IPA Bulletin Recent Advances - Volume 26, Number 2

By Dr. Robert Barber and Professor Robert Baldwin

The heart of the matter…
Depression, stroke and heart disease are all common in later life. Wouts et al from the Netherlands (Archives of General Psychiatry. 65: 596-602, 2008) studied their interaction in predicting incident stroke up to nine years in older adults. Those with baseline cardiac disease and depression were most at risk of later stroke, with a dose response relationship to both severity and chronicity of depression. Explanations include the synergistic effect of depression and vascular disease or perhaps that depressive symptoms reflect severity of underlying cardiac disease. Parker et al (Biological Psychiatry. 64: 660-6, 2008) found it was the onset of depression in the first month after an acute cardiac event that predicted worse cardiac outcomes rather than baseline or prior history of depression. The interested reader can turn to the American Journal of Geriatric Psychiatry, volume 11 2008 where there is an editorial by Nemeroff (857-860) and several relevant articles.

Also heart-centred is a large pharmaco-epidemiological study by Ray from the United States (New England Journal of Medicine. 360: 225-35, 2009) showing, worryingly, new use of antipsychotics, typical or atypical, is associated with an increased risk of sudden cardiac death which is dose-dependent. Users were matched to a ‘propensity group’ that was derived from the predicted probability that a person would be a user of antipsychotic drugs. Many of this group had a mood disorder, a group to whom antipsychotics are increasingly given. Graphs of risk ratios for each antipsychotic are given. Exclusion of adults aged over 74 may limit the generalisability to our specialty, although an accompanying editorial (Schneeweis & Avorn, 294-6) cautions that here the risk is probably greater.

Earthly vessels
From the United States, Mast and colleagues (Biological Psychiatry. 64: 320-326, 2008) examined 1,796 community subjects over 70 to explore the relationship between baseline vascular disease and the two-year incidence of raised depression symptoms (using the CES-D scale). Besides coronary heart disease, hypertension, etc they also looked for the metabolic syndrome and measured the ankle-arm index, adjusting the analysis for level of physical functioning. The cumulative burden of vascular risk and disease was significantly associated with a later rise in depressive symptoms, after allowing for confounders. Specifically, those with four or more vascular conditions were more at risk at two years. Besides supporting the vascular depression subtype, this data emphasises the need for optimum management of vascular disease in depressed subjects.

Sneed et al, also from the United States (Biological Psychiatry. 64: 491-497, 2008), applied the statistical technique of latent class analysis to two naturalistic clinical trials running for eight weeks. Although executive dysfunction, age of onset and subcortical gray matter changes allowed for some group differentiation, deep white matter lesion burden was the most accurate indicator of vascular vs. non-vascular depression. This internal consistency is important for confirming vascular depression as well as possibly suggesting a prototype category for DSM-V, although, as the authors point out, vascular depression may be part of a larger category of syndromes related to white matter disease.

Vitamins and depression…
Almeida and colleagues from Australia (Archives of General Psychiatry. 65: 1286-1294, 2008) studied a community sample of 3,752 men aged over 70 exploring the relationship between depressive symptoms (GDS 15), serum homocysteine and variants of the gene responsible for homocysteine metabolism (MTHFR). They found the risk of depression increased between 2-5% for every unit increase in the concentration of homocysteine (mL/l) and that those homozygous for the MTHFR polymorphism were 22% more at risk. They also performed a meta-analysis of existing studies of homocysteine in depression, concluding that lowering homocysteine could potentially reduce the odds of depression developing in the community. However, the same group (Ford et al. Journal of Clinical Psychiatry. 69: 1203-1209, 2008) was not able to demonstrate any difference in incident depression amongst 299 elderly men randomly allocated to either B group vitamins plus folic acid or placebo. De Lau et al from the Rotterdam Scan Study (J Neurol Neurosurg Psychiatry. 80: 149-157, 2009) studied 1,019 subjects and found an association between low vitamin B12 status and the severity of white matter lesions, especially periventricular abnormality. A much smaller United States study of demented subjects found no difference in mental state findings (including low mood) in low B12 subjects given replacement compared to controls
(van Dyck et al. International Psychogeriatrics. 21: 138-147, 2009).

What about other vitamins? Hoogendijk and colleagues from Holland (Archives of General Psychiatry. 65: 508-512, 2008) examined the relationship between vitamin D and depression in 1,282 residents aged over 65 (depression severity measured with the CES-D). Allowing for other factors, levels of 25-hydroxy vitamin D were significantly lower in individuals with both major and minor depression and level of parathyroid hormone was significantly higher. The authors comment that vitamin D may be important in neuroendocrine development. There are no trials of vitamin D replacement therapy in relation to mood and in studies like these, reverse causality cannot be ruled out (ie those who are depressed not bothering to eat properly). Nevertheless, it is striking that 39% of men and 57% of women met criteria for vitamin D deficiency.

Suicide
From Italy, Pompili et al (American Journal of Geriatric Psychiatry. 16: 727-737, 2008) studied 99 elderly suicides aged over 65 over a 10-year period and compared them to 134 younger victims. Most of the older group faced several difficulties and losses, often lived alone and had poor social support plus lower levels of education. Often, they had lost a partner. However, the major difference arose from physical illness which was up to six times more common than in the younger group. Using data ascertained by interview with physicians and relatives, of those with depressive disorder, the main psychiatric diagnosis, only 25% had received antidepressants. Forty percent of suicides had contact with a primary care physician in the preceding months. This is disappointing when one reads a paper by Kukrowicz and colleagues from the United States (Journal of Affective Disorder. 113: 30-36, 2009) showing that in a group of 343 older adults treated for depression, reduction in depressive symptoms was associated strongly with reduction in suicidal thinking and that this was most pronounced within the first two months of treatment.

New imaging studies in dementia with Lewy bodies (DLB)

Heart or brain when it comes to DLB?
Researchers from Japan compared the usefulness of SPECT versus MIBG myocardial scintigraphy in 25 patients with DLB (Tateno et al. Dement Geriatr Cogn Discord. 26(5): 453-7, 2008). Overall, a decreased uptake in MIBG scintigraphy was more common, occurring in 96% of subjects compared with occipital hypoperfusion, which qualitatively only occurred in 68% of subjects. Of course, this study does not indicate which approach best distinguishes DLB from other dementias.

Diagnostic accuracy of ¹²³I-FP-CIT SPECT in DLB
123I-FP-CIT SPECT can accurately differentiate probable DLB from Alzheimer’s disease, with a 77.7% sensitivity for detecting probable DLB and a 90.4% specificity for excluding non-DLB dementias, mainly Alzheimer’s disease (McKeith et al. Lancet Neurol. 6: 305-13, 2007). Researchers from this original study also wanted to gauge the effectiveness of this technique in situations where the diagnosis is less clear from the outset, such as in patients with possible DLB where there is a lower level of clinical certainty. They were able to complete a 12-month follow-up of 44 patients with possible DLB from the original study (O’Brien et al. BJPsych. 194: 34-39, 2009). After one year, 43% of patients had “converted” to a diagnosis of probable DLB, 16% were judged to have Alzheimer’s disease, and 41% remained unchanged. All the patients who were judged to have AD had a normal scan at baseline, whereas 63% of those patients who went from a diagnosis of possible to probable DLB had an abnormal scan at baseline. The authors concluded that an abnormal scan in someone with possible DLB is strongly suggestive of DLB. Indeed, as argued by the authors, the added value of neuroimaging could be at its greatest in situations where the clinician finds himself starting from a lower level of diagnosis confidence.

Amyloid in patients with Lewy body disease…
Maetzler and colleagues from Germany used [(11) C] PIB-PET to measure beta-amyloid burden in patients with Lewy bodies disease (Neurobiol Dis. Dec 31, 2008). Overall, none of the patients with Parkinson’s disease, but no dementia (n= 0/14) were PIB positive, whereas 4 out of 9 patients with DLB and 4 out of 12 patients with PD, plus dementia were PIB positive. The authors concluded that patients with Lewy body disease who had cortical beta-amyloid showed characteristics similar to those observed in AD.

Effects of antioxidants on Alzheimer-type pathology…
There are potentially many different ways to influence the pathogenesis of Alzheimer’s disease. Dumont and colleagues from New York (J Neurochem. Feb 7, 2009) based their experiments on the notion that oxidative stress could play a vital role in the disease process, and using a transgenic mice model of AD, evaluated the impact of a compound, triterpenoid CDDO-methylamide, which is thought to have antioxidant and anti-inflammatory effects. Intriguingly, the compound was found to improve both spatial memory and pathological markers, including a reduced plaque burden, Abeta42 levels and microgliosis. Where the effects of this compound mediated solely via anti-oxidane mechanisms is however, unclear, as in cell culture assays, synthetic triterpenoids have be shown to have potent multifunctional actions. Depending on the dose, they can suppress inflammation, activate cytoprotective pathways, induce differentiation, inhibit proliferation and induce apoptosis. (Liby et al. Nature Reviews. Vol 7, P357-389, May 2007).

BPSD – evidence from a prospective study underlines their importance
The central importance of behavioural and psychological symptoms in dementia was underscored by the findings from a United Kingdom cohort study (Sawa et al. BJPsych. 194: 212-219, 2009). The study measured the prevalence of 12 behavioural and psychological symptoms in a longitudinal, population-based sample (subjects with dementia n= 587; subjects without dementia n= 2050). These symptoms were found to affect nearly all people with dementia, and apart from sleeping difficulties, occurred more frequently in people with dementia compared to those without dementia (though interestingly, changes in mood, apathy, irritability and feelings of persecution were also seen in a significant proportion of subjects without dementia). Symptoms often co-occurred, and a factor analysis identified four clusters, relating to depression/anxiety, psychosis/apathy, persecution/irritability and wandering/sleep problems. The study also explored the course and correlates of BPSD, and found symptoms varied in their persistence. For example, disorders of mood did not tend to persist, whereas psychotic symptoms did. The relevance of these findings were also discussed in an accompanying editorial by Prof. Alistair Burns (p199-200).

Conventional antipsychotics and causes for increased mortality
Further insights into the adverse effects of antipsychotic medications were published in J Am Geriatr Soc (Setoguchi et al. 56(9): 164-50, 2008). Researchers were able to compare the cause of death in patients aged 65 and over in the first 180 days after initiating treatment with either a conventional (n>12,000) or atypical (n>24,000) antipsychotic. Overall, initiators of conventional antipsychotics had a higher risk of death due to cardiovascular, respiratory and nervous system diseases.

Cholinesterase inhibitors in MCI – more ground for optimism?
The results from a 48-week multicentre randomized placebo-controlled trial of donepezil (10mg/day) in mild cognitive impairment were published in February 2009 (Doody et al. Neurology). Overall, there was a modest improvement in the primary cognitive outcome measure in favour of donepezil, but no differences in the other primary or secondary outcome measures, including functioning. Discontinuation rates were higher in the donepezil group (18.4% vs. 8.3%).

To date, individual RCTs have failed to find any evidence that using cholinesterase inhibitors (CHI) in patients with MCI reduces the risk of developing AD. However, the results from a pooled meta-analysis from four RCTs found that from a total of 1,784 subjects treated with a CHI, 15.4% progressed to AD/dementia compared to 20.4% subjects receiving placebo (n= 1,790) (Diniz et al. Eur Arch Psychiatry Clin Neurosci. Feb 17, 2009). This gave a relative risk of developing dementia 0.75 in favour of CHI. However, patients on active treatment had a greater risk of discontinuation (RR = 1.36).

Thumbnail reports:
All healthy adults have anti-Abeta IgG autoimmune antibodies – but what are their relevance?
Kellner et al aimed to determine whether naturally occurring autoantibodies to beta-amyloid have a role in the disease process (Ann Neurol. 65(1): 4-6, 2009). Using autopsy tissue, they were able to demonstrate that beta-amyloid autoantibodies were indeed both common and appeared to reduce plaque burden.

Melatonin and dementia
A small RCT found that ten days treatment with melatonin failed to improve sleep or agitation in institutionalized patients with Alzheimer’s disease (Gehrman et al. Am J Geriatr Psychiatry. 17(2): 166-9, 2009).

Dopamine and delusions in dementia
A study from the United Kingdom found patients with AD who were delusional had increased striatal dopamine (D2/D3) receptor availability, similar in severity as drug-naïve patients with schizophrenia (Reeves et al. Neurology. 72(6): 528-34, 2009).




 

Reprinted from IPA Bulletin, Volume 26, Number 2