P Tyrer,^1* P Oliver-Africano,¹ R Romeo,² M Knapp,² S Dickens,¹ N Bouras,³ Z Ahmed,⁴ S Cooray,⁵ S Deb,⁶ D Murphy,⁷ M Hare,⁴ M Meade,¹ B Reece,¹ K Kramo,¹ S Bhaumik,⁸ D Harley,⁹ A Regan,¹⁰ D Thomas,¹¹ B Rao,¹ S Karatela,⁹ L Lenôtre,⁵ J Watson,⁸ A Soni,¹² M Crawford,¹ J Eliahoo¹³ and B North¹³

¹Department of Psychological Medicine, Imperial College, London, UK
²Centre for Economics of Mental Health, Box P024, Institute of Psychiatry, De Crespigny Park, London, UK
³Mental Health in Learning Disabilities Centre, King's College London, Institute of Psychiatry, Estia Centre, Guy's Hospital, London, UK
⁴Welsh Centre for Learning Disabilities Clinical Studies, University of Wales College of Medicine, Cardiff, UK
⁵Central North West London Foundation NHS Trust, Kingsbury Community Unit, Brent, London, UK
⁶Department of Psychiatry, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham, UK
⁷Section of Brain Maturation, Institute of Psychiatry, London, UK
⁸Leicestershire Partnership NHS Trust, Leicester Frith Hospital, Leicester, UK
⁹Queensland Centre for Intellectual and Developmental Disability (QCIDD), School of Population Health, University of Queensland, Brisbane, Australia
¹⁰Harrow Primary Care NHS Trust, Orme Lodge, Stanmore, Middlesex, UK
¹¹North East London Mental Health NHS Trust, Redbridge Learning Disability Service, Barkingside, Essex, UK
¹²West London Mental Health NHS Trust, Hammersmith & Fulham Mental Health Unit, London, UK
¹³Statistical Advisory Service, Imperial College, London, UK

*Corresponding author

Objectives:

To assess the effects and cost-effectiveness of haloperidol, risperidone and placebo on aggressive challenging behaviour in adults with intellectual disability.

Design:

A double-blind randomised controlled trial of two drugs and placebo administered in flexible dosage, with full, independent assessments of aggressive and aberrant behaviour, global improvement, carer burden, quality of life and adverse drug effects at baseline, 4, 12 and 26 weeks, and comparison of total care costs in the 6 months before and after randomisation. At 12 weeks, patients were given the option of leaving the trial or continuing until 26 weeks. Assessments of observed aggression were also carried out with key workers at weekly intervals throughout the trial.

Setting:

Patients were recruited from all those being treated by intellectual disability services in eight sites in England, one in Wales and one in Queensland, Australia.

Participants:

Patients from all severity levels of intellectual disability; recruitment was extended to include those who may have been treated with neuroleptic drugs in the past. Exclusion criteria: treatment with depot neuroleptics/another form of injected neuroleptic medication within the last 3 months; continuous oral neuroleptic medication within the last week; those under a section of the Mental Health Act 1983 or Queensland Mental Health Act 2000.

Interventions:

Randomisation to treatment with haloperidol (a typical neuroleptic drug), risperidone (an atypical neuroleptic drug) or placebo using a permuted blocks procedure. Dosages were: haloperidol 1.25–5.0 mg daily; risperidone 0.5–2.0 mg daily.

Main outcome measures:

Primary: reduction in aggressive episodes between baseline and 4 weeks using Modified Overt Aggression Scale. Secondary: Aberrant Behaviour Checklist; Uplift/Burden Scale; 40-item Quality of Life Questionnaire; Udvalg for Kliniske Undersøgelser scale; Clinical Global Impressions scale. Economic costs recorded using a modified version of Client Service Receipt Inventory for 6 months before and after randomisation.

Results:

There were considerable difficulties in recruitment because of ethical and consent doubts. Twenty-two clinicians recruited a total of 86 patients. Mean daily dosages were 1.07 mg rising to 1.78 mg for risperidone and 2.54 mg rising to 2.94 mg for haloperidol. Aggression declined dramatically with all three treatments by 4 weeks, with placebo showing the greatest reduction (79%, versus 57% for combined drugs) (p = 0.06). Placebo-treated patients showed no evidence of inferior response in comparison to patients receiving neuroleptic drugs. An additional study found that clinicians who had not participated in clinical trials before were less likely to recruit. Mean total cost of accommodation, services, informal care and treatment over the 6 months of the trial was £16,336 for placebo, £17,626 for haloperidol and £18,954 for risperidone.

Conclusions:

There were no significant important benefits conferred by treatment with risperidone or haloperidol, and treatment with these drugs was not cost-effective. While neuroleptic drugs may be of value in the treatment of aggressive behaviour in some patients with intellectual disability, the underlying pathology needs to be evaluated before these are given. The specific diagnostic indications for such treatment require further investigation. Prescription of low doses of neuroleptic drugs in intellectual disability on the grounds of greater responsiveness and greater liability to adverse effects also needs to be re-examined.

Trial registration:

Current Controlled Trials ISRCTN 11736448.

© 2009 Crown Copyright