IPA Bulletin
Recent Advances - Volume 21, Number 3
By Professor John O'Brien, Dr. Robert Barber, and
Professor Robert Baldwin
Do cholinesterase inhibitors really work?
Courtney et al. (Lancet 363(9427):2105-15) aimed to determine whether treatment with donepezil produces worthwhile improvements in disability, dependency, behaviour, carers' psychological wellbeing, or delay in institutionalisation. Just under 500 patients with Alzheimer’s disease completed a 12-week run-in period during which they were randomly allocated to donepezil (5 mg/day) or placebo. They were then re-randomised to either donepezil (5 or 10 mg/day) or placebo, with double-blind treatment continuing as long as judged appropriate. Primary endpoints were entry to institutional care and progression of disability.The authors found highly significant benefits for patients receiving active treatment in terms of MMSE scores (improved by 0.8 points) and a measure of functionality (by 1.0 points) over the first 2 years. No significant benefits were seen with regard to institutionalisation, progression of disability, behavioural and psychological symptoms, carer psychopathology, formal care costs, unpaid caregiver time, deaths, or between 5 mg and 10 mg donepezil. The authors concluded that treatment with donepezil was not cost effective, with benefits below minimally relevant thresholds.
In contrast, Galasko et al. (J Am Geriatr Soc 2004; 52:1070-6) conducted a secondary analysis of the original 5-month trial of galantamine in Alzheimer’s disease and found patients on active treatment maintained or improved their level of basic and instrumental activities of daily living, with the greatest difference being observed in the more severe disease, compared to those on placebo.
Abeta Vaccine – effects in non-human primates?
Animal studies modelling the potential therapeutic benefits of Abeta vaccine in Alzheimer’s disease continue to show grounds for optimism. On this occasion, Lemere and colleagues (Am J Pathol 2004; 165:283-97) demonstrated the vaccine lowered cerebral Abeta in the vervet monkey. Though the sample was small, this was the first study to show the effects in non-human primates. Results from part of the same group (Gandy et al. Alz Dis Assoc Disord 2004; 18(1):44-6) also showed immunized rhesus monkeys developed high anti-Abeta titers and increase in the plasma level of Abeta. Heppner et al. (Alz Dis Assoc Disord 2004; 18(1):38-43) review the current concepts and future prospects for vaccines in AD.
Relevance of lipids, homocysteine and alcohol in dementia – new epidemiological studies
A cluster of studies from researchers from New York have examined the relationship between lipids, homocysteine, alcohol and dementia. Overall, the most positive association (in terms of lower risk of AD) was for a moderate consumption of wine!
Reitz et al. (Arch Neurol 2004; 61 (5):705-14) conducted a cross-sectional and prospective community-based cohort study of 4316 Medicare recipients, 65 years and older, residing in northern Manhattan. They found lipid levels and the use of agents to lower lipids were not associated with the risk of Alzheimer's disease (AD), and there was only a weak relation between plasma lipids levels and vascular dementia.
In a separate study, researchers from the same team followed up a cohort of Medicare recipients for 3,206 person-years to test the association between homocysteine levels and AD (Luchsinger et al. Neurology. 2004; 62:1972-6). They found high homocysteine levels were not associated with AD nor were they related to a decrease in memory scores over time. In contrast, a study from Japan showed high levels of homocysteine were associated with an increased risk of stroke (Iso et al. Circulation 2004; 109:2766-72).
Saving alcohol to the last, Luchsinger et al. (J Am Geriatr Soc 2004; 52(4):540-6) examined the relationship between alcohol intake and Alzheimer's disease and dementia associated with stroke. Using the same cohort as their homocysteine study, they found daily consumption of up to three servings of wine was associated with a lower risk of AD in elderly individuals without the APOE epsilon-4 allele. However, the intake of liquor, beer, and total alcohol was not associated with a lower risk of AD.
Agitation and aggression in Alzheimer’s disease – is it in the genes?
The significance of behavioural and psychological symptoms of dementia is now well recognised, but the aetiology remains unclear. One contributing factor could be genetic differences, perhaps involving the pre-frontal serotonergic circuitry which is thought to regulate the control of negative emotions. To test this hypothesis, Craig et al. (Neurosci Lett. 2004; 363(3):199-202.) determined the polymorphism of the tryptophan hydroxylase gene in around 400 subjects with Alzheimer’s disease (AD). They found male patients with a history of agitation/aggression were more likely to possess C-containing genotypes (OR = 1.65), supporting the notion that agitation in AD could be genetically linked to polymorphic variation at the tryptophan hydroxylase gene.
Advances in molecular imaging
If a suitable probe can be found to selectively detect the burden of amyloid in the human brain during life, this would open up exciting opportunities for the early detection and diagnosis of Alzheimer’s disease and also provide a direct measure of the efficacy of new therapies.
Poduslo and colleagues from the Molecular Neurobiology Laboratory, Mayo Clinic, Rochester reported their latest findings involving a derivative of human amyloid-beta peptide that is capable of targeting individual amyloid plaques in transgenic mice (Biochemistry. 2004;43(20):6064-75). Of course, challenges ahead involve translating these findings into clinical practice, but if successful, these techniques could change the way we diagnosis dementias from a clinical to a pathological paradigm.
Supporting and training carers: does it work?
The results of two very different studies suggest specific interventions targeted at caregivers of patients with Alzheimer’s disease (AD) and strokes can be beneficial.
Mary Mittelman and colleagues from New York (Am J Psychiatry 2004;161(5):850-6) randomly assigned over 400 spouse-caregivers of patients with AD to either a group receiving enhanced counselling and support treatment or a group receiving usual care (control group). They concluded that the intervention led to sustained benefits in reducing depressive symptoms in the caregivers, and should be made widely available to families.
The second study from the UK used a single, blind, randomised controlled trial design to evaluate the benefits of training care givers in basic nursing and facilitation of personal care techniques to the caregivers of patients with stroke disease (Kalra et al. BMJ 2004;328(7448):1099). Importantly, they demonstrated that the intervention reduced rehabilitation costs and caregiver burden while improving psychosocial outcomes in caregivers and patients at one year.
Reducing risks from lithium toxicity
Lithium toxicity is a serious problem. Over a 10 year period in Canada, Juurlink et al found the risk of Lithium toxicity was found to be significantly higher in drug naďve patients who were put on to loop diuretics or ACE inhibitors (Journal of the American Geriatrics Society, 2004; 52:7945-798). This association was particularly strong within the first month of initiating therapy. This is not a new message for psychiatrists but perhaps physicians are not always aware of this risk.
Risk factors for depression
The prevalence of depression varies across cultures and ethnic groups. Miller et al (Journal of The American Geriatric Society, 2004; 52:741-8) use the CES-D to assess depression in subjects identified in the African American Health Study (AAH study). Prevalence of clinically relevant depression was a fifth, higher than predicted. Low income and reduced social support were the main predictors of depression and, interestingly, so were obesity or being markedly underweight. Only a fifth of those identified with significant depression were on treatment. The authors suggest special vigilance in this patient group.
Depression predicts cognitive decline
What is the relationship between depression and dementia? Wilson et al (Journal Neurology, Neurosurgery and Psychiatry, 2004; 75:126-130) examined over 4,000 people living in Chicago followed up with repeated CES-D measures over 5 years. In those who reported 4 depressive symptoms cognitive decline was about 20% more rapid than non-depressed subjects, suggesting that depressive symptoms predict cognitive decline.
Do infarcts explain the relations between depression and dementia?
Cognitive impairment and depression are strongly linked. Could cerebral infarctions be the mediating process? Bennett et al (American Journal of Geriatric Psychiatry 2004; 12: 211-219) studied this question in relation to an important neuropathological- clinical correlation study of older persons members of religious orders in the US. About a third of the sample had cerebral infarcts and these were related to cognitive impairment. However, whether by location or volume cerebral infarcts did not seem to contribute to the relationship between depression and cognitive functioning, suggesting different mechanisms. The authors consider various mechanisms, including stress, although these priests and nuns were rather low on depressive symptomatology, making the search for correlations more difficult. Nevertheless post-mortem studies in psychiatry are rare.
Progression of white matter lesions
White matter disease is thought to be important in dementia and depression although sometimes it has been regarded as part of “normal ageing”. Cook et al (American Journal of Geriatric Psychiatry 2004; 12: 190-200) add to a small but growing literature showing that white matter hyperintensities do progress. In a study of 29 subjects of mean age 75 scanned at least 2 years apart, white matter hyperintensities (both deep subcortical and periventricular) increased in 90% of the sample. There was little association with cognitive performance but the main predictive factor appeared to be the baseline Hachinski Scale, suggesting that where there is vascular disease then white matter hyperintensities do generally worsen, with implications for prevention and management.
Antipsychotic prescription in nursing homes
Recent concerns about risks associated with prescribing risperidone and olanzapine to patients with dementia make a paper by Bronskill et al (Journal of American Geriatric Society, 2004; 52: 749-755) particularly pertinent. Using a huge database they ascertained a number of new prescriptions for neuroleptic therapy of patients admitted to nursing homes in part of Canada. Almost 1 in 5 of older adults admitted to a nursing home with no previous neuroleptic exposure received a neuroleptic drug within 100 days of admission and a quarter within a year of a nursing home admission. Dementia was the main associated condition, doses were often higher than recommended and specialists were often not involved in a decision to treat. Closer regulation may be crucial in curtailing overuse of these drugs in dementia.
Are frailty and depression linked by inflammatory mechanisms?
In a themed edition of the American Journal of Geriatric Psychiatry devoted to depression, Gatz (American Journal of Geriatric Psychiatry, 2004; 12: 1-5) makes the point that like several geriatric “syndromes”, such as gait disturbance and depression too may be a marker of frailty. Not only is there an overlap in the symptoms which define frailty and those of depression (for example exhaustion, weight loss, slowing and decreased activities) but new research suggests that cytokine-mediated processes, perhaps themselves linked to ageing and accumulated diseases, lead to inflammatory processes which can precipitated and fuel depression. Several papers explore the fascinating bi-directional relationship between somatic illness and depression.
Screening for depression
Screening instruments for depression are popular. How good are they? Two papers from the same journal provide rather contrasting results. In one from the US, Watson et al (International Journal of Geriatric Psychiatry, 2004; 19: 278-285) found that the GDS and CES-D were fairly mediocre in screening for major and minor depression in a community sample of fit healthy retired subjects aged on average 80. The sample though was quite small at just over 80 of whom only 6 had subthreshold depression. More positively, Goring et al (International Journal of Geriatric Psychiatry, 2004; 19: 465-471) found that the 4 item GDS and a short orientation-memory-concentration test (OMC) performed satisfactorily at cut-offs of 1/2 and 10/11 respectively when compared with longer instruments in elderly general medical patients.
Is major depression in the elderly more common than previously reported?
For a long time the epidemiologic catchment area (ECA) study of the 1980s has troubled clinicians working with older people as the prevalence rates in later life were very low. In a large study of almost 10,000 participants aged over 50 (the USA Health and Retirement Study) Mojtabai and Olfson (Psychological Medicine, 2004; 34: 623-634) found that 4% of those aged over 65 experienced major depression in the course of a year. This is much higher than the ECA studies although, as with the ECA, the prevalence rate fell with advancing years. As at other times of life, depression tended to be persistent. A subgroup was identified who appeared to be particularly prone to poor prognosis. They had persistent symptoms of loss of interest, feelings of worthlessness and thoughts of death.
Death from a broken heart?
What causes the increased mortality associated with depression? One factor might be heart rate variability. In a pilot study deGuevara and colleagues (Journal of Affective Disorders, 2004; 80: 257-262) studied 38 patients with myocardial infarction or angina aged over 60 and found that those with the higher mortality at 6 months also had a higher Hamilton score but interestingly worsening depressive symptoms was associated with a decrease in measures of spectral heart rate variability. This suggests impairment of cardiac autonomic function in depression.
John T. O’Brien, Robert Barber, and Robert Baldwin are the
Research Editors of the IPA Bulletin. They welcome readers’ comments via email
(J.T.O'Brien@ncl.ac.uk).
