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Meta-Analyses Blur Boundaries Between Antipsychotic Classes

15 December 2008. Taken together, two new meta-analyses argue that classifying antipsychotic drugs as “first-generation” or “second-generation” makes no scientific sense; each drug should be evaluated individually. Led by Stefan Leucht of the Technische Universität München in Munich, Germany, the studies examined head-to-head comparisons of individual drugs in the treatment of schizophrenia. In the December 5 cyber-version of Lancet, Leucht and colleagues find substantial heterogeneity in efficacy and side effects within each drug class and a lack of systematic differences between the two classes. The other study, published online in the American Journal of Psychiatry on November 17, suggests that individual second-generation drugs differ in efficacy against positive, but not negative, symptoms.

Even though second-generation antipsychotics (SGAs) cost considerably more than their off-patent predecessors, at least three-quarters of all antipsychotic prescriptions in the United States and Europe specify one of these newer drugs. Beliefs that these drugs work better against negative symptoms, such as blunted affect, social withdrawal, and low motivation, have helped fueled their rise. However, evidence that they minimize the risk of irreversible extrapyramidal side effects such as parkinsonism and other movement disorders have swayed prescribers as well.

No class-wide edge
Even so, some studies have cast doubts on SGAs’ supposed superiority (see SRF news story; news story; news story). In the Lancet study, Leucht—along with collaborators in Munich, Shanghai, Chicago, and Baltimore—compared drugs in both classes for their efficacy in the treatment of schizophrenia and their potential to cause side effects. They found that open-label studies “systematically favoured” SGAs, so they limited their meta-analysis to double-blind ones. Specifically, they examined 150 studies that enrolled 21,533 subjects who had schizophrenia or a related disorder.

The results suggest that only four SGAs—clozapine, amisulpride, olanzapine, and risperidone—relieve positive and negative symptoms better than first-generation antipsychotics (FGAs). The other SGAs studied—aripiprazole, quetiapine, sertindole, ziprasidone, and zotepine—worked only as well as FGAs against both kinds of symptoms.

When Leucht and colleagues sought to compare industry-sponsored versus other-sponsored studies, they found adequate data for only four SGAs. Clozapine and risperidone showed possible sponsorship effects; olanzapine and quetiapine did not. Dropping industry-sponsored studies from the analysis narrowed the efficacy advantage for clozapine and nixed it for risperidone.

All SGAs triggered fewer extrapyramidal side effects than haloperidol, the comparison FGA used in 95 of the studies. However, choosing haloperidol as the benchmark biases trials against FGAs, warns a Lancet editorial on the study. Peter Tyrer and Tim Kendall, of the Imperial College London and the Royal College of Psychiatrists’ Research Unit in London, note that this high-potency FGA seems highly prone to causing these side effects. They write, “On present evidence from all sources it is difficult not to conclude that the trials of the second-generation antipsychotics seem to be driven more by marketing strategy than to clarify their role for clinicians and patients.”

Results of the meta-analysis underscore their point. The few trials that tested low-potency FGAs, such as chlorpromazine, found that these drugs cause no more extrapyramidal side effects than most SGAs. Only clozapine, olanzapine, and risperidone produced fewer of these symptoms.

Metabolic disturbances like weight gain can threaten the health of people who take antipsychotic drugs (see SRF related news story; related news story). Again, the question of which drug class produces more side effects depends on the yardstick used. Compared to haloperidol, all SGAs except aripiprazole and ziprasidone added more pounds to patients. However, low-potency FGAs caused similar weight gain.

These findings remind us that what we find depends on where we look and the width of our lens. “Improper generalization creates confusion,” Leucht and colleagues note. They recommend dropping the classification scheme altogether. Instead, clinicians should weigh each drug’s own efficacy, side effects, and cost.

Class standouts—for efficacy, anyway
To help clinicians do so, another Leucht-led team tackled the question of which SGAs work best in schizophrenia. The researchers—who hailed from Temuco, Chile, as well as Chicago and Munich—conducted a meta-analysis of 78 trials that involved 13,558 subjects who had schizophrenia or a related disorder. They focused on randomized, blinded trials that directly compared the efficacy of at least two SGAs.

Using the Positive and Negative Syndrome Scale (PANSS) as the main outcome measure, the researchers found better results with olanzapine than with aripiprazole, risperidone, quetiapine, or ziprasidone. Amisulpride and clozapine worked as well as olanzapine. Risperidone outshone quetiapine and ziprasidone; clozapine surpassed only zotepine.

Since the individual drugs differed little in their effects on negative symptoms, their ability to control positive symptoms seemed to drive these findings. Although efficacy differences between drugs ranged from small to medium, Leucht and colleagues write, “Schizophrenia afflicts patients for life, and even a small benefit may be important.”

Evidence that olanzapine controls symptoms particularly well must be balanced against the drug’s minuses. Leucht and colleagues point out that olanzapine appears especially likely to cause metabolic side effects, such as weight gain and a rise in blood sugar.

Nearly 70 percent of the trials relied on drug companies as their main sponsor. Whether funding came from industry or other sources affected outcomes only for the matchup between clozapine and risperidone—the same drugs that hinted at sponsorship effects in the other meta-analysis.

Clozapine—still a special case?
It is often lamented in the clinical research community that clozapine, despite reported superiority to all other antipsychotic drugs, is not studied more. It certainly comes with the full baggage of metabolic side effects (see SRF related news story; related news story), and the potentially deadly side effects on the immune system are an important consideration, though close monitoring of white blood cells in patients is very effective. Tyrer and Kendall close with the statement, "The only second-generation antipsychotic that is obviously better than other drugs in resistant schizophrenia is clozapine." Despite the lack of a clear outcome in favor of clozapine in the American Journal of Psychiatry meta-analyses, Leucht and colleagues write, "In our opinion, clozapine is a more efficacious drug because it has consistently been shown to be more effective than first-generation antipsychotics (Davis et al., 2003; Geddes et al., 2000; Chakos et al., 2001), as well as other second-generation antipsychotics in CATIE Phase 2 and in the Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), which could not be included here (McEvoy et al., 2006; Stroup et al., 2006; Lewis et al., 2006)." The reason for the surprising lack of superiority in this meta-analysis, the researchers write, may relate to clozapine dosing—600 mg/day is deemed optimal, but most studies that were analyzed used lower doses. Leucht and colleagues suggest that further study of this topic is needed, particularly in treatment-resistant patients.

Beyond the clinical usefulness of these two meta-analyses, they argue against viewing "first-" and "second-generation" antipsychotics as homogeneous classes. As Tyrer and Kendall put it, “The time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction.”—Victoria L. Wilcox.

Leucht S, Komossa K, Rummel-Kluge C, Corves C, Hunger H, Schmid F, Lobos CA, Schwarz S, Davis JM. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry. Published online 2008 Nov 17. Abstract

Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: A meta-analysis. Lancet. Published online 2008 Dec. 5. Abstract

Tyrer P, Kendall T. The spurious advance of antipsychotic drug therapy. Lancet. Published online 2008 Dec. 5. Abstract

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