Health Evidence Bulletins - Wales

Literature searches completed on: 19th April 1999

5:Drug Therapy

This bulletin is a supplement to, not a substitute for, professional skills and experience. Users are advised to consult the supporting evidence for a consideration of all the implications of a recommendation.

The Statements The Evidence
5.1 Behavioural Disturbance
5.1a. 26.5% of people with an intellectual disability can be treated effectively, 47.1% fairly effectively, 23.5% with intermittent success and 2.9% cannot be treatedi.
Pharmacological procedures are the least effective interventions. Response contingent procedures are significantly more effective than other procedures.
(Health gain notation – 2 "likely to be beneficial")
Internally maladaptive and socially disruptive behaviors can be treated more effectively than externally destructive behaviors.
(Health gain notation – 2 "likely to be beneficial")
Undertaking functional analysis prior to treatment is significantly associated with treatment success.
(Health gain notation – 2 "likely to be beneficial")
i. Didden R, Duker PC, Korzilius H. Meta-analytic study on treatment effectiveness for problem behaviors with individuals who have mental retardation. American Journal of Mental Retardation 1997; 101(4): 387-99
(Type III evidence – systematic review and meta-analysis of 482 empirical studies (no randomised controlled trials) on treatment of problem behaviors of individuals with mental retardation)
5.1b. There is no good evidence that antipsychotic medication helps, in managing behaviour, or harms people with intellectual disability. Further research is requiredi.
(Health gain notation – 4 "unknown")
i. Brylewski J, Duggan L. Antipsychotic medication for challenging behaviour in people with learning disability (Cochrane Review). In: The Cochrane Library. 1999; 4: Oxford: Update Software
[accessed 8.12.00]
(Type I evidence - systematic review of 500 citations with 3 sound randomised controlled trials)
5.1c. It is possible to reduce or even withdraw neuroleptics in severely and profoundly intellectually disabled adultsi,ii,iii.
At least 60% of patients on long-term treatment can eventually be managed without psychoactive medication. Transient behavioural deterioration during drug reduction may be prolonged (up to two years), but then returns to baseline without further pharmacological intervention.
Although 40% demonstrate persistent deterioration following drug withdrawal and require some type of psychoactive medication, very few will need to recommence neuroleptics. Those that do tend to be older and well controlled but receiving higher baseline doses of neuroleptics.
(Health gain notation – 3 "trade off between beneficial and adverse effects")
i. May P, London EB, Zimmerman T, et al. A study of the clinical outcome of patients with profound mental retardation gradually withdrawn from chronic neuroleptic medication. Annals of Clinical Psychiatry 1995; 7(4):155-60
(Type IV evidence - naturalistic study of 23 severely and profoundly intellectually disabled adult male patients undergoing slow "diagnostic" neuroleptic taper)
ii. Branford D. Factors associated with the successful or unsuccessful withdrawal of antipsychotic drug therapy prescribed for people with learning disabilities. Journal of Intellectual Disability Research 1996; 40(4): 322-329
(Type III evidence – non-controlled study of 123 patients who had reduction of their antipsychotic medication)
iii. Ahmed Z, Fraser W, Kerr MP et al. Reducing antipsychotic medication in people with a learning disability. British Journal of Psychiatry 2000; 176: 42-46
(Type II evidence – randomised controlled trial of 67 subjects in whom antipsychotic medication was used to treat behavioural problems. A 25% reduction in dosage per month led to one third of patients sucessfully coming off the medication and a further 19% having the dose reduced by half. Environmental factors influenced success in drug reduction rather than subject characteristics)


5.1d. Using multiple assessment measures, Clomipramine was effective in reducing the frequency and intensity of one or more stereotyped behaviour, hyperactivity and irritabilityi.
60% showed significant improvement, 30% had treatment limiting side effects and 10% showed no improvement.
(Health gain notation – 2 "likely to be beneficial")
i. Lewis MH, Bodfish JW, Powell SB, Golden RN. Clomipramine treatment for stereotype and related repetitive movement disorders associated with mental retardation. American Journal of Mental Retardation 1995; 100(3): 299-312
(Type II evidence - double blind placebo controlled cross- over study involving 10 severely or profoundly intellectually disabled adults )
5.1e. There is limited evidence that Risperidone is effective in improving a range of behavioural disturbances in people with varying levels of intellectual disability. Further research is neededi.
(Health gain notation – 4 "unknown")
i. Natarajan D, Martin AJ, Tesh D. Risperidone therapy in the control of behavioural disturbances in patients with learning disability. Irish Journal of Psychological Medicine 1997; 14(2): 69-71
(Type IV evidence - retrospective audit of seventeen long term inpatients with mild to severe intellectual disability: did not use recognised audit tool)
5.1f. Antidepressants with a specific 5-HT action should be used with caution in people with intellectual disability and autism. It may cause agitation, physical aggression and SIB and sleep disturbance related to the role of serotonin in autistic symptoms.
(Health gain notation – 5 "unlikely to be beneficial")
In autistic adults, Fluvoxamine, a selective serotonin reuptake inhibitor, produces a significant reduction in repetitive thoughts and behvaiours, agression, and maladaptive behaviours compared to placebo. Fluvoxamine had a 53% response rate.
(Health gain notation – 2 "likely to be beneficial")
i. Perry DW, Hinder S, Krishnan VHR, Roy A. The use of specific serotonin re-uptake inhibitors in people with learning disability, autism and depression: Letter to the Editors. Human Psychopharmacology 1996; 11: 425-6
(Type IV evidence - case study of two patients)
ii. McDougle CJ, Naylor ST, Cohen DJ et al. A double-blind placebo-controlled study of Fluvoxamine in adults with autistic disorder. Archives of General Psychiatry 1996; 53: 1001-1008
(Type II evidence – randomised controlled trial of 30 adults with autism. A mean dose of Fluvoxamine (277 42mg) was compared to placebo. A significant improvement with Fluvoxamine was seen after 4 weeks. Robust study design with standardised rating scales and thorough statistical analysis)
5.2 Self-Injurious Behaviour


5.2a. There is growing evidence that serotonergic drugs are effective in the reduction of self-injurious (SIB) and aggressive behaviour in people with intellectual disability. Sertraline, a serotonin reuptake inhibitor, has been shown to be more effective (when measured by Clinical Global Impressions) and have fewer side effects than traditional neurolepticsi,ii,iii,iv.
Further trials are recommended.
(Health gain notation – 4 "unknown")
i. Sandman CA, Matrick WP. Opiate mechanisms in self injury. Mental Retardation and Developmental Disability Research Review 1995; 1: 130-136
(Type I evidence – systematic review showing a 35-75% reduction in self-injurious behaviour in adults with severe and profound intellectual disability after treatment with oral Naltrexone)
ii. Sandman CA, Metrick W, Taylor DV et al. Dissociation of POMC peptides after self-injury preducts responses to centrally acting opiate blockers. American Journal on Mental Retardation 1997; 102(2): 182-199
(Type II evidence – double-blind, placebo controlled crossover study of 8 men and 2 women with self-injurious behaviour treated with Naltrexone following plasma measurement of beta-endorphin. The study showed that an elevated beta-endorphin level indicated a good response to Naltrexone, suggesting that such individuals may be addicted to endogenous opiates released following self-injury)
iii. Thompson T, Hackenberg T, Cerutti D et al. Opioid antagonist effects on self-injury in adults with mental retardation: Response form and location as determinants of medication effects. American Journal on Mental Retardation 1994; 99(1): 85-102
(Type II evidence – double-blind randomised controlled trial of 8 adults with severe or profound intellectual disability treated with 50 mg and 100 mg of Naltrexone. Both doses significantly reduced self-injurious behaviour. Naltrexone showed no side effects at either dose including no effect on sleep pattern)
iv. Hellings JA, Kelley LA, Gabrielli WF, et al. Sertraline response in adults with mental retardation and autistic disorder. Journal of Clinical Psychiatry 1996; 57(8): 333-6
(Type III evidence - open trial, nine consecutively admitted adult intellectually disabled outpatients presenting with target behaviours of self-injury and/or aggression. Six were mildly or moderately mentally retarded by DSM-III-R criteria; five had comorbid autistic disorder)
5.2b. There is limited evidence that Naltrexone may be effective in reducing self-injurious behaviour (SIB) in adults with profound intellectual disability and that this benefit might be both durable to environmental changes and continue long after cessation of therapyi.
(Health gain notation – 4 "unknown")
i. Crews WD Jr, Rhodes RD, Bonaventura SH, et al. Cessation of long-term naltrexone administration: longitudinal follow-ups. Research in Developmental Disabilities 1999; 20(1): 23-30
(Type IV evidence - case study of one patient)


5.2c. There is limited evidence that Risperidone is effective in the management of aggressive and self-injurious behaviour (SIB) in people with moderate to profound intellectual disability. Side effects are mild and primarily those of sedation and restlessnessi.
(Health gain notation – 4 "unknown")
i. Cohen SA, Ihrig K, Lott RS, Kerrick JM. Risperidone for aggression and self-injurious behavior in adults with mental retardation. Journal of Autism & Developmental Disorders 1998; 28(3):229-33
(Type IV evidence - tracking of maladaptive behaviours in 8 adult patients following initiation of risperidone)
5.3 Attention-Deficit Hyperactivity Disorder
5.3a. Amphetamine is effective in the treatment of attention-deficit hyperactivity disorder (ADHD) in childreni.
It has been shown to reduce inattention, hyperactivity and other disruptive behavioural problems and tends to improve the results in Wechsler Intelligence Scale for Children. Measured benefits last at least one year and adverse effects are few and mild.
(Health gain notation – 2 "likely to be beneficial")
i. Gillberg C, Melander H, von Knorring AL, et al. Long term stimulant treatment of children with attention-deficit hyperactivity disorder symptoms. Archives of General Psychiatry 1997; 54(9): 857-64
(Type II evidence - multicentre double blind placebo controlled RCT involving 62 children aged between 6 & 11 years )
5.3b. There is limited evidence that both Methylphenidate and Fenfluramine may be effective treatments for attention-deficit hyperactivity disorder (ADHD) in children with intellectual disability or borderline IQi.
(Methylphenidate: Health gain notation – 4 "unknown")

Fenfluramine is a controversial drug. At higher doses (>1.5mg/kg/day) it causes drowsiness, dizziness and anorexia. There are reports of possible neurotoxicity with long-term depletion of serotonin in laboratory models.


(Fenfluramine: Health gain notation – 6 "likely to be harmful")

i. Aman MG, Kern RA, Osborne P, et al. Fenfluramine and methylphenidate in children with mental retardation and borderline IQ: clinical effects. American Journal of Mental Retardation 1997; 101(5):521-34
(Type II evidence - double-blind placebo-controlled crossover study of methylphenidate (0.4 mg/kgday) and different doses of fenfluramine (1.0, 1.5, or 2.0 mg/g/day) in 35 children aged 5-14 years with mental retardation or borderline IQ and ADHD)


Health Evidence Bulletins: Wales, Duthie Library, UWCM, Cardiff CF14 4XN. e-mail: weightmanal@cardiff.ac.uk