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