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Tackling aggression with oestrogen

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VOL: 97, ISSUE: 33, PAGE NO: 34

Mark Greener

Dementia is often far from a silent decline into the characteristics of old age, as most nurses working with older people know only too well. Many patients with dementia show sexually, physically and verbally aggressive behaviours that complicate their management and may be distressing for health care professionals. However, treatment is often difficult.

Dementia is often far from a silent decline into the characteristics of old age, as most nurses working with older people know only too well. Many patients with dementia show sexually, physically and verbally aggressive behaviours that complicate their management and may be distressing for health care professionals. However, treatment is often difficult.

Against this background, the results of the first randomised controlled study of oestrogen therapy suggest that it may help aggressive patients with moderate-to-severe dementia. This article explores the use of oestrogen therapy and its relevance in treating people with dementia.

The epidemiology of aggression
Aggression is common among elderly people with dementia. Three examples underline this. Patel and Hope (1992) reported that almost half of their sample of 90 hospitalised elderly psychiatric patients showed at least mild aggression. Eastley and Wilcock (1997) reported that 52% of 262 patients with Alzheimer's disease exhibited some aggressive behaviour - 35% displaying verbal aggression while 18% assaulted carers. Men were more than twice as likely to assault their carers than women, while dyspraxia increased the relative risk of assault by about three times. Overall, about a fifth of these patients assaulted their carers. In addition Deutsch et al (1991) commented that about 30% of 209 patients with possible or probable Alzheimer's disease who were followed for up to 4.5 years showed physical aggression.

Health professionals and informal carers may find such behaviour difficult to manage (Kyomen et al, 1999). One recent study examined the relationship between dementia-related aggressive behaviour and nurse's stress levels (Rodney, 2000). It showed that nurses appeared to cope remarkably well with the demanding task of caring for such patients. Aggressive behaviour by residents significantly increased nurse's stress levels, but it was the perceived threat of aggressive behaviour by a patient that predicted the highest levels.

In another study, staff on special care units for dementia were found to be less distressed by disruptive behaviour than their colleagues on traditional units, even though they had to manage difficult patients more often (Middleton et al, 1999). The authors say these differences reflect 'different perceptions of intent to harm and expectations of physical aggression as 'part of the job.'' They suggest better education and support would enhance the quality of life of residents and staff working in units with disruptive patients.

Management strategies
It is not surprising that even a brief MEDLINE search reveals numerous management strategies for dementia-related aggression, including behavioural and pharmacological therapies such as music, neuroleptics, sedatives, anticonvulsants, antidepressants and lithium (Kyomen et al, 1999; Clark et al, 1998). But the sheer variety suggests that none is universally effective.

Indeed, only 18% more patients respond to neuroleptics than to a placebo (Kyomen et al, 1999), although carbamazepine may be more effective. A six-week placebo-controlled study (Tariot et al, 1998) of 51 nursing home patients with agitation and dementia showed that carbamazepine (average dose 300mg/day) decreased the mean total Brief Psychiatric Rating Scale (BPRS) score by 7.7 points and improved Clinical Global Impression (CGI) ratings by 77%. Among placebo users, the reductions were 0.9 points and 21%, respectively.

A hormonal approach
In the search for new management strategies, researchers began to look at the effects of oestrogen and the results showed promise. The link between hormonal status, mood and aggression, especially in patients with dementia, is well established.

Although the pathological and neurochemical basis is uncertain, it is clear that oestrogen alters neurochemical pathways controlling mood and behaviour. For example, oestrogen and testosterone alter serotonin function in the brain (Fink et al, 1999) and oestradiol appears to regulate the expression of gene coding for certain 5-HT receptors in rats (Osterlund et al, 1999).

Part of the effect on mood may reflect oestrogen's action on dopamine. Studies suggest that oestrogen and some other steroids increase dopamine activity while progesterone removes GABAergic (gamma-aminobutyric acid) inhibition from the dopaminergic system (Kalia et al, 1999). Sawada and Shimohama (2000) found oestradiol protected dopaminergic neurones in parts of the brain. Several mechanisms contribute to this, including an antioxidant action. This may explain the male predominance in conditions such as Parkinson's disease.

Levels of most reproductive hormones, such as oestrogen and testosterone, decrease with age. Epidemiological studies show that twice as many women as men develop Alzheimer's disease, suggesting that oestrogen may play a pathogenic role (Henderson et al, 2000). Moreover, some research suggests that oestrogen replacement may protect against the development of Alzheimer's disease (Tang et al, 1996), although results are mixed (Henderson et al, 2000).

Ongoing research is also clarifying the general impact of hormones on cognitive function. For example, in one recent study men aged between 59 and 89 with low oestradiol and high testosterone levels performed better in several tests of cognitive function than other volunteers (Barrett-Connor et al, 1999).

Another recent study (Duka et al, 2000) suggests that oestrogen replacement therapy improves some aspects of healthy elderly women's cognitive abilities. Transdermal oestradiol was administered over three weeks to 19 women who did not have postmenopausal symptoms and had never taken hormone replacement therapy. The study compared memory, frontal lobe functions and visuospatial abilities with 18 controls. Treatment increased plasma oestradiol levels to those seen in fertile women. Memory function and visuospatial abilities improved significantly after oestradiol, independent of any effect on mood or well-being. Frontal lobe functions were not affected.

On the other hand, Barrett-Connor and Kritz-Silverstein (1999) failed to confirm previous suggestions that oestrogen deficiency contributes to age-related memory loss among postmenopausal women. They argued that if the theory was correct, men should lose less memory more slowly than women. But after studying 800 women and 551 men aged between 65 and 95, they found that, overall, performance worsened with advancing age to a similar extent in both sexes.

Oestrogen, dementia and aggression
A growing body of evidence suggests that oestrogen may lessen dementia-related physical and sexual aggression (Shelton and Brooks, 1999). In two recent cases, conjugated oestrogens reduced the number of aggressive episodes by 75% in one man. In another, oestrogen reduced physical and sexual aggression by 80% and the number of sexual comments by 55%.

The first randomised controlled study (Kyomen et al, 1999) to evaluate oestrogen's ability to decrease aggressive behaviours enrolled 12 women and two men with moderate-to-severe dementia., The average age was 84. Eight patients received oestrogen.

The study lasted only four weeks. Nevertheless, oestrogen reduced total aggression scores and decreased the frequency of physical aggression. Indeed, the benefits emerged after just one week's treatment. Verbal aggression also decreased, although this difference was not statistically significant. On the other hand, oestrogen therapy did not reduce resistive aggression, sexual aggression or self-directed aggression.

The study leaves a number of issues unresolved. For example, the follow-up was not long enough to evaluate the effect of chronic therapy and it is not clear whether the less marked decline in verbal aggression reflects the study size or a differential effect on linguistic behaviour.

Nevertheless, oestrogen is already entering clinical practice. The team from Harvard Medical School's division on aging found oestrogen replacement therapy extremely helpful in patients who had moderate-to-severe dementia and exhibited treatment refractory, physically aggressive behaviours (Kyomen et al, 1999).

The oestrogen therapy was used after the usual treatments had failed. The team also made sure that other medical and psychiatric conditions that may cause severe behavioural disturbances had been ruled out.

Conclusion
Dementia-related aggression is common and presents management difficulties for health care professionals. There is a therapeutic deficit, with no universally effective management strategy. But if further studies confirm early results, oestrogen replacement therapy may be an effective treatment for patients with moderate-to-severe dementia who display treatment refractory, physically aggressive behaviours. Whether it can reduce aggression in dementia per se remains to be seen.

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