shows the greatest correlation to specific functional outcomes, and it’s easy to posit how it could negatively impact memory, attention, and any cognitive process where information has to be processed sequentially. If your cognitive processing is extraordinarily slow, everything else can seem to be really fast.”

Targeting cognition in schizophrenia is a complex problem. Increasingly vast resources are being directed toward this goal, and although substances aimed at specific molecular targets have shown little success, the efficacy of more widely acting substances such as amphetamine and the benefits of studies of computer-based cognitive remediation is cause for cautious optimism. “It may turn out,” Dr. Harvey says, “that, as with so many other psychiatric advances, we find the right drug through pure chance.”

Disclosure: Dr. Harvey is a consultant to AstraZeneca, Bristol-Meyers Squibb, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi-Aventis, and Wyeth; and receives grants from Bristol-Meyers Squibb, Janssen, and Pfizer.