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.

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.

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.

FDA data have reported depressive symptoms were observed in 27 (0.59%) of the 4,593 people, especially 40–49-year-old women, treated with ganciclovir from 1997 to 2022 (46). However, many of these patients were infected with cytomegalovirus, human immunodeficiency virus, or had acute lymphocytic leukemia (hematological malignancy), and many were also steroid users (46). It is possible that these patient characteristics were highly associated with depressive symptoms, and the mechanism of the association with ganciclovir is not clarified. Therefore, whether ganciclovir treatment causes depression requires careful interpretation. Side effects other than depression reported in the FDA data included cytomegalovirus infection, febrile neutropenia, pancreatitis, stress and anxiety, decreased hemoglobin, decreased weight, decreased hematocrit, thrombocytopenia, nosebleed, and urinary tract infection (46). Ganciclovir is primarily indicated for the treatment of CMV, so its administration to depressed patients is not indicated (47). In addition, it is administered with caution to patients with psychiatric disorders, and informed consent should be obtained prior to use in a clinical trial. Drug label information does not specifically list interactions with antidepressants, but warnings generally list hematologic toxicity, reproductive impairment, fetotoxicity, mutagenicity, and carcinogenicity (47).

Neuroinflammation alone is not enough to explain MDD; psychological, social, environmental and cultural factors are also involved (48–51). Several clinical trials of anticytokine therapy for the neuroinflammatory hypothesis have been reported. Two clinical trials of the TNF-α inhibitor infliximab in depression showed no overall significant efficacy (52, 53). In addition, a meta-analysis of anticytokine therapy found a significant antidepressant effect, but the subjects were patients with chronic inflammatory diseases such as psoriasis and Crohn's disease, and depressive symptoms were measured only as a secondary outcome, so the results cannot be generalized as a therapeutic effect of anticytokine therapy for depressed patients (54). Toll-like receptor (TLR) 2/4 has been shown to be an important mediator of microglial activation in the medial prefrontal cortex by repeated social defeat stress, leading to neuronal and behavioral changes through inflammatory cytokines (55). The antimicrobial agent minocycline has been shown to inhibit inflammatory cytokine production by blocking phosphorylation of downstream molecules in the TLR 4 pathway (56). A pilot study of adjunctive minocycline treatment in patients with treatment-resistant depression showed an improvement in depressive symptoms in the minocycline group compared to placebo (57), but a randomized controlled trial of the efficacy of minocycline and celecoxib in combination or as monotherapy in bipolar depression found no significant difference in either group compared to placebo (58). Thus, at this time, clinical trials have not demonstrated sufficient power to support the neuroinflammation hypothesis. In addition, as noted above, HHV infection does not explain all causes of MDD.

We reviewed data from basic (in vitro and in vivo) and observational studies on MDD and HHV, as well as basic neuroinflammation experiments (in vitro and in vivo) on MDD and the STING pathway. In addition, we presented an early-stage study on the potential therapeutic use of ganciclovir for MDD. Ganciclovir may be a potential therapeutic candidate for MDD from two different perspectives: antiviral activity against herpesviruses and inhibition of neuroinflammation through activation of the STING pathway, as shown in Figure 1. If we can measure the presence or absence of viral infection and antibody titers or the degree of neuroinflammation in patients with MDD as future work, we may be able to select subjects with MDD for whom ganciclovir is effective. We hope that validation by further clinical research can expand the range of treatment options because many patients with MDD still show a poor response to treatment.

KI, HT, YM, and HI contributed to conception and methodology of the manuscript and wrote sections of the manuscript. KI performed data curation. KI and HI wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.