IPA Bulletin
Recent Advances - Volume 22, Number 2
By Professor John
O'Brien, Dr. Robert Barber, and Professor Robert Baldwin
Cholinesterase inhibitors in early AD, Multiple Sclerosis and Frontotemporal dementia
The value of using cholinesterase inhibitors in mild to moderate Alzheimer’s disease (AD) is well established. But there is, of course, interest in evaluating the
effectiveness of this treatment across the spectrum of severity. In a recent 24-week week study, 153 patients with early-stage AD were randomised to either donepezil (70%
completed) or placebo (81% completed) (Seltzer et al, Arch Neurol. 2004 Dec;61(12):1852-6). Subjects with AD were included if they had an MMSE score of 21-26, Clinical Dementia Rating (CDR) of 0.5 or 1.0 and only minimal impairment of activities of daily living (ADL). At week 24 the drug-placebo difference was approximately 2.3 points on the ADAS (p=0.008) and 1.8 points on the MMSE (p=0.002) in favor of donepezil. No significant differences were observed on CDR-Sum (proxy for ADL) or Patient Global Assessment Scale, a
finding the authors suggested reflected the relative high functioning of subjects at recruitment. Nevertheless, this leaves the question of the wider
benefits to patients, their family and indeed society still open to further study.
There is also interest in exploring the limits of the effectiveness of cholinesterase inhibitors in non-AD populations where cholinergic
deficits are at least, hypothetically, possible. Krupp et al (Neurology. 2004 Nov 9;63(9):1579-85.) completed a 24-week single-center double-blind placebo-controlled trial (n=69) to evaluate the effects of donepezil (10mg daily) in patients with multiple sclerosis associated with
cognitive impairment. The researchers used a different primary outcome measure than that normally applied to trials involving Alzheimer’s disease — namely the change in verbal learning and memory on the Selective Reminding Test (SRT). Donepezil-treated patients showed
significant improvement in memory performance on the SRT compared to placebo. Clinicians were also more likely to report cognitive improvement in patients on active treatment. The medication appeared to be well tolerated, save for an increase in abnormal dreams.
A much smaller, open-label study investigated the effects of rivastigmine (3-9mg/day) in 20 patients diagnosed with frontotemporal dementia (FTD) (Moretti et al, Drugs Aging. 2004;21(14):931-7.). Though active treatment did not appear to prevent deterioration in MMSE scores, pa-tients were less behaviourally impaired, and caregiver burden was reduced, at 12 months, compared with baseline.
The authors of both these studies recognise the need for further replication and extension of these preliminary
findings, but in the meantime they add to the debate surrounding the generic effects of cholinesterase inhibitors.
Antipsychotics and dementia
The use of atypical antipsychotic in dementia raises a number of uncertainties and indeed controversies. This partly stems from concerns about their over use and adverse effects, but also about the evidence-base for their effectiveness. In this regard, Rabinowitz et al (J Clin Psychiatry. 2004 Oct;65(10):1329-34.) conducted a post hoc analysis of 3 randomized, controlled trials of risperidone versus placebo in treating 1150 nursing home residents with behavioral and psychological symptoms of dementia. Using standardised measures, risperidone was more effective in treating a range of behaviours including hitting, injuring self or others, cursing or verbal aggression, repetitive questions, scratching, restlessness, grabbing, physical threats and/or violence, agitation and delusions. The authors concluded that risperidone is more effective than placebo in treating a variety of non-cognitive symptoms associated with dementia.
Immunotherapy of Alzheimer’s disease As argued by Nitsch there are a number of important reasons why beta-amyloid plaques are potential immunotherapeutic targets in AD (Alzheimer Dis Assoc Disord. 2004 Oct-Dec;18(4):185-9). However, as previously reported, clinical trials were discontinued owing to the development of an autoimmune, cell-mediated meningoencephalitis. Could a different approach to immunotherapy circumvent this problem? Qu et al (Arch Neurol. 2004 Dec;61(12):1859-64) set about seeing whether gene vaccination could be used to generate an immune response to Abeta(42) that produced antibody response but avoided an adverse cell-mediated immune effect. Encouragingly, their studies in mice showed this was possible, indicating this immunotherapeutic approach could provide an alternative form of active
immunization in the treatment and prevention of AD. Furthermore, on-going
findings from Alzheimer’s transgenic mice show that life-long immunization with human beta-amy-loid (1-42) protects mice against cognitive impairment well into older age (Jensen et al, Neuroscience. 2005;130(3):667-84).
Can neuropsychological changes be detected before the onset of Alzheimer’s disease?
The answer seems to be “yes” according to findings from a longitudinal study from the United States (Saxton et al, Neurology. 2004 Dec 28;63(12):2341-7). Researchers annually tracked 693 individuals for a medi-an of 7.4 years. The seventy-two individuals who were ultimately diagnosed with AD had poorer scores on baseline neuropsychological measures than subjects who remained free of dementia.
Interestingly, although individuals closest to the onset of illness (ie, 1.5 to 3.4 years) had, as would be expected, the worst performance, cognitive impairment was detected in individuals who did not develop AD until 5 to 8 years later. These
findings parallel those from a smaller study tracking the evolution of symptoms in patients with familial Alzheimer’s disease over a 10 year period (Godbolt et al, Arch Neurol. 2004 Nov;61(11):1743-8.). Patients were found to have a long prodromal phase of several years characterised by subtle deficits of
general intelligence and memory, while spelling, naming, and perception were relatively preserved until a late stage. MMSE was not sensitive to early disease detection.
17 Factors associated with cognitive decline in later life and in Alzheimer’s disease
6,102 individuals aged 65 years or older underwent regular follow-up for an
average of 5.3 years as part of an epidemiologic study of risk factors for Alzheimer’s disease (AD) and other common conditions (Barnes et al, Neurology. 2004 Dec 28;63(12):2322-6.). Individuals with greater social networks and level of social engagement had higher initial levels of cognitive function, and both resources were also associated with a reduced rate of cognitive decline. A second
longitudinal study, also from Rush Alzheimer’s Disease Center, Chicago, tracked patients (n=494) with established AD for 4 years (Wilson et al, Neurology. 2004 Oct 12;63(7): 1198-202). Overall, a more rapid decline in cognitive function was found in both in younger patients and those with higher educational level.
The intriguing relationship between “vascular risk factors” and Alzheimer’s disease (AD) was the subject of a further study by Bellew et al (Alzheimer Dis Assoc Disord. 2004 Oct;18(4):208-13.). They investigated the effect of hypertension and cognitive decline (over 6 months) in more than 700 patients with AD. Cognitive decline among patients older than 65 years was comparable for hypertensive and normotensive subjects, but patients younger than 65 years with hypertension had greater cognitive decline than without hypertension. However, in this study treatment with antihypertensives appeared not to provide protection from cognitive decline, though the follow-up period was relatively short.
Neuroimaging in Alzheimer’s disease
Understanding brain changes in dementia could help with in vivo diagnosis, provide a biological paradigm to measure the effectiveness of an intervention in clinical trials, and help to link clinical symptoms with biological change. Rusinek et al (Neurology. 2004 Dec 28;63(12):2354-9.) found serial measurements of medial temporal lobe atrophy could distinguish patients with AD from normal controls with an accuracy of 92%, supporting the notion that increased annual atrophy rate in this region is a potential diagnostic marker of the progression of Alzheimer’s disease. Another study (Ezekiel et al, Alzheimer Dis Assoc Disord. 2004 Oct;18(4):196-201) found, in line with previous studies, that AD patients had approximately 2.5 times greater whole brain atrophy rates and more than 5 times greater medial temporal lobe (hippocampal and entorhinal cortex) atro-phy rates than controls. The effect size and power calculations suggest that entorhinal cortex and hippocampal measurements were the most sensitive marker for detecting AD progression and the potential effects of disease modifying agents. A functional study using SPECT found underactivity in the right middle medial temporal region was an important neural correlate of aggression in patients with AD (Lanctot et al, Arch Neurol. 2004 Nov;61(11):1731-7.). Finally, as reported in previous Bulletins, researchers continue in their endeavours to develop in vivo imaging techniques that can detect beta-amyloid plaques in Alzheimer’s disease, which ultimately could permit
presymptomatic diagnosis (Verhoeff et al, Am J Geriatr Psychiatry. 2004 Nov-Dec;12(6):584-95).
Changing service provision to improve management of depression
New models of depression management have not been greeted with a blaze of publicity but have produced extremely important new data. In the latest of these Bartels and colleagues (American Journal of Psychiatry, 2004; 161: 1455-62) examined whether access to mental health care could be improved by re-engineering services to be integrated (co-located) with primary care compared to a more traditional model of separate clinics. In a study of over 2000 subjects 71% of patients in the integrated model compared to 49% in the specialist model engaged in treatment. Traditional models of accessing specialist care are there-fore under scrutiny.
Another model that has become popular but largely untested is that of a nurse-led mental health service for patients on general medical wards. Baldwin et al (Age & Ageing, 2004; 33:472-78) described the introduction of a generic liaison service in a District General Hospital in the North of England. Patients were randomly allocated via intervention delivered by a Specialist Mental Health Nurse or usual care. Of the 153 subjects, there were no
significant group differences on a generic measure of outcome nor on the MMSE but those in the intervention group had
significantly lower depression scores at 6-8 weeks later. Because depressive symptoms are so prevalent this modest improvement could be important. The authors suggest though that for other improvements in mental health care scarce resources need to be targeted either by psychiatric diagnosis (eg delirium) or to
specific groups (eg rehabilitation wards or stroke units).
Do antidepressants improve cognition in dementia?
Alzheimer’s disease is associated with a heightened risk of major depression and depressive symptoms. Munro et al (American Journal of Geriatric Psychiatry, 2004; 12: 491-98) conducted a secondary analysis of patients in the “Depression in Alzheimer’s Disease Study” (DIADS). The main study examines the role of sertraline in treatment. This study explored whether
cognitive function improves. Over a 12 week time period there were no
significant differences in cognitive function for those whose depression had responded either wholly or partially and in among those who had not responded at all although numbers were small (n=36 completing all measures). The authors speculate that perhaps the lack of cognitive improvement could be related to the presence of microvascular disease causing cognitive impairment rather than low mood. This is clearly and area worth exploring.
Traumatic experiences may last a lifetime
Childhood sexual abuse is known to predispose to depression in earlier and middle life. What about old age? In a preliminary but interesting report Talbot et al (American Journal of Geriatric Psychiatry, 2004;12:536-38) examined the relationship between self-reported childhood sexual abuse and suicidality. Of 127 female
participants 14% had a history of such abuse. Importantly, this history was associated with multiple suicide attempts. Clearly the
retrospective design limits the generalisability but it suggests that such painful experiences cast a long shadow.
Recognising depression in primary care
Do primary care physicians overlook depression? This has been an ongoing debate over many years. Volkers and colleagues (Journal of Affective Disorders, 2004;82: 259-63) analysed data from a Dutch primary care survey which uses a standardised psychiatric interview (CIDI). This
identiffied 55 older patients who had major depressive disorder, nearly all of whom had at least one contact with primary care in the preceding 12 months. Only one fifth of these were
recognised as having depression whilst another third were regarded as having other
psychological problems. Interestingly, higher age in itself did not predict diagnostic accuracy. Rather, these primary care physicians seem to have difficulty in differentiating
depressive disorder from other complaints which might resemble depression, such as anxiety and distress caused by social
difficulties.
Antidepressants for minor depression
Linked to this is the topic of ‘minor depression’. In a study of mixed-aged patients (averaging in their 40s but going up to age 72), Judd et al (American Journal of Psychiatry, 2004;161:1864-71) found that fluoxetine was superior to placebo in a carefully selected group of patients
suffering from operationally defined (DSM IV) minor depression. Although depressive symptoms improved psychosocial outcomes did not. The authors comment that it may take longer than the 12 weeks of the study for effects on psychosocial functioning to occur. Since minor depression is so common in the elderly it would be important to
replicate these findings in an older group who may have different risk factors for minor depression.
Depression and pain
We have written previously on the link between depression and pain. Un-utzer et al (Journal of the American Geriatric Society, 2004;52:1916-22) report on the pharmacotherapy of pain in depressed older adults drawing on their very large earlier study of 18 primary care clinics in the US (the IMPACT study). Depressed patients, (major depression or dysthymia) had high rates of pain, with 50% experiencing
chronic pain. Only half were receiving any analgesic medication. Besides the under-treatment of pain in this depressed sample, the authors noted a striking variation, up to 5 times, in the amount of opioid analgesia used across the participating sites. This contrasted with the more stable level of antidepressant use of between 35% and 53%. However, almost a third received no treatment for either depression or pain.
Prevention programmes for depression may be effective
The group from the McGill University in Canada who produce various meta-analyses of depression prognosis have turned their attention to prevention. In a systematic review Cole and Dendukuri (International Journal of Geriatric Psychiatry, 2004;19: 1019-25) found 10 trials which met their inclusion criteria and which were aimed at providing brief interventions for the
prevention of depression in older people. Many of the studies listed are not ones that will be familiar to many of us who research
depression and therefore this is new territory. Despite the heterogeneity of the sample, individual work aimed at older bereaved subjects deemed “at risk,” educational
interventions for subjects with chronic illness, CBT and life review were all effective. The key seemed to be to empower the individual and reduce negative thinking.
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).
