Einstein Francisco Camargos

Trazodone for the treatment of sleep disorders in dementia: an open-label, observational and review study

Sleep disorders (SD) in patients with dementia are very common in clinical practice. The use of antidepressants with hypnotic actions, such as trazodone, plays an important role in these cases. The aim of this study is to present a profile of the use of trazodone in demented patients with SD, as well as a review of trazodone hydrochloride in SD. We evaluated 178 elderly patients with Alzheimers disease and other dementias, clinically presenting SD and treated with hypnosedative medications. In the one-year period comprising the study, 68 (38.2%) of the 178 had sleep disorders. Most patients (114; 64%) had a diagnosis of Alzheimers disease. Approximately 85% of patients with SD used hypnosedative drugs. Trazodone was the most commonly used drug among patients (N = 35), with an effectiveness of 65.7%. Trazodone has been shown to be a good option for treatment of the elderly with dementia and associated SD.

Wrist actigraphy for measuring sleep in intervention studies with Alzheimer's disease patients: Application, usefulness, and challenges

Sleep disorders are common in patients with Alzheimers disease (AD). An important aspect of intervention studies in patients with sleep disorders is the choice of assessment strategy. This paper presents a literature review concerning assessment strategies for measuring sleep in intervention studies with AD patients, with a focus on actigraphy. Thirty-seven articles were selected for this review, having analysis of sleep/nocturnal rhythm disturbances by actigraphy as the primary or secondary outcome. The advantages and limitations of actigraphy were discussed vis-à-vis polysomnography and subjective interventions. The following methodological aspects were addressed: impact of experimental design and patient setting, inclusion and exclusion criteria, placement of the actigraphy device, adherence to the regimen, duration of recordings and the choice of sleep parameters. Our analyses suggest that the methods used in intervention studies encompassing sleep disorders and dementia could be improved by increasing accuracy of diagnosis, categorization of sleep disturbances, adherence to actigraphy, and by clearly defining the variables and endpoints in each study. Also, controlling variables that could interfere with sleep and describing the data processing and analysis might improve interpretation of results.

Amerindian Genetic Ancestry Protects against Alzheimer's Disease

Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide, and bears remarkable evidence for a differential prevalence among continental populations. In this scenario, estimating ancestry proportions in recently admixed populations is a strategy that can help increasing knowledge about the genetic structure of this complex trait. Aim/Methods: Our purpose was to assess mean ancestry estimates for the three main parental contributors to the Brazilian contingent (European, African and Amerindian) using a panel of 12 ancestry informative markers. Outpatients with the late-onset form of AD (n = 120) were compared for ancestry levels with non-cognitively impaired subjects (n = 412) in the Midwest Brazil, controlling for classic clinical, social and anthropometric risk factors. Results: Our findings show a 3-fold greater genetic Amerindian content among control subjects compared to AD patients (p < 0.001). Conclusion: Our results suggest that the allelic architecture of Native Americans can confer protection against the onset of the disease.

Use of psychotropic medications by caregivers of elderly patients with dementia: is this a sign of caregiver burden?

This study evaluated the consumption of psychotropic medications by caregivers of elderly patients with or without dementia. This was a cross-sectional study conducted at all geriatric units in Brasília, Brazil, during a two-month period. Structured interviews were performed with 311 caregivers of people with or without dementia and they completed questionnaires. Among the caregivers, 196 (63%) were caregivers of patients with dementia and 115 (37%) were caregivers of patients without dementia. Forty-four caregivers (14.1%) were taking psychotropic drugs (benzodiazepines or antidepressants), and this usage was more frequent among caregivers of patients with dementia (p<0.01). Twenty-two caregivers of patients with dementia (11.4%) had used sleeping pills after beginning care, compared with only five (4.3%) caregivers of patients without dementia (p<0.01). In conclusion, this study found that caregivers of patients with dementia took psychotropic drugs (benzodiazepines and antidepressants) more frequently than the ones of patients without dementia.

Cytokine gene polymorphisms and Alzheimer's disease in Brazil.

Background: Single-nucleotide polymorphisms in genes encoding immunological mediators can affect the biological activity of these molecules by regulating transcription, translation, or secretion, modulating the genetic risk of inflammatory damage in Alzheimers disease (AD). Nonetheless, the Brazilian contingent is highly admixed, and few association trials performed herein with AD patients have considered genetic ancestry estimates as co-variables when investigating markers for this complex trait. Methods: We analyzed polymorphisms in 10 inflammatory genes and compared the genotype distribution across outpatients with late-onset AD and noncognitively impaired subjects from Midwest Brazil under a strict criterion, and controlling for ancestry heritage and ApoE genotype. Results: Our findings show an almost 40% lower chance of AD (p = 0.004) among homozygotes of the IL10 -1082A allele (rs1800896). Dichotomization to ApoE and mean ancestry levels did not affect protection, except among those with greater European or minor African heritage. Conclusion: The IL10 locus seems to affect the onset of AD in a context sensitive to the genetic ancestry of Brazilian older adults.

Circadian rhythm in Alzheimer disease after trazodone use.

A circadian rhythm is a cycle of approximately 24 h, responsible for many physiological adjustments, and ageing of the circadian clock contributes to cognitive decline. Rhythmicity is severely impaired in Alzheimer disease (AD) and few therapeutic attempts succeeded in improving sleep disorders in such context. This study evaluated sleep parameters by actigraphy in 30 AD patients before and after trazodone use for 2 weeks, and we show a significant improvement in relative rhythm amplitude (RRA), compatible with a more stable daytime behavioral pattern. So, trazodone appears to produce a stabilization of the circadian rhythms in individuals with AD.

Mirtazapine does not improve sleep disorders in Alzheimer's disease: results from a double-blind, placebo-controlled pilot study

The aim of this study was to test the efficacy and safety of mirtazapine in the treatment of sleep disorders in patients with Alzheimers disease by means of a randomized, double‐blind, placebo‐controlled trial. Measurements were obtained for 7 days before intervention (baseline) and for 2 weeks after the onset of treatment.

Trazodone and cognitive performance in Alzheimer disease.

To the Editors: Cognitive impairment is well recognized as a common adverse effect of sleeping pills, such as benzodiazepines and ‘‘z-drugs.’’ There are few studies about the effect of antidepressants (including trazodone) on cognition. Despite its approval by the Food and Drug Administration to treat depression, insomnia is the most frequent reason for trazodone prescription. It exerts hypnotic actions at low doses (25 to 150 mg of dose range) due to blockade of 5-HT2A receptors as well as of H1 histaminic and >1 adrenergic receptors. In a recent study, Roth et al evaluated the cognitive and psychomotor effects of 50 mg of trazodone for 7 days in 16 primary insomniacs (mean age, 44 years) in a randomized, double-blind, placebo-controlled trial, resulting in small but significant impairment of short-term memory, verbal learning, balance, and arm muscle endurance among users. On the other hand, a double-blind, crossover trial from Rush et al compared the acute, subject-rated performance-impairing effects of trazodone (50, 100, 200 mg) and of triazolam (0.125, 0.25, 0.50 mg) with placebo in healthy subjects, which produced significant impairment in learning, recall, and performance skills with triazolam, but not with trazodone. Recently, our group published the results of a randomized, double-blind, placebo-controlled trial to examine possible improvements in sleep parameters in Alzheimer disease (AD) patients admitted with sleep disorders (SDs) after use of trazodone 50 mg. Briefly, patients were assessed by wrist actigraphy for a period of 7 to 9 days at baseline (to establish a sleep profile) and for 2 weeks during intervention when receiving 50 mg once daily at 10:00 P.M. (or placebo, in a 1:1 ratio). This trial was registered at clinicaltrials.gov, accession #NCT01142258. The results concerning the primary aim (trazodone effect on SD of AD patients) are presented therein along with detailed aspects of our methods and procedures. As secondary aim, our hypothesis was that trazodone 50 mg can be used in AD patients with no worsening of cognitive skills, and the scope of the present letter relies on discussing this important finding. With approval of the protocol by the institutional Research Ethics Committee, written informed consent was obtained from all (participants and/or caregiver), including for this complementary investigation. In brief, a neuropsychological inventory was put together to comprise a cast of cognitive assessments based on the criteria of being easy-to-handle and producing useful information by covering a range of cognitive abilities usually impaired in AD patients, so to justify their frequent usage in clinical and research scenarios in view of the author’s experience. These instruments were as follows: Mini Mental State Examination (MMSE); Paired Associate Learning Test-Form I (short-term memory) and Paired Associate Learning Test-Form II (long-term memory) of the Wechsler Memory Scale; and Digit Span Test, Arithmetic, Letter-Number Sequencing, Digit Symbol-Coding and Symbol Search of the Wechsler Adult Intelligence Scale (third edition, WAIS-III). Prior and after intervention, all tests were performed by one single trained neuropsychologist, blinded, with assessment and reassessment done in the same interviews in which the actigraphic device was placed or returned, respectively. Tests were applied in the morning (10Y12 hours) after the most recent dose. This routine of trazodone use and reassessments probably reduced biases related to major intersubject variance in bloodstream concentration of the drug, whose elimination half-life in the male and female elderly ranges from 8.2 and 7.1 hours, respectively. Thirty-six participants were randomized to either the active treatment (n = 19) or the placebo group (n = 17). One subject of the trazodone group was excluded for not complying with regular use of the prescribed antihypertensive and antiarrhythmic drugs, evolving into heart failure. One patient of the placebo group was also excluded because of an episode of agitation and consequent arm fracture. Complete analyses comprised 34 patients: 18 in active treatment and 16 in placebo. Comparing baseline measures of the 2 groups using the W test for categorical variables or the Student t test for continuous variables (Mann-Whitney U test for non-Gaussian distributed traits), no differences could be devised. The mean age of the whole group was 81.0 T 7.5 years, with women comprising 66.7% of the sample. The mean MMSE score was 11.2 T 6.2 and the most frequent clinical dementia rating scores were 2 and 3. Demographic and descriptive variables (age, sex, marital status, educational level, clinical dementia rating, Cornell depression scale) were the same (P Q 0.05) across intervention groups. None of these variables were reexamined at the end point stage. On what concerns medication use, it is probably worth mentioning that the frequency of users of the most common drugs to treat AD (donepezil, galantamine, rivastigmine, and memantine) as well as of users of antipsychotic drugs was no different across treatment arms. Patients were not allowed to change medications during the study period. Posttreatment scores were herein expressed as the value of absolute, net change in each test, compared using analysis of covariance between treatment arms taking baseline scores as covariables. Our main finding was no differential cognitive performance of trazodone-treated subjects compared to placebo-treated equals, with results shown here (in parenthesis) as the observed net difference followed (in brackets) by the range of its 95% confidence interval and by (after semicolon) the significance level achieved: MMSE (0.1 [j0.9 to 1.1]; P = 0.866), forward/backward digit span task (0.9 [j0.3 to 2.3]; P = 0.150), letter-number sequencing (0.0 [j0.9 to 0.9]; P = 0.958), arithmetic (0.2 [j0.4 to 0.9]; P = 0.453), digit-symbol coding (0.6 [j1.3 to 2.4]; P = 0.528), and symbol search (j0.9 [j2.4 to 0.5]; P = 0.191). The Paired Associate Learning Tests of the Wechsler Memory Scale could not be performed due to the severity of the dementia, and the authors advise other research groups to rule out the instrument whether investigating moderate to severe statuses. All in all, on top of improving sleep of AD patients (as described in our primary report), trazodone demonstrates the property of not impairing (nor improving) cognitive functions. A body of evidence helps advocating in favor of our conclusion. A double-blind, crossover study evaluated the use of trazodone 100 mg in healthy adults aged 60 years or older in comparison with amitriptyline and placebo and did not observe effects on either information processing, attention or visual-motor skills. Another study evaluating continuous nocturnal doses of mirtazapine 15 mg, trazodone 25mg, or placebo for 8 days in healthymen showed that trazodone did not impair driving or cognitive skills. In the largest prospective cohort so far (4414 cognitively preserved participants; aged 50 years or older), trazodone was not implicated in decline of psychometric performance. Some reasons might explain the disparities between these former (including our) Letters to the Editors Journal of Clinical Psychopharmacology & Volume 35, Number 1, February 2015

Lack of association between apolipoprotein E genotypes and cognitive performance in the non-demented elderly

The ε4 alelle of the apolipoprotein E gene is known to be a key genetic risk factor for Alzheimers disease and possibly for other neurological disorders. Some evidence in the literature indicates that the ε4 allele interferes with human cognition independently of chronological age and diagnosis of Alzheimers disease. The present study investigated the correlation of allelic variants of apolipoprotein E with the cognitive performance of elderly individuals without apparent cognitive impairment.

Outpatient treatment of sleep disorders in Alzheimer patients

Sleep disorders are common in patients with Alzheimer dementia and affect the quality of life of patients and of their caregivers. Despite the rising number of studies in the area, almost all of them are about non-pharmacological treatment. Our objective was to review the literature concerning pharmacological and non-pharmacological approaches to treat sleep disorders of elderly patients with Alzheimer dementia in the ambulatory setting. The treatments revised consisted of sleep hygiene and/or use of intense light coupled or not with use of melatonin, cholinesterase inhibitors, antipsychotics, hypnotics or antidepressants. In addition to the non-pharmacological measures, there is evidence that the use of trazodone may aid the treatment of sleep disorders of older individuals with Alzheimer dementia. More studies are necessary to examine the non-pharmacological and pharmacological treatments revised herein.