Dr. Bob's Psychopharmacology Tips Biological Therapies in Psychiatry Alan J. Gelenberg, M.D.

New Antipsychotics

By coincidence, serendipity, and astute clinical observations, chlorpromazine (Thorazine and others) was recognized in the 1950s as a new and potent antidote for symptoms of psychosis. The "mother" of all antipsychotics, chlorpromazine spawned a family of similar agents. While their chemical structures, milligram potency, and side-effect liabilities varied, virtually all antipsychotics of this generation were comparable in what they could and could not do to combat the scourge of mental illness.

Clozapine (Clozaril) brought something new to the treatment of psychotic disorders. Synthesized in the 1960s and introduced into clinical research in the 1970s, clozapine was finally marketed in the United States in 1990. It is unquestionably superior in efficacy to drugs of the first generation, and it has a much lower risk of producing extrapyramidal disorders. But it carries a host of potentially lethal risks, including agranulocytosis, seizures, and cardiorespiratory complications, as well as a number of annoying side effects, such as weight gain.

Determining what makes clozapine a superior neuroleptic and how to reproduce its benefits without its many untoward effects has remained an elusive goal. Many pharmaceutical companies have spent much time and money in the pursuit of a better and safer neuroleptic. Clues about clozapine's unique pharmacologic effects have led to drugs that reproduce some of its brain receptor activity -- including its blockade of serotonin receptor subtypes and its unique actions at various dopamine receptors.

Risperidone (Risperdal) was introduced in 1994. In the lower dosage range, risperidone causes fewer extrapyramidal effects than typical antipsychotics. While it appears to be equal in efficacy to first generation agents, it may not be as effective as clozapine -- particularly in treatment-resistant patients. Nonetheless, it has been a welcome addition to the antipsychotic armamentarium. Now, two more atypical neuroleptics have been introduced in the United States -- both serotonin-dopamine antagonists -- olanzapine (Zyprexa) and sertindole (Serlect).

Olanzapine has a relatively high affinity for muscarinic, anticholinergic, 5-HT-2, and dopamine D-1, D-2, and D-4 receptors. (1) Its blockade at alpha-2 receptors is weaker than that of clozapine or risperidone. Like typical neuroleptics, but unlike clozapine, it produces a modest rise in prolactin levels.

In a study of patients suffering acute exacerbations of schizophrenic psychosis, doses of olanzapine between 7.5 and 17.5 mg/day were comparable in antipsychotic effect to haloperidol (Haldol and others), 10 to 20 mg/day, and superior to placebo. (2) High doses of olanzapine (12.5 to 17.5 mg/day) did better than low doses (2.5 to 7.5 mg/day) and produced superior results against negative symptoms compared with haloperidol. On the down side, more subjects taking a high dosage of olanzapine had elevated serum glutamic-pyruvic transaminase than those taking placebo or haloperidol. High-dose olanzapine also produced greater elevations in prolactin levels than placebo but less than haloperidol.

Dystonia occurred in 13% of haloperidol-treated patients, but in no patient taking olanzapine at any dosage. The most common side effects with olanzapine are agitation, nervousness, headache, insomnia, anxiety, somnolence, dizziness, weight gain, and dyspepsia. Anticholinergic effects, such as constipation and dry mouth, and liver enzyme elevation occur more at the higher doses of olanzapine, which are also associated with an increased need for antiparkinson medications. (2, 3)

Like olanzapine, sertindole is a potent blocker of cortical 5-HT-2 and dopamine receptors. Efficacy at a dose of 20 mg/day is superior to placebo and comparable to haloperidol, 16 mg/day. (2) Extrapyramidal effects with 20 mg/day of sertindole occurred in only 1.9% of patients compared to 20.9% of patients taking haloperidol. Moreover, while 7.6% of haloperidol-treated patients required benztropine (Cogentin and others), none of the sertindole-treated patients required this antidote. Akathisia became more severe in haloperidol-treated patients but actually improved among those taking sertindole. Common side effects with sertindole, 20 mg/day, were nasal congestion, abnormal ejaculation, and somnolence. Fewer than 5% of subjects experienced threefold or greater elevations in liver function tests.

A concern with sertindole is that it can prolong the cardiac QT interval. Although this effect is usually clinically nonsignificant, in patients with a congenitally long QT interval or in those taking other drugs that can slow cardiac conduction, it could lead to a potentially fatal ventricular arrhythmia, such as torsade de pointes. As of June 1, 1996, twenty-seven deaths had occurred among 2194 patients participating in sertindole trials: 16 of these were due to adverse cardiac events and 13 were "sudden deaths," which occurred without warning. (4)

Clinical trials that lead to the approval of a new drug are typically conducted in highly selective patient populations -- ie, patients without comorbidity from medical illnesses, substance abuse, or other "real-life" problems. Once a drug is available for use in clinical practice, we tend to learn much more about it.

For olanzapine, sertindole, and other antipsychotics soon to come, many questions remain. How will they compare to typical neuroleptics, clozapine, and one another in difficult-to-treat psychotic populations? How often will they produce extrapyramidal effects at higher doses? Or, put another way, what is the dose-response relationship for efficacy compared to the dose-response relationship for producing extrapyramidal effects? Will they cause tardive movement disorders or the neuroleptic malignant syndrome? With what frequency? Will they have withdrawal reactions? How dangerous will sertindole's cardiac effects be? Will occasional patients experience serious hepatotoxicity with olanzapine? (In selected patients, the physician should consider electrocardiographic monitoring with sertindole and liver function tests with olanzapine.) What about drug interactions? Are there any rare but serious hazards of which we are not yet aware?

As of this writing, olanzapine at a dose of 10 mg/day is slightly less expensive than risperidone, 6 mg/day, but will be more expensive than risperidone if the usual daily dose is 20 mg. Prices for sertindole are not yet available, but we expect it also will be priced competitively with risperidone.

Psychoses are serious and debilitating conditions, causing profound suffering to patients and their loved ones. Not surprisingly, there is great eagerness for new agents and hope that they will bring greater relief with fewer complications. But they are expensive, and there are many uncertainties. We are reminded of Ben Franklin's admonition to "make haste slowly." Or, in the words of Sir William Osler, "Do not rashly use every new product of which the peripatetic siren sings."

1. Moore NA: Is the "A" in atypical really due to alpha(2)-adrenoceptor antagonism? J Psychopharmacol 1995; 9: 155.
2. Borison RL: Clinical efficacy of serotonin-dopamine antagonists relative to classic neuroleptics. J Clin Psychopharmacol 1995; 15(Suppl 1): 24S-29S.
3. Beasley CM, Tollefson G, Tran P, Satterlee W, Sanger T, Hamilton S, Fabre L, Small J, Ereshefsky L, True J, Nemeroff C, Risch SC, Perry PJ, Potkin SG, Borison RL, James S, Meltzer HY, Iqbal N, Fann WE, Gewirtz GR, Landbloom R, Roy-Byrne PP, Tuason VB, Carman JS, Stokes PE: Olanzapine versus placebo and haloperidol: Acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996; 14: 111-123.
4. Barnett AA: Safety concerns over antipsychotic drug, sertindole. Lancet 1996; 348: 256.

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Original article copyright 1996 Biological Therapies in Psychiatry.
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