The neurobiology of aggression: implications for the pharmacotherapy of aggressive challenging behaviour by people with intellectual disabilities.

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Journal of Intellectual Disability Research

doi: 10.1111/jir.12120

1

Invited review

The neurobiology of aggression: implications for the pharmacotherapy of aggressive challenging behaviour by people with intellectual disabilities Paul Willner Department of Psychology, Swansea University, Swansea, UK

Abstract Aim The aim of this review is to summarise current understanding of the neurobiology of aggression and within this context to consider the evidence base for the pharmacotherapy of aggressive challenging behaviour by people with intellectual disabilities (ID). Evidence Aggressive encounters involve a variety of psychological processes and progress has been made in understanding the brain mechanisms involved. However, the role in aggression of the neurotransmitters serotonin, dopamine and γ-aminobutyric acid is no longer as clear as it once appeared, with the result that predictions cannot be made with confidence about drug effects on aggression. There have been relatively few controlled trials of pharmacotherapy for aggression in people with ID, or, indeed, in the general population, and their outcomes have largely been negative. Conclusion With the possible exception of risperidone, there is no reliable evidence that antidepressant, neuroleptic or anticonvulsant drugs are effective treatments for aggression by people with ID. Correspondence: Prof. Paul Willner, Psychology, Swansea University, Swansea SA2 8PP UK (e-mail: [email protected]).

Keywords aggression, anticonvulsant, antidepressant, intellectual disability, neuroleptic, pharmacotherapy

Introduction Aggressive acts can be defined by harm to others, or the intent to cause harm or threaten others, and the key neural circuits in the brain related to acts of aggression are linked to the regulation of social behaviour (Nelson & Trainor 2007). A recent review of studies of aggressive challenging behaviour among people with intellectual disabilities (ID) reported that over half of the population display some form of aggression (Benson & Brooks 2008), and people with ID are also significantly more likely to be victims of aggression (Hughes et al. 2012). Aggression is one of the main reasons that people with ID are referred to specialist services (Willner et al. 2013a). Perhaps this is not surprising, because people with ID rarely refer themselves for psychological or psychiatric help: rather, they are usually referred when their behaviour becomes a problem for someone else. It may also be for this reason that most of the research on psychotherapeutic interventions with this population concerns anger and

© 2014 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd

Journal of Intellectual Disability Research 2 P. Willner • Neurobiology of aggression

aggression (Willner et al. 2013a). The fact that people are commonly referred for help by others also highlights the inter-personal nature of aggression. Aggressive outbursts can make it difficult to form and maintain relationships and lead to exclusion from educational, work and social settings, as well as the breakdown of living situations (Allen 2000; Antonacci et al. 2008). The aim of this review is to summarise current understanding of the neurobiology of aggression and within this context to consider the evidence base for the pharmacotherapy of aggressive challenging behaviour by people with ID. As such, the paper provides a brief account of the brain structures thought to be involved in the preparation for and commission of acts of aggression, and a more detailed account of the neurochemical systems that form the substrate for psychotropic drug action. This provides a context for understanding not only why certain drugs have been considered as candidates to decrease aggression, but also why clinical trials of those drugs have been disappointing. In order to achieve a comprehensive perspective on the current status of drug treatment of aggression in people with ID, the sections that follow which deal with this issue are based on a PubMed search (August 2012) using the keywords ‘aggression or anger’, ‘drug’ and [‘(intellectual or learning) disability’ or ‘mental retardation’]. (A repeat of this search in August 2013 did not reveal any additional publications.) The discussion is based primarily on randomised controlled trials where they exist, but also cites studies that used weaker designs where they do not.

Types of aggression Aggression may be reactive or proactive. Reactive aggression refers to a tendency to react in an immediate and angry fashion to a perceived threat, slight or problem; proactive (or instrumental) aggression refers to situations in which someone behaves aggressively as a means of achieving a particular goal. Reactive aggression is usually considered to be part of the defence system – the ‘fight’ element of the ‘fight or flight’ response to threat. This set of biologically programmed instincts exists universally throughout the vertebrate kingdom.

However, reactive aggression is not purely reflexive: experience determines which threatening situations are more effectively managed by fight or flight, or by a third response option, social withdrawal (‘freezing’). Learning about the consequences of aggression also operates to shape its components, such as whether aggression is expressed verbally or physically or how intensely it can safely be expressed. By contrast, proactive aggression is offensive, and serves a different neurobiological function, securing access to resources. Proactive aggression is the mechanism that individuals at the top of a social hierarchy use to maintain their social dominance, or that non-social animals use to defend territory. A common expression of offensive aggression within human social groups is bullying, but it might also reflect the effort of an individual of low social rank to achieve higher social status or influence. Reactive and proactive aggression can, with some difficulty, be distinguished in the general population (Little et al. 2003), but the situation in people with ID is less clear (Matlock & Aman 2011). In practice, aggressive encounters may involve both reactive and proactive elements as the situation develops and the social relationship evolves (Jahoda et al. 2001). Nevertheless, There is good reason to suppose that the incidence of proactive aggression decreases as the extent of ID increases. Proactive aggression is expressed mainly by people who perceive themselves as having high social status and the objective basis for such a self-perception decreases the more extreme a person’s disability. Also, whereas reactive aggression is typically impulsive in its expression, proactive aggression may often be planned, and this may be beyond the capacity of people with more extensive ID. For both of these reasons, people with more severe disabilities are far more likely to be victims of proactive aggression than perpetrators, and the aggression that they display may be more likely to be reactive in nature. There is preliminary evidence to support this trend (Matlock & Aman 2011). This view is apparently at odds with a report that those with more severe disabilities presented more aggression of all types (Cooper et al. 2009). However, that study only included aggressive participants without any other clinically significant mental health problems. Mental health problems are far more difficult to detect



among people with more significant impairments, who are unable to provide verbal reports of their distress, potentially resulting in a higher proportion of those with significant impairments being categorised as aggressive. This discrepancy also highlights the difficulty of categorising the aggressive behaviour of people with more severe ID, who are less able to reflect on their actions or the harm caused to others.

Behavioural processes and brain mechanisms in aggression Reactive aggression may arise either from an increased propensity to behave aggressively, or by a decreased ability to inhibit the expression of aggressive behaviour: so-called ‘bottom-up’ and ‘topdown’ mechanisms. This concept is common both to a neurobiological analysis of aggression and to social information-processing models, which have been used to explain social behaviours, including aggression, by outlining the sequence of cognitive processes that occur between encountering and processing social cues, and enacting a response (Crick & Dodge 1996; Larkin et al. 2013). There is an extensive literature on the neurobiology of defensive/reactive/impulsive aggression, based on studies in rodent and primate models, and in humans who display irritable or impulsive aggression. The ‘bottom-up’ propensity to behave aggressively involves both input systems (the appraisal of aggression-provoking cues) and output systems (the organisation of aggressive acts) (Nelson & Trainor 2007; Siever 2008). The recognition of emotions in voices and faces involves primarily activity in the superior temporal gyrus and sulcus, respectively, with onward transmission of information to the amygdala and prefrontal cortex (Fruhholz & Grandjean 2012; Said et al. 2012). The key brain structure in social cognition is the medial prefrontal cortex, acting through extensive networks of cortical-subcortical connections. The appraisal of the emotional significance of incoming self-relevant information involves a ventral network comprising the ventromedial prefrontal and anterior cingulate cortices and subcortical structures including the amygdala and nucleus accumbens (Phillips et al.

2003; Ochsner et al. 2004; Northoff et al. 2006; Schmitz & Johnson 2007; Forbes & Grafman 2010). The amygdala is the major brain structure implicated in the propensity to respond aggressively. The amygdala performs the general function of computing the affective value of stimuli in the environment (Morrison & Salzman 2010). It is activated by threat stimuli and these responses are greater in individuals who display high levels of anger (Coccaro et al. 2007; Siever 2008). This appraisal is transmitted to output structures, including the nucleus accumbens and other parts of the basal ganglia, and the periaqueductal grey which has a specific role in the generation of species-specific aggressive behaviours. Activation of the amygdala also propagates to other ‘emotional’ brain structures such as the hypothalamus, leading to an increase in circulating levels of corticosteroids, the classic biological marker of an acute emotional state. In rodents, lesions of the medial amygdala decrease aggression (Nelson & Trainor 2007; Siever 2008). The ‘top-down’ control of aggressive behaviour, which involves planning and decision-making, and the initiation, sequencing and termination of patterns of behaviour (Nelson & Trainor 2007; Siever 2008), derives from the ventromedial prefrontal cortex, which, as described above, also plays a major role in the appraisal of social information (Forbes & Grafman 2010). Damage to ventral frontal regions causes social disinhibition and increased aggression, and levels of activity in these regions are low in individuals who display high levels of reactive aggression (Nelson & Trainor 2007), particularly when exposed to experimental manipulations designed to induce aggressive responses (Siever 2008). The top-down control by the ventromedial prefrontal cortex is exerted primarily over the amygdala, so there is a reciprocal relationship between activity in these two structures: reactive aggression is associated with low levels of activity in the ventromedial prefrontal cortex and a disinhibited amygdala. In contrast to the rich literature on reactive aggression, less is known about the neurobiology of offensive/proactive aggression (Haller & Kruk 2006). The major finding is that proactive aggression is in several respects diametrically opposite to reactive aggression: it tends to involve ‘cold’ emotion, which in individuals with antisocial



personality disorders is associated with low levels of circulating corticosteroids (Kim & Haller 2007) and of amygdala activity (Blair 2004). These neurobiological differences suggest that individuals characterised by high levels of proactive or reactive aggression might require different treatment approaches. However, there is also evidence for hypofunction of ventral prefrontal cortical regions in people with antisocial personality disorders (Koenigs 2012), suggesting that self-management of both reactive and proactive aggression would benefit from an improved ability to exercise inhibitory control. A number of genetic syndromes causing ID are associated with high levels of aggression, involving different psychological mechanisms: for example, aggression in Smith–Magenis syndrome is maintained by attention from carers (Taylor & Oliver 2008), but aggression in Angelman syndrome is not (Strachan et al. 2009). In Fragile X syndrome, one of the most common forms of inherited cognitive impairment, abnormalities of face processing have been reported, associated with abnormal patterns of activation in the amygdala and anterior cingulate cortex (Schneider et al. 2009). These findings in Smith–Magenis and Fragile X syndromes indicate that discrete relationships between specific brain mechanisms and specific aspects of aggression are possible; in practice, however, such relationships have rarely been identified. In some conditions, including Fragile X syndrome (Schneider et al. 2009) and Rett syndrome (Fyffe et al. 2008), identification of the specific genetic abnormality has enabled the creation of genetically modified mouse strains that carry the same mutation, which can then be used to investigate the neurobiological pathway linking gene to behaviour. However, these genetic studies are the exception: in general, the neural mechanisms underlying aggression in people with ID, and whether or to what extent they differ from those that operate in the general population, are largely unknown.

Neuropharmacology and pharmacological treatment of aggression Many neurotransmitters are known to be implicated in aggressive behaviour, but there is considerable

uncertainty regarding the specific behavioural processes and brain regions in which they are involved. A simple account of the neurochemistry of aggression links γ-aminobutyric acid (GABA), dopamine and serotonin (5-hydroxytryptamine: 5-HT), respectively, to appraisal of aggression-provoking cues, organisation of aggressive acts, and ‘top-down’ inhibition of aggressive behaviour via actions in the amygdala, nucleus accumbens and prefrontal cortex respectively. These relationships give rise to clear predictions for how drugs interacting with these systems might be expected to influence aggressive behaviour, and if confirmed, would support the use of mood stabilisers (some of which are GABA agonists), neuroleptics (which are dopamine antagonists) and antidepressants (which potentiate 5HT) to control aggressive challenging behaviour. However, each of these neurotransmitters is located in neurones projecting (dopamine and 5HT) or intrinsic (GABA) to multiple brain regions, and there is very little evidence to support anatomical specificity of drug actions on aggressive behaviour. Because drugs interact with neurotransmitters in a diversity of brain regions there is a corresponding diversity of behavioural outputs, and they also act via an array of receptors with different properties, some of which counteract one another. There are also extensive interactions between neurotransmitter systems. As a result, many discrepancies are apparent, which seriously undermine the prospects for specific anti-aggressive drugs.

5HT These problems are well illustrated by research involving the neurotransmitter that has been most studied in this context, 5HT. A decrease in wholebrain 5HT turnover was first identified as a correlate of depression, later narrowed to suicide, then broadened to aggression (self- and other-directed), and now understood to relate to a trait of impulsivity and an involvement in a wide range of psychopathological conditions characterised by risky and impulsive decision-making (Homberg 2012). Consistent with these observations, aggression is typically increased in rodents and primates by brain lesions and other manipulations that decrease 5HT function, and decreased by drugs that increase 5HT function, such as specific serotonin reuptake



inhibitors (SSRIs) or agonists at 5HT1A or 5HT1B receptors (Siever 2008). However, this is not the whole story. For example, while acute treatment with SSRIs generally decreases aggression, chronic treatment increases aggression by subordinate animals (Mitchell 2005). And while 5HT1A receptor agonists do potently decrease aggression, this effect is seen only at doses where other behaviours are also compromised. Also, 5HT1A receptors are found in many cortical and subcortical brain areas and it is far from certain that the prefrontal cortex is the site of their anti-aggressive action. It is also uncertain whether these drugs achieve their antiaggressive effects by increasing 5HT function through an action at postsynaptic receptors or by decreasing 5HT function through an action at inhibitory presynaptic receptors (Miczek et al. 2002; Takahashi et al. 2011). Similar problems apply to 5HT1B receptor agonists, which are sometimes described as ‘serenics’ because they were claimed to have specific anti-aggressive effects: like 5HT1A receptors, 5HT1B receptors are found both postand pre-synaptically, with opposite functional consequences, and in numerous brain regions. Indeed, 5HT1A and 1B receptor agonists have been found to decrease aggression when administered in 5HT cell body regions (so decreasing 5HT release) and to increase some forms of aggression, while decreasing others, when administered in some terminal regions, including medial prefrontal cortex (Takahashi et al. 2011). To complicate matters even further, anti-aggressive effects are also seen with drugs that act as antagonists at 5HT2A/3C receptors, although similar effects are also seen with agonists at these same receptors; again, drug doses that produce these effects also tend to compromise other behaviours (Miczek et al. 2002; Takahashi et al. 2011). Finally, in contrast to the putative association between aggression and low levels of 5HT activity in prefrontal cortex, aggression is promoted by high levels of 5HT in the amygdala (Hariri et al. 2002). A simple summary of this research area is that progress has obscured a picture that was once deceptively clear. Antidepressant treatment Specific serotonin inhibitor (SSRI) antidepressants are used in the management of aggression on the

basis of the old idea that 5HT inhibits aggressive behaviour, but as discussed above, this idea is no longer persuasive. For example, a recent study reported that depletion of brain 5HT, which ‘should’ increase aggression either had no effect or decreased aggressive responses to provocation in volunteers playing a competitive game (Krämer et al. 2011). In the general population, the evidence to support the use of SSRI medication to manage aggressive behaviour is at best weak (Goedhard et al. 2006). There are no controlled studies of anti-aggressive effects of antidepressants in people with ID. A systematic review identified eight studies reporting uncontrolled case series, all but one of which included aggression alongside other target problem behaviours (Sohanpal et al. 2007). These studies included reports of increases, decreases and no change: the overall impression is that, in people with ID, antidepressant medication has no noticeable effect on aggression. One review commented ‘Given the high rate of SSRI use in this population, the complete dearth of well conducted studies for this class of medications is surprising’ (Ulzen & Powers 2008).

Dopamine Neurochemical studies in rodents have identified increased release of dopamine in the frontal cortex and nucleus accumbens during the initiation and performance of aggressive behaviours. Consistent with this evidence, antagonists at D1 and D2 dopamine receptors decrease aggression, while drugs that increase dopamine activity in some circumstances increase aggression. However, all of these observations also hold for submissive behaviour (de Almeida et al. 2005). Dopamine is known to play a general permissive role in arousal and behavioural programming, and it is likely that these general functions account for the anti-aggressive properties of dopamine receptor antagonists, rather than a specific anti-aggressive effect. Neuroleptic treatment Antipsychotics (neuroleptics) are the drugs most commonly used to manage challenging behaviour in people with ID. They represent around half of all



psychotropic prescribing to people with ID (Robertson et al. 2000; Paton et al. 2011) with over 85% of prescriptions in force for more than 12 months (Paton et al. 2011). Challenging behaviour represents around 30% of these prescriptions (Deb & Fraser 1994), the majority of which are for people who are not psychotic (Tsiouris 2010; Paton et al. 2011). The drugs most commonly used are the second-generation (atypical) antipsychotics risperidone, olanzapine and quetiapine, and the first-generation (typical) antipsychotics chlorpromazine and haloperidol, with the former typically prescribed on a long-term basis and the latter as PRN medication (Paton et al. 2011). A review of randomised controlled trials of antipsychotic treatment of aggression in the general population concluded that there was some evidence to support an anti-aggressive action of atypical antipsychotics, but little evidence to support the use of typical antipsychotics (Goedhard et al. 2006). This conclusion was supported in a head to head comparison of atypical and typical antipsychotics (Krakowski et al. 2006). Indeed, there is some evidence that, in children and adolescents, the effectiveness of atypical antipsychotics is greater for aggression than for psychotic symptoms (Zuddas et al. 2011). The main difference between typical and atypical antipsychotics is that the former act primarily as dopamine receptor antagonists while the latter also have a prominent action as 5HT2A receptor antagonists (as well as affinity to other receptors). As dopamine receptor antagonists do not appear to have specific anti-aggressive (as distinct from general behaviour-suppressant) properties, the clinical superiority of atypical antipsychotics may reflect their action at 5HT2A, rather than dopamine, receptors. A Cochrane review of antipsychotic treatment of aggression in people with ID concluded that there was ‘no evidence of whether antipsychotic medication helps or harms adults with learning disability and challenging behaviour’ (Brylewski & Duggan 2004). However, all of the work surveyed in this review was published before 1999, and most of it before 1990. Later reviews have reached more positive conclusions, at least regarding risperidone (Deb et al. 2007; Ulzen & Powers 2008; Haessler & Reis 2010). Most of the evidence is from placebocontrolled studies in children and adolescents

(Findling et al. 2000; Buitelaar et al. 2001; Aman et al. 2002; Snyder et al. 2002) and one study that included both children and adults (Zarcone et al. 2001), all of which reported positive effects of risperidone. A later randomised controlled trial in adults again found risperidone to be superior to placebo (Gagiano et al. 2005). These results from controlled trials are supported by a substantial body of single and multiple case reports of anti-aggressive effects of the atypical antipsychotics risperidone, clozapine, olanazapine and quetiapine (Deb et al. 2007; Haessler & Reis 2010), and evidence of relapse following withdrawal of antipsychotic medication (Janowsky et al. 2006, 2011; Haessler et al. 2007). In contrast to these positive reports, a much-cited randomised controlled trial by Tyrer et al. (2008) reported that not only were risperidone and haloperidol not superior to placebo in the treatment of aggressive challenging behaviour, there was actually a tendency for drug-treated patients to do worse. However, the interpretation of these results is complicated by the presence of a massive placebo effect: all three groups showed around a 70% improvement within the first week of treatment, which is so far removed from clinical experience as to question the relevance of these findings. A more recent single-blind study reported substantial decreases in verbal and physical aggression in patients switched from typical antipsychotics to risperidone or olanzapine (Amore et al. 2011), again supporting their clinical efficacy. The dopamine releasing agent methylphenidate is used routinely in the treatment of children with attention-deficit hyperactivity disorder (ADHD), including those with a co-morbid ID (Rowles & Findling 2010). There is some evidence that methylphenidate decreases aggression in this context (Aman et al. 2003; Pearson et al. 2003), but the effect is less robust than in more intellectually able children, and is assumed to be secondary to improvements in the presentation of ADHD rather than an effect on aggression per se.

GABA Levels of GABA in subcortical structures have been found to correlate inversely with aggressiveness in both animal and human studies, and drugs that



increase the stimulation of GABA receptors, including benzodiazepines and anticonvulsants such as sodium valproate, also typically decrease aggressive behaviour (Miczek et al. 2002). Given the anxiolytic properties of GABA agonists, these anti-aggressive effects are thought to reflect a decrease in ‘irritability’, with the amygdala a likely candidate for the site of action (Siever 2008). However, again there are inconsistencies. Some GABA agonists, notably alcohol, increase aggression in some individuals, and other GABA agonists that typically decrease aggression increase aggression in some circumstances. Two hypotheses that have been advanced to explain these discrepancies are that GABA agonists may decrease reactive aggression but increase proactive aggression (Miczek et al. 2002), or that their effect on aggression is related to their affinity for different subunits of the GABA-A receptor complex, which differs in its subunit composition in different brain areas (de Almeida et al. 2005). Anticonvulsant treatment Mood stabilisers are the other major drug class that has been used to treat aggression. These drugs include anticonvulsants, which are GABA agonists (in addition to actions at other targets such as NMDA glutamate receptors and ion channels) (Söderpalm 2002) and lithium, which indirectly increases GABAergic neurotransmission (Malhi et al. 2013). A review of controlled trials in the general population concluded that these drugs appeared to decrease aggression, with significant effects reported for phenytoin, oxcarbamazepine/ carbamazepine and lithium (six studies in all). However, when studies with a high risk of bias were removed from the analysis, the effects disappeared (Jones et al. 2011). Again, there are no controlled trials in people with ID. A review of this area surveyed three uncontrolled trials of the effects of valproate or topiramate on a range of behaviour problems including aggression (Deb et al. 2008). All three studies claimed to demonstrate some degree of beneficial effects, but these results are uninterpretable without a placebo control group to compare against. There are also some small studies of lithium administration to people with ID, including a double-blind trial (Tyrer et al. 1993) and a

randomised controlled trial (Craft et al. 1987), both of which reported greater anti-aggressive effects with lithium than with placebo. However, these are old studies that would not have met current methodological standards. Moreover, a third, even earlier, controlled trial found no effect of lithium on aggression (Tyrer et al. 1984). Given the toxicity of lithium, the consequent need to monitor blood levels rigorously, and the paucity of positive evidence of antiaggressive effects in the general population, it is unlikely that lithium will re-emerge as a candidate drug for the treatment of aggression in people with ID.

Discussion We have focused on serotonin, dopamine and GABA because these are the neurochemical systems that, directly or indirectly, mediate the effects of almost all of the drugs that have been used to treat aggressive disorders. Unsurprisingly, considering the complexity of aggressive behaviours and the neural systems that control them, a variety of other neurotransmitters have also been implicated in aggression, including noradrenaline, the neurosteroids testosterone and oestrogen, the neuropeptides vasopressin and oxytocin, and endogenous opioids (Nelson & Trainor 2007; Siever 2008). In all cases, further work is needed to establish the behavioural specificity of these effects and/or the site of action. Drugs affecting these systems have not been tested for their effects on aggression in people with ID. On balance, the evidence supports the use of low doses of risperidone for the treatment of aggression by people with ID: more studies, particularly in adults, are needed. However, the neurobiological mechanism of this effect is uncertain, and animal studies suggest that, as with other ‘anti-aggressive’ agents, the anti-aggressive effect of risperidone is an aspect of a more general behavioural inhibition (Rodríguez-Arias et al. 1998; Ricci et al. 2007). Indeed, risperidone is approved in the USA and UK for the treatment of ‘irritability’ in children and adolescents with autism, including those with co-morbid ID (Stigler & McDougle 2008). The ‘third-generation’ neuroleptic aripiprazole has also been found to decrease ‘irritability’ in children and adolescents with autism, but the reports of these



studies provide no information about the intellectual ability of the participants (Farmer & Aman 2011). There is weaker evidence for other atypical neuroleptics, while the evidence does not support the use of typical neuroleptics, except as PRN medication. The evidence does not support the use of any other drugs to manage aggression. As aggression can decrease spontaneously and show large placebo effects, reliable evidence of drug effects can only come from well-designed controlled trials, and such evidence is both rare and, for the most part, old. Set alongside the literature on drug treatment, there is some evidence that aggression by people with ID can be managed effectively by behavioural (British Psychological Society 2005; Brosnan & Healy 2011) or cognitive behavioural (Nicoll & Beail 2013; Willner et al. 2013a,b) interventions, including a recent large randomised controlled trial (Willner et al. 2013a,b). There is a complete absence of evidence as to whether people receiving risperidone who are non-psychotic – the majority (Tsiouris 2010; Paton et al. 2011) – do better than they would if they received best-practice psychological support. This is a challenging research question (Courtemanche et al. 2011) but an important one because atypical antipsychotics, including risperidone, while safer than typical antipsychotics, do have significant side-effects, including sedation and weight gain (Deb & Unwin 2007; Maher et al. 2011).

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Accepted 12 December 2013


Behavioural and cognitive-behavioural interventions for outwardly-directed aggressive behaviour in people with intellectual disabilities.

Exploring Carers' Judgements of Responsibility and Control in Response to the Challenging Behaviour of People with Intellectual Disabilities.

Systematic review of restraint interventions for challenging behaviour among persons with intellectual disabilities: focus on experiences.

Modification of motivational interviewing for use with people with mild intellectual disability and challenging behaviour.

People with Intellectual Disabilities Talk About Sexuality: Implications for the Development of Sex Education.

Use of medication for challenging behaviour in people with intellectual disability.

Functional analysis of challenging behavior in people with severe intellectual disabilities.

A systematic review on the effect of exercise interventions on challenging behavior for people with intellectual disabilities.

Practice Leadership at the Front Line in Supporting People with Intellectual Disabilities and Challenging Behaviour: A Qualitative Study of Registered Managers of Community-based, Staffed Group homes.

New ways of seeing and being: Evaluating an acceptance and mindfulness group for parents of young people with intellectual disabilities who display challenging behaviour.

Assessing the Impact of Psychotropic Medication Changes on Challenging Behavior of Individuals with Intellectual Disabilities.

or autistic spectrum disorder--a systematic review.

The impact of health checks for people with intellectual disabilities: an updated systematic review of evidence.

Optimizing the uptake of health checks for people with intellectual disabilities.

The challenges of providing palliative care for people with intellectual disabilities: a literature review.

Global initiative of the special olympics movement for people with intellectual disabilities.

'It's my life': autonomy and people with intellectual disabilities.

Comparing two frailty concepts among older people with intellectual disabilities.

The meaning of 'community' in the lives of people with intellectual disabilities: an historical perspective.

[Frailty in people with intellectual disabilities: operationalization, risks and detection].

Biochemical measures and frailty in people with intellectual disabilities.

How do people with intellectual disabilities view abuse and abusers?

The experiences of people with dementia and intellectual disabilities with surveillance technologies in residential care.

Expanding Public Health Surveillance for People with Intellectual and Developmental Disabilities in the United States.