Methodological considerations on the comparison of first and second generation antipsychotics

LETTERS TO THE EDITORS

Methodological considerations on the comparison of first and second generation antipsychotics

Robert Rosenheck

New Haven, CT

Mr. editor,

Drs. Silva de Lima and Garcia de Oliveira Soares suggest that, in view of the large number of studies of second generation antipsychotics (SGAs) that have been conducted over the years, our finding of limited benefit for olanzapine as compared to haloperidol may be attributable to chance. This assertion rests on the assumption that all the studies of SGAs, including ours, used the same methodology. We believe that it is such methodological differences that explain the differences in results. The most revealing outcome difference between our study and the International Collaborative Trial (ICT),¹ the major study of olanzapine, is that while adherence to olanzapine was the same in both studies adherence to haloperidol was far superior in ours, almost certainly because we used prophylactic anticholinergics with haloperidol while the ICT use anticholinergics on an "asneeded" basis, for only 50% of patients.

While this could clearly explain the lack of differences in Parkinsonian side effects, could it also explain the difference in symptoms? First it should be pointed out that the ICT found no significant difference between olanzapine and haloperidol on positive symptoms, but only on negative symptoms and depression.¹ Furthermore, as we pointed in our paper these symptom findings may have been an artifact of two serious methodological flaws that appear in the ICT and many studies of SGAs: 1) failure to continue to collect outcome data until the end of the trial on all subjects including those who changed medication, combined with 2) use of last observation carried forward (LOCF) analysis.

In addition, there is an extensive literature showing that one extrapramidal symptom, akinesia, can be indistinguishable from negative symptoms of schizophrenia and depression.² and this EPS side effect could explain the differences between our study and the ICT. In a recent meta-analysis, Leuct found SGAs to have lower relapse rates than first generation antipsychotics (FGAs).³ However, 91% of the studies in this meta-analysis used haloperidol as the comparator and only 20% of these prescribed prophylactic anticholinergics. Reanalysis of these data shows that only when haloperidol was used without prophylactic anticholinergics there was risk of relapse, all cause failure and early termination less with SGAs than with haloperidol.

But could this meta-analysis of only 10 studies be generalizable to the many other studies of SGAs? A much larger meta-analysis involving 124 studies by Davis et al.⁴ showed that two-thirds of all controlled trials of SGAs used haloperidol without prophylactic anticholinergics as the comparator, and thus were likely to have been seriously biased as noted above.

Taking all of the more than130 studies reviewed in three large meta-analyses together,^3-5 about two-thirds of the studies gave an unfair advantage to SGAs by comparing them with haloperidol without prophylactic anticholinergics, while the remainder, using low potency FGAs, did not find a robustly significant advantage for SGAs.

Drs. Silva de Lima and Garcia de Oliveira Soares also suggests that our study was under-powered and unrepresentative. We presented a power analysis in the methods section showing the first claim to be unlikely. We have also reanalyzed the data using only younger subjects and found the same results.

References

1. Tollefson GD, Beasley Jr CM, Tran PV, et al. Olanzapine versus haloperidol in the treatment of schizophrenia and schizoaffective and schizophreniform disorders: results of an international collaborative trial. Am J Psychiatry 1997;154:457-65.

2. Van Putten T, Marder SR. Behavioral toxicity of antipsychotic drugs. J Clin Psychiatry 1987;48 Suppl:13-9.

3. Leucht S, Barnes TR, Kissling W, Engel RR, Correll C, Kane JM. Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials. Am J Psychiatry 2003;160:1209-22.

4. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 2003 60:553-64.

5. Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 2003;361:1581-9.

Publication Dates

• Publication in this collection
  28 Oct 2004
• Date of issue
  June 2004