A Double-blind Placebo-controlled Discontinuation Study of Zuclopenthixol for the Treatment of Aggressive Disruptive Behaviours in Adults with Mental Retardation – Secondary Parameter Analyses

Abstract

Introduction: Earlier studies showed risperidone to be effective in the treatment of aggression and self-injurious behaviour in adults with mental retardation but also having adverse side effects. This study was conducted to evaluate the effects of zuclopenthixol withdrawal.

Methods: After open treatment with zuclopenthixol (n=49) responders were randomly assigned to continue (n=19) or discontinue (n=20) zuclopenthixol treatment during a 12-week double-blind, placebo-controlled period. Effects were measured using the Disability Assessment Schedule (DAS), improvement on the Clinical Global Impression Scale (CGI-I), and the Nurse's Observation Scale for Inpatient Evaluation (NOSIE).

Results: Ten patients (20%) discontinued the study due to insufficient therapeutic effect or adverse events in the open period. Efficacy: The superiority of zuclopenthixol over placebo among all randomized patients was supported not only by primary efficacy measure but also by the comparisons of mean scores of all secondary efficacy measures tested in a step-down-procedure (DAS, p<0.001; CGI-I, p<0.002, NOSIE, p<0.005). Safety: In both groups, one patient discontinued (5%) for adverse events. Adverse events were generally mild or moderate in severity.

Discussion: Zuclopenthixol proved to be safe and effective to keep a low rate of aggressive behaviour in adults with mental retardation.

References

• 1 Aman MG, Smedt G, Derivan A, Lyons B, Findling RL. Double-blind, placebo-controlled study of risperidone for the treatment of disruptive behaviours in children with subaverage intelligence.  Am J Psychiatry. 2002;  159 1337-1346
• 2 Ballinger BR, Ballinger CB, Reid AH, MacQueen E. The psychiatric symptoms, diagnoses and care need of 100 mentally handicapped patients.  Br J Psychiatry. 1991;  158 251-254
• 3 Baumeister AA, Sevin JA, King B. Neuroleptics. In: Reiss S, Aman MG, eds. Psychotropic Medications and Developmental Disabilities. The International Consensus Handbook. Columbus Ohio State University, Nisonger Center 1998: 133-150
• 4 Baumeister AA, Todd ME, Sevin JA. Efficacy and specificity of pharmacological therapies for behavioral disorders in persons with mental retardation.  Clin Neuropharmacol. 1993;  16 271-294
• 5 Coccaro EF, Harvey PD, Kupsaw-Lawrence E, Herbert JL, Bernstein DP. Development of neuropharmacologically based behavioural assessments of impulsive aggressive behaviour.  J Neuropsychiat Clin Neurosci. 1991;  3 44-55
• 6 Goedhard LE, Stolker JJ, Nijman HLI, Egberts ACG, Heerdink ER. Aggression of psychiatric patients associated with the use of as-needed medication.  Pharmacopsychiatry. 2007;  40 25-29
• 7 Guy W. ECDEU Assessment Manual for Psychopharmacology, Revised. Washington, DC: U.S. Department of Health, Education and Welfare publication (ADM) 1976: 218-222 284–285, 300–302
• 8 Haessler F, Glaser T, Beneke M, Pap AF, Bodenschatz R, Reis O. Zuclopenthixol treatment in adults with learning disabilities showing aggressive behaviours: discontinuation study.  Br J Psychiat. 2007;  190 1-2
• 9 Haessler F. Psychopharmacotherapy in mentally retarded adults.  Psychopharmakotherapie. 1998;  5 76-80
• 10 Holmes N, Shah A, Wing L. The Disability Assessment Schedule: a brief screening device for use with the mentally retarded.  Psychol Med. 1982;  12 879-890
• 11 Honigfeld G, Gillis RD, Klett CJ. NOSIE. Nurse's Observation Scale for Inpatient Evaluation. In: Guy W, editor. ECDEU Assessment Man-ual for Psychopharmacology, Revised Ed. Rockville: Maryland 1976: 265-273
• 12 Izmeth M, Khan SY, Kumarjeewa DI, Shivanathan S, Veall RM, Wiley YV. Zuclopenthixol decanoate in the management of behavioural disorders in mentally handicapped patients.  Pharmacotherapeutica. 1988;  5 217-227
• 13 Karsten D, Kivimaeki T, Linna SL. Neuroleptic treatment of oligophrenic patients.  Acta Psychiatr Scand. 1981;  64 ((suppl)) 39-45
• 14 Kay SR, Wolkenfield F, Murril LM. Profiles of aggression among psychiatric patients.  J Nerv Ment Dis. 1988;  176 539-546
• 15 Lambert TJ. Switching antipsychotic therapy: what to expect and clinical strategies for improving therapeutic outcomes.  J Clin Psychiatry. 2007;  68 ((Suppl 6)) 10-13
• 16 Leuner K, Müller WE. The complexity of the dopaminergic synapses and their modulation by antipsychotics.  Pharmacopsychiatry. 2006;  39 ((Suppl 1)) 15-20
• 17 Malone RP, Maislin G, Choudhury MS, Gifford C, Delaney MA. Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness.  J Am Acad Child Adolesc Psychiat. 2002;  41 140-147
• 18 Malt UF, Nystad R, Bache T, Noren O. Efficacy of zuclopenthixol in comparison to haloperidol in the treatment of mentally retarded with behaviour disorders.  Br J Psychiat. 1995;  166 374-377
• 19 Matson JL, Wilkins J. Comment: Antipsychotic drugs for aggression.  Lancet. 2008;  371 9-10
• 20 MacCracken JT, MacGough J, Shah B, Cronin P, Hong D, Aman MG. Risperidone in children with autism and serious behavioural problems.  New Engl J Med. 2002;  347 314-321
• 21 Meins W, Auwetter J, Krausz M, Turnier Y. Behandlung mit Psychopharamka in unterschiedlichen Einrichtungen für geistig Behinderte [Psychotropic drug treatment in different types of residential care for the mentally retarded].  Der Nervenarzt. 1993;  64 451-455
• 22 Mikhail AG, King BH. Self-injurious behaviour in mental retardation.  Curr Opin Psychiat. 2001;  14 457-461
• 23 Oliver C, Petty J. Self-injurious behaviour in people with intellectual disability.  Curr Opin Psychiatry. 2002;  15 477-481
• 24 Santosh PJ, Baird G. Psychopharmacotherapy in children and adults with intellectual disability.  Lancet. 1999;  354 233-242
• 25 Singh I, Owino WJ. A double-blind comparison of zuclopenthixol tablets with placebo in the treatment of mentally handicapped inpatients with associated behavioural problems.  J Intellect Disabil Res. 1992;  23 541-549
• 26 Tyrer P, Oliver-Africana PC, Ahemd Z, Bouras N, Cooray S. Risperidone, haloperidol, and placebo in the treatment of aggressive challenging behaviour in patients with intellectual disability: a randomised controlled trial.  Lancet. 2008;  371 57-63
• 27 Werry JS. Severe conduct disorder-some key issues.  Can J Psychiatry. 1997;  42 577-583
• 28 Yudofski SC, Silver JM, Jackson W, Endicott J, Williams D. The overt aggression scale for the objective rating of verbal and physical aggression.  Am J Psychiatry. 1986;  143 35-39

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