Low Neuroactive Steroids Identifies a Biological Subtype of Depression in Adults with Human Immunodeficiency Virus on Suppressive Antiretroviral Therapy

Shibani S Mukerji, Vikas Misra, David R Lorenz, Sukrutha Chettimada, Kiana Keller, Scott Letendre, Ronald J Ellis, Susan Morgello, Robert A Parker, Dana Gabuzda, Shibani S Mukerji, Vikas Misra, David R Lorenz, Sukrutha Chettimada, Kiana Keller, Scott Letendre, Ronald J Ellis, Susan Morgello, Robert A Parker, Dana Gabuzda

Abstract

Background: The prevalence and mortality risk of depression in people with human immunodeficiency virus (HIV) infection receiving antiretroviral therapy (ART) is higher than in the general population, yet biomarkers for therapeutic targeting are unknown. In the current study, we aimed to identify plasma metabolites associated with depressive symptoms in people with HIV receiving ART.

Methods: This is a prospective study of ART-treated HIV-infected adults with or without depressive symptoms assessed using longitudinal Beck Depression Inventory scores. Plasma metabolite profiling was performed in 2 independent cohorts (total n = 99) using liquid and gas chromatography and tandem mass spectrometry.

Results: Participants with depressive symptoms had lower neuroactive steroids (dehydroepiandrosterone sulfate [DHEA-S], androstenediols, and pregnenolone sulfate) compared with those without depressive symptoms. The cortisol/DHEA-S ratio, an indicator of hypothalamic-pituitary-adrenal axis imbalance, was associated with depressive symptoms (P < .01) because of low DHEA-S levels, whereas cortisol was similar between groups. The odds of having depressive symptoms increased with higher cortisol/DHEA-S ratios (adjusted odds ratio, 2.5 per 1-unit increase in z score; 95% confidence interval, 1.3-4.7), independent of age and sex. The kynurenine-to-tryptophan ratio showed no significant associations.

Conclusions: These findings suggest that altered neuroactive steroid metabolism may contribute to the pathophysiological mechanisms of depression in ART-treated HIV-infected adults, representing a potential biological pathway for therapeutic targeting.

Keywords: depression; DHEA; HIV; HPA axis; acylcarnitines; metabolomics; neuroactive steroids.

© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Schematic of the workflow used to define study populations and identify metabolites altered in human immunodeficiency virus (HIV)–infected cohorts with or without high depressive symptoms, in discovery and validation cohorts. Abbreviations: BDI, Beck Depression Inventory; eGFR, estimated glomerular filtration rate; HNRC, HIV Neurobehavioral Research Center; NNTC, National NeuroAIDS Tissue Consortium; VL, viral load.
Figure 2.
Figure 2.
Low neuroactive steroids and acylcarnitines distinguish between human immunodeficiency virus (HIV)–infected adults with high versus low depressive symptoms. A, Metabolites significantly altered (P < .05; t test) between participants with high versus low depressive symptoms in the 2 cohorts (right). Arrows indicate direction of mean differences; boldface font denotes 11 metabolites significantly altered in both cohorts. B, Box plots show mean differences for 9 of the 11 overlapping metabolites altered in participants with high versus low depressive symptoms. Dashed horizontal bars represent medians; error bars, interquartile ranges. Two overlapping metabolites (5α-androstan-3β,17β-diol monosulfate [2] and androstenediol [3β,17β] disulfate [2]) are not shown. These metabolites have the same chemical formulas and expected mass as metabolites shown with (1), with minor differences in the mass-to-charge ratio. Abbreviation: DHEA-S, dehydroepiandrosterone sulfate. P values are displayed for each comparison.
Figure 3.
Figure 3.
High cortisol/dehydroepiandrosterone sulfate (DHEA-S) ratio is associated with high depressive symptoms in human immunodeficiency virus (HIV)–infected adults receiving antiretroviral therapy. A, Volcano plots in the discovery (top; n = 55) and validation (bottom; n = 44) sets, illustrating statistical significance of the fold change for neuroactive steroid metabolites (blue data points) and cortisol/steroid ratios (red data points) in participants with high versus low depressive symptoms. B, Beeswarm plots illustrating individual participant levels of cortisol (left panels), DHEA-S (middle panels), and cortisol/DHEA-S ratios (right panels) in participants with low versus high depressive symptoms in discovery (top panels) and validation (bottom panels) cohorts. DHEA-S levels are lower in participants with high versus low depressive symptoms, while cortisol levels are similar. Low DHEA-S accounts for high cortisol/DHEA-S ratios observed in participants with high depressive symptoms (P < .01). Horizontal bars represent means; error bars, standard deviations. Significance was calculated using unpaired t tests, and P values are shown for comparisons. C, Receiver operating characteristic (ROC) curve from logistic regression models assessing classification of participants with low versus high depressive symptoms using cortisol/DHEA-S ratio (z score) or cortisol/DHEA-S ratio with androstenediol (3β,17β) monosulfate (1) (androstene) and pregnenolone sulfate in the discovery (left panels) and validation (right panels) cohorts. Abbreviation: AUC, area under the ROC curve.
Figure 4.
Figure 4.
Interrelationships between neuroactive steroids, acylcarnitines, and the kynurenine-to-tryptophan (K/T) ratio in human immunodeficiency virus (HIV)–infected adults with or without depressive symptoms. A, Heat map from unsupervised hierarchical clustering analysis of the combined cohort (n = 99). Included metabolites were altered in discovery and validation cohorts in participants with high versus low depressive symptoms (P < .05), K/T ratio, and cortisol. Columns represent individual participants; rows, metabolites. Color scale indicates relative expression levels of metabolites using z score transformation across all samples. Dendrograms indicate sample cluster (top) and metabolite cluster (left). Age, sex, Beck Depression Inventory (BDI) score, and depression classification are annotated above the heat map (top bars, columns) according to the legend. B, Schematic model of the hypothalamic-pituitary-adrenal axis biochemical pathway with metabolites that had significant differences between participants with high versus low depressive symptoms shown in red (decreased) and blue (no change). In vitro, DHEA activates protein phosphatase 2a (PP2A) (dashed gray arrow), leading to increased proliferator-activated receptor α (PPARα)–mediated gene transcription and downstream fatty acid β-oxidation. Long chain acylcarnitines are converted to large chain fatty acids with acyl coenzyme A (LCFA-coA), which then enters the β-oxidation cycle to yield free carnitine and, under certain conditions, acylcarnitines [41].

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