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Question. My 18-year-old son was diagnosed schizophrenic two years ago. Currently hospitalized, he is receiving clozapine and Haldol as anti-psychotics and Paxil for depression. He was moved directly to clozapine from Risperdal and has gained over 60 lbs. in three months. I’ve heard that olanzapine acts much like clozapine, but with fewer side effects. Is it normal to move to “older” drugs before exhausting newer ones?

Answer. I appreciate how confusing some of these medication issues can be for parents and families of individuals with schizophrenia. Terms like “older” and “newer” can be confusing when applied to medications for psychosis or mood. For example, how “new” or “old” an antipsychotic is has more to do with marketing and approval processes than with how effective or safe it is.

Generally speaking, clinicians distinguish two broad groups of antipsychotic agents: older “typical” agents, also called neuroleptics, and the newer “atypical” agents. The latter group includes clozapine (Clozaril), the first atypical released; risperidone (Risperdal), which came out next; and then olanzapine (Zyprexa) and quetiapine (Seroquel). As a group, the atypicals are generally more effective for so-called negative symptoms of schizophrenia (apathy, social withdrawal), and are less likely to cause neuro-muscular problems like muscle spasms, stiffness, and abnormal movements (tardive dyskinesia).

However, the atypical agents are not without side effects. On rare occasion clozapine can cause a serious white blood cell problem called agranulocytosis, and it does tend to promote significant weight gain. On the other hand, many clinicians believe clozapine to be the most effective agent, old or new, for severe, refractory schizophrenia. Several studies do suggest clozapine is somewhat more effective than risperidone, though risperidone tends to have fewer side effects (such as weight gain). Olanzapine, as you note, is closely related to clozapine, but it is not yet known if it is as effective. Though olanzapine is generally better tolerated than clozapine and does not cause the white blood cell problem, it can also contribute to weight gain.

Regarding your son, many clinicians would argue that a failure to respond well to risperidone justifies a direct move to “the gold standard,” clozapine. Others (probably including me) might give olanzapine a try first, then go to clozapine. But this isn’t a matter of old vs. new as much as a matter of balancing risks and benefits on a case-by-case basis. The same applies to Paxil (which, compared to many agents on the market, is actually quite “new”). By the way, sometimes the older agents (such as haloperidol) are used to augment newer agents, as seems to be the case with your son.

To summarize, the changes in medication you have described aren’t “wrong,” but your son’s response is hard to predict. Clozapine certainly gives him a very good chance of recovery. The other atypical agent now available, quetiapine, has not really been compared in good studies with clozapine; my own impression is that quetiapine is a useful agent, but “no clozapine.” We are expecting yet another atypical agent, ziprasidone, in the next 6-10 months, and this agent appears to cause little if any weight gain. It may also have antidepressant properties, and could be useful for your son. But it’s not at all clear that it will out-perform clozapine.