The effects of trazodone on human cognition: a systematic review

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Here is an example of systematic review about an anti-depressant which has also putative benefits in human neurodegenerative diseases.

A systematic review are designed to provide an exhaustive summary of current evidence relevant to a research question. This should not be confused with meta-analysis. A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. A key benefit of this approach is the aggregation of information leading to a higher statistical power. 

However most meta-analysis are cheap attempts at publishing without doing real research. Systematic reviews must follow strict protocols. There is no cheap or easy way to do a systematic review. enter image description here.

Although it is FDA-approved only for use in the treatment of major depression, trazodone is widely used off-label to control agitation and insomnia in Alzheimer’s disease (AD) and other diseases. Yet the list of trazodone side-effects is long and some of them are frightening.

Trazodone hydrochloride and dibenzoylmethane were identified by the National Institute of Neurological Disorders and Stroke (NINDS) small-molecule library screening performed on 1040 drugs. Both drugs reversed p-eIF2α mediated translational attenuation and were neuroprotective in two mouse models of neurodegeneration. In prion-diseased mice, both drugs restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival.

Furthermore, in an animal model of tauopathy-FTD (frontotemporal dementia), these compounds rescued memory deficits and hippocampal atrophy. Finally, both compounds were not toxic to the pancreas.

A common factor in neurodegenerative diseases, and beyond many chronic diseases is a cellular stress response that is abnormally prolonged. The response to this cellular stress (UPR, ISR and others) involves the shutdown of functions that are essential for the proper functioning of the body.

A cell main purpose is to produce proteins. This production is done in several steps: a blueprint is assembled from RNA fragments copied from DNA (a very long molecule). This blueprint is used by ribosomes to produce linear chains of amino acids. Ribosomes are often located in the rough endoplasmic reticulum, probably the most complex organelle in the cell. The endoplasmic reticulum folds this linear chain of amino-acids, thereby giving it new properties and sends it where it is needed.

When there is a cellular stress response, the endoplasmic reticulum stops working, so the newly produced proteins stay in the cytosol where they form protein aggregates named stress granules. Normally this state is of short duration, so quickly the endoplasmic reticulum works again and the stress granules are disposed by the proteolysis mechanism. In a state of stress response, there is hardly any protein production but the protein consumption resulting from metabolism continues, so if the stress response persists a long time the cells become gradually beyond repair and are destroyed by apoptosis.

A drug able to end the anomalous cellular stress response would therefore be very interesting. Indeed it would be valuable only in early phases of the disease, before too much cells died. And canceling completely the UPR mechanism is a bad idea.

UPR acts as a cellular mechanism for the regulation of protein homeostasis when there are misfolded proteins and coordinates this process through three ER transmembrane proteins: PERK, inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6).

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, restoring neuronal protein synthesis rates, enabling a boost of memory and preventing neurodegeneration in mice models.

In summary of the systematic review, 12 of 16 clinical studies demonstrated a neutral or even a beneficial effect of trazodone on cognitive functions. The majority of these studies demonstrated a positive effect that is possibly not due to the direct effects of trazodone on cognition, but is instead mediated through an improvement in sleep disorders and depressive symptoms.

The results also highlight the possibility of a dose-independent dual effect of trazodone on human cognition, with acute utilization associated with impaired cognitive function and longitudinally long-term use with prevention of cognitive deterioration.

None of the studies evaluated its effects on the UPR pathway, and there was no evidence that trazodone could be used as an active treatment of neurodegenerative diseases itself, although this review suggests that trazodone can be integrated into the therapeutic arsenal in these cases as a safe and well-tolerated adjuvant treatment for dementia comorbidities, with minimal adverse events.

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