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Published online by Cambridge University Press:  02 January 2018

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Abstract

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Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Copyright © 2001, The Royal College of Psychiatrists

Oosthuizen and colleagues essentially repeat caveats outlined in the original article and make some more specific observations. The study by Kapur and co-workers (2000) appeared during the publication process of the article and so could not be included. This important trial of 22 patients with first-episode schizophrenia found that the likelihood of efficacy, hyperprolactinaemia and extrapyramidal symptoms increased significantly at striatal dopamine D2 receptor occupancies by haloperidol of 65%, 72% and 78%, respectively. However, the difference in occupancy between efficacy and adverse effects was said to correspond to less than 0.5 mg/day haloperidol for a given patient. Thus, although this study appears to have discovered a ‘therapeutic window’ for haloperidol, it is unlikely to be clinically relevant, especially given the inter-individual variability in occupancy in patients given the same dose and the impracticality of receptor occupancy evaluation in clinical practice. It may also explain why the trials cited in the original article could not separate therapeutic and adverse effects.

In regard to the study by McEvoy et al (1991), it is difficult to see how the findings were misrepresented. Of 106 subjects given haloperidol 2 mg daily, 49 (46%) showed “an increase in cogwheel rigidity from baseline” at this dose and 15 of these required a dose decrease because of “excessive rigidity”. Of 48 patients continued on the “neuroleptic threshold” dose, four were removed “due to severe EPSEs”. The study did suggest that increasing to dosage above the neuroleptic threshold “did not lead to greater improvement in measures of psychosis but… regularly lead to significant increases in distressing extrapyramidal side effects”. However, no justification is given for the numbers of subjects recruited, so equivalence in efficacy certainly cannot be assumed. Overall, this study demonstrated that extrapyramidal symptoms (albeit largely mild ones) were induced at very low doses of haloperidol; doses that were effective but that were by no means proven to be optimally so. Moreover, extrapyramidal side-effects and efficacy seemed again to be inexorably linked.

As your correspondents point out, this issue is far from resolved. However, the burden of proof surely now lies with those who support the continued wide-spread use of typical antipsychotics. If data relating to atypical drugs are to be scrutinised and criticised from every angle, then the sparse data supporting the existence of a ‘therapeutic window’ for typical antipsychotics are inevitably liable to potent censure. In this respect, it is noteworthy that Oosthuizen and colleagues present no cogent data to counter the conclusions of the original article but resort instead to vague and unsubstantiated accusations of bias.

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