The term ‘executive function’ covers a range of brain activities which are essential to modern human existence. The ‘dysexecutive syndrome’ is a constellation of symptoms which can significantly impair function and quality of life and lead to significant carer distress. There is no specific pharmacological treatment for the dysexecutive syndrome. This is partly because this is a heterogeneous group of conditions presenting differently in different people and is caused by pathology in different areas of the brain (around a third of brain substance may be involved in executive tasks). However, some pharmacological treatments can target specific areas of function and lead to improvements.
Broadly speaking, there are three areas of executive function that may be targeted by pharmacological agents:
♦ problems with inhibition, including irritability, sexual and social disinhibition, and aggressive behaviour
♦ problems with drive and initiation
♦ problems with organization, concentration, and mental focus.
There are differing rationales for the choice of treatments in these three areas. Some treatments are tried because they have been successfully used to manage similar problems in other disorders. An example of this is the use of stimulant medications to improve concentration and mental focus. This beneficial effect is seen in children and adults with attention deficit–hyperactivity disorder and in normal adolescents. Other treatments are tried because there is a rationale in terms of the underlying pathology. An example of this is the use of dopamine receptor agonists such as bromocriptine in drive disorders said to be caused by damage to dopamine pathways between the midbrain and the orbitofrontal cortex. On occasion, there may be conflicts in rationale—a drug which may help with one area of executive function may lead to problems in another. For instance, some drugs which reduce irritability and aggression may directly reduce drive and initiation (examples of this include dopamine blocking agents). Conversely, medicines which increase drive and initiation may lead to problems with disinhibition and disorganized behaviours (an example of this is bromocriptine).
There are a number of methodological problems in the study of pharmacological treatments of dysexecutive syndrome. Brain injuries are a highly heterogeneous group of conditions, varying in type and location. This makes patient selection difficult in trials and can limit generalization of results. Executive dysfunction is broadly defined and exists on a spectrum with normal function. This again creates difficulties in defining the boundaries of the syndrome for the purposes of research. Numbers are relatively small and so the majority of studies are underpowered. Some of the rating scales used may not have been defined specifically for people with brain injury, and this may affect reliability and validity. Finally, communication problems in relation to brain injury can affect consent and data gathering in research.
Treating irritability and disinhibition after brain injury
Irritability is relatively common after brain injury, occurring in around 35 per cent of brain-injured individuals in the first year (Deb et al. 1999). Irritability may occur as a direct consequence of brain injury or may arise from secondary causes, which need to be fully explored before direct pharmacological treatments for irritability are tried. Irritability may be secondary to a variety of primary psychiatric disorders, including depression, anxiety disorders, and psychosis, which require assessment and treatment in their own right. The frustrations of physical and specific cognitive impairments may be a direct cause of irritable behaviour. Systemic illnesses, particularly infections, can lead to irritable behaviour, and pain is a strong trigger for irritability. Misunderstandings caused by cognitive problems can lead to aggressive behaviour. Examples of this include patients with receptive aprosodias who may perceive a friendly verbal approach as threatening and react accordingly. Irritability may also be a long-standing trait not related to the brain injury at all.
There is no clear explanation for the genesis of irritability. One possible explanation takes in two aspects of executive dysfunction—multi-tasking problems and disinhibition. An individual with a brain injury is faced with an everyday situation which requires multi-tasking that they had previously found easy to perform (e.g. making a cup of tea or organizing a visit to a friend). Realization that this task is now extremely difficult leads to an increase in anxiety and arousal. A disinhibited individual may then express this increased arousal as paroxysmal verbal or physical aggression.
What treatments work for irritability or temper control after brain injury?
If underlying causes for irritability have been identified and treated as far as possible, primary irritability may still remain and often requires treatment. A wide variety of treatments have been tried in the treatment of irritability; however, trials have been on relatively small numbers of patients and randomized controlled trials (RCTs) are sparse. A recent Cochrane review (Fleminger et al. 2003) identified only six RCTs on the treatment of aggressive behaviour. Four of these studies looked at the effectiveness of beta-blockers (two studies examined propranolol and two examined pindolol) in a total of 43 patients (Greendyke and Kanter 1986; Greendyke et al. 1986, 1989; Brooke et al. 1992). The doses used were very high (520 mg of propranolol daily in one study and up to 420 mg daily in another) and a number of the patients had been non-responsive to other treatments. In all the studies, beta-blockers produced a reduction in frequency of outbursts. In at least one of the studies (Greendyke et al. 1986) marked adverse effects were reported.
One trial of the stimulant methylphenidate (MPH) examined its effect on anger or temper in 38 people using a randomized placebo-controlled single-blind design over 6 weeks (Mooney and Haas 1993). The treatment led to a decrease in anger-type symptoms with no measurable effect upon cognitive function. The final RCT reported in the Cochrane review was a trial of amantadine (Schneider et al. 1999). This was a crossover trial in 10 brain-injured individuals and showed no differences between the treatment and placebo arms.
The conclusion of the Cochrane review was that there was some evidence for the efficacy of beta-blockers in the treatment of agitation after brain injury and that the drug effects are seen early (within 2–6 weeks of starting medication). The authors also recommend that ‘if no benefit (is) observed by the end of six weeks, then the drug should be tailed off and another one tried after a suitable interval’.
Apart from the RCTs, a range of smaller and less robust trials of the treatment of irritability/aggression have been reported. These are described in the Cochrane review (Fleminger et al. 2003) and summarized by Deb and Crownshaw (2004). There are six case reports of the use of buspirone, a partial agonist at 5-HT2A receptors and an anxiolytic, in a total of 38 patients with a mixed response. Even allowing for publication bias, only 16 patients were said to respond to treatment, with 22 either not responding or getting worse. In one study (Gualtieri 1991) five of the drop-outs were in relation to adverse effects. In the largest case series relating to buspirone, Stanislav et al. (1994) reported 14 brain-injured patients of whom only four or five responded to treatment within the first month. They required relatively high doses to have an effect (30–60 mg daily).
Neuroleptic medications have commonly been used to control irritable behaviour following brain injury, but evidence for their effectiveness is lacking. In the largest of the existing trials, Maryniak et al. (2001) examined the effect of methotrimeprazine in the first 3 months following brain injury and found that most of the patients improved in the domain of agitation. This trial was severely limited in that there was no control group, the data were retrospective, and the outcome measures used were not validated. Other small trials indicated that neuroleptics may worsen cognitive function after acquired brain injury (ABI) and, especially in the instance of clozapine, may lower the seizure threshold (Michals et al. 1993).
Reports on lithium in agitated behaviour are largely from case reports or small case series, the largest of which (Glenn et al. 1989) involved 10 cases of brain injury with very mixed results, including three patients who deteriorated (one of whom had an epileptic seizure).
Two case series using selective serotonin-reuptake inhibitor (SSRI) in agitated brain-injured patients have been reported. Kant et al. (1998) used therapeutic doses of sertraline in 13 cases and found reductions in aggression and independent improvement in mood. Fann et al. (2000) found similar results from a similar methodology, but used the Brief Anger and Aggression Questionnaire as an outcome measure. There are also two case series of tricyclic antidepressant usage. Jackson et al. (1985) reported 35 cases, two-thirds of whom had reduced agitation with either amitriptyline or desipramine. However, those people with previous psychiatric diagnosis were excluded, leading to a significant bias in the study. Mysiw et al. (1988) described 20 cases of agitated TBI patients treated with therapeutic doses of amitriptyline, 13 of whom responded within a week of treatment.
There is surprisingly little published data on the use of anticonvulsant drugs in the management of agitated, aggressive, or irritable brain-injured patients, even though this group of drugs is probably still the most widely prescribed group in agitated brain-injured patients. Azouvi et al. (1999) reported an 8-week open trial of carbamazepine in agitated patients using a variety of outcome scales (Neurobehavioural Rating Scale–Revised, the Katz Adjustment Scale and the Mini Mental State Examination). Out of a total of 10 cases, five improved on treatment, a ‘moderate effect’ was seen in three further cases, and a ‘negligible’ effect in two cases. Four of the the cases reported drowsiness during the treatment on doses of up to 800 mg daily. Chatham-Showalter (1996) used larger doses of carbamazepine (up to 1600 mg daily) in a case series of seven patients and found a decrease in ‘combative behaviour’ as measured by the Rancho Los Amigos scale. This allowed for the reduction in other medications such as neuroleptics or benzodiazepines.
There are two reported studies of valproate in agitated brain injury patients (Chatham-Showalter and Kimmel 2000; Kim and Humaran 2002). Both are limited by the fact that they are retrospective studies with no control groups. The two studies had a total of 40 patients, the vast majority of whom showed improvement in agitation and impulsiveness following treatment.
Managing hypersexuality and disinhibition
No good epidemiological studies exist to inform us of the prevalence of hypersexuality following traumatic brain injury. Case reports suggest that in fact hyposexuality is the most common form of sexual problem after brain injury (probably in relation to abulia). However, hypersexual behaviour and altered sexual preference have been clearly described and, at times, this can lead to significant risk.
There are only 10 cases in the literature reporting the use of hormone treatments to reduce sexual behaviour (Arnold 1993; Emory et al. 1995; Britton 1998). In the first of these (Emory et al. 1995), the cases of eight men who had developed hypersexual behaviours following brain injury were reviewed. They were treated with medroxyprogesterone acetate (Depo-Provera) at a dose of 400 mg weekly for 6 months. Testosterone levels were also measured and dropped very significantly during treatment. None of the patients exhibited significant inappropriate behaviour during the study, and increases in attention span were noted as well as reduction in impulsivity and emotional lability. This study is compromised by the lack of a control group and of standardized measures.
Summary of treatments for aggressive, irritable, and disinhibited behaviours
There is very little high-quality evidence to support the use of any pharmacological treatments in this area. Almost all the studies have at least one major methodological flaw. However, the absence of good-quality evidence does not mean that these treatments are necessarily ineffective. Indeed, most of the available evidence points towards the effectiveness of beta-blockers, antidepressants, and anticonvulsants as well as the effectiveness of hormonal treatments on sexually aggressive behaviour. Further randomized studies are needed in this area.
Problems with drive, initiation and focus
Problems with initiating and maintaining goal-directed behaviours are common following brain injury. Two main classes of drugs, stimulants and dopamine agonists, are used in the management of this group of problems.
Stimulants have a reasonable adverse effect profile in the area of brain injury. Alban et al. (2004) studied tolerability and vital signs in 35 adults with TBI as part of another trial. They found that reduction in appetite was the only adverse effect that was significantly higher in the treated group. They also found a small rise in heart rate (+7 beats/minute) and blood pressure (+2.5 mmHg) in the treated patients. There are four published RCTs on the effects of stimulants on attention and drive following brain injury. Whyte et al. (1997) reported on 19 patients who participated in an RCT of MPH. They used cognitive tests to assess sustained arousal, phasic arousal, distraction, choice reaction time, and behavioural inattention. They found that MPH increased the speed of mental processing, but motor speed and most aspects of sustained attention were unaffected. Speech et al. (1993) used a crossover design in 12 chronically head-injured patients and found that MPH had no significant effect on a variety of tests of attention and processing speed, including digit span, Stroop Interference Test, Complex Reaction Time Test, and others. In contrast, Gualtieri and Evans (1988) found significant improvements in cognition in 14 of 15 patients using a similar methodology and similar dosages (0.15–0.3 mg/kg) but different outcome measures. The measures in this study included the Selective Attention Test, the Verbal Fluency Test, the Non-verbal Fluency Test, the Selective Reminding Test, the Continuous Performance Test, and the Benton Visual Retention Test. Finally, Plenger et al. (1996) randomized 23 patients to MPH (0.3mg/kg) or placebo in the post-acute phase. This trial was underpowered because of patient drop-out. However, at 30 days into treatment, the MPH group performed significantly better on tests of attention and motor performance. These differences disappeared at 90 days, but this may have been due to the low power of the study to detect a difference between groups. Thus the existing trials provide a ‘mixed bag’ of results clouded by a relative underpowering of studies.
Decelerating injuries to the brain commonly affect areas rich in dopaminergic neurons including the basal forebrain and pathways to this area from the midbrain (Gennarelli et al. 1982). These pathways have also been associated with executive function problems, especially initiation of new behaviours and changing the cognitive or behavioural set. There is a little evidence from rodent models that dopaminergic drugs could prevent brain damage and enhance recovery. Kline et al. (2004) showed how the oxidative stress induced by brain injury could be attenuated by bromocriptine. A similar pattern was found using cognitive outcome measures in rats who had sustained ischaemic brain damage (Micale et al. 2006). O’Neill et al. (1998) showed how a variety of dopamine 2 agonists (including bromocriptine and pergolide) could protect against ischaemia-induced hippocampal damage.
There are a number of potential problems in the usage of dopaminergic medications in patients who lack drive and focus following brain injury. One practical problem, mentioned earlier, is that an increase in drive and focus could lead to a higher level of inappropriate and aggressive behaviours which may actually diminish the rehabilitation potential of the individual. Dopamine agonists as a group have been associated with exacerbation of psychotic symptoms. In addition, abrupt withdrawal of dopamine agonists can trigger a neuroleptic malignant syndrome.
There are two RCTs of dopamine agonists looking specifically at cognitive outcomes. Meythaler et al. (2002) studied 35 subjects using a randomized crossover design. One of their outcome measures, the FIM-Cog score, was a measure of cognition in relation to function (Heinemann et al. 1991). Other scales used in this study included MMSE, the Disability Rating Scale, and the Glasgow Outcome Scale. Although trends in favour of amantadine were reported, the comparisons did not reveal significant differences between the groups (amantadine 200 mg vs. placebo).
McDowell et al. (1998) looked at a range of cognitive tasks in a double-blind crossover trial of low-dose bromocriptine after TBI. Their results were particularly interesting as they showed a preferential effect of bromocriptine on cognitive functions served by the prefrontal cortex in 24 patients. Tasks which were significantly better on bromocriptine included Trail Making, Stroop, the FAS Test, and the Wisconsin Card Sorting Test. However, tests of working memory and non-executive tasks were no different between the treatment and the placebo group. The authors concluded that bromocriptine had a specific effect on some types of cognitive function and did not exert its effect through a non-specific increase in arousal, attention, or response speed. A smaller less robust trial looked specifically at the use of dopaminergic medications for motivational problems. Powell et al. (1996) studied 11 patients in an open-label trial and gave bromocriptine in gradually escalating doses; they reported increases in motivation by their own rating scale which was separate from any effect upon mood.
Ethical and legal considerations of the use of pharmacological treatments in brain-injured people
In most cases pharmacological treatments require consent from the patient. However, there are a number of scenarios where this is problematic. These include the following:
♦ the patient is unconscious or semi-conscious
♦ the patient is not able to understand the nature or effects of the proposed treatment because of receptive language problems
♦ the patient has difficulty communicating their consent
♦ the patient is actively refusing treatment which the clinicians and/or carers feel is in their best interests.
In the case of the unconscious or semi conscious patient, decisions about treatment should be made collaboratively within the clinical team, informed by significant carers or relatives and mindful of any previous wishes expressed by the patient prior to the injury. In this case, treatment would probably be parenteral (intramuscular, intravenous, subcutaneous, or through gastrostomy). The Mental Capacity Act now provides a statutory framework for decision-making in these cases. This Act now puts the onus on clinicians to have tried all reasonable methods for eliciting capacity. In cases where the patient does not have the capacity to make or communicate decisions, these decisions have to be made in the ‘best interests’ of the patient, in consultation with significant relatives or carers, the multidisciplinary team and, where appropriate, an independent mental capacity advocate (IMCA).
In cases where consent is hampered by communication problems, every effort should be made to secure informed consent to treatment. A full assessment of language function is needed and augmentative methods of communication investigated. Non-verbal behaviour, especially in relation to oral medication, can provide information about non-consent in particular, but the problem of patients passively receiving mediation without full consent may remain.
At times patients can actively refuse treatment which the clinicians and carers feel is in their best interests. This is particularly true for patients with irritable or disinhibited behaviours for which they have no insight. In the acute phase, if there is a clear threat to the patient, carer, or health professional, medication may be given under common law to prevent or manage a crisis situation. In this situation, medication is often given via the intramuscular route.
If medication needs to be given over a period of time against the wishes of the patient, then the Mental Health Act 1983 should be used. This legislation applies predominantly to England and Wales. For the most part, it does not apply to Scotland and Northern Ireland. Section 3 of the Mental Health Act allows the treatment of in-patients against their wishes with the following provisos:
(1) that they are suffering from a mental illness of a ‘nature or degree’ which makes it appropriate for them to be treated in a hospital (or registered unit)
(2) that it is necessary for the patient’s health or safety or the protection of others that he receives treatment
(3) that the treatment cannot be provided in any other way.
Are problems with executive function treatable as ‘mental illness’ under the Mental Health Act?
It is very clear that people with dysexecutive syndrome can in many cases be deemed to be mentally ill from a legal standpoint. The Mental Health Act takes the international classifications of disease as a yardstick to decide whether someone has mental illness. The most pertinent category in the ICD-10 Classification of Mental Disorders (World Health Organization 1992) is F07.0: Organic personality disorder. The diagnostic guidelines for this category include ‘consistently reduced ability to persevere with goal-directed activities’, ‘emotional lability’, ‘expression of needs and impulses without consideration of consequences or social convention’, and ‘altered sexual behaviour’.
It is also worth noting that a patient does not have to be deemed ‘dangerous’ in order to be subject to detention under the Mental Health Act. As long as admission for treatment is justifiable in the ‘interests of the patient’s health’, this is sufficient, provided that the other criteria are met. Finally, section 3 (the main treatment section) only allows for treatment in a hospital or registered setting, which includes some specialist residential and nursing facilities.
The Mental Health Act can be used in the setting of executive dysfunction in two main situations. First, it can be used if a patient requires treatment of any kind, including care intervention to which they are clearly not consenting or are resisting. In this situation, detention under the Act can protect the rights of staff who might otherwise be open to charges of assault. The second situation is one where the patient has clearly expressed a wish to leave an inpatient setting but, because of their executive dysfunction, they are unable to see or deal with risk outside an inpatient setting. In this situation, the Act can provide a frame of reference for detention against the patient’s wishes. The Act specifies time periods for detention and includes rights for legal representation of the patient and independent tribunals to verify the legality of detention. Finally, some sections of the Act put a duty upon local health and social services providers to fund appropriate care over the long term.
Section 117 specificies that ‘It shall be the duty of the District Health Authority and of the local social services authority to provide…after-care services for any person to whom this section applies until such time…the person concerned is no longer in need of them’.
This section of the Act empowers the judge of a Mental Health Review tribunal to subpoena the directors of primary care trusts or social services to appear and explain why funding for further placement is not forthcoming. In an era where people with brain injury are often excluded from the mainstream debate about health funding, this can often provide leverage to fund appropriate longer-term placements.
However, patients who have been subject to detention under the Mental Health Act can have difficulties in obtaining visas for travel to some countries and may experience discrimination in employment if they declare it.
In this chapter it has been shown that when executive function following brain injury is broken down into separate groups of symptoms, each group can be managed by different classes of drug treatment. This field is still in its infancy. Functional neuroimaging after brain injury may help us to narrow down further those pathways responsible for the different elements of executive function. From this information, more specific treatments could be developed to improve outcome. As in many fields, larger trials with standardized outcome measures are the priority for further research in this promising area.
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