pattismith
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Two possible mechanisms of ganciclovir for treatment of major depressive disorder
1. Introduction
The annual prevalence of major depressive disorder (MDD) in the US is 6.7% (1), and an estimated 35 million US adults will be affected by MMD during their lifetime (1–3).However, MDD is a global problem with an economic burden estimated at 83.1 billion USD in 2000 (2, 4).
Furthermore, the prevalence of psychiatric disorders, including MDD, has increased during the COVID-19 pandemic (5).
MDD is considered to be a multifactorial disorder caused by both environmental and genetic factors, but the mechanism underlying its pathogenesis is not fully understood (6).
It is likely that there are multiple underlying mechanisms of pathogenesis (2, 6), given the existence of multiple patient subgroups with different characteristics.
Current treatments for MDD, including pharmacotherapy, have not yet achieved satisfactory results (7–9).
We hypothesize that ganciclovir may be a potential therapeutic candidate for MDD based on not only its antiviral action, but also its modulation of innate immune pathways in the brain that are activated in response to stress.
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3. Antiviral mechanism of intervention and previous studies on efficacy for the various viruses
Although HHV-6 has no established treatment, anti-cytomegalovirus agents including ganciclovir are known to be effective (37, 38).Ganciclovir is also effective against herpesviruses such as HHV-1, herpes zoster virus, and Epstein–Barr virus (38–40).
In an open label study of valganciclovir (a prodrug of ganciclovir), 75% of patients with high immunoglobulin G antibody titers to HHV-6 and Epstein–Barr virus and four or more of the following symptoms for at least 1 year, cognitive dysfunction, slow processing speed, sleep disturbance, short-term memory impairment, fatigue, and symptoms consistent with depression, achieved almost complete resolution of symptoms, and all returned to work or full-time activities (41).
A phase I clinical trial of valganciclovir treatment for CMV positive patients with MDD is currently underway (ClinicalTrials.gov Identifier: NCT04724447).
Based on these findings, it is conceivable that the antiviral effect of ganciclovir on herpesviruses is beneficial in the treatment of MDD.
4. Effects of ganciclovir on neuroinflammation with STING pathway activity
The relationship between stress and MDD is well-known, with stress causing activation of the brain's innate immune response pathways (42).Stimulator of interferon genes (STING), an adaptor protein expressed in microglia, plays an important role in regulating innate immune signaling processes in the central nervous system by detecting abnormal cytoplasmic DNA (43). Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) catalyzes the generation of 2′3′-cyclic-GMP-AMP (cGAMP), a second messenger that binds and activates STING. STING then recruits and activates TANK-binding kinase 1 and the transcription factor interferon regulatory factor 3 to produce interferon-β (IFN-β) (43).
In an experimental mouse model of chronic restraint stress, decreased levels of STING and activation of its downstream molecules were observed in the hippocampus and prefrontal cortex (44).
In addition, the mice exhibited depression-like behavior and elevated levels of the inflammatory cytokines tumor necrosis factor α, interleukin (IL)-6, and IL-1β in the brain (44).
Activation of STING by the agonist cGAMP was shown to enhance phagocytosis of microglia in the brains of the mice, suppress the release of inflammatory cytokines, and exert antidepressant effects (44).
Ganciclovir inhibited neuroinflammation by stimulating INF-β production in microglia depending on the STING pathway activation level (45).
These findings suggest that the second point of action of ganciclovir is to promote phagocytosis of microglia by increasing INF-β production through activation of the STING pathway, which may lead to the improvement of MDD symptoms by suppressing neuroinflammation.
https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1109723/full
