In terms of comparators, all comparators were accepted without restriction. The dose of 25 mg was chosen because it is the minimum dose used that is capable of producing some effects of the drug observed in clinical practice. Consequently, we excluded studies that only tested the acute effects of trazodone by using it in a one-time-only fashion. The targeted intervention was a minimum dose of 25 mg of trazodone daily, for at least 1 week, to observe the chronic effects of this drug and not the effects obtained after a single dose. We excluded animal studies, since our focus was on the consequences in humans in order to assess the implications for clinical practice. The diseased patients could have all types of illness, from atherosclerotic disease to psychiatric conditions. Our target population was healthy or diseased adults aged 18 years or older.
Thus, we aimed to establish the effects of trazodone on human cognition and to determine whether there was evidence that it could be used in the treatment of neurodegenerative diseases in humans.įollowing PRISMA guidelines, we conducted a systematic review, without a meta-analysis, of studies that evaluated the effect of trazodone on human cognition. Establishing the effect of trazodone on cognition and neurodegeneration would have significant implications for clinical practice, given the increasing prevalence of neurodegenerative diseases and the extensive use of trazodone in this patient population. 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, or as a result of the sleep improvement this drug offers. As a result, this drug appears to have utility as a novel disease-modifying treatment for neurodegenerative diseases in humans. Hence, trazodone has been shown to prevent the effects of UPR overactivation observed in neurodegenerative diseases and restore neuronal protein synthesis, preventing neurodegeneration in mouse models. Trazodone acts downstream of eIF2α-P, preventing it from reducing levels of the ternary complex and allowing protein translation to occur (see Supplementary Fig. Trazodone is now recognized as having a novel mechanism of action, its effect in the unfolded protein response (UPR) pathway.
Additionally, it reduces behavioural and psychological symptoms in AD and frontotemporal dementia. Future studies should explore the role of trazodone in the UPR pathway and the implications in neurodegenerative diseases in humans.Īlthough it is FDA-approved only for use in the treatment of major depression, trazodone, a drug created in the 1960s, is widely used off-label to control agitation and insomnia in Alzheimer’s disease (AD) and in anxiety, schizophrenia, bulimia, substance abuse, fibromyalgia, and post-traumatic stress disorder. There was no clinical evidence that trazodone could be used as a specific treatment of neurodegenerative diseases. 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. 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 search was run in MEDLINE, Web of Science, and CENTRAL from the Cochrane databases, yielding a total of 16 studies after selection. This mechanism may have a role in dementia-modifying treatment. To explore the effects of trazodone on human cognition and to search for clinical evidence of its putative benefits in human neurodegenerative diseases, a systematic review was conducted for studies that evaluated the effect of a minimum dose of 25 mg of trazodone daily, for at least 1 week, on cognition in adult humans. This drug is now recognized as having a new mechanism of action, an effect on the unfolded protein response (UPR) pathway, restoring protein translation and slowing neurodegenerative progression in mice. Trazodone is a widely used antidepressant that is also useful in the control of agitation and insomnia in Alzheimer's disease.
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