Valproate preparations for agitation in dementia.

BACKGROUND: Agitation has been reported in up to 90% of people with dementia. Agitation in people with dementia worsens carer burden, increases the risk of injury, and adds to the need for institutionalisation. Valproate preparations have been used in an attempt to control agitation in dementia, but their safety and efficacy have been questioned. OBJECTIVES: To determine the efficacy and adverse effects of valproate preparations used to treat agitation in people with dementia, including the impact on carers. SEARCH METHODS: We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 7 December 2017 using the terms: valproic OR valproate OR divalproex. ALOIS 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: Randomised, placebo-controlled trials that assessed valproate preparations for agitation in people with dementia. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the retrieved studies against the inclusion criteria and extracted data and assessed methodological quality of the included studies. If necessary, we contacted trial authors to ask for additional data, including relevant subscales, or for other missing information. We pooled data in meta-analyses where possible. This is an update of a Cochrane Review last published in 2009. We found no new studies for inclusion. MAIN RESULTS: The review included five studies with 430 participants. Studies varied in the preparations of valproate, mean doses (480 mg/day to 1000 mg/day), duration of treatment (three weeks to six weeks), and outcome measures used. The studies were generally well conducted although some methodological information was missing and one study was at high risk of attrition bias.The quality of evidence related to our primary efficacy outcome of agitation varied from moderate to very low. We found moderate-quality evidence from two studies that measured behaviour with the total Brief Psychiatric Rating Scale (BPRS) score (range 0 to 108) and with the BPRS agitation factor (range 0 to 18). They found that there was probably little or no effect of valproate treatment over six weeks (total BPRS: mean difference (MD) 0.23, 95% confidence interval (CI) -2.14 to 2.59; 202 participants, 2 studies; BPRS agitation factor: MD -0.67, 95% CI -1.49 to 0.15; 202 participants, 2 studies). Very low-quality evidence from three studies which measured agitation with the Cohen-Mansfield Agitation Index (CMAI) were consistent with a lack of effect of valproate treatment on agitation. There was variable quality evidence on other behaviour outcomes reported in single studies of no difference between groups or a benefit for the placebo group.Three studies, which measured cognitive function using the Mini-Mental State Examination (MMSE), found little or no effect of valproate over six weeks, but we were uncertain about this result because the quality of the evidence was very low. Two studies that assessed functional ability using the Physical Self-Maintenance Scale (PSMS) (range 6 to 30) found that there was probably slightly worse function in the valproate-treated group, which was of uncertain clinical importance (MD 1.19, 95% CI 0.40 to 1.98; 203 participants, 2 studies; moderate-quality evidence).Analysis of adverse effects and serious adverse events (SAE) indicated a higher incidence in valproate-treated participants. A meta-analysis of three studies showed that there may have been a higher rate of adverse effects among valproate-treated participants than among controls (odds ratio (OR) 2.02, 95% CI 1.30 to 3.14; 381 participants, 3 studies, low-quality evidence). Pooled analysis of the number of SAE for the two studies that reported such data indicated that participants treated with valproate preparations were more likely to experience SAEs (OR 4.77, 95% CI 1.00 to 22.74; 228 participants, 2 studies), but the very low quality of the data made it difficult to draw any firm conclusions regarding SAEs. Individual adverse events that were more frequent in the valproate-treated group included sedation, gastrointestinal symptoms (nausea, vomiting, and diarrhoea), and urinary tract infections. AUTHORS' CONCLUSIONS: This updated review corroborates earlier findings that valproate preparations are probably ineffective in treating agitation in people with dementia, but are associated with a higher rate of adverse effects, and possibly of SAEs. On the basis of this evidence, valproate therapy cannot be recommended for management of agitation in dementia. Further research may not be justified, particularly in light of the increased risk of adverse effects in this often frail group of people. Research would be better focused on effective non-pharmacological interventions for this patient group, or, for those situations where medication may be needed, further investigation of how to use other medications as effectively and safely as possible.

Antipsychotics for treatment of delirium in hospitalised non-ICU patients.

BACKGROUND: Guidelines suggest limited and cautious use of antipsychotics for treatment of delirium where nonpharmacological interventions have failed and symptoms remain distressing or dangerous, or both. It is unclear how well these recommendations are supported by current evidence. OBJECTIVES: Our primary objective was to assess the efficacy of antipsychotics versus nonantipsychotics or placebo on the duration of delirium in hospitalised adults. Our secondary objectives were to compare the efficacy of: 1) antipsychotics versus nonantipsychotics or placebo on delirium severity and resolution, mortality, hospital length of stay, discharge disposition, health-related quality of life, and adverse effects; and 2) atypical vs. typical antipsychotics for reducing delirium duration, severity, and resolution, hospital mortality and length of stay, discharge disposition, health-related quality of life, and adverse effects. SEARCH METHODS: We searched MEDLINE, Embase, Cochrane EBM Reviews, CINAHL, Thomson Reuters Web of Science and the Latin American and Caribbean Health Sciences Literature (LILACS) from their respective inception dates until July 2017. We also searched the Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment Database, Web of Science ISI Proceedings, and other grey literature. SELECTION CRITERIA: We included randomised and quasi-randomised trials comparing 1) antipsychotics to nonantipsychotics or placebo and 2) typical to atypical antipsychotics for the treatment of delirium in adult hospitalised (but not critically ill) patients. DATA COLLECTION AND ANALYSIS: We examined titles and abstracts of identified studies to determine eligibility. We extracted data independently in duplicate. Disagreements were settled by further discussion and consensus. We used risk ratios (RR) with 95% confidence intervals (CI) as a measure of treatment effect for dichotomous outcomes, and between-group standardised mean differences (SMD) with 95% CI for continuous outcomes. MAIN RESULTS: We included nine trials that recruited 727 participants. Four of the nine trials included a comparison of an antipsychotic to a nonantipsychotic drug or placebo and seven included a comparison of a typical to an atypical antipsychotic. The study populations included hospitalised medical, surgical, and palliative patients.No trial reported on duration of delirium. Antipsychotic treatment did not reduce delirium severity compared to nonantipsychotic drugs (standard mean difference (SMD) -1.08, 95% CI -2.55 to 0.39; four studies; 494 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (SMD -0.17, 95% CI -0.37 to 0.02; seven studies; 542 participants; low-quality evidence). There was no evidence antipsychotics resolved delirium symptoms compared to nonantipsychotic drug regimens (RR 0.95, 95% CI 0.30 to 2.98; three studies; 247 participants; very low-quality evidence); nor was there a difference between typical and atypical antipsychotics (RR 1.10, 95% CI 0.79 to 1.52; five studies; 349 participants; low-quality evidence). The pooled results indicated that antipsychotics did not alter mortality compared to nonantipsychotic regimens (RR 1.29, 95% CI 0.73 to 2.27; three studies; 319 participants; low-quality evidence) nor was there a difference between typical and atypical antipsychotics (RR 1.71, 95% CI 0.82 to 3.35; four studies; 342 participants; low-quality evidence).No trial reported on hospital length of stay, hospital discharge disposition, or health-related quality of life. Adverse event reporting was limited and measured with inconsistent methods; in those reporting events, the number of events were low. No trial reported on physical restraint use, long-term cognitive outcomes, cerebrovascular events, or QTc prolongation (i.e. increased time in the heart's electrical cycle). Only one trial reported on arrhythmias and seizures, with no difference between typical or atypical antipsychotics. We found antipsychotics did not have a higher risk of extrapyramidal symptoms (EPS) compared to nonantipsychotic drugs (RR 1.70, 95% CI 0.04 to 65.57; three studies; 247 participants; very-low quality evidence); pooled results showed no increased risk of EPS with typical antipsychotics compared to atypical antipsychotics (RR 12.16, 95% CI 0.55 to 269.52; two studies; 198 participants; very low-quality evidence). AUTHORS' CONCLUSIONS: There were no reported data to determine whether antipsychotics altered the duration of delirium, length of hospital stay, discharge disposition, or health-related quality of life as studies did not report on these outcomes. From the poor quality data available, we found antipsychotics did not reduce delirium severity, resolve symptoms, or alter mortality. Adverse effects were poorly or rarely reported in the trials. Extrapyramidal symptoms were not more frequent with antipsychotics compared to nonantipsychotic drug regimens, and no different for typical compared to atypical antipsychotics.

Light treatment for neuropsychiatric behaviors in Alzheimer's disease.

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.

Psychiatric services in nursing homes in Israel: should the American legislation be adopted?

BACKGROUND: Nursing homes provide care for the elderly who require medical, nursing or rehabilitation services. Legislation for the public health model of mental health care for nursing home residents in the USA was enacted in 1987. OBJECTIVE: To determine whether the USA act regulating psychiatric care for nursing homes may be applied in Israel. METHODS: Publications analyzing the outcome of the USA regulations demonstrate improved care as reflected by decrease in restraints and better use of psychotropic compounds. The shortcomings as well as benefits of the USA legislation are tested as to their relevance to the specific economic, environmental and medical issues in Israel. CONCLUSIONS: The adoption of USA legal acts regulating nursing home residents' psychiatric care may not be feasible in Israel. However, quality of care in nursing homes can be significantly improved if such regulations were "tailored" to Israel's unique structure of nursing homes.

Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease.

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.

Effect of timed bright light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease.

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.

Effect of morning bright light treatment for rest-activity disruption in institutionalized patients with severe Alzheimer's disease.

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.