The Use of Medication for the Management of Problem (Challenging) Behaviour in Adults who have Intellectual Disabilities

Professor Shoumitro (Shoumi) Deb, MBBS, FRCPsych, MD, Imperial College London, Department of Medicine, Division of Brain Sciences (s.deb@imperial.ac.uk).

Introduction

Psychotropic medications such as antipsychotics, anti-depressants, mood stabilisers including anti-epileptic medications and lithium, anti-anxiety medications including benzodiazepines, psycho-stimulants, beta-adrenergic blockers, and opioid antagonists are used widely among people with intellectual disabilities (ID). The rate of use of these medications varies between 32% and 85%; some of these studies have reported the rate of antipsychotic use alone. These medications are used in addition to existing high use of medication for physical problems. These medications are used for both mental illness and also problem (challenging) behaviour for which they are not licenced. The expectation that the use of psychotropic medication will decrease considerably once people with ID move out of long-stay institutions into the community has never materialised. All the studies on this have found that the rate of psychotropic use has remained the same after discharge from institutions, some showing a decrease in antipsychotic use at the expense of increased anti-depressant use, although overall there is an increase in the use of new generation replacing old generation antipsychotics.

There is public concern regarding the use of psychotropic medication in individuals with ID for the management of problem behaviour in the absence of a diagnosed psychiatric disorder (see case study below). Some of the reasons for this concern are:

(a) excessive use of medication (poly-pharmacy, use of higher than recommended dose of antipsychotics); (b) long term use without reviews;

(c) worry about adverse effects which could be difficult to assess, and inappropriate concomitant use of drugs to counteract adverse effects;

(d) overall lack of evidence to support the effectiveness of psychotropic medications to manage problem behaviour including aggression;

(e) out of licence use of psychotropic medications;

(f) use of medication without explicit patient consent which often occurs in ID;

(g) difficulty in carrying out necessary investigations such as serum lithium level or blood tests for other adverse effects.

Despite the widespread condemnation of and lack of evidence for the use of poly-pharmacy (simultaneous use of more than one) of antipsychotic medications, this practice remains widespread. On the other hand, the merits and demerits of combining an antipsychotic with another group of psychotropic medication specifically for the management of problem behaviour in adults with ID are currently unknown.

Case study: Polypharmacy of psychotropic medication in people with intellectual disabilities.

• Risperidone 2.5 mgs
• Carbamazepine 2000 mgs
• Sodium Valproate 2700 mgs
• Lamotrigine 400 mgs
• Lithium Carbonate 1200 mgs
• Methylphenidate 5 mgs
• Procyclidine 15 mgs
• Ferrous Fumarate + Vitamins + Lactulose + cod liver oil + various skin ointments
• PRN (as required medication): Clobazam + Lorazepam
• Rectal diazepam + buccal midazolam as rescue medication for status epilepticus.

The above is not an atypical list of daily dose of medications for adults with intellectual disabilities. Notice the poly-pharmacy of psychotropic medication here; antipsychotic (risperidone) + antiepileptics (carbamazepine, sodium valproate, lamotrigine) + lithium (mood stabiliser) + psycho-stimulant (methylphenidate) + anticholinergic (procyclidine), and also the combination of three antiepileptic medication at a high dose. Both sodium valproate and carbamazepine are used at a higher than recommended dose. If used simultaneously with sodium valproate, the dose of lamotrigine should be lower. If risperidone and antiepileptics are already used why is lithium needed to be added to control behaviour? Also why is a psycho-stimulant used if already a number of psychotropics are used to control behaviour? If this is used for ADHD, why are the other psychotropics used for behaviour control? It seems that a number of psychotropic medications have been combined here in desperation without a proper formulation/rationale for this drug regime. Also, note that regular use of procyclidine with antipsychotics can precipitate tardive dyskinesia in a person with an underlying brain damage. Also, note the prescription of a large number of medications here for medical conditions over and above the psychotropic medication.

Although these cannot be seen as indications but psychiatrists usually consider psychotropic medications for the management of problem behaviour in individuals with ID under the following circumstances:

(a) failure of non-medication based interventions,

(b) risk/evidence of harm to others, property and self,

(c) high frequency and severity of problem behaviours,

(d) to treat an underlying psychiatric disorder or anxiety,

(e) to help with the implementation of non-medication based interventions such as positive behavioural support (with concurrent use of medication),

(f) risk of breakdown of the individual’s community placement,

(g) lack of adequate or available non-medication based interventions (although this should not be used as a rationale for using medication),

(h) good response to medication in the past,

(i) patient/caregiver choice.

Safety and tolerability

The issue of safety and tolerability is paramount in the case of people with ID as they may have a different metabolism than the general population that may create different pharmacokinetics and pharmacodynamics. They may be vulnerable to developing more adverse effects than usual and communication difficulties may make detection of adverse effects difficult. There is very little evidence available to guide clinicians on the safety and tolerability of psychotropic medication in the ID population. Therefore, the therapeutic drug monitoring remains an effective way to minimize the risk of adverse effects or toxicity. Some of the common and important adverse effects are listed below.

(a)  Hyperactivity, restlessness, irritability and aggression may be observed with treatments with Selective Serotonin Re-uptake Inhibitors (SSRIs) and sometimes benzodiazepines.

(b)  Serotonin syndrome is rare but serious, usually associated with the use of SSRIs (particularly more than one SSRI is used). Symptoms include tachycardia, sweating, raised blood pressure and body temperature, dilated pupils, myoclonus leading to shock. Treatment is symptomatic and immediate withdrawal of SSRI and if necessary use of serotonin antagonist such as cyproheptadine.

(c)  SSRI withdrawal may cause withdrawal symptoms in the form of increased restlessness and agitation. Therefore, it is necessary to start with a low dose and increase the dose gradually. If necessary re-start slowly or use a different SSRI.

(d)  Obesity, metabolic syndrome and diabetes, if not promptly treated, may lead to a significant increase in the risk of premature death.

(e)  Disorders of the extrapyramidal system such as akathisia (may be confused with agitation and improperly treated as such), oculogyric crisis and Parkinsonian motor symptoms appear primarily during treatment with old generation antipsychotics, but may also occur from risperidone and other new generation antipsychotics. These symptoms may be misinterpreted as part of ID phenotypes.

(f)  Neuroleptic malignant syndrome (NMS) a rare but life-threatening adverse effect is associated with antipsychotic treatment. Symptoms include raised body temperature, fluctuating blood pressure, muscle stiffness, sweating and other evidence of autonomic dysregulation. Muscle CPK is raised and treatment is symptomatic and immediate withdrawal of antipsychotics.

(g)  Constipation, if neglected, can cause severe distress (e.g., headache, depression, abdominal pain) which, in people with ID, may be expressed as sleep disorders, loss of appetite, agitation and aggression. This is mainly associated with treatments with old generation (tricyclic) antidepressants and some antipsychotics.

(h)  Anticholinergic syndrome, associated with the use of tricyclic antidepressants and some antipsychotics may lead to agitation, motor restlessness, dysarthria, disorientation, hallucinations and convulsions. More severe symptoms include severe constipation, urinary retention, dry mouth, fever and tachycardia.

(i)  Sedation, drowsiness and lethargy are associated with many psychotropic medication uses.

Mahan et al (2010) showed that among 80 individuals with ID in the USA poly-pharmacy of psychotropic medication from different classes increased the likelihood of adverse effects. A number of measures have been used either in their original form or in adapted versions in order to assess adverse effects of psychotropic medications in individuals with ID. Some of these are; Udvalg for Kliniske Undersøgelser (UKU) scale, Abnormal Involuntary Movement Scale (AIMS), the Dyskinesia Identification System Condensed User Scale (DISCUS), Barnes Akathisia Rating Scale-Revised, Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS), and Simpson-Angus Scale. Some scales were specifically designed for use among individuals with ID such as the Matson Evaluation of the Drug Side Effects (MEDS), CLAMPS, and Monitoring of Side Effects Scale (MOSES).

Most studies are on adverse effects of antipsychotic medications as they are the most widely used psychotropic medication for individuals with ID. Most studies reported adverse effects associated with old generation antipsychotic medications such as haloperidol, chlorpromazine etc. For the old generation antipsychotic medications, extrapyramidal adverse effects such as Parkinsonism, akathisia and tardive dyskinesia are reported in most studies.

In general, it has been shown that the new generation antipsychotic medications produce less adverse effects, particularly extrapyramidal symptoms, than the old generation antipsychotics, although these adverse effects have also been reported among individuals with ID who have been treated with risperidone and also olanzapine. There are also anecdotal reports of risperidone causing serious adverse effects such as neuroleptic malignant syndrome (NMS) in individuals with ID. However, for the new generation antipsychotic medications, the metabolic syndrome including weight gain, diabetes mellitus, change in lipid profile and hyperprolactinemia are more commonly described adverse effects. Only a handful of studies have assessed these symptoms in individuals with ID. However, interestingly a number of studies have reported dyskinesia and other extrapyramidal symptoms upon withdrawal of antipsychotic medication in a high proportion of individuals with ID (60% in one study). This phenomenon may suggest that these symptoms may sometimes have been suppressed by the use of antipsychotic medications.

Withdrawal studies

Withdrawal studies specifically of antipsychotic medications have shown that in 25% to 66% (average 50%) of cases antipsychotic medications could be either withdrawn completely or the dosage reduced after long-term use. Encouragingly, Janowsky et al (2006) found 66.3% (55/83) of individuals remained antipsychotic-free almost 10 years after withdrawal. However, in a subsequent study, Janowsky et al (2008) demonstrated that unfortunately, it becomes difficult to withdraw antipsychotic medications altogether in a very high proportion of those who showed a relapse of problem behaviour after one or two attempts of drug withdrawal. However, the withdrawal is only possible if an active programme of withdrawal is implemented. A number of authors have highlighted the influence of staff perception on withdrawal studies.

Some studies showed either no change in behaviour or improvement after withdrawal of antipsychotics in the majority of cases but others showed worsening of behaviour in a higher proportion of cases. A number of studies showed that withdrawal of antipsychotics (particularly the old generation ones like chlorpromazine, haloperidol, thioridazine) may precipitate extrapyramidal symptoms (mostly demonstrated by an increase in DISCUS score), particularly dyskinesia. This may cause deterioration in behaviour in a number of people who have had their antipsychotics withdrawn. However, most studies show that DISCUS score comes back to baseline after a few weeks and months and dyskinesia improves at a follow-up. This is an indicator for the clinicians who are considering withdrawal of antipsychotics that instead of re-instating antipsychotics straight away because of the resurgence of problem behaviour after withdrawal of antipsychotics, they should wait (if necessary with the help of PRN prescription) until the behaviour improves.

Evidence base

There are a number of old controlled trials involving old generation antipsychotics. The systematic reviews have found that the highest number of randomised controlled trials (RCTs) are on new generation antipsychotics, particularly risperidone and aripiprazole. There are also primarily crossover RCTs on the opioid antagonist naltrexone involving children and adults with autism spectrum disorder (ASD) and/or ID. There are also a few poor quality dated RCTs on the mood stabiliser lithium and one on carbamazepine that included only 10 participants. There is a small crossover RCT of an antidepressant clomipramine that recruited only 10 patients in the study.

Risperidone

There are three RCTs of risperidone among adults with ID. Two of these studies showed that risperidone was significantly better than placebo in improving problem behaviour but one study did not find a significant difference in outcome among groups treated with risperidone, haloperidol and placebo. There are six RCTs among children with ID with or without ASD. Research Units on Pediatric Psychopharmacology (RUPP) (2002) and Shea et al (2004) primarily included children with ASD, some of whom also had ID whereas Aman et al (2002) and Snyder et al (2002) primarily included children with ID but excluded those who had ASD. Of these four studies, only the RUPP study (2002) was not sponsored by a pharmaceutical company. All these studies showed a significant improvement in problem behaviour in the risperidone group compared with the placebo group. Three of the RCTs involving children were continued for many weeks using open-label designs. These studies showed that the efficacy of risperidone had been maintained over 52 weeks and medication adverse effects were by and large tolerable. Croonenberghs et al’s (2005) open-label one-year follow-up study of 504 risperidone treated children with ID reported long-term efficacy and tolerability. Seventy-three percent of the children completed the study with a mean dose of 1.6 mgs/day risperidone. The most common adverse events were somnolence (30%), rhinitis (27%), headache (22%) and weight increase (17.3%). Overall 91.7% had some adverse events. The incidence of movement disorders was low, and no clinically significant changes in mean laboratory values were noted, except for a transient increase in serum prolactin levels. Improvements in behaviour which were first observed within the first week or so of treatment initiation were maintained at the follow-up and significant improvements were also noted in positive social behaviour. McDougle et al (1998) in an RCT showed that some core symptoms of ASD improved significantly in the risperidone group compared with the placebo group. Many of these children also had ID and some showed problem behaviour such as aggression as well.

Aripiprazole

Deb et al (2014) have published a systematic review on the efficacy of aripiprazole in the management of problem behaviour among people with ID with or without ASD. The authors reported two RCTs that included 75 and 218 children with ASD with and without ID respectively that used parallel design over an eight-week period. Both these studies have been carried out by the pharmaceutical company that produces aripiprazole and it is not clear whether there is any overlap among the participants in these two studies. Both studies have reported significant improvement in behaviour in the aripiprazole group compared with the placebo group. There was an open-label extension of one study following the RCT that included 330 children, which showed that the improvement shown in the aripiprazole group during the RCT lasted for 52 weeks and the adverse effects were tolerable. Deb et al (2014) have also found another 12 non-controlled studies of either prospective or retrospective case reports that reported improvement in most people with ID treated with aripiprazole. The authors concluded that there is a need for more carefully designed RCTs into the use of aripiprazole in the management of problem behaviour including aggression in people with ID and/or ASD independent of pharmaceutical companies.

Other newer antipsychotic medication

Singh et al (2010) reviewed studies on clozapine for the management of problem behaviour in individuals with ID. They included 13 small studies, of which only three seem to be controlled studies with a very small number of participants of one, two and three respectively. Adverse effects reported included extrapyramidal effects, vomiting, drowsiness, weight gain, hypersalivation, tachycardia, hypotension as well as hypertension, urinary incontinence, leukopenia (reported in one study) and seizures (reported in one study that used 10 mgs to 300 mgs daily dose). There are a small number of non-RCT prospective or retrospective case studies on olanzapine, quetiapine, ziprasidone and asenapine involving people with ID. Ziprasidone has been withdrawn from the UK market because of its serious cardiac adverse effects.

Antidepressants

It is difficult to draw any conclusion on the efficacy of antidepressants in managing problem behaviour in people with ID as apart from a small crossover RCT the rest of the studies included in the systematic review by Sohanpal et al (2007) are case reports. Improvements were largely reported in self-injurious behaviour (SIB) and perseverative/compulsive behaviours in the context of depression and anxiety for which these drugs are indicated. In a number of cases, deterioration in behaviour is reported which may have been caused by the adverse effects of some of the antidepressants.

The existing evidence on the use of antidepressants for the management of problem behaviour in adults with ID is scant. Responses to the SSRIs were varied whereby some studies reported clear favourable results, some showed negative effects and others demonstrated both positive and negative outcomes. This discrepancy in findings, therefore, makes it difficult to come to a definite conclusion regarding the effectiveness of antidepressants in this context.

In general, the majority of the evidence is based on open trials and case series studies were fraught with methodological concerns. The small sample sizes meant that the studies were statistically underpowered and often control groups were not included. There was a dearth of validated outcome measures utilized and where more than one assessor conducted the outcome measurements, inter-rater reliability was not carried out.

Mood stabilisers (Lithium and antiepileptic medications)

Deb et al’s (2008) systematic review revealed three small primarily crossover RCTs of lithium of which only two were published in peer-reviewed journals and the other one was published as a book chapter. Although all these studies showed that a proportion of patients treated with lithium improved, it was not clear whether this improvement was significant compared with the placebo group and also the outcome measures used were not validated and standardised. Also as all the participants in these studies were in-patients, it is difficult to generalize these findings to people with ID who live in the community. Therefore, it is difficult to draw any definitive conclusion on the efficacy of lithium for the treatment of problem behaviour in people with ID. There are other concerns regarding the use of lithium such as the need to carry out regular blood tests which may not be possible for a number of people with ID, narrow range between therapeutic and toxic serum level, lithium toxicity, and a high chance of relapse if lithium is withdrawn. Among other mood stabilisers such as anti-epileptics, only a small RCT involving 10 patients is available on the use of carbamazepine and the rest of the studies are case series. As mood stabilisers such as carbamazepine and sodium valproate are used regularly to treat problem behaviour in people with ID, there is an urgent need to carry out properly designed RCTs involving these drugs notwithstanding the practical difficulties of carrying out RCTs in this population.

Currently there is not much evidence for the effectiveness of other mood stabilizers such as sodium valproate, carbamazepine and lamotrigine, which may provide a better alternative to lithium. However, lack of evidence does not mean that there is evidence that these antiepileptic mood stabilizers are not effective in the management of problem behaviour in individuals with ID.

Opioid antagonists

Opioid antagonist drug naltrexone has been used to treat problem behaviour in children with ASD with or without ID. A recent systematic review by Roy et al (2014a) has found 10 studies that used an RCT design. Two studies used a parallel design (n=59) and the rest of the studies used a crossover design. The number of children included in these studies ranged from 4 to 20. Less than half of the studies showed a statistically significant improvement in irritability and hyperactivity in the naltrexone group compared with the placebo group but none has shown any significant effect on the core symptoms of ASD. Roy et al (2014b) in their recent systematic review have included 10 crossover trials of naltrexone for the treatment of primarily SIB in adults with ASD with or without ID. The number of participants included ranged between 4 and 24 and the study period ranged from 4 to 17 weeks. Only two studies found a significant improvement in the naltrexone group compared with the placebo. Eleven (9%) out of overall 124 participants included in these 10 studies reported minor adverse effects. Because of the small number of participants included, a relatively short period of follow-up and lack of significant results, it is difficult to draw any definitive conclusion about the efficacy of naltrexone in the treatment of SIB and other problem behaviours among adults with ASD and/ or ID.

Antianxiety medication

King and Davanzo (1996) reported in a prospective uncontrolled study of 26 adults with ID (age range 25-63 years) (46% male) on the effect of buspirone 25-60 mgs/day (average 52 mgs/day) on aggression and/or SIB in people with ID. This study did not show any improvement from buspirone. There is little evidence currently to recommend any antianxiety medication for the long-term management of problem behaviours in people with ID. The benzodiazepine group of medications carries the risk of tolerance and dependence in the long run. The evidence for the effectiveness of buspirone is currently poor, therefore, cannot be recommended. However, for the general population some SSRIs, Selective Nor-adrenaline Reuptake Inhibitors (SNRIs), an antiepileptic medication pregabalin and an antipsychotic quetiapine are now recommended treatment for anxiety-related disorders (www.nice.org.uk). In the field of ID, some antipsychotics are prescribed in a smaller than antipsychotic dose to manage problem behaviours with the assumption that at a lower dose antipsychotics may work as antianxiety medications, although the evidence to support this assumption currently is not available from the literature.

Beta-blockers

Ward et al (2013) have published a systematic review on the use of beta-blocker medications such as propranolol, nadolol, acebutolol, metoprolol and oxprenolol in the treatment of problem behaviour in children and adults with ID. They found 14 studies primarily on propranolol, dose ranging up to 340 mgs a day that included between 1-19 participants. However as none of these studies are RCTs, it is difficult to draw any definitive conclusion on the efficacy of beta-blocker medications in the treatment of problem behaviour among people with ID.

Psychostimulants

Psychostimulants’ effects on people with ID and Attention Deficit Hyperactivity Disorder (ADHD) are not well established. Among the psychostimulants, methylphenidate (MPH) is the most widely used. A recent systematic review of all the RCTs in people with ID that assessed effectiveness of MPH on the core ADHD symptoms did not find any RCT in adults with ID. Seventeen studies on children and adolescents with ID were found, 13 of which used a crossover design, one used a parallel design and one is an open-label extension follow-up study over 1-5 years after the end of a crossover RCT. Apart from the parallel design study, all other studies included a small number of participants, therefore, making it difficult to draw any definitive conclusion about MPH’s effectiveness on ADHD symptoms among children with ID. Not all studies showed improvement in all participants following treatment with MPH. It seems that overall the effect size of MPH’s effectiveness in ID children (average around 0.5) is lower than that in the non-ID children (average around 0.8-1.3). On average around 40-50% responded to MPH in the ID group whereas around 70-80% response rate is reported among the non-ID children. A higher dose of MPH seems to be associated with a better response rate but perhaps at the expense of a higher rate of adverse effects. Significant adverse effects included sleep difficulties and poor appetite along with weight loss. Other important adverse effects included irritability, social withdrawal and increased motor activities including tic. The type and rate of adverse effects among ID children seem similar to those in the non-ID children (average around 12-24%). Similarly, the placebo effect seen among ID children seems to be similar to that in the non-ID children (average around 12.5%). Among the non-ID children, studies have shown MPH’s efficacy on overt and covert aggression when associated with ADHD. One study used an RCT design to compare MPH with placebo for the management of different problem behaviours among 28 participants (age 13.6 - 26.4 years) with ID. Overall no significant medication effect was found.

International guidelines

On the basis of the scientific evidence currently available, it is difficult either to recommend or to refute the use of psychotropic medications for the management of problem behaviours such as aggression in people with ID. A relatively good quality evidence is available only for risperidone among children with ID and/or ASD. In the absence of an overall evidence for the efficacy of psychotropic medications, guidelines have been developed in order to provide advice to clinicians when using psychotropic medications for the management of problem behaviours in people with ID (see Table 1). These guidelines advise that a thorough assessment of the causes and effects of the problem behaviours including organic, psychiatric, psychological and social factors should be carried out before a medication is prescribed. Prior to initiating medication, a formulation should be documented including the assessment and a rationale for the use of medication. Non-medication based management of problem behaviours should always be considered first and be used either instead of or along with medication when necessary. People with ID and their caregivers, as well as the multidisciplinary team, should be fully involved in the decision-making process from the outset (Hall & Deb, 2008). There are accessible versions of information leaflets (with audio versions) on psychotropic medications (Unwin & Deb, 2007) freely available for downloading from the web (http://www.ld-medication.bham.ac.uk) which should be distributed to people with ID and their caregivers when prescribing psychotropic medications.