IPA Bulletin Recent Advances - Volume 25, Number 1

By Dr. Robert Barber, and Professor Robert Baldwin

Depression

Over-reliance on DSM-defined depressions leads to under-recognition of sub-syndromal depression (SSD) in later life. Lyness and colleagues (American Journal of Geriatric Psychiatry;2007; 15(3):214-223) examined 662 older primary care subjects with major or minor depression or with SSD defined in one of three ways with the hypothesis that SSD subjects would have greater symptoms and functional impairment than nondepressed patients, but not as severe as those with major or minor depression. Largely, their hypothesis was supported, so that SSD states are certainly not benign. A criticism is that SSD may discriminate poorly between physical and psychiatric symptoms, but as the authors comment, the two are so closely intertwined as to make this distinction academic. Future work should tease out which features of SSD might point to intervention, especially to reduce the risk of future major depression.

Korner and colleagues from Denmark (Journal of Clinical Psychiatry 2007; 63: 384-389) explored several rating scales for depression in patients with primary dementia and/or cognitive impairment. Interestingly, of two versions of the Hamilton Depression Rating Scale (HAM-D) - 17 and 6-items - the latter had better external validity than the 17-item version and both the shorter and long version of the Geriatric Depression Scale. The 6-item version comprises: depressed mood, guilt feelings, work and interest, psychomotor retardation, psychic anxiety and somatic symptoms.

Anxiety

Anxiety disorders are frequent in later life and disabling. Cairney and colleagues (American Journal of Geriatric Psychiatry;2007; 15(3):224- 233) from Canada calculated a lifetime and 12-month prevalence estimates of 4.94% and 1.32%, respectively, for social phobia using standard schedules. This is much higher than the earlier seminal Edmonton Study. Most had started early in life with fears which persisted into adulthood; few commenced after age 60. Depression and social phobia frequently co-occurred. As part of the Health Aging and Body Composition study in the US, Brenes and colleagues (American Journal of Geriatric Psychiatry;2007;15(3):262-265) screened 3015 older people (aged 70- 79) for anxiety using three questions from the Hopkins Symptom Checklist, showing a prevalence of 3.3%. Anxious older black, but not white adults, had significantly higher mortality over a seven-year period than expected, even after controlling for confounding factors. Differences in health-seeking behaviour may in part explain the ethnicity findings, otherwise, the authors wonder whether some individuals are simply ‘scared to death’. In contrast, data (n=2940) from the Health Aging and Body Composition study (Mehta et al Journal of the American Geriatric Society; 2007, published online 08 Jan 2007) reported no objective decline in physical function over five years for older anxious compared to nonanxious subjects, but the former selfreported mobility difficulties more often. Treatment data are sparse, but in a relatively recent trial, Schuurmans and colleagues from Holland (American Journal of Geriatric Psychiatry. 200614(3):255-63) showed in 52 subjects a small effect size for Cognitive Behaviour Therapy, but a larger one for sertraline (compared to waiting list controls).


ECT and rTMS

International Psychogeriatrics has a themed issue on ECT. Dombrovski and Mulsant (International Psychogeriatrics, 2007; 19: 10-14) argue that research evidence favours ECT as the preferred treatment for severe depression in later life, but think that it is often relegated to one of last resort, after multiple trials of antidepressants. However, Wilkinson (International Psychogeriatrics, 2007; 19: 14-18) argues that the evidence base for ECT, specifically for older people, is weak and that psychological interventions are under-used, including in in-patient settings where interventions can be targeted to specific symptoms, coping strategies, treatment adherence and long term education about depression. Tharyan (International Psychogeriatrics, 2007; 19: 19-23) points out that the use of a treatment which has spanned 70 years, despite its critics, suggests that it must be achieving some positive outcome. In an associated commentary, Flint (pages 24-35) highlights problems with ECT, such as cognitive impairment and the risk of some retrograde amnesia that may not be reversible, although these may depend upon technique. Also, ECT does not appear to prevent relapse. Perhaps, as Flint argues, the real issue is not ECT versus psychological interventions, but whether the combination could play an important role in minimising residual symptoms and relapse, one of the main challenges that we face. br> br> In a UK equivalence study of ECT versus rTMS in non-psychotic depression (Eranti et al, 2007 Am J Psychiatry 164:73-81), the average age of the participants was 68 and 64 respectively, making it quite relevant to geriatric psychiatry. A total of 45 patients (23 rTMS and 22 ECT) were compared on the Hamilton depression score. Those in the rTMS group did not do as well at the end of 15-day treatment period, while at six months, the depression scores were equivalent, although other measures favoured ECT. Interestingly, cognitive measures between the two groups did not differ.

Brain changes in depression

Brain lesions are known to be important in late life depression and, in one study, Janssen and colleagues (Journal of Neurology, Neurosurgery and Psychiatry, 2007, 78: 638-640) reported that, in females with late life depression, 13 with an early onset compared with 15 with a late onset (against 22 controls), the early onset group had reduced hippocampus volumes, whereas the late onset group had a greater prevalence of larger, subcortical, white matter lesions. The implication is that there are different aetiological pathways, perhaps neurodegenerative in early onset, and vascular in late onset. This is not a new idea, but it could be relevant to prognosis and outcome, the subject of another paper by the same group, Janssen et al (International Journal of Geriatric Psychiatry, 2007; 22: 468-474), in which 42 patients received MR scanning as part of an antidepressant drug trial, with outcome assessed at 12 weeks and 52 weeks. Global cerebral volumes of the orbitofrontal cortex and hippocampus were not associated with treatment response. This is consistent with some data, but not others, but it may be lesion location, more than quantity of lesions, that is important. No mention is made of age of onset as a prognostic factor in this study.

Diffusion Tensor Imaging (DTI) can show microstructural abnormalities in networks of white matter network. Murphy and colleagues (Biological Psychiatry, 2007; 61: 1007-1010) studied 51 patients between 60 and 86 years with major depression who had been part of an SSRI drug trial. They then looked at correlations between the Stroop colour and word interference scores and fractional anisodropy (a measure of white matter integrity). There was a strong correlation between poor response inhibition and reduced fractional anisotropy, particularly in the frontal region. These abnormalities may well be vascular in nature and might confer a predisposition to depression or trigger it. However Ma and colleagures (American Journal of Psychiatry, 2007; 164: 823-826) studied 14 first episode treatment-naïve depressed patients between the ages of 20 and 41 (compared to controls) and found altered fractional anisodropy in these patients too but affecting more the right than the left side of the brain. This suggests that loss of integrity in prefrontal white matter may exist in a variety of age groups in depression. Clearly, aetiology may be different – possibly genetic or developmental in younger age groups and neurodegenerative or vascular in older age groups. These findings have relevance to understanding executive dysfunction which is common in late life depression.

Antipsychotics in Alzheimer dementia: new trial data on aripiprazole but are antipsychotics cost effective?

Finding safe and effective pharmacological treatment for patients with psychotic symptoms in dementia has proved to be more elusive than originally hoped. The limitations, and potential benefits, of both typical and atypical antipsychotics in dementia have been widely documented. Naturally, as new antipsychotics emerge, there is interest in evaluating their usefulness in dementia. Aripiprazole, a relatively new antipsychotic, has a novel mechanism of action: it is a dopamine D2 receptor partial agonist with partial agonist activity at serotonin 5HT1A receptors and antagonist activity at 5HT2A receptors. To assess the value of this drug in the dementia, Mintzer et al from the USA conducted a 10-week multicentre RCT using aripiprazole (2, 5 or 10mg per day) vs. placebo in institutionalised patients (n=487) with Alzheimer’s disease and psychotic symptoms (Am J Geriatr Psychiatry. 2007 Nov;15(11): 918-31). Overall, compared to placebo, there appeared to be a dose-response effect in favour of aripiprazole: aripiprazole 10mg/day was significantly more effective than placebo on a number of outcomes measures including the Neuropsychiatric Inventory-Nursing Homes psychosis scale, the Clinical Global Impression-Severity of Illness, the Brief Psychiatric Rating Scale and the Cohen-Mansfield Agitation Inventory scores. Aripiprazole 5 mg/day showed intermediate benefit whereas aripiprazole 2 mg/day was not efficacious. No deaths in any group were considered to be treatment-related and cerebrovascular adverse events were infrequent in all groups.

However, these findings need to be considered in the context of further results from the Clinical Antipsychotic Trial of Intervention Effectiveness- Alzheimer’s Disease (CATIE-AD) study. As previously reported in the IPA Bulletin, this USA multicentre NIMH sponsored study was designed to assess the effectiveness and safety of second-generation antipsychotics (risperidone, olanzapine and quetiapine) in the treatment of psychosis, aggression, and agitation in Alzheimer’s disease (AD). A detailed cost-benefit analysis of active treatment vs. placebo (“watchful waiting” treatment strategy) was completed and subsequently published in the Archives of General Psychiatry (Rosenheck et al 2007 Nov;64(11):1259-68). Overall, the study found no difference in measures of effectiveness between active treatment or placebo and the placebo group had significantly lower health care costs.

Education, Education and Education!

A series of recent articles have, from varying perspectives, examined the fascinating relationship between education (often measured as “years of formal education”) and dementia.

Aware that individuals with “low education” have different lifestyle and risk factors than those with “high education”, Ngandu et al from the USA undertook a detailed analysis of participants (mean follow-up 21 years, n=1449) from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study (Neurology. 2007 Oct 2;69(14): 1442-50). Their findings replicated the association between low education and the higher risk of developing dementia and Alzheimer’s disease, but interestingly, the associations remained unchanged after adjustments for several demographic, socioeconomic, vascular, and lifestyle characteristics. This lead the authors to assert that the association between low education and dementia is probably not explained by differential lifestyles and that their findings were consistent with the hypothesis that higher educated persons may have a greater cognitive reserve that can postpone the clinical manifestation of dementia.

The biological basis of this “cognitive reserve hypothesis” was scrutinised by Kemppainen and colleagues from Finland (Ann Neurol. 2007 Nov 19). They used in vivo neuroimaging (PET) to examine the burden of amyloid pathology and degree of impaired glucose metabolism in patients with mild AD. Their hypothesis, which was supported by their findings, was that higheducated patients would have evidence of more advanced pathological and functional brain changes than low-educated patients with the same level of clinical impairment (supporting the notion that high-educated patients have greater brain cognitive reserve to buffer the effects of more advanced AD pathology). The advantages of education may, however, be most apparent earlier in the illness and ultimately be overwhelmed by the progression in AD pathology Koepsell et al (Neurology. 2007 Dec 26 [Epub ahead of print]).

Further findings consistent with the “cognitive reserve” hypothesis were reported in studies from Italy Bracco et al (Dement Geriatr Cogn Disord. 2007; 24(6):483-91) and France (Bruandet et al Dement Geriatr Cogn Disord. 2008;25(1):74-80). Both studies found patients with higher premorbid intelligence and years of education respectively had faster cognitive decline. Interestingly, the effects of “education” in later life may also be prognostic. Helzner et al found greater participation in prediagnosis leisure activities, especially intellectual activities, was associated with faster cognitive decline, leading the authors to conclude that the disease course in AD may vary as a function of cognitive reserve (Arch Neurol. 2007 Dec;64(12):1749-54).

Finally, but perhaps not surprisingly, the impact of education may extend to influence treatment outcomes. Johnell and colleagues from Sweden (Dement Geriatr Cogn Disord. 2008;25(1):54-9.) examined prescribing patterns in over 600,000 patients on the Swedish Prescribed Drug Register and found patients with high education were more likely to receive treatment with licensed medication (cholinesterase inhibitors and memantine) for AD.

Neuropsychiatric symptoms in dementia

The importance of neuropsychiatric symptoms was further emphasised in a study by Scarmeas and colleagues from the USA (Arch Neurol. 2007 Dec;64(12):1755-61). Consistent with other studies, “disruptive” behaviours (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) were common, occurring in over 80% of patients, but their presence also increased the risk of cognitive decline, functional decline and institutionalization. Characterising the pattern of neuropsychiatric changes in AD was the focus of a recent study from the “European Alzheimer’s Disease Consortium”. Detailed information was collected using the Neuropsychiatric Inventory in a large cross-sectional sample of over 2,300 patients with AD from 12 centres across Europe. Four neuropsychiatric subsyndromes were identified: hyperactivity, psychosis, affective symptoms and apathy (Aalten et al Dement Geriatr Cogn Disord. 2007; 24(6):457-63). These subsyndromes were not dependent on dementia subtypes, age and gender (Aalten et al Dement Geriatr Cogn Disord. 2008;25(1):1-8).

Light therapy and melatonin in dementia

Disruption (or “desynchronization”) of the circadian rhythm is common in dementias and can in turn lead to aberrant sleep/wake cycles. Therapeutic interventions such as light therapy and melatonin may act as “synchronizing” agents and conceivably improved night and day time sleep and activity patterns. However, findings from clinical trials to date have been inconclusive. Sloane and colleagues from Oregon, USA evaluated the impact of high intensity ambient bright light therapy on patients with dementia in two geriatric units in a psychiatric hospital and a dementia-specific residential care facility (J Am Geriatr Soc. 2007 Oct 55 (10), 1524–1533 and 2007 Nov;55 (11):1817-24).Overall, the most consistent benefit was a modest increase in night time sleep pattern, particularly in patients with more advanced dementia, but the effects on daytime activity were inconsistent and there were no benefits on depressive symptoms. Melatonin is a neurohormone that is secreted by the pineal gland and known to impact the sleep-wake cycle. Dowling et al conducted a 10 week trial of institutional patients with AD to see whether augmenting light therapy with melatonin conferred any additional benefits (J Am Geriatr Soc. 2007 Dec 7 [Epub ahead of print]). Overall, they found light treatment alone did not improve night-time sleep, daytime wake, or rest-activity rhythm but when administered with melatonin there were improvements in daytime wake time and activity levels. Further trials should, for example, help to determine whether melatonin alone would have proved beneficial.  

Reprinted from IPA Bulletin, Volume 25, Number 1

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