Clozapine still stands out in schizophrenia Tx.

TUCSON, ARIZ. -- Clozapine and other atypical antipsychotic drugs offer potentially life-saving tools to help schizophrenia, but significant side effects--particularly weight gain--still make them far from perfect, reported Dr. Alan Gelenberg at a psychopharmacology conference sponsored by the University of Arizona.

A key advantage to these second-generation antipsychotics over typical drugs is their flexibility--the drugs don't constitute a specific class of their own. Instead, they work as very different, uniquely acting agents, unlike first-generation drugs, which are similar in how they work. Clinically, that means if a patient fails on one second-generation drug, there still may be success with another drug, explained Dr. Gelenberg, head of the department of psychiatry at the university, in Tucson.

Among the drugs, however, clozapine (Clozaril) stands out as having substantially better rates of response than standard agents and currently represents the "gold standard" in efficacy in treatment of schizophrenia, Dr. Gelenberg said.

He noted a large study showing a 57% response rate to clozapine among patients with acute schizophrenia, compared with a 36% response rate among standard drugs. And further research has shown that clozapine may be among certain drugs that can help--in ways yet to be discovered--to reduce the risk of suicide.

The thinking is that there may be anti-suicide properties of some medicines (including clozapine) that are different from their ability to treat the underlying disorder, he said. "This follows the suggestion that suicide in itself may be something independent from the disorder we're treating. We've certainly seen this in family tendencies, and we expect that we'll learn more about this as the human genome unfolds," Dr. Gelenberg said.

For all of clozapine's important benefits, there are the side effects. Weight gain and metabolic changes are significant problems with the drugs.

Studies show drugs such as clozapine and olanzapine (Zyprexa) can cause more than 10% weight gain, in addition to increasing the risk for diabetes, altering glucose metabolism and increasing patients' triglyceride levels as much as 39% (J. Clin. Psych. 62 Suppl. 21:7-10, 2001).

"This is a huge concern," he said. "You have people with chronic mental illness who may be spending much of their day watching TV and eating food, and that's the baseline--add weight gain from a drug on top of that and you can really have some weight, as well as lipid issues."

Dr. Gelenberg offered one bit of consolation in the form of research showing that with olanzapine, weight gain is primarily limited to the first year of use (J. Clin. Psychiatry 62[2]:92-100, 2001). "Once they make it past the first year, most of the weight gain has already occurred and it's not likely to get worse in subsequent years," Dr. Gelenberg said.

Not all antipsychotics carry as high a weight gain risk, and Dr. Gelenberg presented one study showing that drugs including molindone and ziprasidone, are among those with the lowest rates of weight gain (Am. J. Psychiatry 156[11]:1686-96, 1999).

Despite the side effects, Dr. Gelenberg emphasized that the alternative of going off the medications can have much more dire consequences, and he presented research showing that even when patients have had just one psychotic episode, the likelihood that there won't be a relapse without medication is extremely slim.

"Until a few years ago, the approach was to just wait and see after just one schizophrenic episode, but we're seeing now that even after that one episode, the chances of going without another are very small," Dr. Gelenberg said.

And while a number of research groups have been looking at targeted therapy approaches, maintenance therapy has been shown to be much more effective in controlling schizophrenic episodes.

To get the best outcome in balancing treatment while trying to keep side effects in control, use maintenance with the lowest possible dose of medication--but not down to zero. When relapses occur, that low dose should increase, he said.

Whether treating with regular or maintenance doses of antipsychotics, one must keep in mind the likelihood of substance abuse and how that can conflict with prescribed medication. "Comorbid substance abuse in people with schizophrenia and other chronic psychotic disorders is the rule--not the exception," Dr. Gelenberg stressed. "[Substance abuse] really complicates the treatment of these patients, and you need to assess whether abuse is coming into play."

BY NANCY A. MELVILLE

Contributing Writer