What was it about schizophrenia that motivated you to move from clinical psychiatry to research?

When I completed my training in psychiatry I was particularly interested in schizophrenia. My experiences with patients with schizophrenia, with the delusions and misinterpretations, just fascinated me. After my residency, I went to the National Institute of Mental Health and worked with a schizophrenia research group there.

  How would you describe the arc of your research over the intervening years?

Initially I became interested in the pharmacological treatment of schizophrenia, but particularly in maintenance treatment. That is, once patients have been stabilized, how do you maintain them in the community? (This is as opposed to acute treatment.) Almost all my early studies focused on the fact that many patients were over-treated with antipsychotics and they suffered from substantial side effects; the most common is akathisia, which is an experience of motor restlessness that is an extrapyramidal side effect of antipsychotic drugs. Parkinsonism is another extrapyramidal side effect of these antipsychotics.

  Could you stop for a second and define extrapyramidal side effects?

Extrapyramidal is related to the extrapyramidal nervous system, which includes the basal ganglia and is a part of the nervous system that actually helps in motor coordination. All the older antipsychotic drugs affect the basal ganglia in the brain. These drugs are dopamine-receptor antagonists and they can actually mimic all the signs of Parkinsonism. Patients demonstrate rigidity, tremor, the kind of gait that Parkinson’s patients get. These are extrapyramidal side effects.

  How severe were these side effects with the early drugs?

They can cause a substantial amount of discomfort. When I was at NIMH I did a study in which I looked at patients who actually seemed to improve when taken off antipsychotic drugs for periods of time. My observation was that they really didn’t improve, they just felt better because they had fewer side effects. Understanding this aspect of antipsychotic drugs was very important for my research. This also led me, when I left NIMH, to move to California where I associated myself with Theodore Van Putten. Van Putten had very much of a similar interest and we continued that research at UCLA. Van Putten had done wonderful studies describing the behavioral side effects and subjective side effects of antipsychotics. We were involved in that kind of work for several years. My early studies focused on strategies for treating patients with side effects, which included lowering the doses of antipsychotic drugs

  Your most highly cited paper is on risperidone treatment of schizophrenia. What is it about risperidone that gives this paper such impact?

Until well into the 1980s, the group of antipsychotic drugs available caused serious extrapyramidal side effects. It was very hard to treat patients without doing so. It was almost as if the art of treating schizophrenic patients with antipsychotics was to be able to get the antipsychotic effect without causing substantial amount of suffering from extrapyramidal side effects. Then a drug called clozapine, which is an antipsychotic that treats schizophrenia without causing substantial extrapyramidal side effects, came along. Clozapine was the first drug that showed it could be done. It had been around for a while, but because it had the potential for causing agranulocytosis, which is a syndrome that occurs when somebody stops making neutrophils, a particular kind of white blood cell necessary for fighting infection. But clozapine led the drug industry to look for agents that would have clozapine’s properties of being an effective antipsychotic without causing extrapyramidal side effects, and risperidone was the first of the drugs that came to market which had those properties. And, in fact, risperidone combined some of clozapine’s properties, both antagonism of dopamine D₂ receptors and antagonism of seratonergic 5HT_2A receptors.

  When did you get involved with the drug studies?

I was involved in the initial study of risperidone. These were studies done in both the United States and Europe. I consulted with Jansen Pharmaceutica, and I got involved with the company particularly after the study was complete, when the data was being analyzed. I played a major role in trying to understand the data. The publication, that 1994 study, comes from a large multicenter trial in the U.S. that compared several doses of risperidone with haloperidol and placebo in acute schizophrenia.

  How would you describe the impact of that 1994 publication?

That study, and a companion study done in Canada, were pivotal studies in the approval of risperidone by the FDA. In addition, it was an important advance in clinical study methodology because we tested more than one dose of the antipsychotic medication.

  Would you say risperidone represented a breakthrough in schizophrenia treatment?

I think the most important impact of risperidone, along with other new drugs that are coming along, is that they are effective antipsychotics that don’t cause a substantial amount of extrapyramidal side effects. Studies also suggest something more, that they may be somewhat more effective than haloperidol not just for positive symptoms but also for the negative and cognitive symptoms of schizophrenia.

  What do you see as the next step in drug treatment?

There are a number of newer antipsychotics. One thing that studies have shown is that risperidone is more effective for acute schizophrenia. And we have data to suggest that people treated with risperidone are more interested in participating in psychosocial treatments and in rehabilitation, which would be a very important advance – that is, if the goal of long-term treatment isn’t just to prevent relapse but to assist in resocialization and rehabilitation of patients. People on risperidone and clozapine seem more interested in these programs. Then there are other new drugs similar to risperidone that are already available or being considered by the FDA for approval. All these show this property of being effective and causing substantially less extrapyramidal side effects. The next question is whether or not any of them have other advantages risperidone doesn’t have. All have some side effects. All seem to cause some weight gain; some are a bit sedating, although they are still a vast improvement over the older drugs.

  What would you like to achieve in schizophrenia treatment in the next ten years?

I would like to make contributions which would improve the overall treatment of schizophrenia by providing a pathway by which clinicians can combine both psychosocial treatments and pharmacotherapy, starting both at the same time. I think the newer drugs may cause a vast improvement in the psychosocial treatments of schizophrenia, which have really lagged behind. There is evidence, for instance, that work outcomes and social outcomes can be improved when newer drugs are combined with psychosocial rehabilitation.

  What do you think have been the most persistent obstacles in your research?

Well, there are many in schizophrenia research. First of all, patients with schizophrenia can be difficult to study and there are ethical issues about whether or not people with schizophrenia have the ability to give true informed consent. When you study a population of such individuals, there are important bioethical concerns you have to deal with. As for other barriers, I think there had been a tendency to set very low goals for people with schizophrenia. Clinicians and sometime even patients and their families had grown to accept outcomes in which patients are merely not relapsed, not becoming psychotic. I think it’s important to focus on social outcomes, to change the thinking so that people will set goals, improve social outcomes, try to get people with schizophrenia back to school and back to work. Another barrier is that there is a stigma associated with schizophrenia, so patients and families might tend not to participate in research on the illness.

  Are you satisfied with what you’ve accomplished in your research?

Yes, but I’m not satisfied with the treatments. I think our work and the work of many others has improved the outcome of schizophrenia, but people with schizophrenia still seem to do substantially poorer than the average person in the community. I think there’s a lot to do. There was a study called Schizophrenia PORT, which stands for Patient Outcomes Research Team, led by Anthony Lehman at the University of Maryland. Schizophrenia PORT showed that a lot of psychosocial treatments that are effective for schizophrenia really aren’t being implemented in the community.

  What lines of research do you consider promising for treating or understanding schizophrenia?

One of the areas of schizophrenia that hasn’t been adequately studied is neurocognition. People with schizophrenia not only have hallucinations and delusions, but also have problems in memory and concentration and the ability to think clearly, and these problems can have major effects on the social outcome of illness. There’s recently been a lot of attention to those areas, and the newer drugs seem to be more effective at treating those deficits. There’s also some optimism that newer specific treatments can be developed for the neurocognitive deficits. At the same time, negative symptoms such as apathy, lack of motivation, disinterest in social relationships can be devastating in schizophrenia. There’s some interest in new pharmacological treatments that may be effective in those areas. I’m involved with other collaborations in studies for drugs that seem very promising for negative symptoms of schizophrenia.

  Do you think you’ll understand this disorder in your lifetime?

It’s probably an illness that affects multiple brain areas. I think we’ll learn more about it and understand it better. But fully understand it? I doubt it.

Dr. Stephen R. Marder
UCLA
Department of Psychiatry and Behavioral Sciences
Los Angeles, CA, USA