531665 research-article2014

JOP0010.1177/0269881114531665Journal of PsychopharmacologyGormez et al.

Original Paper

Pharmacological interventions for selfinjurious behaviour in adults with intellectual disabilities: Abridged republication of a Cochrane systematic review*

Journal of Psychopharmacology 2014, Vol. 28(7) 624­–632 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881114531665 jop.sagepub.com

A Gormez1, F Rana1 and S Varghese2

Abstract We aimed to determine clinical effectiveness of pharmacological interventions for self-injurious behaviour in adults with intellectual disability. We searched the following databases: CENTRAL; MEDLINE; EMBASE; PsycINFO; CINAHL; SCI; SSCI; Conference Proceedings Citation Index - Science; Conference Proceedings Citation Index – Social Science and Humanities; ZETOC; World Cat .We also searched ClinicalTrials.gov,ICTRP and the reference lists of included trials. We included randomised controlled trials that examined drug interventions versus placebo for self-injurious behaviour. We found five double-blind, placebo-controlled trials, which included a total of 50 people. Four trials compared the effects of naltrexone versus placebo and one trial clomipramine versus placebo. We did not identify any relevant placebo-controlled trials for other drugs. We presented a narrative summary, as meta-analysis was not appropriate due to differences in study designs, differences between interventions and heterogeneous outcome measures. There was weak evidence in included trials that any active drug was more effective than placebo for people with intellectual disability demonstrating self-injurious behaviour. Due to sparse data, an absence of power and statistical significance, and high risk of bias for four of the included trials, we are unable to reach any definite conclusions about the relative benefits of naltrexone or clomipramine compared to placebo.

Keywords Self-injurious behaviour, intellectual disability, pharmacological interventions

Introduction Self-injurious behaviour (SIB) among people with intellectual disability (ID) is relatively common and often persistent (Kahng et al., 2002; Murphy, 1999). It is resistant to treatment (Hillery and Dodd, 2007) and presents challenges to those with caring responsibilities. A number of terms are used for ID with varying levels of acceptability across disciplines and professions. These terms include ‘learning disability’, ‘intellectual handicap’, ‘intellectual retardation’, ‘mental retardation’ and ‘mental handicap’. The World Health Organization (WHO) International Classification of Diseases (ICD-10) (WHO, 1992) uses the term ‘mental retardation’. This is defined as a condition of arrested or incomplete development of the mind, characterised by impairment of skills manifested during the developmental period that contribute to the overall level of intelligence, that is, cognitive, language, motor and social abilities. ICD-10 classifies ID on the basis of intelligence quotient (IQ) scores as follows: mild (50 to 70); moderate (35 to 49); severe (20 to 34); profound (under 20). Several definitions exist for SIB. It has been defined as ‘a class of behaviours, often highly repetitive and rhythmic, that result in physical harm to the individual displaying the behaviour’ (Fee and Matson, 1992) and ‘the deliberate alteration or destruction of body tissue without conscious suicidal intent’ (Bhaumik et al., 2005). SIB in those with ID commonly presents as head butting, face slapping and slapping other body parts, hitting body parts against hard surfaces, biting, picking skin/ wounds, scratching, pulling hair/nails, poking/sticking things into anus, nose, ears or mouth and gouging of eyes.

The different terms used for this kind of behaviour include ‘self harm’, ‘self mutilation’, ‘intentional self harm’, ‘deliberate self harm’ and ‘parasuicide’. In this review, we did not include studies where these terms were used for a deliberate suicide attempt. As there are different terms and definitions, prevalence rates from different studies vary greatly. For example, one study found rates of only 4.9% (Cooper et al., 2009), while another study reported rates of 17.4% (Collacott et al., 1998). Borthwick-Duffy (1994) suggests that 10–50% of people with ID might, at some point, display SIB. According to this study, the prevalence in this client group is dependent on where people live, with 8–15% of those in hospital exhibiting SIB compared with generally lower rates for those living in other environments, such as special schools (3–12%), segregated day centres (3–10%) or at home (1–4%). 1Southern

Health NHS Foundation Trust, Psychiatry of Intellectual Disability, Oxford, UK 2Black Country Partnership NHS Foundation Trust, Psychiatry of Intellectual Disability, Wolverhampton, UK *Rana F, Gormez A and Varghese S (2013) Pharmacological interventions for self-injurious behaviour in adults with intellectual disabilities. Cochrane Database of Systematic Reviews Issue 4. Art. No.: CD009084. DOI: 10.1002/14651858.CD009084.pub2. Corresponding author: Gormez A, Southern Health NHS Foundation Trust, Psychiatry of Intellectual Disability, Horspath Driftway, Headington, Oxford, OX3 7JH, UK. Email: [email protected]

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Gormez et al. Studies have generally found an inverse relationship between IQ and the likelihood of self-injury (Hillery, 2007; Rojahn and Esbensen, 2002). An epidemiological study of SIB in adults with ID in the UK (Collacott et al., 1998) found both the chronological age and developmental quotient of individuals displaying SIB were lower than those without SIB and no gender difference was found between those with and without SIB (Rojahn and Esbensen, 2002). Several studies reported higher prevalence of autism spectrum disorders in people with ID (Bhaumik et al., 2010; Saemundsen et al., 2010) and autistic symptoms were found to be more common among those with SIB (Collacott et al., 1998). Personality disorders have also been highly correlated with SIB (Horrocks et al., 2003); however, diagnosis of personality disorder in those with ID is complex and difficult (Alexander, 2003). There are a number of contradictory hypotheses on the aetiology of SIB in people with ID. The theories include SIB as a learned behaviour, a form of communication, the result of neurochemical imbalance, a symptom of organic illness, a symptom of intermittent physical discomfort, a symptom of psychiatric illness such as depression, mania, phobias, psychosis, obsessive compulsive disorder, posttraumatic stress disorder, etc., symptom of grief or trauma or a response caused by over-sensitivity to sensory input (Hillery and Dodd, 2007). SIB may be a result of insecure attachment with the attachment figure at a younger age (Rojahn et al., 2008). SIB may have a self-stimulatory function for those who are cared for in environments that lack both appropriate attention-giving and appropriate stimuli (either under- or over-stimulation) (Emerson and Bromley, 1995; Gates, 2007). People with ID may display SIB because it results in a ‘reward’ for the individual, reinforcing the behaviour and increasing the likelihood that it will be repeated (Gates et al., 1996). SIB is more likely to occur in people with specific conditions or syndromes such as Prader-Willi syndrome, Fragile X syndrome, Tourette’s syndrome, Smith-Magenis syndrome, Cornelia de Lange syndrome and Lesh-Nyhan syndrome (Murphy, 1999).

of the challenges in using behavioural interventions is the dearth of empirical evaluation of these approaches (Emerson, 2001a). One systematic review looking at the efficacy of behavioural approaches found mainly single case studies that yielded mixed results and authors highlighted the need for more research on effectiveness of these approaches (Prangnell, 2010). Many people with ID and SIB have been prescribed psychotropic medications including opioid antagonists such as naltrexone, antipsychotics, antidepressants, mood stabilisers and beta-blockers. Some argue that psychotropic medication is prescribed too often in this population and there are a range of adverse effects reported (Einfeld, 2001). The scientific literature on the benefits of pharmacological agents for intellectually disabled individuals is beset with a number of problems (Deb and Unwin, 2007). Although no form of treatment has been demonstrated conclusively to be of general benefit, the literature suggests that therapeutic trials with treatments having predominant opiate antagonism (for example, naltrexone, naloxone), dopamine antagonism (for example, antipsychotics), serotonin reuptake inhibition (for example, antidepressants) and beta-blockers may be of value. As mentioned earlier, many psychiatric illnesses (as defined by multi-axial classification in Royal College of Psychiatrists, 2001), for example, phobias, psychosis, affective disorders, obsessive compulsive disorder and post-traumatic stress disorder can present with SIB as a secondary manifestation (Hillery and Dodd, 2007). Most of the drugs used in SIB are mainstay treatments for these psychiatric illnesses. Appropriate management of primary psychiatric illness may lead to improvement in SIB. Hence, our review does not include SIB that is a direct consequence of any psychiatric illness.

Objectives To determine the clinical effectiveness of pharmacological interventions in the management of SIB in adults with ID.

Consequences of self-injurious behaviour SIB has physical, psychological and social consequences. There is contradictory evidence on its chronicity in people with ID, with some studies finding high levels of chronicity and others finding low chronicity over follow-up years (Cooper et al., 2009; Emerson et al., 2001; Griffin et al., 1986; Murphy et al., 1993; Totsika et al., 2008). One study showed that 84% of the sample continued to self-injure nearly 20 years on, with no significant mean changes in number of topographies or severity of self-injuries across the group (Taylor et al., 2010). SIB can cause increased stress to carers (Quine and Pahl., 1985), increased risk of suffering physical abuse from carers (Maurice and Trudel.,1982) and increased risk of institutionalisation (Lakin et al., 1983). In addition, people who self-injure are more likely to be given psychotropic drugs (Aman 1993; Johnny and Daniene, 2009) and more likely to be kept on medication (Chadsey-Rusch and Sprague,1989).

Methods Criteria for considering studies for this review Randomised controlled trials including individually randomised, cluster-randomised and cross-over trials in adults with ID (mild to profound), aged 18 years or over, presenting with SIB occurring at least during most weeks of the preceding 6 months (as per diagnostic criteria in Royal College of Psychiatrists, 2001) and without additional psychiatric illness. Pharmacological interventions included any antidepressants, antipsychotics, mood stabilisers, opiate antagonist (naltrexone), beta-blocker (propranolol) and hypnotic (melatonin), regardless of dosage, against placebo. We excluded trials where there were other treatment controls. We included trials where participants had psychological therapies in the past.

Primary outcomes

Description of the intervention SIB remains poorly understood and difficult to ameliorate despite advances in neurobiology and psychological therapies (Symons, 2011). Several interventions have been tried over the years, including pharmacological and psychological/behavioural interventions. One

• • • •

Frequency of SIB. Intensity of SIB. Duration of SIB. Adverse events (effects of medication such as sleepiness, movement disorders, seizures, weight gain, etc.).

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The primary outcomes were measured by client/primary carer reports and validated rating scales.

Secondary outcomes • Attendance at day centre/college. • Engagement in paid/unpaid work/leisure activities. • Carer stress. Secondary outcome measures were measured by client/primary carer reports and validated rating scales.

Search methods for identification of studies We ran the searches in February 2012 covering all available years for each database. No language limits were used. We searched the following electronic databases. • Cochrane Central Register of Controlled Trials (CENTRAL), part of The Cochrane Library, 2012 (Issue 2), last searched 19 February 2012. • CENTRAL, searched via The Cochrane Library (DVD), January 2011, searched 13 April 2011. • Ovid MEDLINE, 1948 to February week 4 2012, last searched 19 February 2012. • EMBASE (OVID), 1980 to week 7 2012, last searched 19 February 2012. • PsycINFO (OVID), 1887 to February week 2 2012, last searched 19 February 2012. • CINAHL (EBSCOhost), 1937 to 19 February 2012. • Science Citation Index (SCI), 1970 to 17 February 2012, last searched 19 February 2012. • Social Science Citation Index (SSCI), 1970 to 17 February 2012, last searched 19 February 2012. • Conference Proceedings Citation Index - Science, 1990 to 17 February 2012, last searched 19 February 2012. • Conference Proceedings Citation Index - Social Science and Humanities, 1990 to 17 February 2012, last searched 19 February 2012. • ZETOC (conference search only), last searched 19 February 2012. • WorldCat (theses search only), last searched 19 February 2012. We used the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE (Lefebvre et al., 2008). Appropriate search terms to identify randomised trials were used in the other databases when necessary. The search platform for PsycINFO changed during the review period and CENTRAL was searched using the DVD version of The Cochrane Library in 2011 because the online version was unavailable. The reference lists of the trials included in this review were searched to identify additional trials. Search histories are reported in Appendix 1 in Supplementary Material.

Data collection and analysis The titles and abstracts yielded by the search were independently screened by two review authors against the inclusion

criteria. The full text of papers or reports for trials that appeared relevant, or for which more information was needed to determine relevance, were obtained and independently screened by two review authors to determine whether they met the criteria for inclusion. Disagreements about eligibility were resolved through discussion and, when disagreements were not resolved, a third review author was used to reconcile any differences. None of the review authors was blinded to the study authors, institutions or the journals of publication of the articles. Two review authors independently extracted data for each trial using a data extraction form. As the overall numbers of dropouts were small and unlikely to make a significant difference to the summary of the overall review, no efforts were made to contact the authors for information on this. Data about the beneficial effects of single-dose naltrexone were not given in the Willemsen-Swinkels et al. (1995) study. Several attempts were made to contact the authors of this paper but we were not successful. A narrative summary was conducted as a meta-analysis was not possible due to differences in study designs (duration, crossover phases within the studies), heterogeneity of interventions (doses of drugs) and differences in how outcome measures were reported. Therefore, it was not relevant to assess heterogeneity between results of trials and we were unable to assess reporting biases using funnel plots or conduct any subgroup analyses or sensitivity analyses.

Results Figure 1 explains the results of the search. The five included trials (Lewis et al., 1996; Sandman et al., 1990; Symons et al., 2001; Thompson et al., 1994; WillemsenSwinkels et al., 1995) randomised 57 participants but we have included and reported on only 50 participants in our review. Willemsen-Swinkels et al. (1995) included seven participants with autism but no SIB (seven out of 33 or 21%). We have not included these seven participants in our review. We included the Willemsen-Swinkels et al. (1995) trial as it would have potentially been a waste of useful information and data on pertinent SIB outcomes. Four trials (Sandman et al., 1990; Symons et al., 2001; Thompson et al., 1994; Willemsen-Swinkels et al., 1995) examined the effect of naltrexone (opioid receptor antagonist) versus placebo and one trial (Lewis et al., 1996) examined clomipramine (serotonin reuptake inhibitor), an antidepressant, versus placebo. All trials were conducted in the USA except the Willemsen-Swinkels et al. (1995) trial, which was conducted in the Netherlands. All were prospective, randomised, double-blinded, placebocontrolled trials and had a cross-over design. The trials lasted 4–19 weeks. Following the publication of our Cochrane review, we found one more study that met our inclusion criteria but was missed in our original search (Barrera et al., 1994). We have summarised this study in Appendix 2 in Supplementary Material. This was a small study with four participants and did not show statistically significant benefits with use of naltrexone. The results of this study would not have made a difference to our conclusion.

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In Sandman et al. (1990), three participants were not on any medication while one was on thioridazine (melaril). In Thompson et al. (1994), one participant was on dilantin and three on carbamazepine for seizure disorders. Two participants in the trial of Symons et al. (2001) had seizure disorder and were maintained on anti-epileptics, while two participants were on antipsychotics. In the trial of Willemsen-Swinkels et al., five had history of epilepsy and were on anti-epileptics. Eleven were receiving neuroleptics. Dosages of co-medications remained fixed throughout the study period. Forms of SIB in the four trials included head banging, body hitting, head hitting (including eye, nose, throat, ear and face), hand hitting, self-biting (including arm and finger biting), selfhitting, hair pulling, face pinching and hitting, self-rubbing or scratching and rocking. Of the four trials examining naltrexone, the Sandman et al. (1990) trial used a double-blind Latin-square design, where the four participants received naltrexone tablets at one of these doses – 0, 25, 50 and 100 mg at 08.00 hours on Monday and Wednesday only. Symons et al. (2001) reported that the naltrexone dose was based on body weight (1.5 mg/kg) and administered orally at 08.00 hours. Each phase lasted for 2 weeks and each phase was separated by 1 week. In the trial of Thompson et al. (1994), each participant received 50 mg or 100 mg/day of naltrexone or placebo for a 2-week period, with periods arranged in a different order for each subject. Half of the participants were randomly assigned to receive clonidine concurrently with naltrexone and the other half received placebo concurrently with naltrexone. All medications were administered once daily at 08.00 hours in the form of three tablets. For the four participants receiving clonidine, placebo was gradually substituted over a 6-day period (clonidine gradually reduced to 0.2 mg for 3 days and 0.1 mg for another 3 days). In the Willemsen-Swinkels et al. (1995) trial at the beginning of week 3, a single dose of naltrexone 100 mg or placebo was administered (33 people). For remainder of that week, all participants received a placebo capsule each day. Subsequently, a 4-week treatment of naltrexone or placebo was given, followed by a 4-week washout period and then a crossover to the other treatment. In the first 4 weeks, 19 participants received 50 mg/day naltrexone. As 50 mg naltrexone had no effect, the long-term dose for the second cohort of 14 participants was 150 mg/day.

Characteristics of the clomipramine trial Figure 1.  Study flow diagram. RCT: random controlled trial.

Characteristics of the four naltrexone trials There were 49 participants in total but only 42 participants with SIB. The seven participants without SIB from the Willemsen-Swinkels et al. (1995) study were excluded. The degree of ID was classified as severe to profound in all trials except in the Willemsen-Swinkels study, where it ranged from mild to profound. The mean age ranged between 24.8 years to 39.3 years. There were 39 males and 10 females, seven of whom from the Willemsen-Swinkels study did not have SIB.

This included eight participants who presented with SIB and had severe to profound ID. The age ranged between 21 and 39 years. Three were female and five were male. Three participants had seizure disorder but were not receiving anticonvulsant medication and had been seizure-free for at least 6 months prior to entering the trial. Five participants were receiving antipsychotic medication. Three were maintained on thioridazine (75–200 mg), one was maintained on same dose of thiozanthene (19 mg/day) and one on same dose of chlorpromazine (125 mg/day) throughout the study period. Type of SIB included hand to face/head hitting, biting hand/ wrist, rubbing, hitting fist to chest, pulling hair and kicking legs. The trial of Lewis et al. (1996) had a single-blind placebo condition (weeks 1–2), which was followed by a double-blind placebo or clomipramine condition (weeks 3–9). This involved a

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titration up phase (weeks 3–5) where clomipramine was increased by 25 mg every other day to a maximum of 3 mg/kg body weight, a maintenance phase (weeks 6–9), during which the dose was 3 mg/kg body weight, and a titration down phase (week 10), where clomipramine was reduced by 50 mg every day. Cross-over manipulation involved a second titration-up phase (weeks 10 to 12), a second maintenance phase (weeks 13 to 16), a second titration-down phase (week 17), followed by a final single-blind placebo condition (weeks 18 to 19).

Outcomes All five trials measured and reported data on SIB rate (frequency) but there were some differences in other outcomes that studies focused on. We present outcomes according to the pharmacological agents used.

Naltrexone.  In the trial of Sandman et al. (1990), SIB and stereotypy were scored in terms of frequency of occurrence of each behaviour by reviewing videotapes. The participants were videotaped for 10 min in their normal surroundings in the mornings and afternoon. Level of activity was rated on a 5-point scale ranging from ‘no activity’ to ‘very high activity’ to see if the effect of naltrexone was purely due to the sedative effect of naltrexone. Differences between placebo and naltrexone were computed when the placebo rate was the highest, during low rate periods and combined morning and afternoon measures. As the participants differed in their base rates during placebo conditions, the data for each participant were normalised for parametric statistical analysis. Normalisation was calculated within participants and the z score transform used in computing t tests of paired observations between treatment conditions. The Connors’ Teachers Rating Scale (Conners, 1969) was adapted and used to record the activity, aggression and emotional lability. The Vineland Adaptive Behaviour Scale (Sparrow et al., 1984) was used to assess the social, motor, maladaptive, communication and daily living domains and presented as raw scores. The Symons et al. (2001) study measured SIB by directly observing and recording its frequency for one participant and frequency and duration for the other three participants. SIB recorded continuously was referred to as a ‘bout’. Direct observation was conducted in the participants’ daytime setting within groups of both staff and peers during activities of daily living. The effects of naltrexone were deemed to be clinically significant if there was at least a 33% reduction in self-injury. The sequential dependency between antecedent staff interaction and self-injury was examined for each participant. Yule’s Q (transformed odds ratio bound by –1.0 and 1.0, which controls for the total number of coded behaviours) was calculated as an index of sequential dependency for self-injury occurring within 5 seconds of staff prompting for time-based analyses or for self-injury occurring as the next event. In the trial of Thompson et al. (1994), the target classes of SIB were the three most frequent patterns shown by each individual as revealed by videotaped samples and interviewing staff. Frequency and intensity of these target behaviours were recorded in 5-min blocks randomly distributed throughout the day programme hours. An average of nine 5-min observations per subject per day were scheduled.

Willemsen-Swinkels et al. (1995) measured SIB rate on a 5-point rating scale that formed part of the Aberrant Behaviour Checklist (ABC) (Aman et al., 1985). A list of target behaviours compiled by authors was rated on a 5-point rating scale. At the end of a treatment period, staff rated the participants’ behavioural change on the Clinical Global Impression Scale (CGIS) (National Institute of Mental Health, 1985), which uses a 7-point scale, ranging from ‘very much improved’ to ‘very much worse’. Participants were observed twice at baseline (at beginning and end of placebo period), 6 and 24 hours after the single dose administration and after 2 and 4 weeks of daily treatment. Each observation was made up of two separate blocks, each being 10 min. Treatment emergent adverse effects were assessed through active questioning of the staff and participants during treatment and at the end point. Liver functions were screened as well. The single-dose study was analysed with repeated measures analysis of variance using SPSS-PC software with drug as within-subject factor and diagnosis as the between-subject factor. The data relating to the long-term treatment were analysed in a similar way but with the additional between-subject factor of time and dose. Baseline scores were used as covariates. The Barlett Box-F was used to test for homogeneity of variance. The Box-M was used as a multivariate test for equality of the variance-covariance matrixes. All testing was two tailed, with alpha = 0.05.

Clomipramine.  In Lewis et al. (1996), frequency of SIB was measured by direct observation by using general definitions for each category of behaviour. Intensity of SIB was quantified using a standard 5-point Likert scale. Measurements in the classroom setting by teachers were obtained at the end of each week of the study period using the ABC (Aman, 1985). Daily care provider ratings of SIB were obtained to assess whether drug treatment affected staff requirements for management of problem behaviours. The criterion for significant improvement was at least 50% reduction in SIB during clomipramine maintenance phase from placebo maintenance phase. Other outcomes reported in the trial included stereotypy, compulsions and selfrestraint. The effects of clomipramine on SIB frequency and intensity were assessed by comparing the placebo maintenance phase to the drug maintenance phase for all participants by paired t test, with alpha = 0.05. Percentage change in outcome measures from placebo to drug and the number of participants exhibiting a clinically significant response to clomipramine were also reported. Individual subject percentage change in SIB from average SIB frequency was reported in the living unit and classroom settings.

Measuring adverse events In the trial of Symons et al. (2001), side effects were monitored daily (vital signs) and weekly (adverse effects). In the trial of Thompson et al. (1994), a drug side effects checklist was constructed as well as general observation and monitoring of side effects, based on the most frequently reported side effects of naltrexone and clonidine. This checklist was administered weekly by a staff member and answered on a 3-point scale, which included ‘not at all’, ‘occasionally’ and ‘frequently’. Willemsen-Swinkels et al. (1995) reported treatment

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to be at ‘low risk of bias’, ‘high risk of bias’ or ‘unclear risk of bias’.

Effects of intervention in naltrexone versus placebo Four trials reported a comparison of naltrexone versus placebo (Sandman et al., 1990; Symons et al., 2001; Thompson et al., 1994; Willemsen-Swinkels et al., 1995). The four trials included 49 participants in total but only 42 participants with SIB.

Figure 2.  Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.  Risk of bias summary: review authors’ judgements about each risk of bias item for each included study.

emergent adverse effects. These were assessed by active questioning of staff and participants during treatment and end point. To evaluate the safety of naltrexone, liver functions were screened (levels of serum aspartate aminotransferase, serum alanine aminotransferase, alkaline phosphatase and bilirubin). Adverse events in the trial of Sandman et al. (1990) were not reported. In the Lewis et al. (1996) trial, nurses recorded weekly medication-related side effects using a modified version of the Treatment Emergent Side Effects Scale (Rapoport et al., 1985).

Risk of bias in included studies We used The Cochrane Collaboration’s tool for assessing risk of bias (Higgins and Green, 2008). The risk of bias within each included trial was assessed based on six domains (see Figures 2 and 3), with review authors judging each risk of bias component

Self-injurious behaviour rate.  Sandman et al. (1990) reported that naltrexone attenuated SIB in all four participants. The effect of naltrexone was dose dependent for three participants and 100 mg produced the largest clinically noticeable decrease in SIB, although one participant responded favourably to 25 mg and 50 mg but not to 100 mg. All ratings on level of activity remained between two and four, which indicated that self-injury reduction was not due to sedation from naltrexone. The 25 mg and 50 mg doses produced a statistically significant decrease in rate of SIB (t = 3.38, p < 0.05 and t = 7.49, p< 0.01 for 25 and 50 mg doses, respectively). However, the 100 mg dose did not achieve statistical significance. The Symons et al. (2001) trial reported that naltrexone had clinically significant effects (≥ 33% reduction) on the daily rates of three of the four participants’ most severe form of self-injury and resulted in modest to substantial reductions in SIB for all participants. The criteria for clinical significance was determined a priori based on previous research findings. Statistical data on change in SIB were not given. This study also examined sequential dependency between antecedent staff interaction and selfinjury for each subject. For all four participants, the magnitude of the sequential dependency between staff behaviour and self-injury was significantly greater during treatment with naltrexone than during treatment with a placebo as shown by Yule’s Q with z and p value. For participant 1, sequential dependency (Yule’s Q = 0.51) between staff prompting and self-injury was significant during naltrexone treatment (z = 2.81, p < 0.001) but not with placebo (Yule’s Q = 0.45). The sequential dependency (Yule’s Q = 0.45) between staff prompting and self-injury for the second participant was significant during naltrexone treatment (z = 2.66, p < 0.004) but not placebo (Yule’s Q = 0.25). For participant 3, sequential dependency (Yule’s Q = -0.31 ) was significant (z = –3.92, p < 0.001) with naltrexone but not placebo (Yule’s Q = 0.02). For participant 4, again the sequential dependency was significant with naltrexone (Yule’s Q = 0.45) with (z = 1.74, p < 0.04). The Thompson et al. (1994) trial reported that the percentage of days (that is, days with low frequency of SIB) in the first quarter of the overall distribution of frequency of SIB during the baseline condition (see description of included studies section for further details) was significantly lower than in the 50 mg drug treatment phase (p < 0.05). The percentage of days in the fourth quarter of the overall distribution in the baseline condition was significantly higher than in the 50 mg drug treatment phase (p < 0.05). The same pattern was found when comparing the baseline condition and the 100 mg drug treatment condition for the first and fourth quarters. These analyses indicate that naltrexone administration was associated with statistically significantly fewer days of high frequency self-injury and significantly more days with low-frequency self-injury. No significant differences

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were found in the percentages of days in the first and fourth quarter of the distribution between 50 and 100 mg naltrexone dosages (p < 0.05) for the first and fourth quarter. Naltrexone had different effects depending on the form/location of the self-injury. Because there were only data for a maximum of 10 days per phase and the measures in question tended to vary considerably from day to day, it was difficult to evaluate treatment effects within individuals. However, the trial reported that hand-to-head and head-to-object self-injury were more likely to be reduced by naltrexone treatment than were other forms of self-injury. In the trial of Willemsen-Swinkels et al. (1995), neither the single dose nor long-term treatment with naltrexone revealed any significant effects on SIB as measured in the ABC questionnaire and the target checklist. In fact, according to the CGIS ratings given by staff, treatment with placebo seemed more beneficial than the 4-week treatment with 50 mg/day naltrexone. In addition, naltrexone treatment tended to be associated with an increase in stereotypic behaviour as rated by the care staff (preand post-treatment values given as mean and SD). This increase was independent of diagnosis or dose. The authors presented results graphically but numerical data were not reported. No significant correlations were found between behavioural changes following a single dose of naltrexone hydrochloride, 100 mg, and following a 4-week treatment with 50 mg or 150 mg.

Stereotypy.  The Sandman et al. (1990) trial reported the average difference of normalised values that reflected changes in stereotypy after treatment with naltrexone. There was no effect of naltrexone, or even a small increase of stereotypy at 50 mg. Inspection of the individual participants suggested that stereotypy decreased in two participants, increased at all doses in one participant and increased precipitously at 50 mg in one participant. None of the effects of naltrexone on stereotypy were statistically significant. In the trial of Willemsen-Swinkelset al. (1995), naltrexone treatment tended to be associated with an increase in stereotypic behaviour as rated by care staff. This increase was independent of diagnosis or dose.

Adverse events.  Thompson et al. (1994) reported physiological measures that included assessing liver enzyme (serum glutamic oxaloacetic transaminase (SGOT) and gamma-glutamyl transpeptidase (GGT)) test values prior to beginning naltrexone, after 2 weeks of 50 mg and 2 weeks of 100 mg of naltrexone per day and during the week following termination of naltrexone. This was assessed using a 2-point rate reaction and a manual method. There were no consistent trends in SGOT and GGT from baseline to either naltrexone dose for any subject and all values fell within the normal reference range. There were no statistically significant differences in SGOT and GGT levels between baseline, the 50 mg dosage condition (SGOT and GGT; p > 0.05) and the 100 mg dosage condition (SGOT and GGT; p > 0.05).Results of liver function profiles for all participants in the Willemsen-Swinkels et al. (1995) trial were normal and did not deviate from the normal range following the administration of naltrexone. Other physiological measures in Thompson et al. (1994) included mean systolic and diastolic blood pressure and mean pulse rate. There were no statistically significant differences in any of these outcomes. It was also interesting to note that there was no statistically significant difference in the duration of sleep

for participants during the naltrexone and clonidine combination phase and their average level of sleep. The trial of Willemsen-Swinkels et al. (1995) reported that one participant complained of nausea and tiredness. No severe adverse events were noted in the trial of Symons et al. (2001). Information on adverse events was not reported in the Sandman et al. (1990) trial.

Effects of intervention in clomipramine versus placebo The trial of Lewis et al. (1996) reported a comparison of clomipramine versus placebo in eight participants. The effects of clomipramine on SIB frequency and intensity were assessed by comparing placebo maintenance phase to drug maintenance phase for all participants by paired t test, with alpha = 0.05. A 50% reduction in SIB during the double-blind clomipramine maintenance phase from the placebo maintenance phase was set as the criterion for establishing clinically significant improvement. The number of participants meeting this criterion was compared to the number of participants who showed a similar level of change from the first to the second single-blind, placebo phase participants. No statistically significant group differences were found when comparing placebo to active drug for any outcome measure.

Self-injurious behaviour rate.  Six of the participants exhibited a clinically significant improvement (≥ 50% reduction from placebo) in the frequency of SIB. Four participants exhibited this level of improvement in the living unit, whereas three met the 50% or greater improvement criterion in the classroom setting. None of the participants exhibited a 50% or greater variation from one single-blind condition to the other in the living unit, whereas two participants did so in the classroom.

Self-injurious behaviour intensity.  Three of the eight participants showed a 50% or greater reduction in the ratings of SIB intensity in the living unit whereas none of the participants met this criterion in the classroom setting. Care provider intervention ratings were recorded as the mean percentage of study days that staff intervention was required for behaviour management for participants in the placebo and clomipramine phases. Behavioural intervention by staff was required on a substantially lower percentage of days during the clomipramine maintenance phase compared to placebo maintenance phase. Altogether, 63% of participants exhibited a clinically significant clomipramine-related reduction from placebo on this measure.

Stereotypy. Three of the eight participants showed a 50% or greater reduction in stereotypy frequency, two of these noted in the living unit and one in the classroom.

Self-restraint. None of the participants exhibited a 50% or greater reduction in self-restraint in the living unit, whereas in the classroom two participants met this criterion.

Compulsive behaviour.  Two participants, in addition to self-injury and stereotypies, exhibited compulsive behaviour. Clomipramine

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Gormez et al. treatment resulted in a marked and clinically significant reduction in this behaviour in one participant.

Adverse events.  A total of eight side effects were reported for all participants during the placebo phase compared to six for participants during the clomipramine phase. Nine adverse events were reported during the trial. Of these six side effects, four (constipation, increased appetite, heart pounding, increased frequency of urination) appeared at increased frequency and severity relative to placebo. None of the above side effects was treatment limiting. The most prevalent clomipramine-related side effect was heart pounding, reported in 50% of the participants. Two of the participants (25%) had treatment limiting side effects other than those listed on the rating scale. These included seizure for one subject and worsening of mood and tachycardia for one subject during clomipramine maintenance phase participants.

Discussion We found five double-blind, placebo-controlled trials that met our inclusion criteria. These trials assessed the effectiveness and safety of drugs in participants with IDs demonstrating SIB. Four trials compared the effects of naltrexone versus placebo and one trial compared clomipramine treatment versus placebo. From this review, there is conflicting evidence that naltrexone is efficacious in management of SIB for people with IDs. It is also difficult to draw any firm conclusions about efficacy of clomipramine as there was only one study in this review although it did report some clinical benefit. The review was incomplete in terms of comparing all available modalities of treatment for SIB, for example, there were no trials comparing antidepressants other than clomipramine, antipsychotics, mood stabilisers or beta-blockers, regardless of dosage, against placebo. Four of the trials in the review appeared to address adverse effects in the active drug and placebo phases of the trial, but again the numbers were small or were specified in the methods but not noted in the results section (so probably were not observed but this is not explicitly stated) so it was not possible to make definite conclusions. It is important to note that all of the studies were done in large, state residential units. In recent years, large institutions have closed and care is being provided in smaller community settings and peoples’ own homes. The participants in the trials were all having severe-profound ID except Willemsen-Swinkels et al.’s (1995) study, which had participants with mild to profound ID. None of the trials lasted more than 19 weeks. Therefore it is difficult to generalise the findings of this review to a community sample. Given their widespread use, there is a need for further research to establish the efficacy, safety and acceptability of pharmacological interventions for SIB in this population. This may necessitate not only efficacy trials of pharmacological interventions (compared with placebo and compared one to another), but trials comparing pharmacological with other, nonpharmacological ways of management. Observational studies may be needed to answer questions of acceptability and safety (or adverse consequences).

Acknowledgements We would like to thank Cochrane Developmental, Psychosocial and Learning Problems Group including Geraldine Macdonald for her useful feedback and Laura MacDonald for her support during the writing of the review.

Conflict of interest The authors declare that there are no conflict of interest.

Funding This review received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Pharmacological interventions for self-injurious behaviour in adults with intellectual disabilities: Abridged republication of a Cochrane systematic review.

We aimed to determine clinical effectiveness of pharmacological interventions for self-injurious behaviour in adults with intellectual disability. We ...
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