On the benefits of antipsychotics in schizophrenia - by Paul Hutton

In a long-awaited publication, Ho and colleagues (2011)¹ report that antipsychotic use in schizophrenia is associated with a progressive reduction in cortical tissue. Both Ho et al and Lewis (2011)² argue the risks must be weighed against the benefits. This raises several questions.

First, what are the benefits? One Cochrane review published last year (to little fanfare) found the multi-billion dollar drug risperidone to be not much better than placebo,³ describing the evidence for its effectiveness as “unconvincing”. Another found little evidence to suggest antipsychotics were better than benzodiazepenes.⁴ A meta-analysis by Leucht and colleagues, published in 2009, found only a moderate superiority of atypicals over placebo,⁵ but 18 of the 38 included studies were missing over half their outcome data. In most cases this data was replaced by using the now discredited⁶ approach of carrying last observation forward; an approach likely to bias outcomes in favour of the active treatment when fewer people leave active treatment early (a well- observed finding in antipsychotic trials but not necessarily attributable to antipsychotic efficacy). A recent survey found consultant psychiatrists, carers and Cochrane researchers agreed that trials with over 25% missing data “lack credibility”⁷ - only 5 comparisons from 4 trials (none of which were long-tem) included in Leucht et al met this criterion, three of which showed no benefit of antipsychotics over placebo. An interesting meta-regression found the superiority of antipsychotics over placebo diminishes as the probability of being randomised to placebo decreases,⁸ a finding consistent with the hypothesis that expectancy and unblinding due to side-effects leads to inflated estimates of drug effectiveness.⁹ Similar results have been found for trials of antidepressants in depression,¹⁰ where a Cochrane review found effect sizes to be much lower in trials which use active placebos to hide the giveaway side-effects of these drugs.¹¹

Indeed, Harrow & Jobe (2007)¹² found that people with a schizophrenia diagnosis who chose not to take antipsychotics had better long-term functioning than those who did. An editorial in this months British Journal of Psychiatry convincingly rebutts the claim that antipsychotics have neuroprotective properties,¹³ while a recent neuroimaging study found that haloperidol given to healthy volunteers produced the fastest (reversible) reduction in brain volume ever seen.¹⁴ Furthermore, a prescient meta-analysis found that brain changes normally attributed to schizophrenia may in fact be caused by antipsychotic use¹⁵ while Vinogradov et al., (2009)¹⁶ reported that greater anticholinergic burden (due to antipsychotics and other psychotropic medications) is associated with a poorer response to intensive computerised cognitive training. Given the above, is it now time for a systematic reappraisal of the benefits of these drugs?

Second, who will be in charge of weighing the risks and benefits? Are psychiatrists going to routinely discuss the dose-related non-trivial risk of sudden cardiac death¹⁷ and progressive loss of cortical tissue associated with these drugs with service users who retain treatment decision-making capacity (i.e., the majority)? Even if tissue loss is evidence of benefit, are service users going to be encouraged to decide if they want to wager their cortical tissue on this being true? Given 74% of service users discontinue antipsychotic medication over 18 months,¹⁸ are their psychiatrists also going to inform them that around 5 will need treatment for 1 to have a clinically significant improvement above placebo, as claimed by Leucht et al?

Finally, in her New York Times interview* , Professor Andreasen argued the findings implied there was a need for greater use of cognitive and social therapies (interventions which appear to be highly acceptable to most service users¹⁹). This recommendation is missing from Ho et al but are they willing to make it now?

*http://www.nytimes.com/2008/09/16/health/research/16conv.html, accessed 13th February, 2011.

References

(1) Ho, B., Andreasen, N. C., Ziebell, S., Pierson, R., & Magnotta, V. Long-term antipsychotic treatment and brain volume: A longitudinal study of first-episode schizophrenia. Archives of General Psychiatry, 68, 2, 128-137.

(2) Lewis, D. A. (2011). Antipsychotics and brain volume: Do we have cause for concern? Archives of General Psychiatry, 68, 2, 126-127.

(3) Rattehalli, R. D., Jayarami, M. B. & Smith, M. (2010). Risperidone versus placebo for schizophrenia. Cochrane Database of Systematic Reviews 1. (http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006918/pdf_fs..... Accessed 4th April 2010

(4) Volz A, Khorsand V, Gillies D, Leucht S. Cochrane Database of Systematic Reviews 2007; 1. Benzodiazepines for schizophrenia. (http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD000967/pdf_fs..... Accessed 4th April 2010

(5) Leucht, S., Arbter, D., Engel, R. R., Kissling, W. & Davis, J. M. (2009a). How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Molecular Psychiatry 14, 429- 447.

(6) Hamer RM, Simpson PM. Last observation carried forward versus mixed models in the analysis of psychiatric clinical trials (Editorial). American Journal of Psychiatry 2009; 16: 639-641.

(7) Xia J, Adams C, Bhagat N, Bhagat V, Bhoopathi P, El-Sayeh H, Pinfold V, Takriti Y. Losing participants before the end of the trial erodes credibility of findings. Psychiatr Bull 2009; 33: 254-257

(8) Mallinckrodt, C. H., Zhang, L., Prucka W. R., & Millen, B. A. (2010). Signal Detection and Placebo Response in Schizophrenia: Parallels with Depression. Psychopharmacology Review, 43, 1, 53-72.

(9) Colagiuri B. (2010). Participant expectancies in double-blind randomized placebo-controlled trials: potential limitations to trial validity. Clin Trials, 7, 246-255.

(10) Papakostas, G. I., & Fava, M. (2009). Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. European Neuropsychopharmacology, 19, 34-40.

(11) Moncrieff, J., Wessely, S., & Hardy, R. (2004). Active placebos versus antidepressants for depression. Cochrane Database of Systematic Reviews 2004; 1. (http://onlinelibrary.wiley.com/o/cochrane/clsysrev/articles/CD003012/pdf_fs.h.... Accessed 13th February 2011.

(12) Harrow, M., & Jobe, T. H. (2007). Factors involved in outcome and recovery in schizopohrenia patients not on antipsychotic medications: A 15-year follow-up study. Journal of Nervous and Mental Disease, 195, 5, 406-414.

(13) Moncrieff, J. (2011). Questioning the ‘neuroprotective’ hypothesis: does drug treatment prevent brain damage in early psychosis or schizophrenia? (Editorial).British Journal of Psychiatry, 198, 85-87.

(14) Tost, H., Braus, D. F., Hakimi, S., Ruf, M., Vollmert, C., Hohn, F., & Meyer-Lindenberg, A. (2010). Acute D2 receptor blockade induces rapid, reversible remodeling in human cortical-striatal circuits. Nature Neuroscience, 13, 920-922.

(15) Moncrieff J, Leo J. (2010). A systematic review of the effects of antipsychotic drugs on brain volume. Psychological Medicine, 40, 1409 –22.

(16) Vinogradov, S., Fisher, M., Warm, H., Holland, C., Kirshner, M. A., & Pollock, B. G. (2009). The cognitive cost of anticholinergic burden: Decreased response to cognitive training in schizophrenia. American Journal of Psychiatry, 166,1055-1062.

(17) Ray, W. A., Chung, C. P., Murray, K. T., Hall, K. & Stein, M. (2009). Atypical anstipsychotics drugs and the risk of sudden cardiac death. The New England Journal of Medicine 360, 225-235.

(18) Lieberman. J. A., Stroup, S., McEvoy, J. P., Swartz, M. S., Rosenheck, R. A., Perkins, D. O., Keefe, R. S. E., Davis, S. M., Davis, C. E., Lebowitz, B. D., Severe, J., Hsiao, J. K. (2005). Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. New England Journal of Medicine, 353, 1209-1223.

(19) Villeneuve, K., Potvin, S., Lesage, A., & Nicole, L. (2010). Meta-analysis of rates of drop-out from psychosocial treatment among persons with schizophrenia spectrum disorder. Schizophrenia Research, 121, 266-270.

Conflict of Interest:

I am a research clinical psychologist within the UK National Health Service (NHS). I provide psychological treatments to people experiencing psychosis within the context of various research trials, all of which are NHS-funded. One of these trials involves the provision of cognitive behavioural therapy to people who are experiencing psychosis yet have refused or declined antipsychotic medication for a period of at least 6 months (http://www.controlled-trials.com/ISRCTN29607432). I have received no financial renumeration from pharmaceutical companies.

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