IPA Bulletin
Recent Advances - Volume 17, Number 1
John O'Brien and Bob Barber
Guns and dementia are perhaps not usually associated in the mind of clinicians, but evidence from one study suggests they should be, at least in the USA (Spangenberg et al. JAGS 1999;47:1183-1186). The researchers assessed over 100 patients with dementia living at home for the presence of firearms and, if present, whether they were loaded. Just over 60% of households owned guns, irrespective of the severity of dementia or associated level of behavioral disturbance and depression. Somewhat alarmingly, nearly 45% of guns were kept loaded, and a further 38% of households were unsure whether the guns were loaded. Greater vigilance was advised!
“Up with corticotropin-releasing factor, down with acetylcholine,” was the teasing headline from a commentary by Nemeroff (Archives of General Psychiatry 1999;56:991-992) following the results of a postmortem study in Alzheimer's disease (AD) published in the same journal (Davis et al. 1999;56:981-987). It has long been known that certain neuronal populations are selectively affected in AD (including those containing acetylcholine, corticotropin-releasing factor (CRF), somatostatin, and neurotensin), while others remain unaffected. Davis and colleagues examined the immunoreactivity of both CRF (CRF-IR) and somatostatin-like (SLI) neuropeptides and although both were reduced in severe dementia, only CRF-IR levels were reduced in early dementia. The full significance of this finding needs to be explored further, but raises the possibility that CRF-IR could serve as an early marker of AD, and opens up options for novel therapeutic strategies directed towards enhancing neuropeptide activity in AD.
An important candidate enzyme thought to be a crucial missing link in the formation of b-amyloid in Alzheimer's disease (AD) has been identified by researchers from the biotech company, Amgen Inc. (Vassar et al. Science 1999;286:735-741). b-amyloid deposition requires proteolytic cleavage of the amyloid precursor protein (APP), a process involving b-secretase. The candidate protease, called beta-site APP-cleaving enzyme (BACE), was cloned and characterized and shown to have features highly consistent with the so-far elusive b-secretase. Other b-secretase candidates are likely to follow, but there is growing optimism that treatments, which inhibit this enzyme, will be developed.
Evidence-based data regarding treatments for behavioral symptoms of dementia are thin on the ground. However, an important study is described by De Deyn et al. (Neurology 1999; 53: 946-955). They conducted a 13-week double-blind study involving 344 patients with dementia randomly assigned to receive placebo, risperidone (0.5 - 4mg), or haloperidol (up to 2 mg). A non-significantly higher percentage of patients receiving risperidone (mean dose 1.1 mg) than placebo show clinical improvement, though the risperidone group did have a significantly greater reduction in standardized schedule of behavioral disturbance (the BEHAVE-AD) than placebo. There were few differences between haloperidol and risperidone in terms of efficacy, though extrapyramidal side effects tended to be higher with haloperidol. This study not only demonstrates a marginal benefit for risperidone, but illustrates the difficulty of performing such trials in patients where placebo response rates are high.
There is increasing evidence to indicate cholinesterase inhibitors can reduce behavioral symptoms in AD. However, predicting which patients will respond to treatment is far from clear. Researchers from the USA have produced evidence which may help guide prescribing (Mega et al. Archives of Neurology 1999;56:1388-1393). Using donepezil (at 10mg/day for 8 weeks), patients with more marked delusions, agitation, depression, anxiety, apathy, disinhibition, and irritability were found to show the greatest benefit, and these effects were independent of changes in cognitive function. The authors suggest that assessing the profile of behavioral symptoms before treatment should lead to more effective targeting of medication.
Readers of the Bulletin may find a review of treatment strategies in AD useful (Mayeux et al. New England Journal of Medicine, 1999, 341, 22, 1670-79).
In the search for diagnostic markers of AD, two recent studies have investigated the utility of measuring tau levels. Based on evidence to suggest cerebrospinal fluid levels (CSF) of tau are increased in AD, researchers from Sweden (Andreasen et al. Neurology 1999;53:1488-1494) measured CSF-tau levels in 407 patients with AD, 28 subjects with depression, and 65 healthy elderly controls. In a proportion of subjects with AD, a repeat measure was also obtained one year later. CSF-tau levels were raised in AD compared to both groups, and the test yielded a high sensitivity (93%) and specificity (86%) in discriminating subjects with AD from controls. The results were relatively stable over time, and elevated levels were even observed in subjects with mild dementia (MMSE > 23). However, work from Belgium (Ingelson et al. Dementia 1999;10:442-445) found no differences in plasma levels of tau in four diagnostic groups (AD, vascular dementia, frontotemporal dementia, and normal controls), leading the authors to conclude that measurement of tau in the plasma had no diagnostic benefit.
The role of informal caregivers in influencing institutionalization was assessed in a study of individuals with dementia living in the community (Ebly et al. Dementia 1999;10:541-548). Caregivers of individuals living alone were less closely involved in day-to-day, hands-on assistance, felt less burdened and depressed, and yet were more likely to contemplate residential care than those living with the demented person.
Nigral transplants have been shown to benefit some patients with Parkinson's disease, leading to a reduction in symptoms and less need for pharmacotherapy. However, whether these gains are maintained in the longer term is uncertain. Piccini et al. (Nature Neuroscience 1999; 2: 1137-1140) described a patient 10 years after a graft in whom dopaminergic function, as assessed by D2 Positron Emission Tomography, appeared to be intact. The authors concluded that, despite an ongoing disease process, grafted neurones can continue for at least a decade to store and release dopamine and so give rise to continuing substantial symptomatic relief.
Neuropathological changes of AD, including plaques and tangles, have hitherto remained hidden to conventional imaging techniques such as Magnetic Resonance (MR) Imaging. However, Ben Veniste et al. (Proceedings of the National Academy of Sciences 1999; 96: 14079-14084) reported MR Microscopy at high field strength (7.1 Tesla) using autopsy specimens from five patients with AD. After staining, a T2* image could detect neuritic plaques as black spherical elements. Although this result is far from clinical application, it provides an important demonstration that MR can, in principal, image the basic neuropathological features of AD.
The possible role that medication plays in the etiology of depression in the elderly was the subject of an investigation by Dhondt et al. (International Journal of Geriatric Psychiatry 1999; 14: 875-881). The authors studied the geriatric wards of three Dutch psychiatric hospitals and found 195 subjects with major depression. They investigated the use of "depressogenic" medication and found that patients with a first admission for major depressive disorder had taken such medications 2.44 times more often than patients who suffered from recurrent depression. The authors concluded that the use of depressogenic medication is an independent, clinically relevant and underestimated etiological factor in late onset depression.
A number of factors have been identified as predicting poor treatment response in elderly patients with depression. Kalayam and Alexopoulos (Archives of General Psychiatry 1999; 56: 713-718) found that poor performance on neuropsychological tests sensitive to frontal lobe dysfunction and prolonged P300 EEG latency predicted poor outcome in terms of improvement in depressive symptoms at six weeks. A composite electrophysiological and neuropsychological score predicted 58% of the variance in the change in depressive symptoms. Although neuroimaging findings were not reported in this study, these findings may fit with other reports that increased white matter lesion burden in elderly depressed subjects predicts poor response to treatment.
ECT is often described as a treatment that is particularly efficacious in the elderly. A new study providing more data to support this view is reported by Tuw et al. (American Journal of Psychiatry 1999; 156: 1865-1870) who investigated 268 patients with unipolar major depression treated with unilateral or bilateral ECT. Although the older (75 plus) group had higher seizure thresholds, response rates of almost 70% were seen, significantly higher than the response rates for subjects under the age of 60 (54%). The authors concluded that, despite a high level of physical illness and cognitive impairment, even very old patients with severe major depression tolerate ECT well and demonstrate better response than younger patients.
The monoaminergic hypothesis of major depression has been the main theoretical concept underlying etiology for the last 30 years. However, direct evidence confirming this is still needed. Meltzer et al. (American Journal of Psychiatry 1999; 156: 1871-1878) investigated 5HT 2A receptor binding in elderly patients with depression compared to those with AD and control subjects. Although 5HT 2A-receptor loss was found in those with AD, depressed subjects did not differ from controls. The authors concluded that 5HT 2A receptor function is not affected in late life depression, but that such receptor changes in AD may explain some of the cognitive and affective features of this disorder.
The optimum treatment for tardive dyskinesia (TD), which particularly affects elderly patients who have previously been treated with antipsychotics, remains unclear. Vitamin E has often been suggested as being useful. However, Adler et al. (Archives of General Psychiatry 1999; 56: 836-841) conducted a prospective, randomized two-year study of 158 subjects with TD who were treated with placebo or Vitamin E (1,600 international units per day). Although Vitamin E was well tolerated, there were no significant differences between treatment groups on any score of abnormal movements. The authors concluded that their study demonstrates no evidence that Vitamin E is superior to placebo in the treatment of TD.
Drs. John O'Brien and Bob Barber are the Research
Editors of the IPA Bulletin. They welcome readers' comments via
e-mail (J.T.O'Brien@ncl.ac.uk) or
fax (+44 191 219 5040). John O’Brien
also is Deputy Editor of the IPA Bulletin.
