Older Antipsychotics Not Ready for Retirement

Chlorpromazine was the first drug used to treat schizophrenia, having been introduced a half century ago. Other drugs have been developed since to alleviate some of that drug's side effects, but chlorpromazine remains in widespread use—and probably should be, given its low cost and familiarity, according to a systematic review issued by the Cochrane Collaboration.

Chlorpromazine's use was limited in large part by the movement disorders it produced as side effects among some patients, namely, parkonsonian syndromes or tardive dyskinesia.

Second-generation antipsychotics produce fewer movement-related side effects but may cause weight gain and other metabolic consequences, sometimes leading to diabetes.

“Reliable evidence about its short-term effects is surprisingly weak but information. .does suggest that chlorpromazine facilitates a global improvement and may decrease the likelihood of behaving in a disturbed manner, at least within the confines of [the] hospital,” wrote Clive Elliott Adams, M.B., of the Cochrane Schizophrenia Group and a professor of adult psychiatry and mental health services research at England's University of Leeds, and colleagues. The Cochrane Collaboration is an independent, international organization that evaluates medical research.

“There's no strong consensus in the field,” said William Carpenter, M.D., of the Maryland Psychiatric Research Center in Catonsville, Md., in an interview. Newer-generation drugs may offer slightly more efficacy, but they have a broader range of side effects even though they avoid some of the problems of first-generation drugs.

Still, those earlier drugs should not be ruled out, said the Cochrane reviewers.

They found 401 relevant studies, of which 99 reports of 50 randomized controlled trials comparing chlorpromazine with placebo met their inclusion criteria. The limited quality of some of the reported trials may overstate the benefits and underestimate the negative effects of using chlorpromazine, they noted. Lack of random allocation (68 percent) or reporting irrelevant outcomes (30 percent) largely accounted for exclusion from the review.

Even some included studies provided inadequate information about blinding methods, treatment withdrawals, or standard deviations. Dosage range also varied widely, from 25 mg/day to 2000 mg/day, adding another variable to psychiatrists' concerns.

Higher-than-necessary doses of the older neuroleptics make the side effects look worse, said Carpenter. “We still have virtually no information on optimal dosing, even after 50 years.”

Patients talking chlorpromazine improved generally and had less severe illness at the end of the trials, reported the Cochrane team, but “very few studies present usable data directly relating to end-point mental states.”

“Schizophrenia is a tough disease,” agreed Carpenter.“ You want to do something to help the patient get better, but there's little guidance.”

Most of the art in prescribing medications for schizophrenia revolves around ways to get patients to stay on their medications by choosing ones with a safer side-effect profile, he said.

The Cochrane review suggests not excluding the older drugs from the list of treatment possibilities.

“Chlorpromazine represents a low-cost choice for clinicians worldwide and merits its position as a benchmark treatment for psychotic symptoms,” concluded Adams and colleagues.

An abstract of “Chlorpromazine for Schizophrenia: A Cochrane Systematic Review of 50 years of Randomised Controlled Trials” is posted at<www.biomedcentral.com/1741-7015/3/15/abstract>.▪