Background

HIV-related neuroinflammation has been proposed as a catalyst for dopaminergic dysregulation in mesocortical pathways, which may contribute to the pathogenesis of depression. Abnormalities in dopaminergic neurotransmission and depression are common in people with HIV (PWH), however the link between dopamine (DA) and depression in PWH is poorly characterized. This study investigated CSF dopaminergic biomarkers, specifically DA and its metabolite, homovanillic acid (HVA), and examined their relationship with depressive symptoms and CSF neuroinflammatory markers in PWH and HIV-seronegative (HIV-) individuals.

Methods

Participants were 102 HIV- individuals and 123 PWH (mean age = 42) who underwent neuropsychiatric evaluations and lumbar puncture. Current depression severity was classified using the Beck Depression Inventory-II (BDI-II). CSF was assayed for DA and HVA using high performance liquid chromatography and neuroinflammatory markers using immunoassays. Linear regressions modelled BDI-II scores as a function of HIV, dopaminergic biomarker z-scores, and their interaction, controlling for psychosocial factors. Correlational analyses examined dopaminergic and neuroinflammatory relationships.

Results

PWH had significantly higher BDI-II scores than HIV- participants. DA and HVA were not associated with HIV status but both significantly moderated the effect of HIV on BDI-II scores, such that PWH exhibited higher depressive symptoms than HIV- participants only at lower concentrations of HVA (z ≤ 0.06) and DA (z ≤ 0.11). In PWH only, lower HVA significantly correlated with higher BDI-II scores and higher neuroinflammation, including higher MCP-1 and IP-10.

Conclusions

Results suggest that the pathophysiology of depression in PWH differs from that in HIV- individuals. Specifically, lower central dopaminergic activity was selectively associated with greater depressive symptoms and neuroinflammation in PWH. With the rise in consideration of DA agonists for the treatment of depression, these results suggest that PWH may show a greater response to these agents than their HIV- peers.

The Met-allele of the COMT Val158Met polymorphism slows metabolism and increases bioavailability of dopamine (DA) in the prefrontal cortex compared to the Val-allele. Healthy Met-carriers outperform Val-carriers on executive function (EF) tests, yet this 'advantage' disappears in methamphetamine (METH) dependence. Met-carriers may be disproportionately vulnerable to METH-related perturbations of DA, yet it is unknown whether COMT modulates METH effects on CSF DA biomarkers. Participants were 75 METH+ and 47 METH- men who underwent neurocognitive testing, COMT genotyping, and lumbar puncture. CSF was assayed for DA and its metabolite, homovanillic acid (HVA). Separate linear models regressed DA, HVA, and HVA/DA ratios on COMT, METH and their interaction. Pearson correlations examined associations between DA and EF. Significant interactions indicated that METH+ had lower DA and higher HVA/DA ratios among Met/Met, but not Val/Met-or Val/Val. Met/Met-exhibited the highest DA levels among METH-, whereas DA levels were comparable between Met/Met-and Val-carriers among METH+. Higher DA correlated with better EF in METH- Met/Met, but did not predict EF in the entire sample. DA was expectedly higher in METH- Met/Met, yet a discordant genotype-phenotype profile emerged in METH+ Met/Met, consistent with the notion that slow DA clearance exacerbates METH-associated DA dysregulation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.