People living with HIV face a high risk of mental illness, especially depression. We do not yet know the precise neurobiological mechanisms underlying HIV-associated depression. Depression severity in the general population has been linked to acute and chronic markers of systemic inflammation. Given the associations between depression and peripheral inflammation, and since HIV infection in the brain elicits a neuroinflammatory response, it is possible that neuroinflammation contributes to the high prevalence of depression amongst people living with HIV. The purpose of this review was to synthesise existing evidence for associations between inflammation, depression, and HIV. While there is strong evidence for independent associations between these three conditions, few preclinical or clinical studies have attempted to characterise their interrelationship, representing a major gap in the literature. This review identifies key areas of debate in the field and offers perspectives for future investigations of the pathophysiology of HIV-associated depression. Reproducing findings across diverse populations will be crucial in obtaining robust and generalisable results to elucidate the precise role of neuroinflammation in this pathophysiology.

People with HIV are at increased risk for depression, though the neurobiological mechanisms underlying this are unclear. In the last decade, there has been a substantial rise in interest in the contribution of (neuro)inflammation to depression, coupled with rapid advancements in the resolution and sensitivity of biomarker assays such as Luminex, single molecular array and newly developed positron emission tomography radioligands. Numerous pre-clinical and clinical studies have recently leveraged these next-generation immunoassays to identify biomarkers that may be associated with HIV and depression (separately), though few studies have explored these biomarkers in co-occurring HIV and depression. Using a systematic search, we detected 33 publications involving a cumulative N = 10 590 participants which tested for associations between depressive symptoms and 55 biomarkers of inflammation and related processes in participants living with HIV. Formal meta-analyses were not possible as statistical reporting in the field was highly variable; future studies must fully report test statistics and effect size estimates. The majority of included studies were carried out in the United States, with samples that were primarily older and primarily men. Substantial further work is necessary to diversify the geographical, age, and sex distribution of samples in the field. This review finds that alterations in concentrations of certain biomarkers of neuroinflammation (interleukin-6, tumour necrosis factor-α, neopterin) may influence the association between HIV and depression. Equally, the chemokines monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) or the metabolic index kynurenine:tryptophan (Kyn:Trp), which have been the focus of several studies, do not appear to be associated with depressive symptoms amongst people living with HIV, as all (MCP-1) or most (IL-8 and Kyn:Trp) available studies of these biomarkers reported non-significant associations. We propose a biomarker-driven hypothesis of the neuroimmunometabolic mechanisms that may precipitate the increased risk of depression among people with HIV. Chronically activated microglia, which trigger key neuroinflammatory cascades shown to be upregulated in people with HIV, may be the central link connecting HIV infection in the central nervous system with depressive symptoms. Findings from this review may inform research design in future studies of HIV-associated depression and enable concerted efforts towards biomarker discovery.

Chronic stress can impact decision-making and lead to a preference for immediate rewards rather than long-term payoffs. Factors that may influence these effects of chronic stress on decision-making are under-explored. Here we used a mouse model to investigate the changes in decision-making caused by the experience of chronic stress and the role of social isolation in exaggerating these changes. To test decision-making, mice were trained to perform a Cost-Benefit Conflict (CBC) task on a T-maze, in which they could choose between a high-reward, high-risk alternative and a low-reward, low-risk alternative. Mice were either housed in groups or alone throughout the experiment. Both groups of mice underwent a seven-day period of repeated immobilization to induce chronic stress. Stress levels were confirmed using behavioral (open field test) and physiological (urine corticosterone ELISA) measures. We found a significant increase in frequency of high-risk decisions after exposure to chronic stress among both socially- and individually-housed mice. Crucially, socially-housed mice showed a significantly smaller increase in high-risk decision-making compared to singly-housed mice. These findings suggest that chronic stress leads to an increase in high-risk decision-making in mice, and that lack of social interaction may exacerbate this stress effect.

Background: Chronic inflammation is associated with psychiatric disorders. If inflammation is linked mechanistically to mental health, people living with chronic inflammatory conditions may experience mental health issues at higher rates than others. Objective: To test this hypothesis, we analysed data from 1 563 155 adults living in the UK within the newly launched UK-wide Our Future Health research cohort. Methods: Participants were split between two groups: people with self-reported lifetime diagnoses of six autoimmune conditions (n=37 808) and those without these diagnoses (n=1 525 347). Findings: Lifetime prevalence (95% CI) of self-reported lifetime diagnoses of any affective disorder (depression, bipolar disorder, anxiety) was significantly higher (p<0.001) among people with autoimmune conditions (28.8% (28.4% to 29.3%)) than in the general population (17.9% (17.8% to 18.0%)), with similar trends observed for individual affective disorders. Prevalence of current depressive symptoms (9-item Patient Health Questionnaire (PHQ-9) ≥10, 18.6% vs 10.5%) and current anxiety symptoms (7-item Generalised Anxiety Disorder Scale (GAD-7) ≥8, 19.9% vs 12.9%) was also higher among people with autoimmune conditions. Odds of experiencing affective disorders, calculated using logistic regression models, were significantly higher in this group compared with the general population (OR (95% CI) = 1.86 (1.82 to 1.90), p<0.001), and these odds remained elevated when adjusting for the effects of age, sex, ethnicity (OR=1.75 (1.71 to 1.79), p<0.001) and additionally, for household income, parental history of affective disorders, chronic pain status and frequency of social interactions (OR=1.48 (1.44 to 1.52), p<0.001). Conclusions: Overall, the risk of affective disorders among people living with autoimmune conditions was nearly twice that of the general population. Clinical implications: Although the observational design of this study does not allow for direct inference of causal mechanisms, this analysis of a large national dataset suggests that chronic exposure to systemic inflammation may be linked to a greater risk for affective disorders. Future work should seek to investigate potential causal mechanisms for these associations.

People living with HIV are at increased risk for depression, though the underlying mechanisms for this are unclear. In the general population, depression is associated with peripheral and central inflammation. Given this, and since HIV infection elicits inflammation, we hypothesised that peripheral and central inflammatory biomarkers would at least partly mediate the association between HIV and depressive symptoms. People living with HIV (n = 125) and without HIV (n = 79) from the COmorBidity in Relation to AIDS (COBRA) cohort were included in this study. Participants living with and without HIV had similar baseline characteristics. All participants living with HIV were on antiretroviral therapy and were virally suppressed. Plasma, CSF, and brain MR spectroscopy (MRS) biomarkers were measured. Using logistic regression models adjusted for sociodemographic factors, we found that participants with HIV were more likely to have Any Depressive Symptoms (Patient Health Questionnaire [PHQ-9] score >4) (odds ratio [95% confidence interval] 3.27 [1.46, 8.09]). We then sequentially adjusted the models for each biomarker separately to determine the mediating role of each biomarker, with a >10% reduction in OR considered as evidence of potential mediation. Of the biomarkers analysed, MIG (−15.0%) and TNF-α (−11.4%) in plasma and MIP1-α (−21.0%) and IL-6 (−18.0%) in CSF mediated the association between HIV and depressive symptoms in this sample. None of the other soluble or neuroimaging biomarkers substantially mediated this association. Our findings suggest that certain biomarkers of central and peripheral inflammation may at least partly mediate the relationship between HIV and depressive symptoms.

Depression is a debilitating illness, and stigma associated with it often prevents people from seeking support. Easy-to-administer and culturally- inclusive tools can allow for early screening for depressive symptoms in primary care clinics, especially in resource-limited settings. In this pre-registered pilot study (Stage 1 Report available at DOI: 10.3389/fpsyt.2022.840912), we produced an open-access isiXhosa-language version of the nine-item Patient Health Questionnaire (PHQ-9), a well-validated measure of depression incidence and severity, using a transcultural translation framework. We validated this isiXhosa PHQ-9 in a sample of N = 47 adolescents living with and without HIV in Cape Town, South Africa who speak isiXhosa at home. Reliability, convergent validity, and criterion validity were assessed, with T scores on the Achenbach System of Empirically Based Assessment Youth Self Report (YSR) form completed previously as reference standard. Our isiXhosa PHQ-9 exhibited satisfactory reliability, with Cronbach’s [ ], inter-item correlations ranging from 0.229 to 0.730, and mean item-total correlation of 0.69. PHQ-9 score and Withdrawn/Depressed component T scores on the Youth Self Report were moderately associated (Spearman’s [ ], indicating acceptable convergent validity. The isiXhosa PHQ-9 showed satisfactory criterion validity (area under the receiver operating characteristic curve, AUC = 0.706), but these analyses were under-powered. Principal component analysis revealed a one-factor solution, with 45.8% of variance explained by the first principal component and all factor loadings above conventional thresholds. Our isiXhosa translation of the PHQ-9 thus exhibited satisfactory psychometric properties in this pilot validation study and performed comparably to other PHQ-9 versions validated in different languages in African and global contexts. This questionnaire may serve as an invaluable culturally-inclusive screening tool for measuring depressive symptoms among isiXhosa speakers. Caution must be exercised as screening tools including the PHQ-9 may over- or under-estimate prevalence of depression. Further validation in larger, independent cohorts may enable wider use of our isiXhosa PHQ-9 as a screening tool in clinics, research studies, and mental health non-profits who serve amaXhosa.