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David Baxter

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Treating the Negative Symptoms of Schizophrenia: An Expert Interview With Joseph Coyle, MD
11/13/2006
Medscape Psychiatry & Mental Health. 2006;11(2)

Editor's Note:
On behalf of Medscape, Jessica E. Gould, BA, interviewed Joseph Coyle, MD, Eben S. Draper Professor of Psychiatry and Neuroscience, Harvard Medical School, Boston, Massachusetts, and Director of the Laboratory of Molecular and Psychiatric Neuroscience, McLean Hospital, Belmont, Massachusetts. Dr. Coyle discussed the significance of negative and cognitive symptoms of schizophrenia, including how they are identified and treated. Dr. Coyle is a member of the NARSAD Scientific Council and has received several awards for his accomplishments.

Medscape: When people talk about the negative symptoms of schizophrenia, to what are they referring?

Dr. Coyle: Schizophrenia can be broken down into 3 major components of symptoms. The positive symptoms include:

  • Psychosis;
  • Hallucinations;
  • Delusions;
  • Secondary agitation; and
  • Thought disorder.
Because these symptoms are quite dramatic, they capture the attention of both clinicians and laypeople. Positive symptoms tend to wax and wane over time and get less severe as patients age.

Cognitive symptoms (which are not as severe as you would see in Alzheimer's dementia, but do significantly impair an individual's ability to perform in complex society) involve deficits in:

  • Memory;
  • Decision making; and
  • Problem solving.
Most evidence has indicated that these symptoms are present at the very beginning, when the disorder is first diagnosed. The diagnosis of schizophrenia typically occurs when the psychosis or the positive symptoms appear. These cognitive symptoms are enduring and they correlate with the third domain, which includes negative symptoms.

Negative symptoms are a little more difficult for people to understand because they involve the absence of something, not the addition. Negative symptoms include:

  • Social isolation;
  • Lack of initiative;
  • Socially awkward behavior; and
  • Discomfort when interacting with people.
The negative symptoms tend to become more prominent over the course of the disorder. Together, negative and cognitive symptoms are associated with the persistent disability that is seen in individuals with schizophrenia.

Medscape: What are the challenges particular to identifying and treating negative symptoms?

Dr. Coyle: Over the last 10-15 years, clinicians and psychiatric researchers have begun to focus on the negative symptoms because it has become apparent that these are the more enduring and disabling components of the disorder.

Another historical reason that there has been more focus on positive symptoms is the drugs that are used to treat schizophrenia -- starting with chlorpromazine (sold as Thorazine and Largactil), discovered over 50 years ago -- are effective for reducing positive symptoms. Someone comes in; they're psychotic; you give them an antipsychotic medication; over a period of a couple of days to a week, they become much less agitated; their delusions become attenuated; and that is really quite striking.

Unfortunately, even though the US Food and Drug Administration (FDA) considers these drugs to be appropriate for the treatment of schizophrenia, there are 2 major problems:

  • First, psychosis is not unique to schizophrenia. It occurs in serious depression, bipolar disease, and Alzheimer's disease. In all of these cases, antipsychotic drugs work.
  • Second, even though psychosis can be managed, the patient remains, to a considerable extent, seriously impaired because of the negative symptoms and underlying cognitive impairments. Therefore, getting rid of the psychosis does not mean that the individual can go out and live independently, get a job, get married, and live happily ever after. It is clear that these drugs only treat a component of the disorder, not the entire disorder.
Clozapine
That said, there is one drug, clozapine, that works similarly to the other drugs, but also has some actions that are very poorly understood. The effects of clozapine suggest that there may be ways to treat the negative symptoms and cognitive impairments in schizophrenia that have not responded to traditional or second-generation antipsychotic medications.

That gets me to how my colleagues and I are looking at this issue. I became impressed that the drugs we currently have, with the possible exception of clozapine, really do not effectively treat all components of the disorder. We thought, therefore, that it would be useful to take a somewhat different look.

Currently, all of the drugs approved by the FDA for treatment of schizophrenia work by the same mechanism. They block the receptor for the neurotransmitter dopamine. For this reason, dopamine has always figured prominently in thinking about the causality of schizophrenia. The limitation in thinking about it that way is that aspirin treats rheumatoid arthritis, but that doesn't mean that rheumatoid arthritis is a problem stemming from not having enough aspirin. That was the same sort of concern that we had about these antipsychotic drugs. They could be like aspirin treating fever, without actually dealing with the underlying problem.

Drugs of Abuse Masquerading as Schizophrenia
A number of the findings converged about 10 years ago. One such discovery was that drugs known as dissociative anesthetics, such as phencyclidine (PCP) and ketamine (called superacid or special K on the street), when abused can produce a syndrome that is very difficult to distinguish from schizophrenia. Having worked in the emergency department in the 1970s and 1980s when there was an epidemic of abuse of these drugs, you would not know whether patients who came in had schizophrenia or whether they were intoxicated on PCP. You would have to wait until you got the urinalysis back to make a decision about how to treat. It was discovered that the mechanism of action of these drugs is to block a receptor for glutamine, the N-methyl-D-aspartic acid (NMDA) receptor. Studies were done on normal volunteers in laboratory settings showing that if you give low doses of ketamine, one of these NMDA receptor blockers, you can see the negative symptoms, the cognitive impairments, and some of the positive symptoms that occur in schizophrenia. These NMDA receptor antagonists were replicating the core features of schizophrenia, including some of the physiologic abnormalities that have been demonstrated to occur in schizophrenia and the first-degree relatives of individuals with schizophrenia, suggesting that negative symptoms and other components of this disorder are inheritable.

Other Trials of the 1980s
We also did, at that time, some postmortem studies and found that an endogenous antagonist of NMDA receptors was elevated in the brains of schizophrenia patients. They had too much of a normally produced, ketamine-like substance in the brain. We and others began to think about how hypofunction of NMDA receptors might contribute to the core features of the disorder, that is, the negative symptoms and the cognitive impairments.

Psychiatric Genetics
Subsequently, the whole area of psychiatric genetics has been moving forward very rapidly, especially over the last 5 years. It is clear that schizophrenia is highly inheritable, but it is not due to Mendelian-type genetics. The genetics are complex; multiple genes of modest effects interact to produce the disorder. In the last 5 years, about 10-15 potential-risk genes for schizophrenia have been identified, and about a third of those are 1? of separation from the NMDA receptor. Genetic studies have given some validity to this hypothesis that arose out of chronologic-challenge studies and postmortem studies that the NMDA receptor hypofunction may contribute to the core features of the disorder.

Ten years ago, my colleague Don Goff, MD, Associate Professor, Department of Psychiatry, Massachusetts General Hospital Schizophrenia Research Program, Boston, Massachusetts, and I decided to test this hypothesis in patients by giving an agent that enhances NMDA receptor function. It is a drug that has been used for 40 years to treat tuberculosis, namely, D-cycloserine. In the initial-dose findings, a study showed that patients with chronic schizophrenia who were treated with D-cycloserine at the optimal dose had a significant reduction in negative symptoms and a significant enhancement in cognitive function.

Since then, there have been a number of different placebo-controlled, blinded studies with several agents that enhance NMDA receptor function that have shown a reduction in negative symptoms and, to a variable degree, an enhancement in cognition in patients with schizophrenia who are receiving psychotic medications. In some cases with D-serine, which is one of the endogenous modulators of the NMDA receptor, and with glycine, another endogenous modulator of the NMDA receptor, they also showed a significant reduction of positive symptoms in patients who are receiving concurrent antipsychotic medications.

Now, there is a good deal of interest in the potential of enhancing NMDA receptor function and dealing with those components of schizophrenia -- again, the negative symptoms and cognitive impairment -- that respond poorly, if at all, to the current antipsychotic medications, except for, possibly, clozapine.

Medscape: Could you speak a bit more about what you are working on right now?

Dr. Coyle: My collaborators and I have the good fortune of being supported by a major grant from the National Institute of Mental Health (NIMH), and we have a number of different investigators involved. We are trying to go from molecular mechanisms in experimental animals to clinical testing of this hypothesis in humans.

On the molecular side, we are making mice that are genetically modified so that they have impairments in the NMDA receptor similar to what we believe is happening in humans, and we are looking at how this affects mouse behavior and how we might correct those behavioral abnormalities with novel treatments.

On the clinical level, my colleagues, Don Goff and Daniel Javitt, MD, PhD, Director of the Program in Cognitive Neuroscience and Schizophrenia, Associate Professor of Psychiatry, New York University School of Medicine, New York, NY, are looking at how the administration of D-serine affects symptoms in schizophrenia, because there is some suggestion that psychosis is sort of a downstream consequence of malfunction in the NMDA receptor. They want to know whether this can forestall the development of psychosis and schizophrenia in individuals who are at high risk.

We are hoping to discover, in the next 5 years, hard evidence that the strategy is effective, if it is. if it is effective, we want to know how it might be optimally effective and provide a whole new way of treating schizophrenia.

Medscape: Thank you very much for your time.

Dr. Coyle: You're welcome. Thank you for having me.

This interview has been published in collaboration with NARSAD: The Mental Health Research Association, and is supported by an educational grant from Pfizer.

Related Links

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Moving Beyond Positive Symptoms: The Importance of Addressing Cognitive and Affective Symptoms in the Treatment of Schizophrenia

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


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