Cerebrovascular Dysfunction is Related to Depressive Symptom Severity in Young Adults

Cerebral vasodilatory responsiveness is blunted in older adults (~70 yrs) with depressive disorders and is thought to contribute to the link between depressive symptomology and increased risk for neurocognitive (e.g., dementia) and cerebral vascular (e.g., stroke) diseases. In young adults with major depressive disorder (MDD), peripheral vascular endothelial dysfunction is present and graded in relation to the severity of depressive symptoms; however, to date, limited investigations have examined cerebral vasodilatory function in young otherwise healthy adults with MDD. PURPOSE: We tested the hypothesis that cerebral vasodilatory responsiveness to a hypercapnic stimulus would be blunted in young otherwise healthy adults with MDD compared to healthy non-depressed adults (HA). Further, we hypothesized, that the magnitude of impairment in cerebrovascular function would be related to depressive symptom severity. METHODS: Ten HA (7 women; 22±2yrs) and 10 adults with MDD (8 women; 22±2yrs; n=5 tested during a major depressive episode) participated. Depressive symptom severity was evaluated with the Patient Health History Questionnaire-9 (PHQ-9) in both HA and adults with MDD. Beat-to-beat mean arterial pressure (MAP; finger photoplethysmography), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), and end-tidal carbon dioxide concentration (PETCO2; capnograph) were continuously measured during baseline (i.e., normocapnia) and rebreathing-induced hypercapnia. Cerebral vascular conductance index (CVCi=MCAv•MAP-1) was calculated at baseline and at the highest common magnitude of hypercapnia achieved by all subjects during rebreathing (∆PETCO2 = 9 Torr). RESULTS: At baseline, there were no differences in MAP or CVCi between groups (both p\u3e0.05). During hypercapnia, there were no group differences in the increase in MAP (∆3±3 HA vs. ∆4±3 mmHg MDD; p=0.78). Further, neither the hypercapnia-induced increase in MCAv (∆29±7 HA vs. ∆26±8 cm•s-1 MDD; p=0.37) nor the increase in CVCi (∆39±12 HA vs. ∆30±12 %baseline MDD; p=0.13) were different between groups. However, greater severity of depressive symptoms was negatively related to cerebral vasodilatory responsiveness (R2=0.219, p=0.04). CONCLUSION: These preliminary data suggest that cerebral vasodilatory responsiveness to hypercapnia is not impaired in young adults with MDD, despite a negative relation between depressive symptom severity and the magnitude of hypercapnia-induced cerebral vasodilation

Cutaneous and Muscle Reactive Hyperemia in Young Adults with Major Depressive Disorder

The reactive hyperemic vasodilatory response to a brief period of tissue ischemia provides an index of microvascular function and is an independent predictor of cardiovascular morbidity and mortality. As such, reactive hyperemia is a non-invasive technique that is commonly utilized to provide an index of vascular health in various patient groups. Major depressive disorder (MDD), a non-traditional risk factor for cardiovascular disease (CVD), has been associated with blunted reactive hyperemia, though this is not a universal finding. Further, to date, the quantification of the reactive hyperemic response in adults with MDD has been limited to the forearm muscle, assessed as Doppler ultrasound derived blood velocity in the brachial artery following a period of suprasystolic cuff occlusion. PURPOSE: Here, we sought to more comprehensively assess microvascular reactive hyperemia in otherwise healthy young adults with MDD. We tested the hypothesis that both muscle and cutaneous vasodilation would be blunted in adults with MDD compared to non-depressed young adults. METHODS: Nine healthy adults (HA; age: 22±2 yrs: body mass index: 26.5 ± 1.8 kg/m2) and ten adults with MDD (non-medicated; age: 22±2 yrs: body mass index: 22.6 ± 4.4 kg/m2) participated. Forearm reactive hyperemia was assessed as the increase in blood velocity in the brachial artery following 5-min of suprasystolic cuff occlusion (distal to the olecranon process). In a subset of adults (n=5 HA; n=4 MDD), cutaneous reactive hyperemia was concurrently assessed via laser Doppler flowmetry-derived flux (perfusion units; PU). Peak and total (area-under-the-curve; AUC) reactive hyperemia were quantified for each methodological approach. RESULTS: Neither the brachial artery Doppler ultrasound-derived peak (HA: 1020±383 vs. MDD: 950±239 s-1; p=0.65) nor the total blood flow (HA: 284±77 vs. MDD: 233±153 a.u.; p=0.41) reactive hyperemic response was different between groups. Further, there were no group differences in cutaneous reactive hyperemia (peak: 83±37 HA vs. 79±15 PU MDD, p=0.85; AUC: 8764±2273 HA vs. 8935±1439 a.u. MDD; p=0.90). CONCLUSION: These preliminary data indicate that neither the muscle nor cutaneous vasodilatory response to a brief period of tissue ischemia is blunted in young adults with MDD, suggesting preserved microvascular function

The Relation Between Cognitive Function and Cerebral Vasodilatory Reactivity in Young Adults with Major Depressive Disorder

Major depressive disorder (MDD) has been associated with an elevated risk of developing neurocognitive diseases (e.g., dementia). Although the precise neurobiological mechanisms remain incompletely understood, cerebrovascular dysfunction is thought to directly contribute, at least in part, to impairments in cognitive function. Cerebral vasodilatory reactivity to a hypercapnic stimulus is blunted in older adults with MDD compared to age-matched non-depressed adults. Further, impaired cerebral vasodilation has been linked to reduced cognitive activity in older adults with depression. However, to date, limited studies have examined the relation between cognitive function and cerebrovascular function in otherwise healthy young adults with MDD. PURPOSE: We tested the hypothesis that greater hypercapnia-induced cerebral vasodilation would be related to greater fluid cognitive ability (i.e., the capacity to process and integrate new information) in young adults with MDD. METHODS: Ten adults with MDD (non-medicated; age: 22±2 yrs: body mass index: 22.8±4.5 kg/m2; education level: all enrolled in a four-year university) participated. Cognitive function was assessed via the NIH Toolbox Cognitive Function Battery (iPad). A composite fluid cognitive ability score was derived from the specific tests within the battery that measure fluid ability [e.g., Flanker, Dimensional Change Cart Sort (DCCS)]; an age-correct standard T-score of 100 indicates ability that is average compared with national data. Beat-to-beat mean arterial pressure (MAP; finger photoplethysmography), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), and end-tidal carbon dioxide concentration (PETCO2; capnograph) were continuously measured during normocapnic baseline and during rebreathing-induced hypercapnia. The hypercapnia-induced (∆PETCO2=9 mmHg) increase in cerebral vascular conductance index (∆CVCi=MCAv/MAP) was used as an index of cerebral vasodilatory reactivity. RESULTS: Hypercapnia elicited an increase in CVCi in all subjects (mean: 30±12%; range: 18-60%). The age-corrected composite fluid cognitive ability standard score was 100±15 (range: 79-119). The increase in CVCi was not related to fluid cognitive ability (slope=-0.12±0.3; r2=0.02, p=0.67). In addition, the increase in CVCi was not related to either the age-corrected standard score for the Flanker task (slope=-0.38±0.4; r2=0.12, p=0.32) or for the DCCS task (slope=0.09±0.3; r2=0.02, p=0.72), both of which specifically measure executive function. CONCLUSION: These preliminary data suggest that cerebral vasodilatory reactivity to a hypercapnic stimulus is not related to fluid cognitive function in otherwise healthy college-aged adults with MDD

Heightened inflammation in bipolar disorder occurs independent of symptom severity and is explained by body mass index

Inflammation is hypothesized to be a key component of bipolar disorder (BP) development and progression. However, findings linking BP prevalence and symptomology to immune functioning have been mixed, with some work suggesting that obesity may play an important role in BP-relevant inflammation. Here we investigate differences in biomarkers of inflammation [C-reactive protein (CRP), interleukin (IL)-1β, IL-6, IL-8, IL-10] between healthy controls (HC) and individuals with BP or other mental illness (MI). Adults with BP, MI, or HC (n = 545, 70% BP, 21% HC, 9% MI) self-reported depressive and manic symptoms close to a blood draw and physical exam that included measurement of height and weight. A composite score was calculated from the four cytokines measured in plasma; follow-up analyses explored a pro-inflammatory composite and IL-10, individually. BP individuals had elevated cytokine concentrations compared to HC (B = 0.197, [0.062, 0.333], t (542) = 2.855, p = .004); this difference was also evident for the pro-inflammatory composite and for IL-10. Cytokine concentrations were not associated with BP mood states. Body mass index (BMI), an indicator of obesity, was significantly higher in BP compared to HC (B = 3.780, [2.118, 5.443], t (479) = 4.457, p < .001) and differences in cytokines between the two groups was no longer significant after controlling for BMI. No differences in CRP were evident between BP and HC. These results suggest that cytokine concentrations are elevated in BP and this difference from HC is associated with obesity. Interventions targeting immune modulators in BP must carefully consider the complex relationships within the BP-inflammation-obesity triangle

A real-world study of the association between cardiovascular risk factors and depression symptom trajectory in individuals with mental illness

Background: We examined the relationship between baseline cardiovascular (CV) disease/risk factors and longitudinally-collected scores on the patient health questionnaire (PHQ-9) depression scale using an outpatient sample of individuals with mental illness (PCARES Registry, 2015–2020). Methods: Individuals with ≥2 repeated PHQ-9 assessments over one-year from the baseline PHQ-9 measurement (N = 2110) were included for trajectory modeling, with five depression symptom severity trajectory groups determined a priori (lowest, lower, middle, higher, and highest). Proportional odds models provided the association between baseline CV disease/risk factors and the odds of belonging to the more severe depression symptom trajectory group. In a sub-sample (baseline PHQ-9 score ≥10), linear-mixed effects models provided the association between baseline CV disease/risk factors and longitudinal PHQ-9 scores (N = 1118). Results: 2110 individuals included 65% females, 87% non-Hispanic white, 50% in lower and middle severity groups, with mean ± SD age: 43.0 ± 16.8 years and PHQ-9 score: 10.8 ± 7.0. Adjusting for socio-demographics and BMI [OR (95% CI)]: individuals with baseline hypertension [1.4 (1.2–1.7)], diabetes [1.3 (1.0–1.6)], dyslipidemia [1.2 (1.0–1.4)], tobacco use [2.0 (1.6–2.6)], and higher number of CV disease/risk factors (P-trend<0.0001) had significantly higher odds of more severe depression symptom trajectories; longitudinal PHQ-9 scores significantly decreased during 1-year follow-up, and the decrease was relatively lesser in individuals with hypertension or ≥1 CV disease/risk factors than those without these conditions. Limitations: Clinic-based patient sample limits generalizability of findings. Conclusions: Presence/absence of baseline CV risk factors significantly influenced longitudinal depression symptom severity among psychiatry outpatients, demonstrating the need for depression screening and surveillance among individuals with CV risk factors