Second-Generation Antipsychotics Not All Superior to Older Drugs

Marlene Busko

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January 2, 2009 — A meta-analysis finds that only 4 of 9 second-generation antipsychotics were more efficacious than first-generation antipsychotics for schizophrenia, with small to medium effect sizes.

In addition, the classification system of typical, first-generation vs atypical, second-generation antipsychotics "creates confusion" and "might be abandoned," the study authors, led by Stefan Leucht, MD, from the Technical University of Munich, in Germany, write.

"Because the second-generation antipsychotic drugs differ in many properties, including efficacy, side effects, cost (some are now generic), and pharmacology (amisulpride is not a serotonin-receptor blocker), they do not form a homogeneous class, and neither do first-generation drugs," they note.

Rather, when choosing a treatment for a patient, clinicians need to look at a patient's history and at a drug's risk/benefit profile and cost. "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," they write.

The study is published in the January 3 issue of the Lancet.

High-Cost, Newer Drugs

The high cost of second-generation, atypical antipsychotics for schizophrenia — with sales of $7.5 billion in the United States in 2003 — has generated continuing debate about whether these drugs are truly better than first-generation compounds, the authors write. Previous meta-analyses have not thoroughly assessed the drugs' adverse effects, and new studies have not yet been included in meta-analyses.

To compare the effects of second-generation antipsychotics with first-generation antipsychotics for schizophrenia, the authors conducted a meta-analysis of 150 double-blind, randomized controlled trials with 21,533 participants.

The studies were mainly short-term, lasting for 12 weeks or less, with only a few studies longer than 6 months.

The trials looked at 9 second-generation antipsychotics: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, and zotepine.

Haloperidol was the first-generation antipsychotic comparator in 95 studies. The other first-generation comparators included chlorpromazine (28 studies), perphenazine (5), fluphenazine (4), and several other drugs investigated in 3 or fewer studies.

The trial outcomes included overall efficacy, positive symptoms, negative symptoms, depression, quality of life, antiparkinsonian medication (a surrogate for extrapyramidal adverse effects), sedation, and weight gain.

Differences in Efficacy, Adverse Effects

Four of 9 second-generation antipsychotics (amisulpride, clozapine, olanzapine, and risperidone) were more effective than first-generation drugs for overall and positive and negative symptoms.

"Importantly for the notion of atypicality, the other 5 second-generation antipsychotic drugs (ie, aripiprazole, quetiapine, sertindole, ziprasidone, and zotepine) were not more effective than first-generation drugs for treatment of negative symptoms," the researchers write.

Only amisulpride, clozapine, and sertindole rated better than first-generation drugs for quality of life, in the few studies where this was investigated.

All second-generation drugs induced fewer extrapyramidal adverse effects than haloperidol (even at low doses), but only clozapine, olanzapine, and risperidone had induced fewer extrapyramidal adverse effects than low-potency, first-generation antipsychotics.

On the other hand, all second-generation drugs except aripiprazole and ziprasidone were associated with more weight gain than haloperidol. Weight gain was similar, however, among second-generation drugs and low-potency, first-generation drugs.

"Public institutions could save costs by funding studies to accurately define selected old compounds, because they were not rigorously studied at the time they were introduced," the researchers write.

Two Decades of Misguided Beliefs

The meta-analysis by Leucht and colleagues, supported by some "powerful" studies, "shows that the name second-generation antipsychotics is inaccurate," Peter Tyrer, MD, from Imperial College London, and Tim Kendall, MD, Royal College of Psychiatrists' Research Unit, in London, the United Kingdom, write in an accompanying editorial.

"Importantly, the second-generation drugs have no special atypical characteristics that separate them from the typical or first-generation antipsychotics," they write.

"But how is it that for nearly 2 decades we have, as some have put it, 'been beguiled' into thinking they were superior?" they ask.

The study by Leucht and colleagues provides some clues, they suggest. First, of the 150 trials, 95 compared second-generation drugs with the highly potent, first-generation drug haloperidol, which was likely to be associated with a high rate of extrapyramidal adverse effects. Also, the trials used high doses of the first-generation drug, again leading to more adverse effects from the older drug.

"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," Dr. Tyrer and Dr. Kendall write.

"The time has come to abandon the terms first-generation and second-generation antipsychotics, as they do not merit this distinction," Drs. Tyrer and Kendall conclude. The only second-generation drug that is "obviously better than other drugs in resistant schizophrenia is clozapine, and it is a very old drug indeed."

Second, they note, clinicians should keep the benefit/risk ratio of each antipsychotic drug in "constant perspective."

"Finally, it is prudent to remember that although science rules during a drug's development, the market usurps control once the drug is released for care of patients," they conclude.

Dr. Leucht has received speaker and consultancy honoraria from Sanofi-Aventis. The financial disclosures for the other authors are listed in the paper. The study was funded by the National Institute of Mental Health. Dr. Tyrer has no financial conflict of interest. Dr. Kendall is involved in updating the schizophrenia guidelines for the National Institute for Health and Clinical Excellence, including a review of antipsychotic drugs in the treatment of schizophrenia.