Podcast: CMV, Neuroinflammation, and Psychiatric Disorders in Postmortem Brain

3/27/2025

Cytomegalovirus (CMV) is a common herpesvirus that establishes lifelong latent infections, undergoes periodic reactivation, and may cause disease in vulnerable populations including neonates and the
immunocompromised. CMV has attracted the attention of the psychiatric field because CMV (a) is neurotrophic and may cause neurological disease [1, 2], (b) it can be reactivated by psychological
stress which is linked with the onset and exacerbation of many psychiatric disorders [3, 4], and (c) it can be reactivated by inflammation [4–6], which is linked with multiple psychiatric disorders including mood disorders and schizophrenia [7–11]. Importantly, lytic CMV replication can in turn worsen inflammation
[12, 13], raising the possibility that poorly-controlled CMV infections may be one source of the systemic or neuroinflammation underlying the development of some cases of mental illness [14, 15]. Most of the evidence linking CMV infections to psychiatric disorders is epidemiological [16]. At least 20 studies have reported either a higher frequency of seropositivity to CMV in depressed samples versus controls or a positive correlation between anti-CMV IgG levels and depressive symptoms [16]. In addition, two prospective studies found that CMV seropositivity was associated with an increased risk of subsequent depression [17, 18].

Similarly, a large Swedish cohort study showed that children hospitalized with a CMV infection were 16.6 times more likely to develop a non-affective psychosis in the future [19] and several studies have
linked schizophrenia with CMV infection [20]. We recently published some of the first work linking CMV
seropositivity to neuroimaging abnormalities in the context of major depressive disorder (MDD). In up to three independent samples, we demonstrated that compared with CMV seronegative individuals with MDD, CMV positive individuals with MDD had widespread reductions in gray matter volume, decreased white matter integrity in a tract connecting the frontal and occipital lobes (inferior frontal occipital fasciculus), and reduced functional connectivity between hubs of the sensorimotor and salience networks [21–23]. Leboyer and colleagues had previously reported that CMV antibody levels were inversely associated with hippocampal volume in individuals with bipolar disorder (BD) and schizophrenia [24]. Similarly, Agartz and colleagues recently found that CMV-positive patients with bipolar or schizophrenia spectrum disorders had smaller dentate gyri [25] and reduced total cortical area as compared with CMV-negative patients [26].

However, whether CMV is playing a causal role in these neuroimaging abnormalities and if so, whether these findings relate to a heightened inflammatory process, is still unclear. At least in vitro, herpesvirus infections trigger the production of a range of cytokines and chemokines by glial cells [27], but to our knowledge the link between CMV infection and inflammation in the central nervous system (CNS) has never been tested in people with psychiatric disorders.
Here, we investigated in a postmortem sample whether CMV serostatus and serum antibody levels to CMV were associated with the odds of: 1) having a psychiatric disorder, 2) dying by suicide, 3) having higher neuroinflammation (based on a previously performed clustering analysis of immune-related gene expression in the dorsolateral prefrontal cortex [9]), and 4) showing increased microglia activation in the dorsolateral prefrontal cortex (i.e., an increased ratio of non-ramified to ramified microglia). We hypothesized that CMV seropositivity and/or higher CMV antibody levels would be associated with increased odds of 1) diagnosis with a psychiatric disorder, 2), suicide, 3) assignment to the “high” neuroinflammation group, and 4) an increased ratio of nonramified to ramified microglia.