No Reason to Prefer Atypical Antipsychotics over Older Drugs

MUNICH, Germany, Dec. 4 -- The common distinction between first- and second-generation antipsychotic drugs has no scientific basis and should be dropped, said researchers here.

A meta-analysis of 150 double-blind studies found little evidence that newer, so-called atypical antipsychotic drugs are more effective than older drugs for symptoms of schizophrenia, reported Stefan Leucht, M.D., of Munich Technical University, and colleagues online in The Lancet.

The researchers also found that although newer drugs induced fewer extrapyramidal effects than haloperidol (Haldol) that was not the case when compared with low-potency first-generation agents.

"Second-generation antipsychotic drugs differ in many properties" -- including structure and mode of action as well as clinical effects -- "and are not a homogeneous class," the researchers concluded.

"Improper generalization creates confusion and, as a result, the classification [of first- versus second-generation agents] might be abandoned," they said.

In an accompanying editorial, two British researchers went further, calling the notion that newer agents are more effective or safer than older drugs "spurious."

"As a group they are no more efficacious, do not improve specific symptoms, have no clearly different side-effect profiles than the first-generation antipsychotics, and are less cost effective," wrote Peter Tyrer, M.D., of Imperial College London, and Tim Kendall, M.D., Ph.D., of the National Collaborating Centre for Mental Health in London.

Both groups of researchers emphasized that these findings do not mean that all antipsychotics are alike.

Rather, as Dr. Leucht and colleagues put it, "This meta-analysis provides data that clinicians could use for individualized treatment of patients with schizophrenia based on efficacy, side-effects, and cost of antipsychotic drugs."

In their analysis, for each efficacy and adverse-effect outcome they studied -- overall symptoms, positive symptoms, negative symptoms, depression, extrapyramidal effects, weight gain, and sedation -- there was no clear pattern favoring newer over older drugs.

They did find that four second-generation agents were significantly more effective than older drugs. They were clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), and amisulpride (Solian, not approved in the U.S.).

Dr. Leucht and colleagues said their findings differed from some earlier meta-analyses partly because they excluded open-label studies that "systematically favored second-generation drugs."

More than half the studies they did include had a different type of bias, Drs. Tyrer and Kendall said -- they used haloperidol as the comparator.

Haloperidol has a high rate of extrapyramidal effects compared with other first-generation drugs.

The result, they suggested, was to make the newer drugs' side effect profile look better than if other comparators had been tested instead.

The researchers said that most of the second-generation drugs "have not been shown to be better than low-potency first-generation antipsychotic drugs [for extrapyramidal effects], and we noted a robust superiority based on more than two studies only for clozapine."

Weight gain is more of an issue for second- than first-generation drugs, they found.

In studies using haloperidol as the comparator, only aripiprazole (Abilify) and ziprasidone (Geodon) did not lead to more weight gain.

There was no difference in weight gain between any second-generation drug and other older agents, the researchers found.

For sedation, no clear pattern emerged to separate first- from second-generation agents.

Many of the results of the meta-analysis echoed those of the prospective CATIE study, in which three newer agents were compared with perphenazine. (See Old or New, Schizophrenia Treatments Modestly Effective)

Dr. Leucht and colleagues said the CATIE trial's use of a comparator other than haloperidol was a major strength and should be repeated in future studies.

They said trials should use mid-potency first-generation agents such as perphenazine as comparators "because they are less likely to cause extrapyramidal side-effects ... and they are not associated with sedation or weight gain."

They added that additional trials focusing on older drugs might be a good idea, "because they were not rigorously studied at the time they were introduced."

Said Drs. Tyrer and Kendall, "Clinicians must remember to keep the benefit-risk ratio of each antipsychotic drug in constant perspective because all are associated in different ways with serious adverse effects, which should be important outcome measures."

The National Institute of Mental Health funded the analysis. Dr. Leucht reported relationships with sanofi-aventis, BMS, Lilly, Janssen, Lundbeck, and Pfizer. Other study authors reported no potential conflicts of interest. Dr. Kendall reported involvement in an ongoing update of the schizophrenia guideline for the U.K. National Institute for Health and Clinical Excellence. Dr. Tyrer reported no potential conflicts of interest.

Primary source: Lancet
Source reference:
Leucht S, et al "Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis," Lancet 2008; DOI:10.1016/S0140-6736(08)61764-X.

Additional source: Lancet
Source reference:
Tyrer P, et al "The spurious advance of antipsychotic drug therapy," Lancet 2008; DOI:10.1016/S0140-6736(08)61765-1.
Additional Schizophrenia Coverage