NEWS & ANALYSIS

Study shows newer treatments no more effective than old

Findings provide clues as to what targets future drugs should avoid.

The first of the newer treatments, known Michael Spedding, Deputy Director of Research Simon Frantz as ‘atypical’ antipsychotics, was clozapine, at Servier. “The trial shows that the wave of A recent study provides evidence that ‘sec- which was discovered almost 50 years ago. newer treatments hasn’t brought about as great ond-generation’ schizophrenia treatments But clozapine, considered the gold-standard a revolution as the first one, but work needed are little better than their older counterparts treatment for schizophrenia in view of its effi- to develop the second-generation compounds (Lieberman, J. A. et al. N. Engl. J. Med. 353, cacy, causes a host of adverse effects, includ- has generated a lot of mechanistic research 1214–1223; 2005). But researchers say there’s ing the blood disorder agranulocytosis, which that has been important in understanding potentially a silver lining in these cloudy find- has limited its prescription to around 10% of schizophrenia,” says Spedding . ings — understanding why these drugs aren’t schizophrenia patients. Spedding says that looking for a third gen- much of an improvement could help make Identifying the secret to clozapine’s effec- eration of treatments will also require better future treatments safer and more effective. tiveness has been difficult, as the drug binds to models. “Screening compounds with these new The CATIE trial, which was funded by the tens of receptors. So researchers made educated models will help us find compounds that are National Institutes of Health, pitted perphena- guesses as to what could be the key receptors quite different from the current batch.” zine, a generic drug available since the 1950s, responsible for clozapine’s efficacy — mainly The NIH is ploughing more funds into head-to-head against olanzapine (Zyprexa; based on the fact that it has weaker dopamine this area, and together with industry, will test

Lilly), quetiapine (Seroquel; AstraZeneca), ris- D2 receptor antagonism and stronger antago- compounds that are approved for use in human peridone (Risperdal; Janssen Pharmaceutica) nism at serotonin 5-HT2A receptors than the research in proof-of-principle studies for cogni- and ziprasidone (Geodon; Pfizer). Olanzapine older treatments — and designed what they tive improvements. The NIH is also beginning performed moderately, yet significantly, better hoped were better drugs with greater selectivity an initiative to find predictors of metabolic than perphenazine, but as a whole the research- for these receptors. problems in individual patients that could be ers saw no substantial advantage in the newer Of the newer drugs, the most successful in used by pharma to refine drug development. medications. the trial, olanzapine, behaves more like clozapine There’s no lack of focus on the problem, There is a potential downside in immedi- than its more targeted contemporaries quetiap- says Roth. “We now know what targets to ately switching to older, cheaper generic treat- ine, risperidone and ziprasidone. “We can infer avoid — now we’re taking a bet on what targets ments though, as there were large differences in that hitting a multiplicity of molecular targets is to add.” patient’s responses to the newer drugs. “What probably better than just targeting two, which is works for one person may not work for another,” what all the other drugs were mainly designed said Jeffrey Lieberman, Principal Investigator of to do,” says Bryan Roth, Director of the National “Understanding why these drugs the CATIE trial and Chair of the Department of Institute of Mental Health Psychoactive Drug aren’t much of an improvement , and Director Screening Program. “The question is what will could help make future treatments of the New York State Psychiatric Institute. make these compounds better — olanzapine’s safer and more effective.” But even taking this into account, the study is so complex.” shows clearly that the newer generation of anti- It’s not just the hunting for how these drugs psychotics isn’t the success it was hoped to be. work that is proving to be a headache. Side effects were a problem in the study: three- quarters of the patients switched medications, and olanzapine was linked to weight gain and unwelcome metabolic changes. It has been proposed that the metabolic

effects could be due to blocking H1 histamine

and 5-HT2C serotonin receptors, which evi- dence suggests can affect appetite. And there are genetic effects too. Lilly has presented unpub- lished data from a whole-genome-wide scan of 1 million single-nucleotide polymorphisms (SNPs), which shows that a huge number of SNPs have a small effect in weight gain, making the detection of causative genes difficult. Although the metabolic effects are proving difficult to anticipate, it would be regrettable if the study results had a negative effect on indus- try’s efforts in schizophrenia research, says

872 | NOVEMBER 2005 | VOLUME 4 www.nature.com/reviews/drugdisc © 2005 Nature Publishing Group