One of the side effects Dr. Meltzer obliquely alludes to is hyperglycemia, or an increased risk of developing diabetes. This issue has been receiving some attention recently.
Psychopharmacologic Innovations in the Treatment of Schizophrenia, Past and Present: An Expert Interview With Herbert Y. Meltzer, MD
Schizophrenia is a profoundly disruptive condition if left untreated. During the early 1990s, atypical antipsychotic medications began to replace conventional antipsychotic agents for treating schizophrenia, both because of improved efficacy and milder side-effect profile. On behalf of Medscape, Jessica Gould interviewed Dr. Herbert Y. Meltzer, Bixler Professor of Psychiatry and Professor of Pharmacology and Director, Psychopharmacology Division, at the Vanderbilt University School of Medicine, Nashville, Tennessee. A leading researcher in the pharmacologic treatment of schizophrenia, Dr. Meltzer played an integral role in the discovery of clozapine, the first atypical antipsychotic to be approved by the US Food and Drug Administration. He is one of the original members of NARSAD: The Mental Health Research Association's Scientific Council and chairs the organization's Young Investigator Review Committee. His research interests include suicide prevention and cognitive impairment in schizophrenia.
Medscape: You conducted some of the original research on the drug clozapine. How did you get involved in that work?
Herbert Y. Meltzer, MD: I got involved, originally, in an attempt to understand why clozapine was producing fewer extrapyramidal side effects in humans and laboratory animals. Prior to the advent of clozapine, it was believed that all antipsychotic drugs acted by blocking D2 receptors in the limbic system and [in that way] caused extrapyramidal side effects.
I came to the conclusion after looking at clozapine that it had to be acting through an additional mechanism other than dopamine because it was too weak as a dopamine blocker to account for its antipsychotic effects at the doses at which it was being used. So I began to study it clinically and preclinically, and in the course of studying it clinically, I realized that it had some special properties that the other drugs didn't -- namely, that it appeared to be more effective than any other antipsychotic drug we had.
I was working with patients for whom a lot of other drugs did not work. So I began to explore it in much greater depth at that time. That research led to, on the one hand, the pivotal study that resulted in the approval of clozapine in the United States, despite its causing agranulocytosis.
On the other hand, I studied its mechanism of action in the laboratory and came up with a general theory about how to make a better antipsychotic without extrapyramidal side effects, or with minimal extrapyramidal side effects. I consolidated other people's work as well as my own into a serotonin-dopamine hypothesis. That led to the development of the so-called atypical antipsychotic drugs such as risperidone and olanzapine.
After clozapine was approved and I began to use it, I made 2 major discoveries that have really held up. One was that clozapine is superior to other antipsychotics in reducing the risk of suicide in highly suicidal patients with schizophrenia or schizoaffective disorder. And second -- and this is probably in the long run more important -- it improves cognition.
Medscape: Tell me about the serotonin-dopamine hypothesis.
Dr. Meltzer: People have always been curious about how clozapine could be an antipsychotic without being a very good dopamine blocker. There are numerous theories. The most common one to account for the extrapyramidal side effects (EPS), or the lack of them, is that it's an anticholinergic. We treat EPS with anticholinergic drugs.
Another theory that came along when I began to work on this was that clozapine acted not as a D2 receptor, but that it was working as a D1 receptor. And then there have been suggestions from a number of different people that clozapine also had anti-serotonin properties. I made the hypothesis that anti-serotonin interacting with weak dopamine was the basis for the low incidence of EPS.
What I did was determine the affinity in a test tube of a number of drugs that had a clozapine-like association of antipsychotic activity. A number of these typical first-generation drugs, such as haloperidol, at the same dose that produce antipsychotic activity, also produce EPS and even produce EPS at lower doses. So, using a simple discriminate function, we found out that it was the weak D2 effect that contributed to the activity of the atypical group, followed by a strong 5H D2a. So the drugs we would develop had to be more potent as the D2a than they were as the D2 antagonist. In that same analysis, we found no contribution of the D1.
That became the serotonin-dopamine hypothesis, or the Meltzer Index. It still works. Just this week, Pfizer came out with a big paper on a whole new series of serotonin-dopamine antagonists that are atypical.
Drugs like clozapine have a number of effects. Clozapine is called a dirty drug; it has a rich pharmacology. The "dirty-ness" means that it's not specific. The really important concept here is that you don't want a highly specific drug. Prior to the advent of clozapine, everyone was looking for highly selective drugs. You find the magic receptor, you block that, you don't affect any other receptors, and maybe you won't have any kind of side effects. Clozapine is associated with numerous side effects, but it also has a unique efficacy.
Medscape: Given these side effects you mention, particularly agranulocytosis, to what extent and when is clozapine used today?
Dr. Meltzer: It's used in only about 5% of patients. Doctors are afraid of this agent even though they shouldn't be. Ironically, it's clearly the number 1 drug in China and has been for 20 or 30 years now. So it's used in tens of millions of Chinese. The reason they use it is that they never respected the patent, so they didn't have to pay very much for it. They still don't. And they're more casual about the monitoring.
Medscape: I know that there's a reluctance to prescribe clozapine and it's not the first-line approach to schizophrenia. So when should providers choose clozapine?
Dr. Meltzer: What they should do is the following: if the patient is suicidal and has made an attempt, the patient should go on clozapine. If the patient has failed 2 or more antipsychotic drugs, whether they be typical or atypical (by "failed" I mean that if, after an adequate trial lasting at least 4 to 6 weeks at adequate therapeutic doses, the patient is still persistently psychotic), he or she should switch to clozapine.
Medscape: Why do people respond so individually to antipsychotic drugs?
Dr. Meltzer: We know that 50% of schizophrenia is genetic and 50% is environmental. These factors interact with each other. The genetics of schizophrenia are very complex. We've already identified probably a dozen different genes, and there are probably at least several dozen more. People don't have to have all of these genes, they just have to have a few of them.
The genetic component is highly variable. And how those classes of genes interact with the environment is going to be variable. Treatment resistance, which is the main indication for clozapine, is a great example of this heterogeneity. At least one third of people who are treatment-resistant never respond to one of the typical antipsychotic drugs. The other two thirds who are treatment resistant initially respond to the drug, and then they lose it. You see 2 different types, and behind that are probably genetic differences.
So what all of this leads to is the next era of sophistication in clinical treatment: the concept of pharmacogenomics -- characterizing each person's genetic make-up, looking for the genes that might influence the response to a drug like clozapine from the point of view of efficacy or tolerability, and then giving the right drugs.
Medscape: What are the most exciting recent discoveries in the psychopharmacologic treatment of schizophrenia?
Dr. Meltzer: I believe that the key thing that has happened over the last 10 years is that [improving the] cognitive deficit has been identified as the key to improving outcome in schizophrenia. Although my results were very controversial when I first reported them, they have now been supported by 40 different studies. Over the last 2 to 3 years, the National Institute of Mental Health (NIMH) and the FDA and industry got together and decided that their key focus is going to be improving the cognitive deficit in schizophrenia through psychopharmacology. They had a series of meetings called the Matrix Program, and out of that they developed a list of targets. The challenge, the major goal, is now in our sights.
The really exciting thing is galvanizing the field to go after cognition through basic research on the mechanism of cognition, determine how the drugs like clozapine work to improve cognition.
Medscape: You spoke of an increasing emphasis on cognition. Do you find any resistance to that?
Dr. Meltzer: Oh yes, a lot of resistance. It's a new idea for many clinicians. They don't know how to assess it themselves, and they can't assess whether someone is delusional or hallucinating. It requires a massive re-education process, which is only 10% to 20% completed.
Medscape: What are some of the other challenges you face in your field?
Dr. Meltzer: One of the major challenges is being able to design and carry out clinical studies that are consistent with current approaches. When you want to do an add-on study, you really want to have people who are only being treated by monotherapy with a particular antipsychotic. But in fact most people today are being treated by a variety of drugs, including antidepressants and mood stabilizers. Even though there are 2 million people with schizophrenia, it's difficult to find people who are willing and able to meet the study requirements, especially in the United States.
The other issue that is significant is the decrease in federal funding for research in this field over the last 2 to 4 years. The last 2 years in particular, the NIMH budget has been put on hold. There never has been much of a budget in the field of clinical trials. The industry has been supportive of this, but we're now running into the complications of the push-back of drug prices, particularly in the field of schizophrenia. So that could have a chilling effect on some of the new research. We need more people to step up to the plate -- government, foundations, and industry -- to take advantage of the real breakthroughs in neuroscience.