IMPORTANCE
​Treatment-resistant depression (TRD) is a major challenge in mental health, affecting a significant number of patients and leading to considerable burdens. The etiological factors contributing to TRD are complex and not fully understood.

OBJECTIVE
To investigate the genetic factors associated with TRD using polygenic scores (PGS) across various traits and explore their potential role in the etiology of TRD using large-scale genomic data from the All of Us (AoU) Research Program.

DESIGN, SETTING, AND PARTICIPANTS
This study was a cohort design with observational data from participants in the AoU Research Program who have both electronic health records and genomic data. Data analysis was performed from March 27 to October 24, 2024.

EXPOSURES
PGS for 61 unique traits from 7 domains.

MAIN OUTCOMES AND MEASURES
Logistic regressions to test if PGSwas associated with treatment-resistant depression (TRD) compared with treatment-responsive major depressive disorder (trMDD). Cox proportional hazard model was used to determine if the progressions from MDD to TRD were associated with PGS.

RESULTS
A total of 292,663 participants (median [IQR] age, 57 (41-69) years; 175 981 female [60.1%]) from the AoU Research Program were included in this analysis. In the discovery set (124 945 participants), 11 of the selected PGS were found to have stronger associations with TRD than with trMDD, encompassing PGS from domains in education, cognition, personality, sleep, and temperament. Genetic predisposition for insomnia (odds ratio [OR], 1.11; 95%CI, 1.07-1.15) and specific neuroticism (OR, 1.11; 95%CI, 1.07-1.16) traits were associated with increased TRD risk, whereas higher education (OR, 0.88; 95%CI, 0.85-0.91) and intelligence
(OR, 0.91; 95%CI, 0.88-0.94) scores were protective. The associations held across different TRD definitions (meta-analytic R2 >83%) and were consistent across 2 other independent sets within AoU (the whole-genome sequencing Diversity dataset, 104 388, and Microarray dataset, 63 330). Among 28,964 individuals followed up over time, 3,854 developed TRD within a mean of 944 days (95%CI, 883-992 days). All 11 previously identified and replicated PGS were found to be modulating the conversion rate from MDD to TRD.

CONCLUSIONS AND RELEVANCE
Results of this cohort study suggest that genetic predisposition related to neuroticism, cognitive function, and sleep patterns had a significant association with the development of TRD. These findings underscore the importance of considering psychosocial factors in managing and treating TRD. Future research should focus on integrating genetic data with clinical outcomes to enhance understanding of pathways leading to treatment resistance.

Approximately 1/3 of individuals with major depressive disorder (MDD) exhibit low-grade systemic
inflammation based on levels of C-reactive protein (CRP); the American Heart Association defines high risk as a CRP as >3mg/L (1). At the behavioral level, anhedonia appears to be the symptom most closely tied to inflammation (2-4). In healthy participants, inflammatory challenge with low-dose lipopolysaccharide (LPS) - a reliable, safe, and well-validated method of inducing robust peripheral and CNS inflammation (5-8) - transiently increases motivational anhedonia and decreases ventral striatal response to anticipatory reward (9-11).
However, to our knowledge, no study has tested whether depressed individuals with and without systemic inflammation show differential anhedonic responses to an acute inflammatory exposure. Such experimental substantiation would constitute clear evidence of a biological subtype of MDD and corroborate previously proposed mechanistic links between inflammation and anhedonia (2-4). This would also have implications for treatment as it has been proposed that clinical trials of immune-modulating therapies in depression are confounded by a failure to selectively recruit participants with evidence of inflammation (12-15). Here, we present results from a randomized controlled trial (NCT03142919) designed to test whether MDD participants with elevated serum CRP levels (≥3mg/L), as compared to those with non-elevated CRP (≤1.5mg/L), display a greater increase in anhedonic symptoms at the approximate peak of the inflammatory response to LPS, i.e. ~1.5 hours post infusion.

Our study team explored how ibuprofen, a common anti-inflammatory medication, influences brain function related to reward processing. Researchers focused on astrocyte-enriched extracellular vesicles (AEEVs), tiny particles that facilitate communication between brain cells. They discovered that ibuprofen increases the levels of miR-23b-3p, a specific microRNA within AEEVs. Higher levels of this microRNA were associated with reduced inflammation and enhanced activity in the brain's reward centers during anticipation of rewards. These findings suggest that ibuprofen may have potential benefits for brain health by modulating inflammation and influencing reward-related brain activity.​

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].
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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.