IPA Bulletin Recent Advances - Volume 24, Number 1

By Dr. Robert Barber, and Professor Robert Baldwin

More Evidence that Depression and Dementia are Linked

Rapp and colleagues (Archives of General Psychiatry, 2006; 63: 161-167) studiedthe brains of 52 patients with Alzheimer’s disease (AD) without a lifetime history of major depression and 50 with AD and a lifetime history of major depression (diagnosed before dementia). Their aim was to see if recurrent depression could be linked to damage in areas such as the hippocampus or whether depression might exacerbate Alzheimer’s pathology. The authors found that neurofibriliary tanglesand amyloid plaques were more pronounced in the hippocampus of patients with a lifetime history of major depression. This supported their hypothesis and they highlighted the importance of interventions in major depression which might even prevent some cases of Alzheimer’s disease. With interest in vascular depression, the authors looked to see if cerebrovascular disease might be a factor but found no major group differences.

More STARS

In a previous edition, we mentioned the STAR*D study. Fava and colleagues from the US (American Journal of Psychiatry, 2006;163: 1161-1172) have produced more data from this important research which addresses response rates in depression of patients who have failed to respond to first-line treatment. After two consecutive failed treatment trials, the effect of switching to either Mirtazapine or Nortriptyline resulted in very mediocre subsequent responses: 12.3 and19.8 percent remission respectively using the Hamilton Scale. The difference between the two drugs was not significant. Although not specific to the elderly, there is no reason toe xpect the data to be different when extrapolated and clearly resistant depression continues to be a major challenge.

Depression, Anxiety and Retirement

Several studies report reduced rates of depression in later life, although some experts question this. Villamil and colleagues from Cambridge UK (Psychological Medicine, 2006; 36: 999-1009) examined the British Psychiatric Morbidity Survey(BPMS) for 2000 and analysed the data from 4128 adults aged 45 and over (29%over 65). In both men and women the prevalence of depressive episode fell markedly after the statutory retirement age. There was a similar pattern for anxiety disorders in men although in women the prevalence declined more smoothly. Having reached the statutory retirement age was amore important factor in reduced anxiety levels than work status or personal retirement age. The authors comment that the expectation of being in the labour market until a certain age may lead to stress which is only relieved when the person reaches the societal age when they are no longer required to work.

…and Anxiety Treatment

Pharmacological studies of anxiety disorders in late life are rare. Blank and colleagues from the US (Journal of Clinical Psychiatry, 2006; 67: 468-472) included 30 patients aged over 60 years of age with generalised anxiety disorder in a trial of Citalopram over 32 weeks. Ten percent discontinued because of side-effects and five out of 30 did not respond. The overall response rate was 57% with some responses occurring as late as 20 weeks. Those who were on the drug the longest appeared to experience the most improvement, particularly in sleep and quality of life.

But Do Antidepressants Work in Depression?

Mixed results from Randomised Controlled Trials (RCTs) have been reported of late. In the latest, Schatzberg and Roose (American Journal of Geriatric Psychiatry, 2006; 14: 361-370) report on a study comparing Venlafaxine (N=93), Fluoxetine (N=99) and placebo (N=96). Mean age was 71 and Hamilton Score means were around 24 at baseline. Over an eight-week trial, there were no differences on the Hamilton Depression Scores and although in an earlier report the authors had reported a possible advantage to Venlafaxine as measured on the Montgomery and Asberg Scale, this more complete data set reveals no significant differences on any of the end points. Both active drugs had higher discontinuation rates from side-effects than did the placebo, although the latter had a higher withdrawal rate from lack of efficacy. This population was an out-patient group with moderate depression and raises the question as to whether antidepressants are really all that effective in less ill depressed patients.

Cognitive Function in Late Life Depression

One certainty in late life depression is that cognitive dysfunction is common. But is it due to multiple deficits in different domains or perhaps mediated by a single factor such as processing speed? Sheline and colleagues from the US (Biological Psychiatry, 2006; 60: 58-65) studied this in 155 patients with major depression, mean age 68.7. A cognitive battery covering language, processing speed, executive function and memory was administered. The authors confirmed a broad range of cognitive impairment but the effects could be accounted for by processing speed and executive function. Age, depression severity, vascular burden and ethnicity all contributed to processing speed. Vascular risk appeared to impair cognitive function more so than did overall medical burden. Processing speed explained somewhat more of the association with cognitive impairment than did executive function, but there was overlap. Both are thought to be mediated by fronto-striatal disconnection and clearly could be linked to white matter changes, although this study had no imaging data. Age of depression onset, said to be a criterion for “vascular depression”, was not an independent predictor of cognitive impairment.

Even More Apathy

Apathy, another subject highlighted previously, may be a core feature of Parkinson’s disease. In a group of patients with Parkinson’s disease, average age 69, Kirsh-Darrow from the US (Neurology, 2006; 67: 33-38) teased out the relationship between apathy and depression. As a control group, they used subjects with dystonia. Apathy was measured using the Apathy Evaluation Scale and depression via the Beck Inventory and the Center for Epidemiologic Studies Depression Scale (CES-D). About 30% of the parkinson’s patients exhibited apathy without depression whereas this was not noted in any of the dystonia patients. Parkinson’s disease may disrupt mesial frontal-anterior cinglulate cortical pathways which seem to be involved in apathy, whereas in depression orbitofrontal subcortical connections may be disrupted. It is therefore important to differentiate apathy and depression, not only in Parkinson’s but in other disorders including late life depression. The treatment of apathy is not yet clear but research is examining dopaminergic agents, atypical antipsychotics and cholinesterase inhibitors.

Under and Over the Threshold

Sub-threshold depression is a risk factor for major depression. This knowledge would be more useful if we knew which patients went from sub-threshold to major depression. Cuijpers and colleagues from Amsterdam (International Journal of Geriatric Psychiatry, 2006; 21: 811-818) explored this with a cohort of 154 subjects who scored above the threshold on the CES-D (> 16) but had no DSM mood disorder, aged 55 to 85. At between three and six years follow-up, one-fifth developed a mood disorder. In univariate analysis with major depression or dysthymia as the outcome variable, older age, low perceived mastery, poor appetite, sleep problems, tiredness, restlessness and slow thinking were predictors. Using regression analysis only two remained significant, appetite and sleep problems. Having both these risk factors significantly increased the risks. Quite why these two factors should be particularly powerful predictors is not clear, but certainly sleep disturbance has been associated with both depression and high mortality.

Personality

The assessment of personality in geriatric psychiatry is not very well researched. From the Netherlands, van Alphen and colleagues (International Journal of Geriatric Psychiatry, 2006; 21: 862-868) assessed 159 elderly patients attending a geriatric psychiatry out-patient department and 96 informants with a purpose designed 16-item “Gerontological Personality Disorders Scale” (GPS). This was divided into “habitual behaviour” (worrying about health, concern about memory, being abandoned or taken advantage of) and biographical information (having been to a psychiatric institution, having had trouble with nerves, treatment, etc). In this preliminary study, the properties of the scale were modest although the biographical questions seemed to perform more robustly than the informant information. This warrants further research.

Can Depression be Prevented Following Stroke?

A recent review article by Paranthaman and Baldwin (International Review of Psychiatry, 2006; 18:453-470) summarised recent research on both this and other aspects of post-stroke depression. The conclusion is that there is no convincing evidence that giving antidepressants to patients post stroke delays ameliorates the onset of depression even though some studies reviewed arrived at opposite conclusions. Therefore the RCT of Almeida and colleagues (Journal of Clinical Psychiatry 2006; 67: 1104-1109) is of interest. Using the Hospital and Anxiety Depression Scale (HADS) there was no statistical difference in the incidence of depression during 24 weeks of Sertraline (50 mg) versus placebo in patients who had had a stroke within the previous 2 weeks (n=111). The dose of Sertraline is quite low but there was a very high rate of discontinuation because of perceived side-effects in both groups. Disappointingly, the review by Paranthaman and Baldwin found that nonpharmacological interventions for poststroke depression have not yielded any convincing evidence of efficacy, so this area is one that requires a lot more research.

Further Insights into the Relationship Between Vascular Brain Disease, MCI, AD and Depression

There can be an added sense of satisfaction when research findings appear to concord with clinical experience. This was apparent in a study from Baltimore, US Gamaldo et al (Neurology, 2006 Oct 24;67(8):1363-9). Researchers followed up with 335 dementia free subjects (mean age 75 years) to try and determine which patients are at the greatest risk of developing dementia following a stroke. Perhaps not surprisingly, individuals who had a stroke (representing 15% of the cohort) were much more likely to develop dementia (odds ratio [OR] 5.55; 95% CI: 2.76 to 11.4). Importantly, and in line with clinical experience, this risk was most pronounced in individuals who had documented mild cognitive deficits before the index stroke. Indeed, there was no increase in the risk of developing dementia in individuals without pre-existing cognitive impairment. Overall having a stroke was a major risk factor for the conversion of mild cognitive impairment to dementia (OR 12.4; 95% CI: 1.5 to 99). Stroke disease can also explain why some patients with Alzheimer’s disease deteriorate. Regan et al (Neurology, 2006 Oct 24;67(8):1357-62) found that patients with AD who had a cerebrovascular accident had a more rapid decline (p < 0.001), although the presence of vascular risk factors per se did not influence outcome. Exploring the potential interface between vascular disease and depression, Salaycik and colleagues (Stroke, 2006 Nov 30; [Epub ahead of print]) completed an eight-year cohort study (n>4000) of subjects from the Framingham Heart Study. They found the risk of developing stroke/TIA was about four times greater (P=<0.001) in subjects aged under 65 years who had depressive symptoms, but this association was not observed in subjects aged 65 and older. The authors remark that the detection of depressive symptoms at younger ages could impact on the primary prevention of stroke.

Diabetes Mellitus and Risk of Developing Alzheimer Disease: Results from the Framingham Study

As reported in previous IPA Bulletins, there is a possible link between diabetes mellitus (DM) and AD but to date, findings are inconclusive. To examine this issue further, Akomolafe et al (Arch Neurology, 2006 Nov;63(11):1551-5.) completed a prospective study (n=2210, mean follow-up 12.7 years) to see whether patients with DM at baseline (n=202) had a greater risk of developing AD than those without DM. Over the course of the study, 8.4% of subjects with DM and 11.0% of those without DM developed AD, giving a relative risk of 1.15 (95% confidence interval, 0.65-2.05). At the level of the overall cohort, therefore, DM was not found to be a risk factor for AD. However, among the subset of individuals without an apolipoprotein E epsilon4 allele or elevated plasma homocysteine levels, individuals with DM were more likely to develop AD than without DM (RR was 2.98; 95% CI, 1.06- 8.39; P = .03). This effect was more apparent in older subjects (75 years or older) where the relative risk increased to nearly 5 (P = .02). In interpreting these findings, the authors suggest DM could be a risk factor for AD in those subjects who lack other known major AD risk factors. Clearly, as with most aetiological hypotheses of AD, further studies are required. Possible pathophysiologic mechanisms and therapeutic implications linking insulin related abnormalities and AD are reviewed by Craft (Alzheimer Dis Assoc Disord, 2006 Oct- Dec;20(4):298-301).

 Impact of “Non-Pharmacological” Interventions in Alzheimer’s Disease

Guidelines on the management of Alzheimer’s disease invariably emphasise the importance of “nonpharmacological” interventions, but the evidence base for the effectiveness of such interventions is limited. The “target” for these interventions may involve the patient but also other people and factors involved in their care. Mary Mittlelman and colleagues (Neurology, 2006 Nov 14;67(9) :1592-9.) set out to evaluate whether non-pharmacological interventions focused on caregivers could yield tangible benefits under the scrutiny of a robust study design. They used a randomized controlled trial of “an enhanced counseling and support intervention” for carers compared with “usual care”, and the main outcome was time to nursing home placement. The study ran for 9.5 years and involved 406 spouse carers of patients with AD living in the community. The “active” intervention consisted of six sessions of individual and family counseling, support group participation, and continuous availability of ad hoc telephone counseling. Overall, they found that patients from the group who received this intervention had a 28.3% reduction in the rate of nursing home placement compared to those receiving “usual care”. Potential reasons for this effect included improvements in caregiver satisfaction, changes in the way caregivers responded to the patients’ behaviour, and improvement in depressive symptoms. Concluding, the authors state that greater access to effective programs of counseling and support could yield considerable benefits for caregivers, patients with Alzheimer disease, and society. Researchers from Italy Farina et al (Alzheimer Dis Assoc Disord, 2006 October/ December;20(4):275-282) evaluated the benefits of a stimulation program mainly based on recreational and occupational activities, associated with a brief cycle of support psychotherapy for patients and caregivers, in mild to moderate Alzheimer’s disease (AD). The study involved 67 patients and 31 controls from two centres, and the interventions were delivered over six weeks with the outcome reviewed at three months. Overall they found patients became less disruptive and the caregivers were able to modify their response to these behaviours.

Findings from the Memantine MEM-MD-02 Study Group

2006 has seen a cluster of published studies from the Memantine MEMMD- 02 Study Group based in the US. The study group has been exploring the benefits of modulating both acetylcholine and glutamate pathways in Alzheimer’s disease, and in particular, evaluating the added value of introducing memantine in patients already receiving a cholinesterase inhibitor. The core study from which the key findings have been drawn was a 24-week, doubleblind, placebo-controlled trial comparing memantine (20 mg/day) with placebo in subjects with moderate to severe AD on stable donepezil treatment. Summarising, treatment with memantine reduced agitation/ aggression, irritability, and appetite/eating disturbances as well as delaying their emergence Cummings et al (Neurology, 2006 Jul 11;67(1):57-63); resulted in higher response rates than placebo for all outcomes with number needed to treat (NNT) ranging from eight to ten, with treatment response defined as stabilization of outcomes van Dyck et al (Am J Geriatr Psychiatry, 2006 May;14(5):428-37); benefited memory, language, and praxis Schmitt et al (Alzheimer Dis Assoc Disord, 2006 October/ December; 20(4):255-262); and post hoc analyses suggest that memantine may impact overall functional levels Feldman et al (Alzheimer Dis Assoc Disord 2006 October/December; 20(4):263-268). Of course, translating findings from such studies into clinical practice is not without its challenges. Indeed, such benefits are not always viewed as being cost effective. For example, in November 2006 the appraisal of anti-dementia treatments by the UK based National Institute for Health and Clinical Excellence concluded that memantine is not recommended as a treatment option for people with moderately-severe to severe Alzheimer’s disease except as part of well-designed clinical studies (http://www. nice. org.uk/guidance/TA111/guidance/pdf /English). A commentary by John O’Brien entitled “NICE and anti-dementia drugs: a triumph of health economics over clinical wisdom?” provides some interesting insights into these dilemmas (Lancet Neurology, 2006 Dec; 5(12):994-6.).

Practice Guidelines in the Management of AD

A comprehensive review of clinical practice with anti-dementia drugs has been published as a consensus statement from the British Association for Psychopharmacology Burns et al J (Journal Psychopharmacol, 2006 Nov;20(6):732-55). Also from the UK, in November 2006, the National Institute for Health and Clinical Excellence published its clinical guidance on dementia (http://www.nice.org.uk/guidance/ cg42). Readers of the IPA Bulletin can also find a US-based “expert opinion statement” on best practices in the treatment of Alzheimer’s disease in managed care Fillit et al (American Journal of Geritriatric Pharmacother, 2006;4 Suppl 1:S9-S24).

Reprinted from IPA Bulletin, Volume 24, Number 1

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