No limits in language or publication year were applied. Trazodone and cognitive performance in Alzheimer disease. CAS In the first phase, articles were chosen by their title and abstract. BackgroundChronic insomnia is common in patients with arteriosclerotic cerebral small vessel disease (CSVD) and aggravates the cognitive impairment caused by CSVD. Trazodone improves sleep parameters in Alzheimer disease patients: a randomized, double-blind, and placebo-controlled study, Preclinical research: Make mouse studies work. Recent studies reveal an association between slow-wave sleep (SWS), amyloid- aggregation, and cognition. A noteworthy exception is trials investigating the beneficial effects of lithium, which may improve cognitive performance in people with dementia. Neurology 55(9):12711278. It is also important to mention that we did not observe a dose-dependent effect of trazodone on cognition, since studies with low and high doses demonstrated either a positive [6, 10,11,12, 16], negative [8, 13, 20, 21], or no effect [7, 9, 14, 15, 17,18,19] of the drug on cognitive functions. https://doi.org/10.1007/BF02307588, Smith HL, Mallucci GR (2016) The unfolded protein response: mechanisms and therapy of neurodegeneration. Wang et al., Alikhani et al., Camargos et al., and Roth et al. Patient characteristics in one of the imputed datasets (of which the final result yielded the least standard error in the primary analysis) are presented for illustration. Ideally, such studies should be done in subjects free of depression and insomnia, utilizing tests that represent all cognitive domains, and exploring the role of trazodone in the UPR pathway. Results of the post hoc analysis showed that the proportion of patients with dementia in the trazodone group became similar to the proportion of patients taking other antidepressants after 3 years (Tables (Tables44 and and55). This is an open access article distributed under the terms of the, GUID:798FDB95-0A4D-4C39-BE9A-1F532C479816, GUID:A835E2A6-DC07-4C36-BDB3-FDFB10C59553, GUID:3C291E86-9C1B-4898-900A-89803EA91722, GUID:3D95D1FF-8C26-49E0-8BFF-E78D6E9B4F79, GUID:E10FB5BF-DE36-429D-8E03-3681440B2F9A, GUID:797A9831-0AB9-48A5-8B9D-43CE7E8A08AA, GUID:230FDBE4-7AEB-46DD-941A-2CC98EB16A9A. By matching patients with similar propensity scores, only patients with similar observed characteristics are compared, and so any observed difference in the outcome between comparison groups is less likely to be due to the underlying patient differences. Race Differences in the Association Between Sleep Medication Use and Risk of Dementia. PubMed Central Predicting dementia risk in primary care: development and validation of the Dementia Risk Score using routinely collected data. Third, we conducted an analysis stratified by length of follow-up after starting trazodone therapy (trazadone use <2 years, 23 years, or >3 years) to assess whether any effect of trazodone varied by duration of treatment. For each study included, the following information was collected: the study author(s), title, year of publication and design, the follow-up period, the study size, the population being studied, its age and sex, the intervention under study, the comparators used, and the outcome measures (Tables 1 and 2). Lebert et al., Lawlor et al., Passeri et al., and Fudge et al. This was a dynamic cohort, with follow-up ending at the earliest of the following: the date the patient left the practice, the date of death, or the date of last data collection (9 January 2017). . including only men [7, 12], one (Leng et al.) government site. could be due to the timing of trazodone utilization: when given in the morning, trazodone impaired performance on memory tests due to sedation and impaired daily functioning [21]. As a library, NLM provides access to scientific literature. Before taking trazodone, tell your doctor and pharmacist if you are allergic to trazodone or any other medications. Firstly, we used a strict definition of AD in which individuals had to have received a Read code specifying AD and have at least two prescriptions for a cholinesterase inhibitor medication, to reduce the likelihood of outcome misclassification. J Gerontol A Biol Sci Med Sci. 1) and sleep deprivation [16]. This approach accounts for the variability between imputed datasets and has been demonstrated as a robust method of applying multiple imputation techniques in propensity score modelling [18]. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. CAS Lawlor et al. and transmitted securely. Dementia diagnoses are more likely to be made and at an earlier stage in patients who are already seeing and receiving treatment from physicians for depression or other neuropsychiatric disorders. Disclaimer. Exposure was determined from prescribing records, using drug codes for individual antidepressant agents (S1 Table). Aberrant waste disposal in neurodegeneration: why improved sleep could be the solution. Effective interventions in the prevention and management of dementia are urgently needed. Complete case analyses yielded similar results (S4 Table). The potential for a predementia neuroprotective effect of trazodone has not been examined in humans. All studies evaluated the effects of continuous doses of trazodone on cognition as a primary or secondary outcome. We were also unable to obtain measurements of biomarkers for neurodegeneration among trazodone users. Leyrat C, Seaman SR, White IR, Douglas I, Smeeth L, Kim J, et al. Only five studies mentioned the adverse effects of drugs used [6, 8, 15, 17, 19]. The . Despite this, none of these results showed a negative effect on cognitive deterioration. Halliday M, Radford H, Zents KAM, Molloy C, Moreno JA, Verity NC, et al. Overall, seven studies showed no effect of trazodone on cognition, five showed a beneficial effect by improving or reducing cognitive decline, and four evidenced impaired cognitive function. The rightmost columns of Tables 1 and 2 display the ultimate effect of trazodone on human cognition. The HR showed an association between use of trazodone and the onset of dementia (HR = 1.80; 95% CI 1.562.09; p < 0.001) (Table 3). official website and that any information you provide is encrypted We consider that further study of trazodone, an old molecule with new perspectives, is crucial for a better understanding of neurodegenerative mechanisms that could open doors for potential sites of action of future anti-dementia drugs. Given its common use in the elderly population, where some degree of cognitive decline is expected, the establishment of its effects on cognition is of paramount importance to prevent accelerated cognitive decline, deterioration of patient quality of life, and caregiver burden. Further studies with longer follow-up periods are needed to understand whether the absence of an effect on cognitive function demonstrated by these studies translates into the prevention of additional cognitive deterioration. For that reason, future studies should evaluate whether this association between trazodone use and cognitive decline is directly due to a negative effect of this antidepressant, or to the detrimental effects that depression exerts on cognitive function. Subsequent mice studies showed that trazodone was associated with markedly reduced neuronal loss [6]. However, no studies have been conducted to assess the effect of trazodone on dementia in humans. 2023 Mar 1;78(3):454-462. doi: 10.1093/gerona/glac180. The standardised difference of all covariates was less than 0.1 for all datasets after PS matching. The incidence of dementia in England and Wales: findings from the five identical sites of the MRC CFA Study, Assessment and management of behavioral and psychological symptoms of dementia, Sleep and Alzheimer disease pathologya bidirectional relationship. sharing sensitive information, make sure youre on a federal The median time to dementia diagnosis for users of trazodone was 1.8 years (interquartile range [IQR] = 0.55.0 years). *Adjusted estimates were obtained after propensity score matching. One could argue that this low dose could be insufficient to have any repercussions on cognition; however, other studies included in this systematic review [14, 15, 17,18,19] also demonstrated no effect with higher doses, suggesting that there is no dose-dependent effect of trazodone on cognition. We excluded potential participants from our analysis if they had any diagnosis of dementia prior to their first prescription for an antidepressant or a record of cognitive impairment, memory symptoms, or confusion. Overall, all study participants tolerated trazodone well, and adverse events were mild and not a major cause of participant drop-out. *Adjusted estimates were obtained after propensity score matching. Dementia affects more than 47 million people worldwide [1]. demonstrated an association between trazodone and delayed cognitive decline [16], and similar results were found by Burke et al. Consequently, addressing cognitive decline also has a role in decreasing caregiver burden and preventing burnout. Propensity score analysis with partially observed covariates: How should multiple imputation be used? This is consistent with our observation that the median time to diagnosis of dementia among trazodone users was much shorter than that among other antidepressants users (1.8 versus 4.1 years), despite controlling for all observable prodromal characteristics using propensity scores. https://doi.org/10.3233/jad-181102, Burke SL, Hu T, Spadola CE, Li T, Naseh M, Burgess A, Cadet T (2018) Mild cognitive impairment: associations with sleep disturbance, apolipoprotein e4, and sleep medications. Along those lines, Teri et al. Slider with three articles shown per slide. UPR acts as a cellular mechanism for the regulation of protein homeostasis when there are misfolded proteins [5] and coordinates this process through three ER transmembrane proteins: PERK, inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). The final result was divided into three categories: no effect (defined as neither improving nor impairing cognition), positive effect (defined as cognition improvement or delayed cognitive decline), and negative effect (defined as cognition impairment). Abbreviations: ADHD, attention deficit hyperactivity disorder; BMI, body mass index; PS, propensity score; SD, standard deviation. However, in concordance with studies mentioned above, trazodone improved cognitive function, providing an indirect beneficial effect in the treatment of insomnia. Continue reading for a comprehensive list of adverse effects. Serotonin is a chemical with various effects, including the regulation of mood. Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom, 8 Unauthorized use of these marks is strictly prohibited. Only one cohort study reported the doses used in the intervention groups [16] (Table 2). The acute effects of trazodone may also be due to its actions on histamine H1 and muscarinic acetylcholine receptors. However, it rather quickly developed a negative reputation. are still plausible because, as Wang et al. As a result, this drug appears to have utility as a novel disease-modifying treatment for neurodegenerative diseases in humans [2]. On the other hand, Leng et al. Data in the THIN database are not collected for research purposes, and lifestyle factors such as exercise and diet are not recorded. Roth et al. -, Fogel SM, Smith CT, Beninger RJ (2009) Evidence for 2-stage models of sleep and memory: Learning-dependent changes in spindles and theta in rats. 20 It is known to prolong the cardiac QT-interval. Brain J Neurol 140(6):17681783. Also, in one experimental study, participants were aware of the intervention they received [12], leading to a possible influence on reporting the outcomes. Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy. In concordance with these findings, Teri et al.. found a significant worsening in MMSE scores in the trazodone treatment group (change score means in MMSESD: -1.973.15) compared with BMT (change score means in MMSESD -0.052.58) after 16weeks [8]. After a 4-week drug-free period, both treatments showed no changes in either immediate or delayed recall [15]. Data were collected manually and independently by the two reviewers and synthesized in tables. demonstrated that very elderly women using trazodone over a period of 5years were three times as likely to progress to MCI and dementia when compared to non-trazodone users (OR=3.48; 95% CI=1.1210.81), even when excluding female participants with depressive symptoms (OR=6.11; 95% CI=1.1632.21) and after adjusting for baseline cognitive and depressive symptoms [13]. Alzheimers disease; dementia; hypnotics; mild cognitive impairment; sleep; treatment. Brain Res Bull 79, 445451. In the last 3 nights, I have taken 50mg of trazodone and a glass of wine. Seek medical attention right away if you have symptoms of serotonin syndrome, such as: . Cochrane Database Syst Rev. PubMed Successful therapies for Alzheimer's disease: why so many in animal models and none in humans? Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls, Some methods of propensity-score matching had superior performance to others: results of an empirical investigation and Monte Carlo simulations, Biometrical journal Biometrische Zeitschrift. Arana A, Wentworth CE, Ayuso-Mateos JL, Arellano FM. In comparison to Riedel et al., Passeri et al. all showed that trazodone improved sleep quality and sleep parameters including sleep efficiency, N3 sleep ratio, and sleep continuity [6], daytime functioning [12], and nighttime sleep percent [17], while not inducing [12, 17] or decreasing daytime sleepiness [6, 20], reducing nighttime awakening [20], minutes of stage 1 sleep, or self-reports of trouble sleeping [20]. Amitriptyline, but not trazodone, caused impairments in both immediate and delayed recall in News recall after a single dose [21]. Below is the link to the electronic supplementary material. Following PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses] guidelines, we conducted a systematic review, without a meta-analysis, of studies that evaluated the effect of trazodone on human cognition. In Rat Brain Regions Relevant for antidepressant Efficacy for neurodegeneration among trazodone users slow-wave sleep ( SWS,. 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