Long-Term Trazodone Use and Cognition: A Potential Therapeutic Role for Slow-Wave Sleep Enhancers

Probably not a substantial claim.

The findings support consideration of trazodone for clinical use as an intervention against cognitive decline.

“Overall, the above findings support for the first time the consideration of trazodone for clinical use, not only toward improving quality of life in older adults by increasing sleep duration [10], but also as an intervention against cognitive decline”

• cites [10] Suzuki, 2002, Effects of trazodone and imipramine on the biological rhythm: An analysis of sleep EEG and body core temperature, J Nippon Med Sch sourceDisputed

  The citation is attached to the claim that trazodone increases sleep duration in older adults; the subsequent proposal concerning cognitive decline is the citing authors’ own conclusion. The Discussion reports no change in sleep period time or other sleep-continuity measures and says the study involved healthy volunteers, not older adults. It therefore does not support the cited sleep-duration claim. (LLM, conf=0.82)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

• AssumptionThe authors state this as an assumption: SWS enhancement delays amyloidβ aggregation in AD models.
• AssumptionThe authors state this as an assumption: SWS enhancement improves sleep-mediated episodic memory consolidation through synaptic potentiation.
• AssumptionThe authors state this as an assumption: SWS enhancement may delay long-term cognitive decline.

It may state two separate claims as one.

Direct wakefulness consolidation indirectly enhances subsequent SWS, and may thus facilitate the hypothesized mechanism for trazodone's benefits.

“In turn, direct wakefulness consolidation indirectly enhances subsequent SWS, and may thus facilitate the hypothesized mechanism for trazodone's benefits [27-29, 36]”

• cites [27] Huber, 2004, Local sleep and learning, Nature sourceNot checked — no full text of the source
• cites [28] Frase, 2016, Modulation of total sleep time by transcranial direct current stimulation (tDCS), Neuropsychopharmacology sourceDisputed

  The Polysomnography results report more wake time after anodal stimulation but virtually identical slow-wave sleep across conditions (4.6%, 4.6%, and 4.4%). The Discussion likewise states that no effects on sleep architecture were observed; the paper does not discuss trazodone. Page numbers were not available in our copy. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [29] Hanford, 2013, Light therapy and Alzheimer’s disease and related dementia: Past, present, and future, J Alzheimers Dis sourcePartly supported

  The Sleep Disturbances section (page unavailable) reports that morning bright light increased daytime wakefulness and improved nighttime sleep in people with Alzheimer’s disease or related dementia. It does not say that consolidated wakefulness enhances subsequent slow-wave sleep (SWS), or connect that proposed mechanism to trazodone. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites [36] Van Dort, 2009, Adenosine A(1) and A(2A) receptors in mouse prefrontal cortex modulate acetylcholine release and behavioral arousal, J Neurosci sourcePartly supported

  The Results report that an adenosine A1 antagonist increased wakefulness and decreased NREM sleep in mice. The Discussion also reports increased slow-wave activity during NREM sleep in a sleep-deprivation context. Neither passage shows that consolidating wakefulness enhances subsequent slow-wave sleep or addresses trazodone’s benefits; no page numbers are available in our copy. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Cognitively non-impaired adults with decreased SWS exhibit increased amyloidβ burden and worse sleep-mediated episodic memory consolidation.

“Furthermore, patients with AD have less SWS, and cognitively non-impaired adults with decreased SWS exhibit increased amyloid𝛃 burden and worse sleep-mediated episodic memory consolidation [6, 7].”

• cites [6] Mander, 2015, beta-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation, Nat Neurosci sourceSupported
• cites [7] Guarnieri, 2012, Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: A multicenter Italian clinical cross-sectional study on 431 patients, Dement Geriatr Cogn Disord sourceCould not verify

  The Discussion addresses sleep disturbances in patients with dementia or cognitive impairment, not the claimed association in cognitively non-impaired adults. Searches of our copy for slow-wave sleep (SWS), amyloid burden, and sleep-mediated episodic memory consolidation found no passage addressing that association. Page numbers were not available for these passages. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

The findings are in keeping with the therapeutic concept of consolidating brain rhythms of sleep and wakefulness toward delaying neurodegeneration and optimizing synaptic plasticity.

“The findings are also in keeping with the therapeutic concept of consolidating brain rhythms of sleep and wakefulness toward delaying neurodegeneration and optimizing synaptic plasticity [16]”

• cites [16] Karageorgiou, 2017, Brain rhythm attractor breakdown in Alzheimer’s disease: Functional and pathologic implications, Alzheimers Dement sourceSupported

• AssumptionThe authors state this as an assumption: SWS enhancement delays amyloidβ aggregation in AD models.
• AssumptionThe authors state this as an assumption: SWS enhancement improves sleep-mediated episodic memory consolidation through synaptic potentiation.
• AssumptionThe authors state this as an assumption: SWS enhancement may delay long-term cognitive decline.

It may state two separate claims as one.

In transgenic mouse models of Alzheimer's disease, SWS restriction accelerates activity-dependent amyloidβ aggregation, whereas SWS enhancement delays aggregation.

“Recent studies in transgenic mouse models of Alzheimer's disease (AD) reveal that SWS restriction accelerates activity-dependent amyloid𝛃 aggregation, whereas SWS enhancement delays aggregation [5].”

• cites [5] Roh, 2014, Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease, J Exp Med sourcePartly supported

  The Results and Discussion section ('Sleep deprivation induced Aβ pathology in OR−/− mice'; page unavailable) reports increased Aβ plaque pathology after sleep deprivation, while increased sleep time with orexin deficiency was associated with reduced pathology. The study does not specifically test restriction or enhancement of slow-wave sleep (SWS), and it presents the neuronal-activity mechanism as supported but not established to the exclusion of other mechanisms. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Sleep consolidation can be directly achieved through medications that consolidate sleep rhythms, as well as indirectly by consolidating rhythms of wakefulness that in turn allow deeper rhythms in subsequent sleep.

“sleep consolidation, as defined by integrity of sleep continuity and architecture, can be directly achieved through medications that consolidate sleep rhythms [26], as well as indirectly by consolidating rhythms of wakefulness that in turn allow deeper rhythms in subsequent sleep [27, 28]”

• cites [26] Walsh, 2014, Weaker circadian activity rhythms are associated with poorer executive function in older women, Sleep sourceNot checked — no full text of the source
• cites [27] Huber, 2004, Local sleep and learning, Nature sourceNot checked — no full text of the source
• cites [28] Frase, 2016, Modulation of total sleep time by transcranial direct current stimulation (tDCS), Neuropsychopharmacology sourcePartly supported

  The source is relevant to the indirect pathway cited at [27, 28]: its Discussion suggests that stimulation during wakefulness may alter cortical arousal and subsequent sleep continuity. But the Polysomnography results report less total sleep time after anodal stimulation and no difference in sleep architecture; they do not show consolidated wakefulness rhythms producing deeper subsequent sleep. The medication clause is attached to [26], not to this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Probably not a substantial claim.

Hippocampal and prefrontal areas are involved in sleep-mediated effects via SWS enhancement on short-term memory and executive cognitive domains.

“considering known involvement of hippocampal and prefrontal areas in sleep-mediated effects via SWS enhancement on these cognitive domains [3, 37]”

• cites [3] Fogel, 2009, Evidence for 2-stage models of sleep and memory: Learning-dependent changes in spindles and theta in rats, Brain Res Bull sourceNot checked — no full text of the source
• cites [37] Nofzinger, 2002, Human regional cerebral glucose metabolism during non-rapid eye movement sleep in relation to waking, Brain sourcePartly supported

  The Discussion reports increased hippocampal metabolism during NREM sleep and suggests a role for hippocampal activity in mnemonic processes, while saying its relationship to any specific memory function remains unclear. The Cerebral cortex section suggests NREM sleep could affect regions involved in higher-order processing. The paper does not establish that SWS enhancement acts through hippocampal and prefrontal areas to improve short-term memory or executive function. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

The eIF2α-P/UPR pathway is also induced during sleep deprivation of wild type mice, providing an additional mechanistic explanation through which improving disturbances in sleep may be neuroprotective.

“the eIF2 𝛂 -P/UPR pathway is also induced during sleep deprivation of wild type mice, providing an additional mechanistic explanation through which improving disturbances in sleep may be neuroprotective [45]”

• cites [45] Naidoo, 2005, Sleep deprivation induces the unfolded protein response in mouse cerebral cortex, J Neurochem sourceSupported

It may state two separate claims as one.

ChEi users benefit from improved attention and alertness through enhancement of cholinergic transmission and may thus perform at ceiling throughout the follow-up period.

“ChEi users benefit from improved attention and alertness through enhancement of cholinergic transmission and may thus perform at ceiling throughout the follow-up period [31]”

• cites [31] Birks, 2006, Cholinesterase inhibitors for Alzheimer’s disease, Cochrane Database Syst Rev sourcePartly supported

  The Background (page unavailable) says ChEIs enhance cholinergic neurotransmission, and the Results (page unavailable) report a small benefit on cognitive-function measures compared with placebo. The review does not establish improved attention or alertness specifically, or suggest that users perform at ceiling throughout follow-up. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

In the MAPT P301L mouse model of tauopathy, trazodone use was associated with less memory deficits, preserved hippocampal neuronal counts, delayed gross brain atrophy, and prolonged survival.

“in the MAPT P301L mouse model of tauopathy, trazodone use was associated with less memory deficits, preserved hippocampal neuronal counts, delayed gross brain atrophy, and prolonged survival [44]”

• cites [44] Halliday, 2017, Repurposed drugs targeting eIF2alpha-P-mediated translational repression prevent neurodegeneration in mice, Brain sourcePartly supported

  The Results section on the rTg4510 tauopathy model reports rescued object-recognition memory, reduced CA1 neuronal loss, and less hippocampal atrophy with trazodone. It does not establish that gross brain atrophy was delayed over time. Crucially, the same section says survival studies in these mice were not possible; the reported lifespan increase was in prion-infected mice, not the tauopathy model. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Probably not a substantial claim.

SWS enhancement shows promise towards neuroprotection.

“which in turn shows promise towards neuroprotection [16]”

• cites [16] Karageorgiou, 2017, Brain rhythm attractor breakdown in Alzheimer’s disease: Functional and pathologic implications, Alzheimers Dement sourceSupported

It may state two separate claims as one.

The effect of changes in sleep from baseline was driven by improvement in sleep at follow-up (p =0.0006) but not by stable (p =0.326) or worsening (p =0.176) sleep.

“the latter being driven by improvement in sleep on the follow up visit ( p =0.0006) but not for stable ( p =0.326) or worsening of sleep ( p =0.176) in the follow up visit.”

It may state two separate claims as one.

Secondary outcomes on processing speed, disability scores, and visual recall worsened faster in trazodone non-users, though none were significant after correcting for multiple comparisons.

“Secondary outcomes on processing speed, disability scores, and visual recall also worsened faster in trazodone non-users, though none of the results were significant after correcting for multiple comparisons.”

It may state two separate claims as one.

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 the primary outcome.

“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”

It may state two separate claims as one.

Significant effects of trazodone on longitudinal MMSE performance were observed for presence of sleep problems at baseline (p =0.006) and changes in sleep from baseline (p =0.006).

“significant effects were observed for both presence of sleep problems at the baseline visit ( p =0.006) and changes in sleep from baseline ( p =0.006) (Fig. 3)”

It may state two separate claims as one.

In post-hoc analysis with shorter follow-up periods, trazodone non-users declined 2.0-fold faster on MMSE than trazodone users, at an estimated inter-evaluation interval averaging 3.59 years, with each group retaining the same annual rate of decline (0.3 versus 0.7 points per year); these effects were marginally nonsignificant (p =0.054).

“Still, trazodone non-users declined 2.0-fold faster on the MMSE than trazodone users, at an estimated inter-evaluation interval averaging 3.59 years, with each group retaining the same annual rate of decline (0.3 versus 0.7 points per year on MMSEfor trazodone users versus non-users). These effects of trazodone on MMSE were marginally nonsignificant ( p =0.054, compare to Table 1).”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Six participants in each group used ChEi.

“Six participants in each group used ChEi.”

It may state two separate claims as one.

Prior to correcting for multiple comparisons, the most notable apparent beneficial effects of trazodone were in short-term visual memory, processing speed, calculations, and phonemic fluency.

“Prior to correcting for multiple comparisons, most notable were the apparent beneficial effects of trazodone in short-term visual memory, processing speed, calculations, and phonemic fluency (Table 3).”

It may state two separate claims as one.

Trazodone effects on MMSE retained significance when accounting for overall concomitant sedative and stimulant use, with non-users declining 1.94-fold faster than trazodone users.

“These effects varied in significance when accounting for co-administered medications, retaining significance when accounting for overall concomitant sedative and stimulant use, with non-users declining 1.94-fold faster than trazodone users.”

It may state two separate claims as one.

Secondary outcomes of other cognitive and functional scores had variable worsening in non-users and varied in significance when accounting for co-administered medications and multiple comparisons.

“Secondary outcomes of other cognitive and functional scores had variable worsening in non-users and varied in significance when accounting for co-administered medications and multiple comparisons.”

It may state two separate claims as one.

The post-hoc exploratory analyses indicate delayed cognitive decline in trazodone users with baseline sleep problems and, even more, in trazodone users who improved their sleep on followup evaluation.

“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 followup evaluation (Fig. 3)”

Probably not a substantial claim. The paper may give no reason why it holds.

Trazodone is rarely, if ever, given as an antidepressant in our cohort.

“trazodone is rarely, if ever, given as an antidepressant in our cohort”

Probably not a substantial claim.

The analysis was planned a priori with inter-evaluation intervals as a covariate.

“We anticipated that follow-up intervals would not be identical for paired participants in the two groups to allow for propensity matching of inter-evaluation intervals, and thus planned our analysis a-priori with inter-evaluation intervals as a covariate.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

To address possible non-linear effects of inter-evaluation interval differences between groups, shorter follow-up periods were selected for the trazodone nonusers post-hoc, making intervals comparable between groups, and the analysis was repeated.

“Nonetheless, to address possible non-linear effects of inter-evaluation interval differences between groups, we selected shorter follow-up periods for the trazodone nonusers post-hoc , making intervals comparable between groups, and repeated the analysis.”

It may state two separate claims as one.

The trazodone users and non-users were similar on age, sex, education, diagnostic group, type and severity of sleep deficit, and baseline MMSE, indicating successful propensity matching.

“These measures were similar between trazodone users and non-users, indicating successful propensity matching (Table 1).”

It may state two separate claims as one.

Sleep disorders increase in frequency with aging, and their manifestation, even in cognitively non-impaired individuals, can be a harbinger of subsequent cognitive decline.

“Sleep disorders increase in frequency with aging, and their manifestation, even in cognitively non-impaired individuals, can be a harbinger of subsequent cognitive decline [1].”

• cites [1] Yaffe, 2014, Connections between sleep and cognition in older adults, Lancet Neurol sourceNot checked — no full text of the source

Probably not a substantial claim.

The primary outcome was a priori defined as the change in MMSE between baseline and final visits.

“Our a priori defined primary outcome was the change in MMSE between baseline and final visits.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Significance testing on secondary outcomes and post-hoc analyses accounted for multiple comparisons by applying Bonferroni correction.

“Significance testing on secondary outcomes and post-hoc analyses accounted for multiple comparisons by applying Bonferroni correction.”

It may state two separate claims as one.

There were no cognitive side effects or daytime somnolence after a 2-week intervention period with trazodone in patients with AD.

“Furthermore, there were no cognitive side effects or daytime somnolence after a 2-week intervention period, thus diminishing concerns for possible cholinergic, 𝛂 -adrenergic, or histaminergic antagonistic effects in sleep-promoting doses [12, 13].”

• cites [12] Camargos, 2014, Trazodone improves sleep parameters in Alzheimer disease patients: A randomized, double-blind, and placebo-controlled study, Am J Geriatr Psychiatry sourceNot checked — no full text of the source
• cites [13] Camargos, 2015, Trazodone and cognitive performance in Alzheimer disease, J Clin Psychopharmacol sourceNot checked — no full text of the source

It may state two separate claims as one.

The discrepancy 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 associated with chronic trazodone use.

“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”

Probably not a substantial claim.

One-tailed significance testing was performed given the a priori hypothesis that trazodone is associated with delayed cognitive decline.

“Significance level was set at 0.05, and one-tailed significance testing was performed given the a priori hypothesis that trazodone is associated with delayed cognitive decline.”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Data were not imputed for analyses.

“We did not impute data for our analyses.”

It may state two separate claims as one.

Sleep changes with aging include decreased total sleep time and efficiency, increased waking after sleep onset, and decreased slow wave sleep (SWS).

“Sleep changes with aging include decreased total sleep time and efficiency, increased waking after sleep onset, and decreased slow wave sleep (SWS) [2].”

• cites [2] Ohayon, 2004, Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: Developing normative sleep values across the human lifespan, Sleep sourceNot checked — no full text of the source

It may state two separate claims as one.

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.

“the current results indicate a potential cognitive benefit for patients with MCI that is not verified in ChEi trials, wherebenefits are more definitively shown for mild to moderate AD”

Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.

Cognitive benefits via SWS enhancement may be dependent on a person's age, with younger patients potentially benefitting most in executive function versus older ones in short-term memory.

“they may be dependent on a person's age, with younger patients potentially benefitting most in executive function versus older ones in short-term memory”

Probably not a substantial claim. It may state two separate claims as one.

The current retrospective study and group matching were not structured to answer mechanisms of trazodone benefits, nor answer whether longitudinally improving sleep in general delays cognitive decline.

“Given that the current retrospective study and group matching were not structured to answer mechanisms of trazodone benefits, nor answer whether longitudinally improving sleep in general delays cognitive decline”

It may state two separate claims as one.

Antidepressant doses of trazodone are usually much higher than doses for insomnia that were prescribed for our participants, and often relate to carry-over cognitive deficits the following day, albeit less severe than those observed with certain other antidepressants.

“antidepressant doses of trazodone are usually much higher than doses for insomnia that were prescribed for our participants, and often relate to carry-over cognitive deficits the following day, albeit less severe than those observed with certain other antidepressants [40-43]”

• cites [40] Burns, 1986, A comparison of the effects of trazodone and amitriptyline on skills performance by geriatric subjects, J Clin PsychiatryNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [41] Moskowitz, 1986, Cognitive performance in geriatric subjects after acute treatment with antidepressants, Neuropsychobiology sourceNot checked — no full text of the source
• cites [42] Rakel, 1987, The greater safety of trazodone over tricyclic antidepressant agents: 5-year experience in the United States, Psychopathology sourceNot checked — no full text of the source
• cites [43] Gerner, 1987, Geriatric depression and treatment with trazodone, Psychopathology sourceNot checked — no full text of the source

Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.

The effectiveness of trazodone may be achieved by decreasing amyloidβ aggregation and pathologic tau burden, as well as by improving sleep-mediated memory consolidation.

“The effectiveness of trazodone, possibly achieved by decreasing amyloid𝛃 aggregation and pathologic tau burden, as well as by improving sleep-mediated memory consolidation, can be further explored through controlled clinical trials”

• AssumptionThe authors state this as an assumption: SWS enhancement delays amyloidβ aggregation in AD models.
• AssumptionThe authors state this as an assumption: SWS enhancement improves sleep-mediated episodic memory consolidation through synaptic potentiation.
• AssumptionThe authors state this as an assumption: SWS enhancement may delay long-term cognitive decline.

Probably not a substantial claim.

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

“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”

• AssumptionThe authors state this as an assumption: SWS enhancement delays amyloidβ aggregation in AD models.
• AssumptionThe authors state this as an assumption: SWS enhancement improves sleep-mediated episodic memory consolidation through synaptic potentiation.
• AssumptionThe authors state this as an assumption: SWS enhancement may delay long-term cognitive decline.

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Possible adverse effects of trazodone were not explicitly reported during the assessment of participants' medication regimen.

“Possible adverse effects of trazodone were not explicitly reported during the assessment of participants' medication regimen”

Probably not a substantial claim. The paper’s conclusions may not depend on it.

Prior work indicates its active metabolite may have different effects on alertness compared to trazodone itself.

“given that prior work indicates its active metabolite may have different effects on alertness compared to trazodone itself [38]”

• cites [38] Lawlor, 1997, Plasma levels of m-chlorophenylpiperazine following single oral dose administration of m-chlorophenylpiperazine and trazodone in human volunteers, Biol Psychiatry sourceNot checked — no full text of the source

Probably not a substantial claim. The paper’s conclusions may not depend on it.

There are inherent limitations to our study, primarily due to its retrospective nature.

“There are also inherent limitations to our study, primarily due to its retrospective nature”

It may state two separate claims as one.

None of our patients had moderate or severe dementia, so inferences of trazodone use on more advanced disease cannot be made.

“None of our patients had moderate or severe dementia to allow for inferences of trazodone use on more advanced disease”

Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

Cognitive benefits via SWS enhancement may vary depending on a patient's specific syndrome.

“cognitive benefits via SWS enhancement may vary depending on a patient's specific syndrome (e.g., late age-of-onset AD, early age-of-onset AD, logopenic variant primary progressive aphasia, posterior cortical atrophy)”

It may state two separate claims as one.

Even though there are no prospective long-term studies of trazodone for insomnia in elders, long-term persistent benefits have been observed in depression.

“Even though there are no prospective long-term studies of trazodone for insomnia in elders, long-term persistent benefits have been observed in depression [39]”

• cites [39] Fabre, 1983, Long-term therapy for depression with trazodone, J Clin PsychiatryNot checked yet

• AssumptionRests on an assumption: There are no prospective long-term studies of trazodone for insomnia in elders.