The effects of trazodone on human cognition: a systematic review

Abstract

Trazodone is a widely used antidepressant that is also useful in the control of agitation and insomnia in Alzheimer's disease. 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. 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. The search was run in MEDLINE, Web of Science, and CENTRAL from the Cochrane databases, yielding a total of 16 studies after selection. 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. 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. There was no clinical evidence that trazodone could be used as a specific treatment of neurodegenerative diseases. Future studies should explore the role of trazodone in the UPR pathway and the implications in neurodegenerative diseases in humans.

Keywords: All cognitive disorders/dementia; Alzheimer's disease; Executive function; Memory; Trazodone.

Fig. 1

UPR overactivation and trazodone site of action in the PERK branch of the UPR pathway. In protein misfolding disorders there is a disruption in protein homeostasis through endoplasmic reticulum (ER) stress, leading to the activation and dysregulation of the UPR response [5]. 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). Thus, in the face of misfolded proteins, PERK dimerizes, autophosphorylates, and becomes activated. Subsequently, PERK phosphorylates the α-subunit of eIF2, preventing the formation of the ternary complex, resulting in a consequent blockage of proteins crucial for learning, memory, synaptic maintenance, and neuronal survival [5]. On the other hand, PERK activation culminates with the translation of activating transcription factor 4 (ATF4), which upregulates proteins that restore cellular homeostasis and CHOP [5]. Trazodone acts in the PERK branch of the UPR pathway downstream of eIF2α-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]. UPR: unfolded protein response; PERK-P: phosphorylated RNA (PKR)-like ER kinase; eIF2α: α-subunit of eukaryotic initiation factor 2; ATF4: activating transcription factor 4; CHOP: CEBP homologous protein

Fig. 2

PRISMA 2009 flow diagram