IPA Bulletin Recent Advances - Volume 26, Number 3

By Dr. Robert Barber and Professor Robert Baldwin

3-D films
Finding out which parts of the brain are affected in late-life depression is explored by Butters and colleagues (American Journal of Geriatric Psychiatry. 17: 4-12, 2009). Using sophisticated 3-D image analysis, they have mapped the surface area and volume of the caudate nucleus in late-life depression. Total volumes were significantly less in both left and right caudate in depressed subjects (n=23) compared to controls (n=15) and these volume reductions correlated with depression severity. In the authors’ view, that the anterior portion of the caudate was especially affected supports the notion of striatal circuitry disruption and is consistent with vascular depression.

Sleep
Cho and colleagues from California (American Journal of Psychiatry. 165: 1543-1550, 2008) set out to address whether sleep predicts depression or depressive disorder predicts poor sleep. A total of 145 subjects had a prior depression history and 206 never had depression. They were all administered the Pittsburgh Sleep Quality Index and reassessed 6-monthly up to two years. Most of those who developed depression had a prior history of it and within this group poor sleep independently predicted depression recurrence. So in terms of recurrence, poor sleep may be an early warning sign and a predictor.

Blood pressure
There is an ongoing debate about blood pressure and depression. Licht and colleagues (Hypertension. 53 (May 16th online ahead of print), 2009) studied 590 community control subjects, 1384 persons with either depression or anxiety not on antidepressants and 664 with depression or anxiety on an antidepressant. Although the mean age was only 40, there is relevance to later life. First, subjects with major depression had significantly lower systolic blood pressure whilst anxious patients had a higher mean diastolic blood pressure compared to controls. Second, patients using a tricyclic antidepressant had a significantly higher systolic and diastolic blood pressure compared to controls and non-medicated patients at high risk of being clinically hypertensive. This effect was found to be mediated by the anticholinergic effects of tricyclics on vagal control of the heart. The low blood pressure is hard to explain. As has been suggested in late-life depression, it may be that hypotension is a risk factor for depression rather than the other way round. However, the main point of the article is to demonstrate that not all antidepressants affect blood pressure in the same way.

Bones and Depression
Depression may be associated with low bone mass. Rosen (New England Journal of Medicine. 360: 957-959, 2009) provides an overview of the intriguing links between serotonin and bone metabolism. It seems that it is well established that the brain can influence bone re-modelling and bone loss as there are serotonin receptors in bone as well as the brain. What does this mean? Rather worrying evidence cited by Rosen is that SSRI use is associated with twice the annual rate of bone loss compared to tricyclic usage. Given the ubiquity of their use, this obviously requires studies of clinical populations of patients with depression and may be particularly relevant to later life.

Depression in Parkinson’s disease
By convention, Parkinson’s disease depression is treated with an SSRI. However, Menza and colleagues (Neurology. 72: 886-892, 2009) conducted a study of 52 patients with Parkinson’s disease allocated to paroxetine slow release, placebo or nortriptyline. The average age was 62. This is the largest placebo-controlled trial of its kind. Surprisingly, nortriptyline was significantly more effective in improving the Hamilton Rating Scale compared to the placebo; paroxetine was not effective. The number-needed-to-treat for nortriptyline was 3.5, based on responder status. Both drugs were tolerated well and had similar drop out rates. This interesting finding challenges conventional wisdom.

So too does a preliminary study from Brazil of omega-3 fatty-acid supplementation in depressed patients with Parkinson’s disease (Moralez da Silva. Journal of Affective Disorders 111: 351–359, 2008). Significantly more of those taking fish oil reduced their Montgomery & Asberg depression score by 50% compared to controls, but this was a small study. Moreover, as previously reported (van de Rest. Am J Clin Nutr. 88: 706–13, 2008), a large Dutch study did not report any mental health benefits among independently living individuals aged 65 years and over with either 1800 mg/d EPA_DHA, or 400 mg/ d EPA_DHA.

Recognition of Depression in Primary Care
It is often said that depression in primary care is under-recognised and under-treated. Kendrick et al from England (British Medical Journal. 338: 761, 2009) described prescribing practice in 2294 patients who had been assessed for depression using depression severity questionnaires. A total of 1658 were assessed using the PHQ-9, 584 with a Hospital Anxiety and Depression Scale (HADS) and 52 with a Beck Depression Inventory (BDI). The level of agreement between these questionnaires was quite poor although rates of intervention were quite similar. Of interest to our specialty, the odds of intervention or of a referral to a specialist were lower in older patients and those with physical co-morbidity. An accompanying editorial (Weel et al, p 726) comments on this surprising finding and suggests that general practitioners rely more on their clinical judgement than on questionnaires and possibly seek alternative ways of treatment for older physically infirm patients, for example lifestyle changes rather than an antidepressant.

Which antidepressant?
Hotly debated is a report in the Lancet by Cipriani et al (Lancet. 373: 746-58, 2009) – 117 RCTs (N=25,928) of adults with unipolar major depression and 12 “new” generation antidepressants. Although not a study specifically of older patients, it is highly relevant. Reboxetine, fluoxetine, paroxetine and duloxetine were the least efficacious and least well tolerated drugs, whereas mirtazapine, escitalopram, venlafaxine and sertraline were more efficacious although mirtazapine and venlafaxine were somewhat less acceptable in terms of side-effects and drop outs. The authors go as far as to say that sertraline should be considered as the new comparator in any future controlled trials of antidepressants. There is a lot of ensuing journal correspondence!

This paper fits nicely with another concerning newer antidepressants by Nelson et al (American Journal of Geriatric Psychiatry. 16: 558-567, 2008). This examined placebo controlled trials (it is important to recognise the Cipriani trial looked only at comparisons of antidepressants with each other), finding ten unique trials covering 2377 older patients with active drug and 1788 with placebo. Four of the studies included had not been published previously. The authors found that the newer “second” generation antidepressants were more effective than placebo for patients aged over 60 with major depression but that the treatment effects were rather modest. They calculate that for every 100 patients treated, eight would show a response and five remission in excess of placebo treatment. This in itself has to be weighed up against adverse events and for every two patients who responded to drug treatment, one discontinued because of adverse effects. Importantly, the authors found that trials of between 10 and 12 weeks showed better effects than 6 to 8 weeks. Although this sounds rather gloomy, we know already that placebo response rates in RCTs have been increasing over the years and that sub-groups such as those with more severe depression seem to do the best. The authors argue that the heterogeneity in response rates they found suggests substantial variability amongst individuals and that the next task is to find out which factors predict or moderate response to antidepressants.

Delirium accelerates cognitive decline in Alzheimer’s disease
There is something reassuring when a research study confirms what clinicians already “know”. A cohort study found individuals with Alzheimer’s disease who developed delirium experienced a significant acceleration in their rate of cognitive decline compared to those who did not develop delirium (Fong et al. Neurology. 72(18): 1570-5, 2009). This finding underlines the clinical importance of delirium, and raises important questions about the underlying pathophysiology of delirium.

Hypertensive drug use in later life can reduce risk of developing dementia
Although evidence is still not uniform, a number of longitudinal epidemiological studies have suggested optimizing control of vascular risk factors such as hypertension, diabetes, heart disease and smoking may help to reduce the risk of developing Alzheimer’s disease, and dementia more generally.
Exploring this topic, Haag and colleagues from The Netherlands reported their findings from a longitudinal study of antihypertensive use and dementia (Neurology. 72: 1727-34, 2009). The study involved over 6,000 participants (mean age 68 years) followed up from baseline (1990-1993) to 2005. Encouragingly, antihypertensive use was associated with an 8% reduction in dementia per year of use in individuals aged 75 years or below, and 4% in those aged over 75 years. Similar findings were also observed for patients where Alzheimer’s disease was specifically identified.

Amyloid toxicity and temporal lobe atrophy in Alzheimer’s disease
Medial temporal lobe atrophy is a well-recognised change in Alzheimer’s disease. The reason why neurones in this area have a predilection to the Alzheimer-type pathology is not clear, but a recent imaging study found brain atrophy in this area was associated with increased amyloid pathology using an in vivo imaging marker of amyloid (Frisoni et al. Neurology. 72: 1504-11, 2009). There was no link between atrophy and amyloid in other neocortical areas, leading the authors to conclude that the medial lobe appears to be more susceptible to amyloid toxicity than other neocortical areas.

MCI, donepezil and depression
Results from a RCT using donepezil in mild cognitive impairment (MCI) found participants with higher depression scores (measured using the Beck Depression Inventory) at baseline were more likely to develop Alzheimer’s disease (Lu et al. Neurology. 72(24): 2115-21, 2009). Furthermore, among the subjects with higher depression scores, treatment with donepezil appeared to delay this progression to AD, particularly in the first two years of the three-year study.

Relationship between neuropathology and dementia varies with age
Understanding the relationship between age and the neuropathology of Alzheimer’s disease was the focus of a population-based clinico-pathological study from the UK (Savva et al. N Eng J Med. 360(22): 2302-9, 2009). Interestingly, the study found an association between AD-type pathology and dementia in the “young old” (75 years), but by 95 years the link was considerably attenuated. In contrast, atrophy was greater in the dementia cohort at both age ranges. The authors concluded that age must be taken into account when assessing the likely effects of interventions against dementia on the population.

Does treatment of vascular disease in Alzheimer’s disease work?
A multicentre RCT from the Netherlands explored the impact of interventions designed to optimise control of vascular risk factors in patient with AD and cerebrovascular disease (n=130) (Richard et al. J Am Geriatr Soc. 57(5): 797-805, 2009). Active intervention included pharmacological strategies to reduce cholesterol and blood pressure, as well as non-pharmacological interventions, such as changes to lifestyle and exercise. After two years, there were no differences in clinical outcome across a range of measures compared to standard care. Methodologically, this is a challenging area to investigate, and the findings do not rule out the possibility that earlier, longer or more aggressive control of the risk factor may prove to be more effective.

Thumbnail therapeutic updates
Oxcarbazepine, a structural derivative of carbamazepine, is an anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy and bipolar disorder. Researchers from Norway completed an eight-week RCT in institutionalized patients with Alzheimer’s disease (n=103) and found no significant effect on agitation and aggression (Sommer et al. Dement Geriatr Cogn Discord. 27: 155-63, 2009).

Further results from the USA based CATIE-AD study (Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer’s disease) found patients treated with citalopram for at least 14 days experienced a 60% reduction in irritability and apathy, though there was no meaningful impact on psychotic symptoms (delusions and hallucinations) (Siddique et al. J Clin Psychiatry. 2009).


 

Reprinted from IPA Bulletin, Volume 26, Number 3