Antipsychotic Use Questioned for Developmentally Disabled

Two new studies of antipsychotic efficacy for nonpsychotic behaviors in persons with developmental disability provide data where there has been relatively little, but their contrary findings leave this a controversial use of medication. A retrospective study published in the February Journal of Intellectual Disability Research suggests that atypical antipsychotics reduce aggression but not self-injurious behavior (SIB),¹ while a randomized controlled trial published in The Lancet in January could not distinguish atypical or traditional neuroleptic antipsychotics from placebo for effects on aggression.² In the placebo-controlled, multi-site trial of haloperidol (Haldol) and risperidone (Risperdal) in 86 nonpsychotic persons with developmental disability (DD) and aggressive, challenging behavior, aggression decreased substantially with all 3 treatments by 4 weeks. Peter Tyrer, FMed Sci, of the department of psychological medicine, Imperial College, London, and colleagues point out that the placebo group showed the greatest numerical reduction in aggression scores on the Modified Overt Aggression Scale (MOAS)-although scores were not statistically significantly greater.

"Furthermore, although no important differences between the treatments were recorded, including adverse events," Tyrer and his coauthors observed, "patients given placebo showed no evidence at any time points of worse response than did patients assigned to either of the antipsychotic drugs."

The investigators acknowledged that their results counter previous studies with risperidone that have demonstrated its efficacy relative to placebo for nonpsychotic behaviors in persons with DD^3,4 but claim that their sample was more representative of this population, with more participants having moderate and severe intellectual disability. They also considered that larger daily doses than their mean 1.78 mg of risperidone and 2.94 mg of haloperidol might have produced different effects but commented that "they would have had to be very great indeed to be significantly better than the substantial improvement shown with placebo after 4 weeks."

In an accompanying commentary, Johnny Matson, PhD, and Jonathan Wilkins, both from the department of psychology, Louisiana State University, Baton Rouge, characterized the use of antipsychotics for aggression or SIB in DD to be "one of the most controversial issues in mental health."⁵ They joined Tyrer and colleagues in arguing against the routine use of antipsychotics for this purpose and called for greater attention to environmental functions of aggression such as attention seeking or escape from demands.

From the retrospective study in 31 participants in a state developmental center, Stephen Ruedrich, MD, of the department of psychiatry at Case Western Reserve School of Medicine, Cleveland, and co-investigators determined that both atypical and neuroleptic antipsychotics were useful in reducing the frequency of aggression but not of SIB over 1 year of treatment.¹ They conducted the study to assess the utility of newer antipsychotics relative to traditional neuroleptics; they identified 31 records of persons with DD and aggression and/or SIB, with 23 having received risperidone, 7 olanzapine (Zyprexa), and 1 quetiapine (Seroquel).

Ruedrich and colleagues found that the number of aggressive events per month during the year were significantly reduced in patients receiving an atypical antipsychotic, while there was no such improvement in those with both aggression and SIB or with SIB alone. The investigators pointed out that the latter group, although small (5 persons), had actually experienced a slight increase in the number of SIB events during the year of treatment with an atypical antipsychotic.

Like Tyrer and colleagues, Ruedrich's group acknowledges that their findings contrast with previous indications of antipsychotic benefit for nonpsychotic behavioral symptoms, including SIB, and particularly with results of trials using risperidone, the atypical antipsychotic most studied in this population.⁶ They also note that consensus guidelines recommend conversion from traditional neuroleptics to an atypical antipsychotic.^6,7 They cite others, however, in suggesting that a more appropriate intervention for SIB in persons with DD may be in "treatment of their specific psychiatric disorder with appropriate psychotropic medication."

Evidence remains incomplete

Tyrer and colleagues conclude that the "routine prescription of antipsychotic drugs early in the management of aggressive, challenging behavior, even in low doses, should no longer be regarded as a satisfactory form of care," although the evidence for either avoiding or employing these medications for this purpose remains incomplete.

In the controlled trial, the failure to distinguish the effect of active agents from placebo brings into question the sensitivity of measurement as well as drug effect, and the investigators acknowledge that low recruitment left the study somewhat underpowered (although this was mitigated by a subsequent low rate of attrition). In addition, the similar results from active and placebo treatments after 4 weeks leave open the question of antipsychotic efficacy at the onset of aggression.

The conclusions from the retrospective review are also confounded by study limitations, including a lack of matched groups treated for the study year with either neuroleptics or atypical antipsychotics. Indeed, there were no pure comparisons to be made because all participants were cross-titrated from neuroleptics to atypicals. Forty-six percent of the individuals did have their neuroleptic antipsychotic stopped at some time during the year, but another 27% had only the dosage reduced while an atypical antipsychotic was added.

The commentary by Matson and Wilkins⁵ does offer a point of agreement for the field. In view of the high rates of use of antipsychotics for these symptoms and the potential for long-term side effects, "despite sparse evidence of drug efficacy for treating aggression in people with intellectual disability," they note, "researchers have continued to stress the urgent need for [additional] research."

References:

References

1. Ruedrich SL, Swales TP, Rossvanes C, et al. Atypical antipsychotic medication improves aggression, but not self-injurious behavior, in adults with intellectual disabilities. J Intellect Disabil Res. 2008;52(pt 2):132-140.

2. Tyrer P, Oliver-Africano PC, Ahmed Z, et al. Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behavior in patients with intellectual disability: a randomised controlled trial. Lancet. 2008;371:57-63.

3. Vanden Borre R, Vermote R, Buttiens M, et al. Risperidone as an add-on therapy in behavioral disturbances in mental retardation: a double-blind placebo-controlled cross-over study. Acta Psychiatr Scand. 1993; 87:167-171.

4. Gagiano C, Read S, Thorpe L, et al. Short- and long-term efficacy and safety of risperidone in adults with disruptive behavior disorders. Psychopharmacol (Berl). 2005;179:629-636.

5. Matson JL, Wilkins J. Antipsychotic drugs for aggression in intellectual disability. Lancet. 2008;371: 9-10.

6. Aman MG, Gharabawi GM; Special Topic Advisory Panel on Transitioning to Risperidone Therapy in Patients With Mental Retardation and Developmental Disabilities. Treatment of behavior disorders in mental retardation: report on transitioning to atypical antipsychotics, with an emphasis on risperidone. J Clin Psychiatry. 2004;65:1197-1210.

7. Expert Consensus Guideline Series: Treatment of psychiatric and behavioral problems in mental retardation. Am J Ment Retard. 2000;105:159-226.