Publications

BACKGROUND

Disturbances in rest-activity rhythm are prominent and disabling symptoms in Alzheimer's disease (AD). Nighttime sleep is severely fragmented and daytime activity is disrupted by multiple napping episodes. In most institutional environments, light levels are very low and may not be sufficient to enable the circadian clock to entrain to the 24-hour day. The purpose of this randomized, placebo-controlled, clinical trial was to test the effectiveness of morning bright light therapy in reducing rest-activity (circadian) disruption in institutionalized patients with severe AD.

METHOD

Subjects (n = 46, mean age 84 years) meeting the NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke--the Alzheimer's Disease and Related Disorders Association) AD diagnostic criteria were recruited from two large, skilled nursing facilities in San Francisco, California. The experimental group received one hour (09:30-10:30) of bright light exposure (> or = 2500 lux in gaze direction) Monday through Friday for 10 weeks. The control group received usual indoor light (150-200 lux). Nighttime sleep efficiency, sleep time, wake time and number of awakenings and daytime wake time were assessed using actigraphy. Circadian rhythm parameters were also determined from the actigraphic data using cosinor analysis and nonparametric techniques. Repeated measures analysis of variance (ANOVA) was used to test the primary study hypotheses.

RESULTS AND CONCLUSION

Although significant improvements were found in subjects with aberrant timing of their rest-activity rhythm, morning bright light exposure did not induce an overall improvement in measures of sleep or the rest-activity in all treated as compared to control subjects. The results indicate that only subjects with the most impaired rest-activity rhythm respond significantly and positively to a brief (one hour) light intervention.

BACKGROUND

Disturbances in rest-activity rhythm are prominent and disabling symptoms in Alzheimer's disease (AD). Nighttime sleep is severely fragmented and daytime activity is disrupted by multiple napping episodes. In most institutional environments, light levels are very low and may not be sufficient to entrain the circadian clock to the 24-hour day.

METHOD

The purpose of this randomized clinical trial was to test the effectiveness of timed bright light therapy in reducing rest-activity (circadian) disruption in institutionalized patients with AD. The experimental groups received either morning (9.30-10.30 am) or afternoon (3.30-4.30 pm) bright light exposure ( > or = 2500 lux in gaze direction) Monday through Friday for 10 weeks. The control group received usual indoor light (150-200 lux). Nighttime sleep, daytime wake, and rest-activity parameters were determined by actigraphy. Repeated measures analysis of variance was employed to test the primary study hypotheses.

RESULTS

Seventy institutionalized subjects with AD (mean age 84) completed the study. No significant differences in actigraphy-based measures of nighttime sleep or daytime wake were found between groups. Subjects in either experimental light condition evidenced a significantly (p < 0.01) more stable rest-activity rhythm acrophase over the 10-week treatment period compared to the control subjects whose rhythm phase delayed by over two hours.

CONCLUSIONS

One hour of bright light, administered to subjects with AD either in the morning or afternoon, did not improve nighttime sleep or daytime wake compared to a control group of similar subjects. However, exposure to one-hour of bright light in either the morning or afternoon may provide sufficient additional input to the circadian pacemaker to facilitate entrainment to the 24-hour day.

BACKGROUND

Delirium occurs in up to 30% of hospitalised patients and is associated with prolonged hospital stay and increased morbidity and mortality. Recently published reports have suggested that the standard drug for delirium, haloperidol, a typical antipsychotic that may cause adverse extrapyramidal symptoms among patients, may be replaced by atypical antipsychotics such as risperidone, olanzapine or quetiapine, that are as effective as haloperidol in controlling delirium, but that have a lower incidence of extrapyramidal adverse effects.

OBJECTIVES

To compare the efficacy and incidence of adverse effects of haloperidol with risperidone, olanzapine, and quetiapine in the treatment of delirium.

SEARCH STRATEGY

The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 7 August 2006 using the search terms:haloperidol or haldol or risperidone or risperdal* or quetiapine or seroquel* or olanzapine or zyprexa* or aminotriazole or sertindole or leponex* or zeldox* or ziprasidone.

SELECTION CRITERIA

Types of studies included unconfounded, randomised trials with concealed allocation of subjects. For inclusion trials had to have assessed patients pre- and post-treatment. Where cross-over studies are included, only data from the first part of the study were examined. Interrupted time series were excluded. Length of trial and number of measurements did not influence the selection of trials for study. Where indicated, individual patient data were requested for further examination.

DATA COLLECTION AND ANALYSIS

Two reviewers extracted data from included trials. Data were pooled where possible, and analysed using appropriate statistical methods. Odds ratios of average differences were calculated. Only 'intention to treat' data were included. Analysis included haloperidol treated patients, compared with placebo.

MAIN RESULTS

Three studies were found that satisfied selection criteria. These studies compared haloperidol with risperidone, olanzapine, and placebo in the management of delirium and in the incidence of adverse drug reactions. Decrease in delirium scores were not significantly different comparing the effect of low dose haloperidol (< 3.0 mg per day) with the atypical antipsychotics olanzapine and risperidone (Odds ratio 0.63 (95% CI 10.29 - 1.38; p = 0.25). Low dose haloperidol did not have a higher incidence of adverse effects than the atypical antipsychotics. High dose haloperidol (> 4.5 mg per day) in one study was associated with an increased incidence of extrapyramidal adverse effects, compared with olanzapine. Low dose haloperidol decreased the severity and duration of delirium in post-operative patients, although not the incidence of delirium, compared to placebo controls in one study. There were no controlled trials comparing quetiapine with haloperidol.

AUTHORS' CONCLUSIONS

There is no evidence that haloperidol in low dosage has different efficacy in comparison with the atypical antipsychotics olanzapine and risperidone in the management of delirium or has a greater frequency of adverse drug effects than these drugs. High dose haloperidol was associated with a greater incidence of side effects, mainly parkinsonism, than the atypical antipsychotics. Low dose haloperidol may be effective in decreasing the degree and duration of delirium in post-operative patients, compared with placebo. These conclusions must be tempered by the observation that they are based on small studies of limited scope, and therefore will require further corroborating evidence before they can be translated into specific recommendation for the treatment of delirium.

Neuropsychiatric behaviors are common in people with Alzheimer's disease (AD) and make both professional and lay caregiving difficult. Light therapy has been somewhat successful in ameliorating disruptive behaviors. This randomized trial tested the effects of morning or afternoon bright light exposure compared with usual indoor light on the presence, frequency, severity, and occupational disruptiveness of neuropsychiatric behaviors in nursing home residents with AD. Light was administered for 1 hr daily (Monday-Friday) for 10 weeks. The Neuropsychiatric Inventory-Nursing Home was used to assess behavior at baseline and end of the intervention. Analyses revealed statistically significant differences between groups on agitation/aggression, depression/dysphoria, aberrant motor behavior, and appetite/eating disorders. The magnitude of change was small and may not represent clinically significant findings. Agitation/aggression and nighttime behaviors commonly occurred and were highly correlated with occupational disruptiveness. Interventions that decrease the presence and/or severity of neuropsychiatric behaviors have the potential to significantly decrease caregiver burden.

OBJECTIVES

To test whether the addition of melatonin to bright-light therapy enhances the efficacy in treating rest-activity (circadian) disruption in institutionalized patients with Alzheimer's disease (AD).

DESIGN

Randomized, controlled trial.

SETTING

Two nursing homes in San Francisco, California.

PARTICIPANTS

Fifty subjects (mean age 86) with AD.

INTERVENTION

Experimental subjects received 1 hour of morning light exposure (> or = 2,500 lux in gaze direction) Monday to Friday for 10 weeks and 5 mg melatonin (LM, n=16) or placebo (LP, n=17) in the evening. Control subjects (n=17) received usual indoor light (150-200 lux).

MEASUREMENTS

Nighttime sleep variables, day sleep time, day activity, day:night sleep ratio, and rest-activity parameters were determined using actigraphy.

RESULTS

Linear mixed models were employed to test the primary study hypotheses. No significant differences in nighttime sleep variables were found between groups. At the end of the intervention, the LM group showed significant improvement in daytime somnolence as indicated by a reduction in the duration of daytime sleep, an increase in daytime activity, and an improvement in day:night sleep ratio. The LM group also evidenced a significant increase in rest-activity rhythm amplitude and goodness of fit to the cosinor model.

CONCLUSION

Light treatment alone did not improve nighttime sleep, daytime wake, or rest-activity rhythm. Light treatment plus melatonin increased daytime wake time and activity levels and strengthened the rest-activity rhythm. Future studies should resolve the question of whether these improvements can be attributed to melatonin or whether the two zeitgebers interact to amplify efficacy.

BACKGROUND

As people live longer, there is increasing potential for mental disorders to interfere with testamentary distribution and render older people more vulnerable to "undue influence" when they are making a will. Accordingly, clinicians dealing with the mental disorders of older people will be called upon increasingly to advise the courts about a person's vulnerability to undue influence.

METHOD

A Subcommittee of the IPA Task Force on Testamentary Capacity and Undue Influence undertook to establish consensus on the definition of undue influence and the provision of guidelines for expert assessment of risk factors for undue influence.

RESULTS

International jurisdictions differ in their approach to the notion of undue influence. Despite differences in legal systems, from a clinical perspective, the subcommittee identified some common "red flags" which might alert the expert to risk of undue influence. These include: (i) social or environmental risk factors such as dependency, isolation, family conflict and recent bereavement; (ii) psychological and physical risk factors such as physical disability, deathbed wills, sexual bargaining, personality disorders, substance abuse and mental disorders including dementia, delirium, mood and paranoid disorders; and (iii) legal risk factors such as unnatural provisions in a will, or provisions not in keeping with previous wishes of the person making the will, and the instigation or procurement of a will by a beneficiary.

CONCLUSION

This review provides some guidance for experts who are requested by the courts to provide an opinion on the risk of undue influence. Whilst international jurisdictions require different thresholds of proof for a finding of undue influence, there is good international consensus on the clinical indicators for the concept.

BACKGROUND

Delirium occurs in 30% of hospitalised patients and is associated with prolonged hospital stay and increased morbidity and mortality. The results of uncontrolled studies have been unclear, with some suggesting that benzodiazepines may be useful in controlling non-alcohol related delirium.

OBJECTIVES

To determine the effectiveness and incidence of adverse effects of benzodiazapines in the treatment of non-alcohol withdrawal related delirium.

SEARCH STRATEGY

The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 26 February 2008 using the search terms: (deliri* or confusion) and (benzo* or lorazepam," or "alprazolam" or "ativan" or diazepam or valium or chlordiazepam).The CDCIG Specialized Register contains records from major health databases (including MEDLINE, EMBASE, CINAHL, PsycINFO, CENTRAL, LILACS) as well as many ongoing trial databases and grey literature sources.

SELECTION CRITERIA

Trials had to be unconfounded, randomized and with concealed allocation of subjects. Additionally, selected trials had to have assessed patients pre- and post-treatment. Where crossover design was present, only data from the first part of the trial were to be examined.

DATA COLLECTION AND ANALYSIS

Two reviewers extracted data from included trials. Data were pooled where possible, and were to be analysed using appropriate statistical methods. Odd ratios or average differences were to be calculated. Only "intention to treat" data were to be included.

MAIN RESULTS

Only one trial satisfying the selection criteria could be identified. In this trial, comparing the effect of the benzodiazepine, lorazepam, with dexmedetomidine, a selective alpha-2-adrenergic receptor agonist, on delirium among mechanically ventilated intensive care unit patients, dexmedetomidine treatment was associated with an increased number of delirium- and coma-free days compared with lorazepam treated patients (dexmedetomidine patients, average seven days; lorazepam patients, average three days; P = 0.01). One partially controlled study showed no advantage of a benzodiazepine (alprazolam) compared with neuroleptics in treating agitation associated with delirium, and another partially controlled study showed decreased effectiveness of a benzodiazepine (lorazepam), and increased adverse effects, compared with neuroleptics (haloperidol, chlorpromazine) for the treatment of acute confusion.

AUTHORS' CONCLUSIONS

No adequately controlled trials could be found to support the use of benzodiazepines in the treatment of non-alcohol withdrawal related delirium among hospitalised patients, and at this time benzodiazepines cannot be recommended for the control of this condition. Because of the scarcity of trials with randomization of patients, placebo control, and adequate concealment of allocation of subjects, it is clear that further research is required to determine the role of benzodiazepines in the treatment of non-alcohol withdrawal related delirium.

BACKGROUND

Agitation affects up to 70% of older people with dementia. Valproic acid derivatives have been used for the past 10 years to control agitation in dementia, but no systematic review of the effectiveness of this treatment has been published to date. A systematic review of 2004 examined three randomised, placebo-controlled trials of the effect of valproate therapy on older people with dementia who were agitated. The review was updated (October 2008) to include two additional studies.

OBJECTIVES

To determine whether evidence supports the use of valproate preparations in the treatment of agitation of people with dementia.

SEARCH STRATEGY

The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 7 February 2008 using the terms: valproic OR valproate OR divalproex* . The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources.

SELECTION CRITERIA

Randomized, placebo-controlled trials with concealed allocation where agitation and dementia of participants were assessed

DATA COLLECTION AND ANALYSIS

1. Two reviewers extracted data from published trials 2. Odds ratios of average differences were calculated 3. Only "intention to treat" analyses were included 4. Analysis compared participants treated with valproic acid with controls

MAIN RESULTS

Meta-analysis in 2004 of the pooled results was limited because of the following problems.In Porsteinsson 2001, although the physicians having direct responsibility for patient care were blinded, a non-blinded physician, who had no direct contact with these physicians, adjusted divalproex sodium dosage on the basis of reports from blinded raters and from confidential laboratory reports. Therefore, because the physician who controlled therapy knew which patients were receiving divalproex, the trial did not satisfy the criterion of concealed allocation.In Tariot 2001, 54% of the treated patients dropped out compared with 29% of control patients. Of all treated patients, 22% dropped out because of adverse effects, and the study had to be discontinued prematurely.The third trial (Sival 2002) had a cross-over design. No results from the first phase of the study were available, and although the statistical section stated, "the t-test for independent samples is used to analyse the two-period cross-over trial", because the samples were not independent - they are the same patients in the treatment and placebo groups - a question must be raised about the correctness of the analyses.The valproate preparation used in the trials varied - one used short-acting sodium valproate, one long-acting divalproex sodium, and the third early-onset acting divalproex sodium. Average doses differed (480 mg/d - 1000 mg/d), as did duration of therapy (3 weeks - 6 weeks), and ways of evaluating patients and their response to therapy.A limited meta-analysis, pooling the results concerning adverse effects (Porsteinsson 2001, Tariot 2001) revealed the following: sedation occurred more frequently in patients treated with valproic acid than in controls. Urinary tract infection was more common among patients treated with valproic acid than controls.An updated systematic review (October 2008) of two new studies (Tariot 2005, Herrmann 2007) applied meta-analysis to the effect of valproate on agitation in demented patients and also combined these studies with the earlier reports to examine adverse effects among valproate treated patients. Because the study of Herrmann et al involved a cross-over design, only those results from the first part of this study were included in the updated review.The new meta-analysis of pooled results showed no improvement of agitation among valproate treated patients, compared with controls, and showed an increase in adverse events (falls, infection, gastrointestinal disorders) among valproate treated patients.

AUTHORS' CONCLUSIONS

The updated review corroborates the earlier findings that valproate preparations are ineffective in treating agitation among demented patients, and that valproate therapy is associated with an unacceptable rate of adverse effects. More research on the use of valproate preparations for agitation of people with dementia is needed. On the basis of current evidence, valproate therapy cannot be recommended for management of agitation in dementia.

BACKGROUND

Delirium occurs in 30% of hospitalised patients and is associated with prolonged hospital stay and increased morbidity and mortality. The results of uncontrolled studies have been unclear, with some suggesting that benzodiazepines may be useful in controlling non-alcohol related delirium.

OBJECTIVES

To determine the effectiveness and incidence of adverse effects of benzodiazapines in the treatment of non-alcohol withdrawal related delirium.

SEARCH STRATEGY

The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 26 February 2008 using the search terms: (deliri* or confusion) and (benzo* or lorazepam," or "alprazolam" or "ativan" or diazepam or valium or chlordiazepam).The CDCIG Specialized Register contains records from major health databases (including MEDLINE, EMBASE, CINAHL, PsycINFO, CENTRAL, LILACS) as well as many ongoing trial databases and grey literature sources.

SELECTION CRITERIA

Trials had to be unconfounded, randomized and with concealed allocation of subjects. Additionally, selected trials had to have assessed patients pre- and post-treatment. Where crossover design was present, only data from the first part of the trial were to be examined.

DATA COLLECTION AND ANALYSIS

Two reviewers extracted data from included trials. Data were pooled where possible, and were to be analysed using appropriate statistical methods. Odd ratios or average differences were to be calculated. Only "intention to treat" data were to be included.

MAIN RESULTS

Only one trial satisfying the selection criteria could be identified. In this trial, comparing the effect of the benzodiazepine, lorazepam, with dexmedetomidine, a selective alpha-2-adrenergic receptor agonist, on delirium among mechanically ventilated intensive care unit patients, dexmedetomidine treatment was associated with an increased number of delirium- and coma-free days compared with lorazepam treated patients (dexmedetomidine patients, average seven days; lorazepam patients, average three days; P = 0.01). One partially controlled study showed no advantage of a benzodiazepine (alprazolam) compared with neuroleptics in treating agitation associated with delirium, and another partially controlled study showed decreased effectiveness of a benzodiazepine (lorazepam), and increased adverse effects, compared with neuroleptics (haloperidol, chlorpromazine) for the treatment of acute confusion.

AUTHORS' CONCLUSIONS

No adequately controlled trials could be found to support the use of benzodiazepines in the treatment of non-alcohol withdrawal related delirium among hospitalised patients, and at this time benzodiazepines cannot be recommended for the control of this condition. Because of the scarcity of trials with randomization of patients, placebo control, and adequate concealment of allocation of subjects, it is clear that further research is required to determine the role of benzodiazepines in the treatment of non-alcohol withdrawal related delirium.