*Adjusted estimates were obtained after propensity score matching and by combining the effect estimates of the imputed datasets after propensity score matching, using Rubins rule. The following search terms were used to search in PubMed: trazodone; memory; memories; cognition; cognitions; cognitive; cognitively. - 81.169.235.131. Trazodone acts downstream of eIF2-P, preventing it from reducing levels of the ternary complex and allowing protein translation to occur [2] (see Supplementary Fig. The .gov means its official. To our knowledge, this is the first clinical population-based study that has examined the risk of dementia with trazodone use. Bookshelf Since studies included a wide age range, a higher prevalence of cognitive decline in older individuals should be expected, since cognition decreases with age. Propensity scores were estimated by logistic regression with the dependent variable as the treatment of interest (trazodone) and the covariates as follows: observed patient characteristics (age, sex, general practice identifier); lifestyle variables (smoking status [non-smoker, current smoker, or ex-smoker], alcohol consumption status [non-drinker, current drinker, or ex-drinker], and body mass index [underweight, normal weight, overweight, or obese]); other risk factors for dementia (medical history of depression; anxiety; sleep disorder; substance abuse; psychotic disorder; attention deficit hyperactivity disorder; personality disorder; arrhythmia; heart failure; acute or chronic ischemic heart disease, including myocardial infarction, hypertension, cerebrovascular disease; diabetes mellitus [recorded any time using Read codes on or before the index date]); current, past, and non-use of antipsychotic agents, anti-anxiety medications, and drugs listed under BNF Chapter 2 (cardiovascular system), on the basis of use on the index date; number of general practice visits in the 12 months before the index date; and area-level social deprivation (quintile of Townsend score derived from the 2001 census data) [16]. Because trazodone enhances alcohol's effects, it could lead to an overdose more quickly and with less alcohol. demonstrated a small impairment in equilibrium and arm muscle endurance [20], and Sasada et al. PMC What is Trazodone hydrochloride? A black. Below is a partial list of mild side effects of trazodone. Recent studies reveal an association between slow-wave sleep (SWS), amyloid- aggregation, and cognition. Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. The last search was run on November 2, 2020. Data from THIN are demographically representative of the UK population [11]. Other side effects include: syncope, edema, ataxia, confusion, diarrhea, hypotension, insomnia, sedated state, and tachycardia. Google Scholar, Ashford JW, Miller TW (1996) Effects of trazodone on sleep in patients diagnosed with post-traumatic stress disorder (PTSD). The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, 3 Despite its benefits and advantages, many opinion makers in the sleep medicine community do not recommend it. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered. Leyrat C, Seaman SR, White IR, Douglas I, Smeeth L, Kim J, et al. Fifth, in one study, adverse effects were reported by participants spontaneously, some of whom had dementia, which could have led to misrecognition of side effects and reporting bias [17]. For observational studies, Table 4 shows the results obtained using ROBINS-I criteria. demonstrated that trazodone significantly improved concentration and recall abilities in patients with ASVD and insomnia, with increased concentration and recall scores on MoCA after trazodone treatment compared to those at baseline [pre/post-treatment mean (SD) score in concentration and recall: 4.41 (1.57)/5.33 (1.45) and 1.52 (1.03)/2.24 (1.12), respectively]. Trazodone users had an early onset of dementia, which appears to contradict the suggestions from animal studies that trazodone could stop or delay the onset of dementia. 2022 Nov 14;23(22):14041. doi: 10.3390/ijms232214041. Patients were categorised as exposed if they had received two trazodone prescriptions but no exposure to any other antidepressant agent prior to trazodone use. When we censored follow-up at the end of trazodone therapy, our analysis showed a stronger association between the use of trazodone and the risk of dementia compared with the results of the main analysis (HR = 2.57; 95% CI 2.113.11; p < 0.001). Disagreements between reviewers were resolved by discussion and consensus. The effects of trazodone on human cognition were synthesized using a table to represent all scores of the cognitive evaluation scales obtained in order to determine the final result of the effect. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Eur J Clin Pharmacol 40(1):4348. All three nights, I awoke in the middle of the night with a very rigid erection. Thus, in the face of misfolded proteins, PERK dimerizes, autophosphorylates, and becomes activated. Department of Social Work and Social Administration, Faculty of Social Science, The University of Hong Kong, Hong Kong, 6 Trazodone is an antidepressant that belongs to a group of drugs called serotonin receptor antagonists and reuptake inhibitors (SARIs). However, in concordance with studies mentioned above, trazodone improved cognitive function, providing an indirect beneficial effect in the treatment of insomnia. Of the 12 studies included, six had a low overall risk of bias, five had high risk, and one had some concerns. A detailed evaluation is presented in Table 3. Burke et al. Nevertheless, in contrast to Riedel et al., Passeri et al. Matthews F, Brayne C, Medical Research Council Cognitive F, Ageing Study I. Flow chart on participant selection from the UCSF Memory and Aging Center research volunteer cohort based on reported sleep disturbances (insomnia, hypersomnia, or parasomnia), diagnostic group, available medication data, and reported trazodone use. This electronic health records study assessed the association between trazodone use and the risk of developing dementia in clinical practice. https://doi.org/10.1007/bf00315137, El-Fakahany E, Richelson E (1983) Antagonism by antidepressants of muscarinic acetylcholine receptors of human brain. However, it is important to note that in this study, of the total number of participants (n=1234), only 15 used trazodone alone. In contrast, Roth et al. Google Scholar, Sasada K, Iwamoto K, Kawano N, Kohmura K, Yamamoto M, Aleksic B, Ebe K, Noda Y, Ozaki N (2013) Effects of repeated dosing with mirtazapine, trazodone, or placebo on driving performance and cognitive function in healthy volunteers. People were selected for inclusion if they were 50 years of age or older and received two or more consecutive prescriptions for an antidepressant (Chapter 4.3 of the British National Formulary [BNF]), with the first occurrence being at least 6 months after the patients start of follow-up at their general practice (primary care doctors office) to ensure incident prescribing. Trazodone acts in the PERK branch of the UPR pathway downstream of eIF2-P, preventing it from reducing levels of the ternary complex, allowing protein translation to occur [2], restoring neuronal protein synthesis rates, enabling a boost of memory and preventing neurodegeneration in mice models [5]. Since the decision to prescribe a drug is likely to be influenced by a patients characteristics, propensity score matching was used to reduce potential bias due to nonrandomised treatment allocation [14]. However, in the study conducted by Riedel et al., high doses of trazodone (100400mg/day) improved memory and cognitive function in outpatients with depression [11, 22]. Our analysis highlights the possibility of a dose-independent dual effect of trazodone on human cognition, with acute utilization associated with impaired cognitive function and long-term use with preventing cognitive deterioration. While trazodone is not a true member of the selective serotonin reuptake inhibitors (SSRIs) class of antidepressants, it does still share many properties of the SSRIs. Chronic Trazodone and Citalopram Treatments Increase Trophic Factor and Circadian Rhythm Gene Expression in Rat Brain Regions Relevant for Antidepressant Efficacy. Sakulsripong et al. Intervention groups consisted of trazodone (with doses ranging from 25 to 400mg for a minimum of 1week) alone or in association with sleep hygiene training (SHT) and mirtazapine (15mg). 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. Lebert et al. Alikhani et al. -, Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV (2004) Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: Developing normative sleep values across the human lifespan. Developed in the 1960s in Italy, trazodone was created as a potential antidepressant blocking serotonin receptors. demonstrated that over an average follow-up period of 4years, compared to trazodone users, trazodone non-users showed 2.6-fold faster decline in the MMSE score [16]. We searched primary care electronic health records from The Health Improvement Network to identify patients aged 50 years who received at least two consecutive prescriptions for an antidepressant between January 2000 and January 2017 in the UK. There are no other relationships or activities that could appear to have influenced the submitted work. Associations Between Objectively Measured Sleep and Cognition: Main Effects and Interactions With Race in Adults Aged 50 Years. Stata version 14 (College Station, TX) and SAS version 9.4 (Cary, NC) were used for conducting statistical analyses. Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease, Predicting risk of osteoporotic fracture in men and women in England and Wales: prospective derivation and validation of QFractureScores. Am J Geriatr Psychiatry 22(12):15651574. I have read the journal's policy and the authors of this manuscript have the following competing interests: ICKW has received research funding from Bristol-Myers Squibb, Pfizer, Janssen, the Hong Kong Research Grants Council, and the Hong Kong Health and Medical Research Fund outside the submitted work. These results suggest that the clinical use of trazodone is not associated with a reduced risk of dementia. The rightmost columns of Tables 1 and 2 display the ultimate effect of trazodone on human cognition. Cereb Circ Cogn Behav. Sixth, the majority of our experimental studies included few participants in each treatment arm. Our target population was healthy or diseased adults aged 18years or older. Marshall A, Altman DG, Holder RL, Royston P. Combining estimates of interest in prognostic modelling studies after multiple imputation: current practice and guidelines. Only five studies mentioned the adverse effects of drugs used [6, 8, 15, 17, 19]. Dementia is characterised by a decline in cognitive functioning which impacts on activities of daily living [1]. After propensity score matching, all baseline characteristics were balanced between treatment groups (Table 1). 9 In light of the recent literature on anticholinergic drug burden and risk for dementia, we also conducted a post hoc analysis in which we found an evenly distributed baseline exposure to anticholinergic agents (standardized differences <0.1). Lastly, we conducted an analysis with mirtazapine as the comparison drug in an attempt to further minimise the between-group differences in prescribing choice. Most studies demonstrated the effects of trazodone in domains other than cognitive function. J Alzheimers Dis: JAD 67(3):911921. However, no studies have been conducted to assess the effect of trazodone on dementia in humans. This site needs JavaScript to work properly. Randomised controlled trials (RCTs) of trazodone as a sleep aid in people with mild to moderate AD showed no evidence of a positive effect on cognition, and participants experienced potentially detrimental effects on short-term memory [8, 9]. Further, Passeri et al. Of these, 4,716 first-line trazodone users met the inclusion criteria (Fig 1). Dementia prevention, intervention, and care, Global and regional economic costs of dementia: a systematic review, Differences between caregivers and noncaregivers in psychological health and physical health: A meta-analysis, Validity of current clinical criteria for Alzheimer's disease, vascular dementia and dementia with Lewy bodies. In this study, trazodone use and the follow-up period were considerably longer than in other studies included in this review that showed no effect or negative effects of trazodone on cognition. It is known that insomnia contributes to the progression of neurodegenerative diseases since it is associated with cognitive deterioration [6, 10, 12]. CAS 24 April, 2019 Trazodone (Desyrel, Oleptro) is an antidepressant drug belonging to a class of medications known as serotonin antagonist and reuptake inhibitors ( SARIs) 3. Depressive symptoms are also related to cognitive decline [21], as it is associated with poor sleep and anxiety [12] (Figs. Also, in one experimental study, participants were aware of the intervention they received [12], leading to a possible influence on reporting the outcomes. 2019;67(3):923-930. doi: 10.3233/JAD-181106. Seventh, as a selective serotonin reuptake inhibitor, trazodone has a delayed onset of action. Lebert et al., Lawlor et al., and Pirker-Kees et al. . https://doi.org/10.1159/000077171, Roth AJ, McCall WV, Liguori A (2011) Cognitive, psychomotor and polysomnographic effects of trazodone in primary insomniacs. Brain J Neurol 140(6):17681783. Nondifferential misclassification of undiagnosed or wrongfully diagnosed patients may have affected our results. Therefore, the results of observational studies using routinely collected data are relevant. Crude results showed that trazodone users were more likely to be diagnosed with dementia earlier (median = 1.7 years; IQR = 0.44.7 years) compared with users of other antidepressants (median = 4.3 years; IQR = 1.77.8 years). Federal government websites often end in .gov or .mil. Received 2018 Jul 2; Accepted 2018 Dec 13. https://doi.org/10.1016/j.jpsychires.2020.07.043, Article Propensity matching was based on age, sex, education, type of sleep disturbance, diagnostic group, and baseline MMSE. The main limitation of our study is the possibility of indication bias, because people in the prodromal stage of dementia might be preferentially prescribed trazodone. Division of Psychiatry, University College London, London, United Kingdom, 4 However, if trazodone has a role in preventing cognitive decline, it is important to consider whether that effect is mediated through its action in the UPR pathway, by increasing the synaptic concentration of 5-hydroxytryptamine [6], or as a result of the sleep improvement this drug offers. including only women [13], and one (Fudge et al.) On Mar, 30, 2023 15,045 people reported to have side effects when taking Trazodone hydrochloride. Consequently, addressing cognitive decline also has a role in decreasing caregiver burden and preventing burnout. The search was run in MEDLINE, Web of Science, and CENTRAL from the Cochrane databases, yielding a total of 16 studies after selection. This class of medication is often prescribed to help people sleep, or to help with anxiety. documented modest cognitive and motor impairments associated with trazodone, including a decline in short-term memory [Brown-Peterson Memory Test: main effect, F(1,15)=17.3, post hoc t=4.2, p<0.001] and verbal learning [Selective Reminding Test: main effect, F(1,15)=5.01, p=0.037; post hoc t=2.2, p=0.041] with time [20]. The incidence of dementia in the trazodone group was higher than the incidence in the matched comparison cohort (1.8 versus 1.1 per 100 person-years) (Table 2). Patients using trazodone and patients using other antidepressants were matched in a 1:5 ratio by propensity score using a greedy matching algorithm, which has been demonstrated to perform well in both actual and simulation studies [20]. 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). However, these factors are not anticipated to be involved in the decision to prescribe trazodone and other antidepressants and therefore would be unlikely to introduce confounding by indication. JAustin78 1 Nov 2019. Cialis Trazodone hydrochloride and Cialis drug interactions - a phase IV clinical study of FDA data Summary: Drug interactions are reported among people who take Trazodone hydrochloride and Cialis. Preclinical findings that do not translate into clinical settings are particularly common in neurodegenerative disease research due to the complex mechanisms involved that are difficult to mimic in animal models [29,31]. The full analysis procedure was applied on each imputed dataset separately, and the results were combined to obtain an overall estimate. Overall, all study participants tolerated trazodone well, and adverse events were mild and not a major cause of participant drop-out. Whether the observed relationship of trazodone to cognitive function is causal or an indirect marker of other effects, such as treated sleep disruption, and if such effects are mediated through SWS enhancement requires confirmation through prospective studies. demonstrated a mild decremental effect on short-term memory and verbal learning with short-term low doses of trazodone (50mg) in patients with primary insomnia [20]. In contrast, trazodone's adverse behavioral effects have rarely been studied. The standardised difference of all covariates was less than 0.1 for all datasets after PS matching. Functioning which impacts on activities of daily living [ 1 ] the middle of the U.S. Department of Health human... 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