STARTING RISPERIDONE AFTER CLOZAPINE

What is the concern about stopping clozapine to start risperidone? On September 21, 1994, in response to concerns expressed by the families of people with schizophrenia, the National Institute of Mental Health (NIMH) sponsored a workshop to explore the effects of clozapine discontinuation and the availability of risperidone (Risperdal), co-chaired by the authors.

During July and August of 1994, NIMH began receiving telephone reports from patients' families describing individuals with schizophrenia who had been treated with clozapine and who were abruptly discontinued from it and started on the newly available antipsychotic risperidone. In several cases, this rapid shift in medication was associated with dramatic increases in clinical symptoms requiring rehospitalization.

Existing guidelines for clozapine discontinuation indicate that gradual tapering over one or two weeks should take place. Abrupt discontinuation should only occur in response to severe side effects. NIMH staff notified the Food and Drug Administration (FDA), conducted a literature review, and contacted a number of clinical investigators who have studied these drugs as well as representatives of Janssen and Sandoz pharmaceutical companies (the makers of risperidone and clozapine, respectively).

The literature search revealed several case studies reporting what was described as "rebounding psychosis" following discontinuation of clozapine and one controlled clinical trial comparing clinical symptomatology following abrupt discontinuation of chlorpromazine vs. clozapine. In the latter study, a subgroup of patients experienced symptom increases that exceeded the levels originally present. What have clinicians found? Several leading clinical scientists attending the workshop recounted their experience with clozapine discontinuation.

Some noted that patients might experience an increase in symptoms (following withdrawal of clozapine) more rapidly than with standard antipsychotic (AP) medications due to clozapine's shorter elimination half-life and the more rapid dissipation of its clinical effects. Investigators discussed several instances involving people abruptly discontinued from clozapine who then deteriorated clinically. In some cases, there were physical reactions including nausea, diarrhea, and other symptoms that might represent withdrawal of a medication with strong anticholinergic effects. Increases in schizophrenia symptoms, which in a few patients were reported to be more severe than those prior to beginning clozapine, were also reported by several clinical researchers.

It is not known whether worsening of clinical symptoms is more problematic when discontinuing clozapine than standard anti-psychotic medication, and there is very little hard data on this subject, a point emphasized by representatives of Sandoz and the FDA. Therefore, we cannot say with certainty that clinical deterioration is more rapid, severe, or frequent following abrupt clozapine discontinuation, despite anecdotal and small-sample evidence noted above. Additional clinical observations suggested that some patients recently taken off clozapine could also be at increased risk for developing extrapyramidal side effects (EPS). It was noted that some people who had never experienced severe EPS were quite sensitive to them as they were taken off clozapine, although this sensitivity was temporary. If such patients were switched to risperidone, there could be potential problems with the interpretation of these symptoms. Since much of the information on risperidone has emphasized its relative lack of EPS, motor side effects and excitement might be misinterpreted as a worsening of psychosis rather than akathisia, a form a EPS.

What do NAMI and Janssen say?

Dr. Dale Johnson, representing NAMI, indicated that NAMI too had heard reports of clinical deterioration in people removed from clozapine. He noted that a number of people with schizophrenia are bothered by the requirement for weekly blood drawing as well as the side effects of clozapine and may want to try new medications. In some cases, people may be subject to abrupt discontinuation of clozapine in order to switch to alternative treatments. Dr. Jennifer Hardin, representing Janssen, indicated that while many patients are now being treated with risperidone, clinical trials prior to marketing did not use large numbers of patients who had been treated with clozapine (or were non-responders to standard AP treatment), so they could not evaluate its value for such patients. Language in the risperidone packaging originally indicated that patients should be discontinued from other AP medications immediately before starting risperidone. Dr. Hardin noted that labeling instructions were being modified to indicate that patients beginning risperidone should no longer be rapidly discontinued from previous AP treatments. The package insert now states: There are no systematically collected data to specifically address switching from other antipsychotics to Risperdal, or concerning concomitant administration with other antipsychotics. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for other patients. In all cases, the period overlapping antipsychotic administration should be minimized....The need for continuing existing EPS medication should be reevaluated periodically.

What should consumers and families watch for?

To summarize, the NIMH recently brought together a group of psychopharmacology research experts to discuss reports of clinical deterioration (psychotic symptom increases, physical withdrawal symptoms, and EPS) in some individuals with schizophrenia who had been abruptly discontinued from clozapine. Consumers and families are reminded that the recommended withdrawal schedule for clozapine indicates that ONE TO TWO weeks should be expected for tapering off clozapine, and some clinical researchers have suggested longer taper durations.

SWITCHING FROM CLOZAPINE TO RISPERIDONE DOES NOT MEAN THAT SUCH TAPERING IS UNNECESSARY.

We have no evidence that risperidone is responsible for producing the clinical problems reported, as similar reactions have been described in some individuals abruptly discontinued from clozapine due to side effects (prior to the introduction of risperidone). Those who wish to try risperidone should also be aware that it may not produce all of the same benefits as clozapine, and it has not been proven effective for treatment-resistant schizophrenia. People who are doing well on clozapine and are able to tolerate its side effects may not be good candidates for clozapine discontinuation. Questions raised by family members about how best to make transitions from one treatment to another may now stimulate much-needed studies on these important issues and thereby help shape future research designs. by David Shore, M.D., and Jeffrey A. Lieberman, M.D. Note: Dr. David Shore is acting deputy director of the NIMH division of Clinical and Treatment Research in Rockville, MD, and clinical professor of psychiatry at Georgetown University Medical Center. Dr. Jeffrey Lieberman is a professor of psychiatry and co-director of the Clinical Research Center at Hillsdale-Long Island Jewish Medical Center and Albert Einstein College of Medicine in New York. Transmitted: 95-02-24 07:21:50 EST

RISPERIDONE Copyright 1993 National Alliance for the Mentally Ill

In two 8-0 votes, a panel of the U.S. Food and Drug Administration voted on April 29 that risperidone is safe and effective in treating schizophrenia. The medication, much cheaper than clozapine and without the dangerous side effect of agranulocytosis, could reach the American market in a matter of months.

The FDA is still negotiating with risperidone's manufacturer, Janssen Pharmaceutica, over guidelines for marketing the drug in the United States. Great Britain and Canada recently approved it, and Mexico is expected to do so shortly. Risperidone is said to reduce or eliminate psychosis and voices, and it does not appear to cause sedation, blurred vision, impaired memory, or muscle stiffness.

FDA approval of risperidone will mean that "thousands of young people suffering from the life-threatening illness (of schizophrenia) can have a chance to improve their lives -- lives that have been too often ended or totally devastated by its symptoms," declared Martin S. Willick, a psychiatrist, lecturer at Columbia University and NAMI member, at the FDA hearing.

Speaking "as a parent of a schizophrenic son whose life has been overwhelmingly affected by this disease," Willick noted that consumers, family members and mental health professionals were "enormously encouraged by the introduction of clozapine a few years ago. We have seen some dramatic improvements and very many good, though modest improvements." But hundreds of thousands of patients -- including his son -- did not sufficiently respond to clozapine or other medications. His son improved, but developed a potentially fatal blood complication, and had to stop taking clozapine. Still, "the improvement we saw...has given us hope that new drugs like risperidone will help him as well," Willick said.

Thousands of Dollars Cheaper

No price has yet been established for risperidone in the U.S., which will be sold under the brand name Risperdal. But it is expected to be cheaper than the average price of clozapine, which requires expensive weekly blood monitoring, and together the cost is more than $8,000 year. Risperdal is priced at less than $800 in Canadian dollars for a year's supply.

Clinical trials of risperidone have inspired cautious optimism. Wayne Fenton, MD and Beth Lee, RN at Chestnut Lodge Research Institute in Rockville, MD report that several patients who have not responded to other medications are responding well to risperidone. One of the patients at Chestnut Lodge said in a telephone interview that she began to feel better after two weeks of taking the medication. Now, after eight months, she feels like a different per son: "It's better than anything I've ever been on, and I've been on everything. I don't hallucinate any more. I don't have delusions or stereotyped thinking. I have a sense of humor now. I'm able to communicate with people. I have a life now," she exclaimed. Before risperidone, "I was pretty much a vegetable." She has a volunteer job now, and hopes to go back to school in the fall.

Between episodes of her illness, she attended medical school. "I want to catch up on lost time." One NAMI member from Tennessee who has taken risperidone for a year said in a telephone inter view that the medication has alleviated his depression and "I'm thinking about getting a job." Risperidone, he said, "is a pretty good medication, but I'm still looking for a better one. It has caused me to gain a lot of weight, and may be causing visual hallucinations." His doctor speculates that the hallucinations may result more from "the course of the illness than the risperidone," the NAMI member noted.

Not a Miracle Drug

But neither Lee, the nurse at Chestnut Lodge, nor Kenneth Jobsan, a psychopharmacologist in Knoxville, TN want to raise hopes too high. Some patients in Chestnut Lodge's relatively small study did not respond well to risperidone, Lee said, and Jobson said only a few of his patients have done better on it than on clozapine. Three people who took risperidone "had a brief dramatic response and then lost that response. We don't quite know why," Jobson said. Jobson did relate the story of a patient whose life may have been saved by risperidone. The patient had to stop taking clozapine when he was diagnosed with an aggressive lung cancer, for fear of dangerous complications between clozapine and chemotherapy. Risperidone was substituted while the patient underwent chemotherapy. Jobson said the lung cancer remains in remission, and the patient has felt much better on risperidone than he ever did on clozapine.

Families of people with schizophrenia have been anxious to see risperidone available on the U.S. market for more than a year. Many have expressed impatience with the FDA approval process. "Several times a week, we get calls from family members who are desperate because their relatives can't take clozapine or can't afford it. They want to know how they can get risperidone, and how soon other medications will be available," said NAMI Research Advocate James Cromwell. "We have to say, 'It's up to the FDA. But we are encouraged by the action of the advisory committee.'"

Other Drugs in Pipeline About 16 new medications to treat mental illnesses are in development, according to the Pharmaceutical Manufacturers Association. NAMI has asked the FDA to speed up its approval process for these drugs on the grounds that mental illnesses are "life-threatening diseases." Between 10 and 15 percent of patients with schizophrenia, for example, commit suicide. If the FDA put drugs to treat mental illness on a "fast track," they could be approved in six months. In testimony before the FDA, NAMI Legal Affairs Director Ron Honberg urged the FDA to ensure that "promising new treatments for (mental) disorders are made available to those who need them as quickly as possible."

The FDA should "place the same emphasis and priority on research and development of new treatments for schizophrenia as is put into finding cures for other devastating illnesses such as heart disease, cancer and HIV. The magnitude and impact of schizophrenia and other severe mental illness on society and on the individuals who suffer from them is as profound as any other disease affecting Americans today... "New medications can mean the difference between suicide or life-long suffering in back wards of state institutions on the one hand and opportunities to live meaningful, independent and productive lives in society on the other ... "These treatments will also lead to decreases in indirect costs related to dependence on entitlements and lost productivity," Honberg said.

RISPERIDAL HAS BENEFITS Copyright 1995 National Alliance for the Mentally Ill A recent study by Michael H. Konig, M.D., et al, revealed that persons with schizophrenia taking Risperidal (risperidone)--as compared with haloperidol and placebo--experienced fewer movement disorders such as rigidity and tremor, while still receiving relief for symptoms of schizophrenia. Write Dr. Konig at Hillside Hospital, 75-59 263rd Street, Glen Oaks, NY 11004. Transmitted: 95-05-16 15:17:11 EDT