2006 overview: What was new in the psychopharmacological treatment of schizophrenia in 2006

In this year's summary of "what was new in the psychopharmacological treatment of schizophrenia" it is difficult to present new concepts of studies solving general treatment questions so I will mainly focus on some important new clinical trials.

In the February 2006 issue of the American Journal of Psychiatry Heres et al. (ref. 1) presented a review of head-to-head randomised comparisons of new generation antipsychotics showing that the drug company sponsoring the individual studies had a strong impact of the overall result of the study. While this "sponsor bias" had been known for a long time, Heres et al. demonstrated the effect in an elegant way.

After blinding the abstracts for the drugs used, two colleagues – one of them an internist who did not know much at all about antipsychotics – had to rate which drug was better and in 90% of the cases it was the sponsor's drug. A number of factors accounted for this effect and often it was only which parts of the results that were emphasized, but nevertheless the current situation is unsatisfying.

Although without the pharmaceutical industry, we would still be in the stone age, in these excellent studies the credibility suffers from many points of view.

Honer et al. (ref. 2) published a blinded study in which non-responders to clozapine either received risperidone or placebo added to clozapine. The addition of risperidone did not lead to higher efficacy. Although the study was published in the prestigious New England Journal of Medicine, it was small and a similar trial published in the American Journal of Psychiatry the year before had shown a beneficial effect Josiassen et al. (ref. 3). Although combinations of antipsychotics are frequently used in clinical practice, this area is completely under-researched in terms of randomised controlled trials.

The second part of the famous CATIE study in which drop-outs due to inefficacy in the first phase were randomised to four atypical antipsychotics or clozapine confirmed the superiority of clozapine in treatment resistant patients, although a limitation of the current study was that it was not blinded (ref. 4). Drop-outs due to side-effects were randomised  to either olanzapine, quetiapine, risperidone or ziprasidone. Olanzapine and risperidone were more efficacious than quetiapine and ziprasidone (ref. 5).

CUtLASS (ref. 6) was a British counterpart to the CATIE study. Here, patients with schizophrenia were randomised to either the group of atypical antispychotics or typical antipsychotics. The study was single-blind and funded by the government. Within these two classes switching was allowed. At the end of 1 year there were no significant difference in terms of the primary outcome quality of life, but also not in secondary outcomes, not even extrapyramidal side-effects.

One factor that may have contributed to this finding may have been that in the typical antipsychotic group sulpiride was chosen in about one third of the cases by the physicians. Sulpiride is very similar to amisulpride and may thus be a cheap atypical antipsychotic. In addition, switching between groups was also allowed limiting the interpretation of the findings.

Hugenholtz et al. (ref. 7) reviewed randomised controlled comparisons between atypical antipsychotics and haloperidol and found that in 80% of the cases the mean haloperidol doses used were above recommended doses by American and British formularies. They discussed that this may have biased the results in favour of the atypicals. But a problem is that the optimum haloperidol dose has never been well-defined. Therefore, the schizophrenia treatment guideline indicates a broad optimum haloperidol dose range between 2 and 20 mg/day.

Finally, Lecrubier et al. (ref. 8) published a comparison of olanzapine 5 mg, olanzapine 20 mg, amisulpride 150 mg and placebo in patients with schizophrenia and predominant ("primary") negative symptoms. Olanzapine 5 mg/day was the only drug dose that separated significantly from placebo. This study is worthwhile mentioning, because there is a dearth of studies in patients with primary negative symptoms – the only firm proof whether a compound has an effect on negative symptoms.

References

1. Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S. Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. American Journal of Psychiatry 2006; 163 (2); 185-194

2. Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, et al. Clozapine alone versus clozapine and risperidone with refractory schizophrenia. New England Journal of Medicine 2006; 354 (5); 472-482

3. Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. American Journal of Psychiatry 2005; 162 (1); 130-136

4. McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. American Journal of Psychiatry 2006; 163 (4); 600-610

5. Stroup TS, Lieberman JA, McEvoy JP, Swartz MS, Davis SM, Rosenheck RA, Perkins DO, et al. Effectiveness of olanzapine, quetiapine, risperidone, and ziprasidone in patients with chronic schizophrenia following discontinuation of a previous atypical antipsychotic. American Journal of Psychiatry 2006; 163 (4); 611-622

6. Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Archives of General Psychiatry 2006; 63 (10); 1079-1087

7. Hugenholtz GW, Heerdink ER, Stolker JJ, Meijer WE, Egberts AC, Nolen WA. Haloperidol Dose When Used as Active Comparator in Randomized Controlled Trials With Atypical Antipsychotics in Schizophrenia: Comparison With Officially Recommended Doses. Journal of Clinical Psychiatry 2006; 67 (6); 897-903

8. Lecrubier Y, Quintin P, Bouhassira M, Perrin E, Lancrenon S. The treatment of negative symptoms and deficit states of chronic schizophrenia: olanzapine compared to amisulpride and placebo in a 6-month double-blind controlled clinical trial. Acta Psychiatrica Scandinavica 2006; 114 (5); 319-327