IPA Bulletin Recent Advances - Volume 26, Number 1

By Dr. Robert Barber and Professor Robert Baldwin

Bipolar Disorder

Atypical antipsychotics are commonly used now for bipolar disorder. Do they work in older people? Sajatovic and colleagues from the United States (Journal of Clinical Psychiatry. 69: 41-46, 2008) conducted an open-label prospective study of 20 adults with a mean age of 60 over 12 weeks, showing significant improvement in rated mania as well as some improvement in functional status. Adverse effects occurred infrequently (3 patients with restlessness, 3 with greater than 7% weight gain and 2 with sedation). This is a small study, but there is very little literature regarding older people with bipolar disorder specifically, so this is encouraging.

Trials of life…

Kok and colleagues (Acta Psychiatrica Scandinavica. 10: 1-8, 2008) investigated the outcome of a sequential treatment protocol in older patients not responding to a 12-week randomised controlled trial carried out previously by the group with venlafaxine vs. nortriptyline. In the open phase of this trial, the Montgomery Asberg Depression Scale (MADRAS) was performed at 6,9,12 and 36 months after study entry. They were treated consecutively with a tricyclic or venlafaxine, lithium augmentation, a switch to monoamine oxidase inhibitor and ECT. Of 81 patients, 78 achieved a response (50% reduction on the MADRAS) and 68 (84%) were in remission. Twenty-two patients received lithium with a remission rate of two thirds, higher than some other recent studies of lithium augmentation. Interestingly, the study involved mean serum lithium levels of 0.82, perhaps questioning the practice among some geriatric psychiatrists of always using low dose lithium augmentation. This study replicates one by Alistair Fint in the 1990s and shows that persistence pays.

Keeping well…

Once the patient is better, relapse prevention with medication really works. Alexopoulos and colleagues from the United States (American Journal of Geriatric Psychiatry. 16: 21- 30, 2008) evaluated risperidone following remission with citalopram in 63 patients with a mean age of 63.4 years. Those on the combination of risperidone plus citalopram (compared to citalopram plus placebo) had a median time to relapse of 105 days compared to 57 days in those on placebo augmentation. Although this difference was not statistically significant, it did mean a 10% advantage for risperidone over placebo for relapse prevention which may be a significant improvement over other treatment strategies. Interestingly, the dosages used were a mean of 40 mg of citalopram and only 0.8 mg of risperidone.

Theme time…

In a themed issue of the American Journal of Geriatric Psychiatry, anxiety disorders are discussed. Veaudreau and O’Hara (AJ GP. 16: 790-803, 2008) review the literature regarding late-life anxiety and cognitive impairment, focussing on generalised anxiety disorder. Anxiety symptoms may be a prodrome of cognitive impairment and/or anxiety may undermine cognitive reserve particularly for tasks involving attention and concentration. Yet studies have shown that a mild, non-pathological level of anxiety can improve cognitive performance. Generally, studies have supported a link between the presence or severity of morbid anxiety and poorer cognitive performance. This may depend though on the complexity of the neuropsychological task and the interplay of various factors such as depression, serotonin transporter and ApoE status, the HPA axis and co-morbid medical illness. In dementia, reduced acetylcholine may facilitate anxiety symptoms as well as underlying amnesia.

Another interesting area concerns the relationship between anxiety and agitation. In more severe dementia, it is agitation that is mostly reported, but the authors suggest that there is a good degree of overlap between these two concepts. Their conclusion is that clinically significant anxiety symptoms may predict accelerated cognitive decline. Psychological interventions aimed at addressing anxiety among patients with cognitive impairment may lead to significant treatment benefit. Interventions include emotion-focused psychotherapies and problem-solving treatment.

Pharmacotherapy is covered more in the next article by Mohamed and Rosenbec (16: 804-812) on the treatment of older veterans diagnosed with Post Traumatic Stress Disorder in Veterans Administration (VA) hospitals across the United States. They grouped 244/947 patients aged over 45 into five age bands and found that overall antidepressants were the most frequently prescribed (88.3%) followed by anxiolytics (61.2%) and then antipsychotics (32.9%). Use of any medication clearly declined though with older veterans, leading the authors to wonder if the approach taken to older veterans was over-cautious. A clue may also come from an Australian study (Creamer & Parslow. 16: 853-6) which showed that PTSD prevalence reduced with age, with participants aged over 65 reporting negligible rates. Perhaps then, PTSD symptoms become less severe with age. However, a caveat is that in this study, around 10% of the elderly reported re-experiencing symptoms.

Lastly, Andreesu and colleagues from Pittsburgh (AJ GP. 16: 813-818) described a six-item scale developed specifically to assess the severity of Generalised Anxiety Disorder (GAD) symptoms, called the GADSS. They were able to demonstrate good psychometric properties in both younger and older (aged over 60) subjects with GAD. The six items include frequency of worry, distress due to worry, frequency of associated symptoms, severity and distress of associated symptoms, impairment in work and impairment in social function (Depression and Anxiety. 23: 77-82, 2006).

A fishy story?

Fish oil is a popular supplement. It has been suggested that its use may improve symptomatic depression. Some studies have shown an inverse relationship between fish oil intake and depression prevalence. When it comes to the treatment of depression with fish oils, the evidence is mixed. Van de Rest and colleagues from the Netherlands (American Journal of Clinical Nutrition. 88: 706-713, 2008) studied non-demented subjects aged over 65 (mean age 70) who screened positive for depression (CES-D score over 16) and randomly assigned 302 to 3 groups: EPA plus DHA (1800 mg); EPA plus THA (400 mg) and placebo. Subjects were followed up at 13 weeks and 26 weeks. There are no prior studies specifically on older age patients and the results disappointingly showed no group differences. As fish oil is thought to be healthy for arteries, it would be interesting to know whether there is an effect from fish oil on patients with vascular depression, but this would be another study.

Suicide…

Using databases which can recognise names rather than place of birth, McKenzie and colleagues (British Journal of Psychiatry. 193: 406-9, 2008) calculated the suicide rates among South Asians in the United Kingdom during 1993 to 2003. The overall figures were lower than for the previous ten-year period, except for older women who showed an increase. The highest rate was for women over aged 65 and this is an important new finding which, as the authors state, may indicate a target for prevention strategies. The reasons for this increased risk are unclear, but include high rates of bereavement and an increased likelihood of limiting long-term illness.

Olfactory impairment precedes cognitive impairment

Olfactory dysfunction is common in old age, but it may also have clinical relevance. Since the 1970s, changes in olfactory function have been described in patients with established Alzheimer’s disease, and could be linked to the accumulation of neurofibrillary pathology in the central olfactory regions (Wilson et al. JNNP. 78: 30-35, 2007). A recent prospective study (Schubert et al. J Am Geriatr Soc. 56(8): 1517-21, 2008) of nearly two thousand subjects also found an association between olfactory impairment and emergence of cognitive impairment over the five years of the study (odds ratio = 6.62). The sensitivity and specificity was approximately 55% and 84% respectively for the five-year incidence of cognitive impairment. The authors concluded that odor identification tests can usefully identify patients at a high risk of developing cognitive impairment, but are not suitable for screening the general population.

Relationship between blood pressure and cognitive impairment in postmenopausal women

The potential relationship between hypertension and the emergence of cognitive impairment was examined using data from the prospective Women’s Health Initiative Memory Study (Johnson et al. Journal of American Geriatric Society. 56(8): 1449- 58, 2008). Over 7,000 women (mean age 71 years) were followed up for an average of 4.5 years, and although hypertension at baseline was associated with cognitive impairment and a greater risk of dementia, this relationship was not significant when adjusted for cofounders. Understandably, the authors conclude the findings should not detract from the importance of treating hypertension.

Effects of cardiovascular medications on progression of Alzheimer’s disease

The relationship between cardiovascular risk and dementia was also the focus of a further study from the Dementia Progression Study of the Cache County Study on Memory, Health and Ageing. Encouragingly, data from the three-year follow-up indicated that subjects with Alzheimer’s disease who received either statins or beta-blockers experienced a slower rate of functional decline (Rosenberg et al. Am J Geriatr Psychiatry. 16(11): 883-92, 2008). Other cardiovascular medications, however, did not influence decline.

A new therapeutic option in Alzheimer’s disease?

Interesting new evidence based on the amyloid hypothesis of Alzheimer’s disease was reported by researchers from Germany in Nature Medicine (Schilling et al. 14(10): 1106-11, 2008). Using animal models of Alzheimer’s disease, they were able to demonstrate that the oral administration of an inhibitor of the enzyme glutaminyl cyclase reduced A beta peptide burden, plaque formation and gliosis. There was also an associated improvement in functioning. Naturally, further studies will be needed before the full significance of this new finding is realized.

Is there a link between clock drawing difficulties and functional neuroimaging changes in Alzheimer’s disease? Lee and colleagues from Korea demonstrated that the impaired clock drawing test in patients with Alzheimer’s disease was closely correlated to reductions in cerebral glucose metabolism in the right parietal cortex on PET (Dement. Geriatr Cogn Disord. 26(4): 306-13, 2008).
Attitudes toward research participation
Conducting dementia-related research naturally raises important ethical and practical issues. One such ethical dilemma relates to the involvement of subjects with cognitive impairment who may have little to gain directly from research. A study by Karlawish et al (Am J Psychiatry. 2008) focused on this issue, and explored the attitudes of older people toward participating in dementia-related research. Interestingly, they found that there was general support for enrolling non-competent persons with dementia even if that resulted in no direct benefit to the subject. This view was underpinned by a favorable attitude towards biomedical research.

How frequent are neuropsychiatric symptoms in mild cognitive impairment (MCI)?

Geda and colleagues from the United States (Arch Gen Psychiatry. 65(10): 1193-8, 2008) completed a cross-sectional study of subjects with MCI (n = 329) and normal cognition (n = 1640). In summary, they found nonpsychotic symptoms affected around 50% of subjects with MCI and 25% with normal cognition. Symptoms of apathy (Odds Ratio = 4.53), agitation (OR = 3.60), anxiety (OR = 3.00), irritability (OR = 2.99) and depression (OR = 2.06) were all more common in the MCI group. Delusions were rare in both groups, though more prevalent in the MCI group (OR = 8.12).

Lithium treatment in dementia

Researchers from Denmark completed a large, ten-year observational cohort study to see whether lithium may have neuroprotective characteristics (Kessing et al. Arch Gen Psychiatry. 65(11): 1331-5, 2008). The prevalence of dementia was compared in two populations: a sample of over 16,000 individuals who received lithium at least once, and a general population sample of nearly 1.5 million subjects never exposed to lithium. Interestingly, individuals treated with lithium at least once had a higher risk of developing dementia compared to those not treated (RR = 1.47), but if treatment with lithium continued then the risk became the same as the general population suggesting it may confer some benefit.

Incidence of early-onset dementia

High-quality epidemiology studies of dementia in working-age adults are few and far between. A six-year study from the United Kingdom was recently published in Neurology (Mercy et al. 71(19): 1496-9, 2008) and found the incidence of dementia in the 45-64 year age range to be 11.5 cases per 100,000 person-years. The incidence for Alzheimer’s disease was the highest at 4.2 cases, followed by fronto-temporal dementia at 3.5 cases.

Treatment studies

Psychosocial intervention for caregivers in dementia…
This RCT study was completed in the United States, United Kingdom and Australia and was designed to evaluate the added value of counseling-based psychosocial interventions for their spouse caregiver (Mittelman et al. Am J Geriatr Psychiatry. 16(11): 893-904, 2008). The patients, who all had Alzheimer’s disease, continued to receive treatment with donepezil. The main caregiver outcome was depressive symptoms, and overall, the study found in favour of the psychosocial intervention.
Growth Hormone in Alzheimer’s disease…
A large (n = 563), one-year, multicenter, double-blind, randomized control trial was completed in the United States to test the efficacy of the growth hormone, secretagogue MK-677 (an inducer of insulin-like growth factor-1: IGF-1) in mild to moderate Alzheimer’s disease (Sevigny et al. Neurology. 71(21): 1702-8, 2008). The rationale for this treatment was based on animal studies showing that IGF-1 increased amyloid clearance. Using standardized outcome criteria, treatment was found to be ineffective at modifying the progression of the illness.
Impact of cholinesterase inhibitors on delaying admission to nursing care…
Encouragingly, a study from Canada found the risk of being admitted to a nursing home for patients with Alzheimer’s disease was reduced by around 30% for each year of treatment with a cholinesterase inhibitor (Feldman et al. Int J Geriatr Psychiatry. 2008).
Responder analysis of patients with severe Alzheimer’s disease treated with donepezil…
 Jelic et al from Sweden analyzed data from a six-month double-blind placebo controlled trial of donepezil in nursing home residents with severe Alzheimer’s disease (Dement. Geriatr Cogn Disord. 26(5): 458-66, 2008). Though treatment of patients with severe AD was associated with stabilization or improvement of symptoms and functioning, there was no difference between responders and nonresponders with respect to baseline demographics and clinical profile.

Reprinted from IPA Bulletin, Volume 26, Number 1