‘Excessive, Premature’ CVD Mortality in Bipolar Disorder Explained?

An early predictor of cardiovascular disease (CVD) has been found in youth with bipolar disorder (BD), in new findings that may explain the “excessive and premature mortality” related to heart disease in this patient population.

Investigators found that higher reactive hyperemia index (RHI) scores, a measure of endothelial function, were tied to mood severity in patients with higher mania, but not depression scores. These findings persisted even after accounting for medications, obesity, and other cardiovascular risk factors (CVRFs).

“From a clinical perspective, these findings highlight the potential value of integrating vascular health in the assessment and management of youth with BD, and from a scientific perspective, these findings call for additional research focused on shared biological mechanisms linking vascular health and mood symptoms of BD,” senior investigator Benjamin Goldstein MD, PhD, full professor of psychiatry, pharmacology, and psychological clinical science, University of Toronto, Canada, told Medscape Medical News.

The study was published online May 1 in the Journal of Clinical Psychiatry.

“Excessively Present”

BD is associated with “excessive and premature cardiovascular mortality” and CVD is “excessively present” in BD, exceeding what can be explained by traditional cardiovascular risk factors, psychiatric medications, and substance use, the researchers note.

“In adults, more severe mood symptoms increase the risk of future CVD. Our focus on endothelial function rose due to the fact that CVD is rare in youth, whereas endothelial dysfunction — considered a precursor of CVD — can be assessed in youth,” said Goldstein, who holds the RBC Investments Chair in children’s mental health and developmental psychopathology at the Centre for Addiction and Mental Health, where he is director of the Centre for Youth Bipolar Disorder.

For this reason, he and his colleagues were “interested in researching whether endothelial dysfunction is associated with mood symptoms in youth with BD.” Ultimately, the motivation was to “inspire new therapeutic opportunities that may improve both cardiovascular and mental health simultaneously.”

To investigate the question, the researchers studied 209 youth, ranging in age from 13 to 20 years (n = 114 with BD and 94 healthy controls [HCs]).

In the BD group, there were 34 BD-euthymia, 36 BD-depressed, and 44 BD-hypomanic/mixed; and within the groups who had depression or hypomania/mixed features, 72 were experiencing clinically significant depression. 

Participants had to be free of chronic inflammatory illness, use of medications that might be addressing traditional CVRFs, recent infectious diseases, or neurologic conditions.

Participants’ bipolar symptoms, psychosocial functioning, and family history were assessed. In addition, they were asked about treatment, physical and/or sexual abuse, smoking status, and socioeconomic status. Height, weight, waist circumference, blood pressure, and blood tests to assess CVRFs, including C-reactive protein (CRP) were also assessed. RHI was measured via pulse amplitude tonometry, with lower values indicating poorer endothelial function.

Positive Affect Beneficial?

Compared with HCs, there were fewer White participants in the BD group (78% vs 55%; P < .001). The BD group also had higher Tanner stage development scores (stage 5: 65% vs 35%; P = .03; V = 0.21), higher body mass index (BMI; 24.4 ± 4.6 vs 22.0 ± 4.2; P < .001; d = 0.53), and higher CRP (1.94 ± 3.99 vs 0.76 ± 0.86; P = .009; d = –0.40).

After controlling for age, sex, and BMI (F 3,202 = 4.47; P = .005; ηp 2  = .06), the researchers found significant between-group differences in RHI.

Post hoc pairwise comparisons showed RHI to be significantly lower in the BD-depressed vs the HC group (P = .04; d = .4). Moreover, the BD-hypomanic/mixed group had significantly higher RHI compared with the other BD groups and the HC group.

BD-euthymic  =  .02; d = .55
BD-depressed  <  .001; d = .79
HC P  =  .04; d = 0.55

RHI was associated with higher mania scores (β = .26; P = .006), but there was no similar significant association with depression mood scores (β = .01; P = .90).

The mood state differences in RHI and the RHI-mania association remained significant in sensitivity analyses examining the effect of current medication use as well as CVRFs, including lipids, CRP, and blood pressure on RHI.

“We found that youth with BD experiencing a depressive episode had lower endothelial function, whereas youth with BD experiencing a hypomanic/mixed episode had higher endothelial function, as compared to heathy youth,” Goldstein said.

There are several mechanisms potentially underlying the association between endothelial function and hypomania, the investigators note. For example, they report, positive affect is associated with increased endothelial function in normative samples, so hypomanic symptoms, including elation, may have similar beneficial associations, although those benefits likely do not extend to mania, which has been associated with cardiovascular risk.

They also point to several limitations in the study. The cross-sectional design “precludes making inferences regarding the temporal relationship between RHI and mood.” Moreover, the study focused only on hypomania, so “we cannot draw conclusions about mania.” In addition, the HC group had a “significantly higher proportion” of White participants, and a lower Tanner stage, so it “may not be a representative control sample.”

Nevertheless, the researchers conclude that the study “adds to the existing evidence for the potential value of integrating cardiovascular-related therapeutic approaches in BD,” noting that further research is needed to elucidate the mechanisms of the association.

Observable Changes in Youth

Commenting for Medscape Medical News, Jess G Fiedorowicz, MD, PhD, head and chief, department of mental health, Ottawa Hospital Research Institute, Canada, noted that individuals with BD “have a much higher risk of CVD, which tends to develop earlier and shortens life-expectancy by more than a decade.” 

This cardiovascular risk “appears to be acquired over the long-term course of illness and proportionate to the persistence and severity of mood symptoms, which implies that mood syndromes, such as depression and mania, themselves may induce changes in the body relevant to CVD,” said Fiedorowicz, who is also a professor in the department of psychiatry, School of Epidemiology and Public Health, and Senior Research Chair in Adult Psychiatry, Brain and Mind Research Institute, University of Ottawa, Canada, and was not involved with the study.

The study “adds to a growing body of evidence that mood syndromes may enact physiological changes that may be relevant to risk of CVD. One important aspect of this study is that this can even be observed in young sample,” he said.

J Clin Psychiatry. Published online May 1, 2023. Full text

This study was funded by the Canadian Institutes of Health Research and a Miner’s Lamp Innovation Fund from the University of Toronto. Goldstein and coauthors declare no relevant financial relationships. Fiedorowicz receives an honorarium from Elsevier for his work as editor-in-chief of the Journal of Psychosomatic Research.

Batya Swift Yasgur MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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