Advances in the Pharmacologic Management of Negative and Cognitive Symptoms of Schizophrenia: An Expert Interview With Stephen R. Marder, MD

June 15, 2006

Editor's Note:
The second-generation antipsychotics offer certain advantages over the first-generation agents, but they remain inadequate treatments for many patients with schizophrenia, as the CATIE results made clear. The cognitive and negative symptoms of the illness are especially disabling and difficult to treat. To discuss the latest research developments in pharmacotherapy for negative and cognitive symptoms of schizophrenia, Randall F. White, MD, FRCPC, spoke with Stephen R. Marder, MD, Professor and Director, Section on Psychosis at the University of California at Los Angeles Neuropsychiatric Institute Dr. Marder is also Director, Desert Pacific Mental Illness Research, Education, and Clinical Center, US Department of Veterans Affairs.

Medscape: Although we can fully treat the positive symptoms of schizophrenia in many patients, the negative and cognitive symptoms are much more difficult. How do those aspects of the illness affect patients?

Stephen R. Marder, MD: If you examine the long-term functional outcomes of people with schizophrenia and their ability to work, to engage in social activity, to return to school, and to be involved in family life, you find that these outcomes are related to the severity of neurocognitive impairment. Functional outcomes are also related to negative symptoms. In fact, a long-term study of negative symptoms indicates that, although the severity of positive symptoms informs clinicians about a patient's requirement for hospitalization and even whether he or she is at risk to commit suicide,[1] positive symptoms are relatively unrelated to a patient's ability to function on a job or engage in social activities.

If we are going to improve the long-term outcomes of schizophrenia, an important goal is to address negative symptoms and cognitive impairments. Unfortunately, the mechanism of action of presently available medications, namely dopamine-2 receptor blockade, is relatively ineffective for improving negative and cognitive symptoms. Many patients whose positive symptoms are adequately treated are left with substantial deficits in these 2 areas and thus have major functional impairment.

At the American Psychiatric Association (APA) 2006 meeting in Toronto, Ontario, Canada, Richard S. Keefe, PhD, presented the findings on cognitive impairment in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).[2] He and the other investigators found that the improvements in cognition during treatment were relatively small, and the second-generation antipsychotics had no advantage over perphenazine in that realm. This finding suggests that, despite the availability of the new antipsychotics, the negative and cognitive symptoms of schizophrenia really deserve specific attention.

Medscape: The excitatory neurotransmitter glutamate, an amino acid, is increasingly implicated in schizophrenia. The glutamate system is complex and involves several receptor types. What are the clinically important aspects of this system?

Dr. Marder: The strongest evidence demonstrating that glutamate is involved in schizophrenia comes from clinical experience with drugs that reduce glutamate function, such as phencyclidine and ketamine.[3] Even in people who don't have schizophrenia, these drugs cause a syndrome that looks a lot like schizophrenia, including positive and negative symptoms and cognitive impairment. I think that's the simplest description of evidence that supports the idea that hypofunction of glutamate could be responsible for some aspects of schizophrenia, and that drugs that improve glutamate transmission might improve schizophrenia.

The problem for clinical researchers is the complexity of glutamate receptors. The 2 most often discussed are the N-methyl-D-aspartate (NMDA) receptor and the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Metabotropic glutatmate receptors also exist in the human brain.

Medscape: Research with the amino acid glycine, an endogenous modulator of NMDA receptors that is secreted by glial cells, has shown some promise in treating negative symptoms, according to a report given by Daniel Javitt, MD, at the APA meeting.[4] What do you think about manipulating glycine as a therapeutic tool, and what kind of drug development is likely in this arena?

Dr. Marder: There is a lot of interest in Javitt's research on modifying the glutamate system to address negative symptoms. Much of this work has focused on agents that act on the glycine modulatory site of the NMDA receptor, and several drugs, including glycine itself when given in large doses, may improve negative symptoms. Several studies have suggested that. But a large trial funded by the National Institute of Mental Health (NIMH), which I was part of and which also included Javitt and William Carpenter as investigators, found no effect of glycine on improving negative symptoms.[5]

Other interesting drugs operate at that same glycine modulatory site on the NMDA receptor, such as D-cylcoserine, which was first used as an antibiotic. Lately, there is interest in D-serine, an endogenous modulator that is more potent than glycine and more readily passes the blood-brain barrier.[6]

Medscape: What other approaches are researchers taking to develop better treatment for negative symptoms?

Dr. Marder: Steve Potkin presented a study of asenapine, a broad-spectrum antipsychotic, at the 2006 APA meeting.[7] The study found that it was more effective than risperidone in treating negative symptoms.

Medscape: How can clinicians optimize therapy, given the available treatments to address negative symptoms?

Dr. Marder: At this stage, no available medications are particularly effective for negative symptoms. That doesn't mean that people with negative symptoms can't benefit from psychosocial treatments that address, for instance, impairment in motivation. But negative symptoms are among the most difficult aspects of the illness to treat, and the treatments we have are totally inadequate. No especially promising medication is coming along; the most promising data appears to be for asenapine, but these findings need to be confirmed in other studies.

Medscape: The cognitive symptoms of schizophrenia have recently begun to receive close attention from researchers and clinicians. You are involved in the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). Can you describe the goals of this project?

Dr. Marder: MATRICS is an NIMH-funded contract to address the obstacles that stand in the way of companies' developing drugs to improve cognition.[8] For example, the US Food and Drug Administration (FDA) had said that a principal obstacle was that investigators hadn't even agreed on how to measure cognitive impairment of schizophrenia. MATRICS brought together people from industry, government, and academia to examine these issues and come up with suggestions. The most tangible contribution was, through a consensus-building process, development of a battery of neurocognitive tests, the MATRICS Consensus Cognitive Battery, recommended by NIMH to the FDA and now viewed as an instrument with broad acceptance for clinical drug trials.[9]

As a consequence of MATRICS, the FDA has now made it clear that it is reasonable for industry to seek approval for medications that enhance cognition in schizophrenia. The MATRICS process has led to standards for clinical trials for cognitive-enhancing agents, and it brought together neuroscientists to help direct pharmaceutical companies toward the most promising molecular targets in order to prioritize pharmaceutical development.

Medscape: What are the 7 domains of cognition that show impairment in schizophrenia as identified in the MATRICS Consensus Battery?

Dr. Marder: They are speed of processing, attention and vigilance, working memory, verbal learning, visual learning, social cognition, and reasoning and problem solving.[9]

Medscape: According to a presentation by Donald Goff, MD, the AMPA receptor is a promising target for cognitive pharmacotherapy in schizophrenia.[10] Yet his randomized controlled trial of an experimental ampakine, CX516, in patients with schizophrenia yielded negative results. What is your appraisal of this line of research?

Dr. Marder: I think it's a very important area of research. The AMPA receptor is an attractive target, and ampakines are therapeutic agents that act on that receptor. I believe that CX516 may not be the most potent ampakine, as Dr. Goff mentioned in his presentation. Although this trial did not show cognitive improvement for those receiving the active agent compared with placebo, a number of ampakines are currently in development, and these drugs are usually modulators of receptor function rather than pure agonists. Clinical trials are at various stages, but it's very promising research overall.

Medscape: What other kinds of agent are under investigation for treating cognitive impairment in schizophrenia?

Dr. Marder: During the MATRICS process, we brought experts to a meeting in June 2004 on the NIMH campus and had 2 days of discussions.[8] The group gave opinions about the most important pharmacologic targets. The top 2 targets identified were dopamine-1 receptor agonists and alpha-7-nicotinic receptor agonists. Drugs that affect glutamate, such as AMPA receptor modulators and glycine reuptake inhibitors, were also of great interest to the group. Medications that target these receptors are at various stages of development, and NIMH has funded a clinical trials network, of which I am the head, which is looking at promising agents.

Medscape: In the meantime, what can clinicians do to help their patients with the cognitive deficits of this disorder?

Dr. Marder: They can be aware of the cognitive aspects of the illness. Clinicians should remember that some of the drugs they use to treat people with schizophrenia, such as benzodiazepines and anticholinergics, might even impair memory. Although no available medication is preferred for treating cognitive impairment, cognitive remediation and cognitive enhancement therapies have been found to be effective.[11] The therapies are not widely available, but there's a growing research base on their efficacy, and I hope clinicians will soon take it seriously.

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