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Trazodone longitudinal effects on primary and secondary outcomes are listed in Tables 2 and 3. Trazodone non-users declined 2. Trazodone effects on MMSE remained significant even when only participants with AD-predicted pathology were included, with non-users declining 2.

These effects varied in significance when accounting for co-administered medications, retaining significance when accounting for overall concomitant sedative and procedia eng use, with non-users declining 1.

Trazodone effects were not significant when accounting only for ChEi use. We further performed additional post-hoc analysis to address a possible non-linear decline in MMSE associated with the longer inter-evaluation interval available for trazodone non-users.

Still, trazodone non-users declined 2. Effects of trazodone use on primary outcome (MMSE). Effects of trazodone on MMSE performance between 25 trazodone users and 25 trazodone non-users over an inter-evaluation interval of 4. Error bars indicate standard error of the mean. Effects of trazodone use on MMSE are dependent on sleep symptom severity at baseline and on their longitudinal improvement. Post-hoc analyses of trazodone effects on longitudinal MMSE performance in 25 trazodone users and 25 trazodone non-users when accounting for (A) presence or (B) absence of sleep complaints at baseline evaluation, and (C) changes (improvement, worsening or stability) in sleep complaints between baseline and final evaluations.

MMSE inter-evaluation interval was 4. See text for details. Secondary outcomes mushrooms effect processing speed, disability scores, and visual recall also worsened faster in trazodone non-users, though none of the Quinupristin and Dalfopristin (Synercid)- FDA were significant after correcting for multiple comparisons.

All but three secondary outcomes revealed a trend that trazodone was beneficial in delaying cognitive decline. Prior to correcting for multiple comparisons, most notable were the apparent beneficial roche bobois rugs of trazodone in short-term visual memory, processing speed, calculations, and phonemic fluency (Table 3).

Indeed, our results, by suggesting an association between longitudinal trazodone use and delayed cognitive decline, are supportive of this hypothesis, since the rate of decline in trazodone users was less than half (39. Notably, it was participants treated with trazodone with concomitant baseline sleep complaints, especially those who reported improvement in sleep quality over time, who had delayed cognitive decline compared to patients with sleep disruption that were not on trazodone.

After post-hoc analyses focusing on shorter inter-evaluation intervals, rates of decline remained relatively unchanged for each group, verifying a quasi-linear effect of inter-evaluation intervals to our primary outcome. However, effects were marginally non-significant, likely indicating a slightly underpowered study in revealing possible trazodone benefits for shorter follow-up periods.

The most likely explanation of such a discrepancy is the difference in duration of trazodone use and follow-up between those studies and ours, i.

This discrepancy also negates the argument that the cognitive benefits observed in our study were the result of a single or a few nights of better sleep allowing people to be more vigilant the following day, and instead reflect a longitudinal effect that is associated with chronic trazodone use.

One explanation on why trazodone cognitive benefits present longitudinally, and not after only few weeks of use, is that it may have protective effects on pathology progression.

Similarly, it is likely that a longer inter-evaluation interval is required to observe cognitive benefits mediated by synaptic plasticity during sleep.

To date, direct evaluation of overnight sleep-mediated memory consolidation through SWS enhancers has not been performed in AD. Longitudinal trazodone use was associated with delayed cognitive decline across diagnostic groups in our study, supporting its possible utility as disorder treatment from cognitively non-impaired to mildly-impaired patients.

None of our patients had moderate or severe mdma pills to allow for Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA of trazodone use on more advanced disease. However, when specifically accounting for ChEi use, trazodone users did not significantly benefit in delayed cognitive decline compared to non-users. This particular finding does not fully detract from our hypothesis that trazodone use may delay cognitive decline, considering that there may be 1) decreased statistical power when accounting for ChEi, 2) common mechanistic effects on sleep-wake rhythm consolidation between trazodone and ChEi, or 3) ceiling effects on cognitive outcomes for ChEi users.

Indeed, the observed rate of decline in MMSE tet 2 all non-users when accounting for ChEi use was slower than anticipated, at 0. Even if ChEi have shared effects Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA trazodone toward delaying cognitive decline, trazodone has certain additional useful clinical qualities.

In addition to directly improving sleep consolidation, the current results indicate a potential cognitive benefit for patients with MCI that is not verified in ChEi trials, where benefits are more definitively shown for mild to moderate AD.

Additionally, trazodone does not have the prevalent side effects of ChEi, such as insomnia, diarrhea, or bradycardia, making it even more favorable for patients who also do not tolerate ChEi. Effects of trazodone in all secondary outcomes were non-significant after correction for multiple comparisons but reveal a trend Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA delayed cognitive decline for almost all measures.

Even though the results cannabis not significant, the observed trend is Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA in pursuing tailored studies that are powered to identify a potential beneficial effect in the specific cognitive domains.

In our cohort of predominantly older amnestic Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA, a trend was observed in both executive and short-term memory tasks. There are also inherent limitations to our study, primarily due to its retrospective nature.

Ideally, we would prospectively standardize medication dosage and timing, after randomized allocation between groups, and monitor medication compliance across a predefined time period. For example, benefits observed in the trazodone group may reflect better overall medical management of participants by their physicians and delayed cognitive decline due to unaccounted factors. It is thus possible there is a biased selection against people who tried but did not tolerate trazodone for inclusion in the trazodone group, but who could have been included in the trazodone non-user group.

Such participants may be more resistant in achieving better sleep consolidation through SWS enhancers. Eventually, optimal accounting for confounders necessitates prospective double-blind randomized trials to confirm that differential rates of cognitive decline are directly caused by trazodone. Such nature versus nurture studies, ideally incorporating interval cognitive evaluations, could also answer whether potential long-term trazodone benefits are due to continuous modulation of brain networks, or whether they primarily reflect early treatment period effects.

Another limitation pertains to whether the observed trazodone effects are primarily mediated through SWS enhancement. In this study, quantified data of SWS were not available for correlating to rate of cognitive decline. Additionally, it is possible that trazodone effects could be mediated through its antidepressant benefits. We do not believe the latter is the case, since trazodone is rarely, if ever, given as an antidepressant in our cohort. Nonetheless, a prospective study would be the optimal approach Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA controlling potential antidepressant-mediated cognitive benefits of trazodone.

This latter inference, that potentially beneficial trazodone effects on cognition may be mediated by reducing sleep disturbance, is supported by the results from our post-hoc exploratory analyses indicating delayed cognitive decline in trazodone users with baseline sleep problems and, even more, in trazodone users who improved their sleep on follow-up evaluation (Fig.

A fine distinction should be highlighted on the above observation in that, although trazodone effects on cognition were mediated by improvement in sleep, which in Cortef (Hydrocortisone Tablet)- Multum raises the possibility that cognitive benefits may relate to improved sleep alone irrespective to trazodone use, the post-hoc analysis Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA indicates that participants who longitudinally improved their sleep while on trazodone had proportionally less cognitive decline compared to participants who improved their sleep but were not on trazodone (Fig.

Given that the current retrospective study and group matching were not structured to answer mechanisms of trazodone benefits, nor answer whether longitudinally Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA sleep in general delays cognitive decline, the above post-hoc observations should be interpreted with caution until prospective intervention studies are completed. Nonetheless, speculating on the current findings, it is possible that the improvement in sleep symptoms could serve as a proxy for trazodone effects in general.

If this finding replicates in future prospective studies, then the entire class of medications decreasing the degree of sleep disturbance, and especially those promoting SWS, can be considered in the prevention of cognitive decline. In summary, the pervasiveness and consistency of the observed trazodone effects, especially after considering disease severity and concomitant medication use, encourages further investigation into its effectiveness on preserving cognition via sleep-wake rhythm consolidation.

Furthermore, potential cognitive benefits of trazodone may be applicable to both cognitively intact older adults and mildly impaired patients with dementia.

French Foundation, the Tau Consortium, and the National Institute on Aging grants P01 AG1972403 and P50 AG023501. Yaffe K Clemastine Fumarate Syrup (Clemastine Fumarate Syrup)- FDA, Falvey CMHoang T (2014) Connections between sleep and cognition in older adults.

Ohayon MMCarskadon MAGuilleminault CVitiello Spf la roche (2004) Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: Developing normative sleep values across the human lifespan.

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