An editorial comment to Assies J et al. ‘Effects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular disease comorbidity’ ()
Oxidative stress: a link between cardiovascular disease and psychiatric illness?
Article first published online: 24 MAR 2014
© Published 2014. This article is a U.S. Government work and is in the public domain in the USA.
Acta Psychiatrica Scandinavica
How to Cite
McCarthy, M. J. (2014), Oxidative stress: a link between cardiovascular disease and psychiatric illness?. Acta Psychiatrica Scandinavica. doi: 10.1111/acps.12269
- Article first published online: 24 MAR 2014
In 1921, Ernst Kretschmer noted that patients with affective illness were prone to obese (pyknic) body types. While controversial over time, the notion that diet and metabolism intersect with mental illness has witnessed a resurgence of late with the recognition that patients with schizophrenia, bipolar disorder and major depression, have high rates of obesity, glucose intolerance and cardiovascular disease (CVD) that lead to premature mortality [1, 2]. Reasons for this elevated disease burden are not clear, but sedentary lifestyle, diet, smoking, and antipsychotic medications have been discussed as important factors. In the present issue of the journal, Johanna Assies, Roel Mocking and colleagues review the literature surrounding metabolism and mental health from the perspective of oxidative stress, and consider how shared biochemical alterations in fatty acid and one carbon metabolism may be predisposing factors to both CVD and psychiatric illness . From their review of the literature, they conclude that CVD (defined broadly as metabolic and cardiac disease) and psychiatric illness are causally related, with each problem stemming directly from the body's inability to manage oxidative stress.
Lipid abnormalities including hypertriglyceridemia, high levels of saturated fats, and low levels of polyunsaturated fats have been recognized as risk factors for CVD for years. As the authors discuss, the same profile is now increasingly recognized in multiple psychiatric conditions. In a similar manner, signs of oxidative stress including depleted antioxidant defenses (glutathione and superoxide dismutase), and higher levels of peroxidized lipid products are increasingly recognized in both CVD and psychiatric illness. While there are gaps in the literature, and small sample size remains the norm in the psychiatric studies compared to CVD and metabolic studies, the preponderance of evidence suggests these phenomena are robust and reproducible.
Lipid metabolism and the one-carbon cycle share common biochemistry in that folate, an essential co-factor involved in methyl group transfer, is also an anti-oxidant. Accordingly, oxidative stress depletes folate in cells. This depletion has two important consequences. First, it shunts homocysteine away from S-adenosyl methionine, and towards the production of the antioxidant, glutathione. Second, by limiting activity in methylation dependent pathways, the ability of cells to elongate short chain fatty acids into longer chain fatty acids is reduced. In the short term, these changes may promote cell survival by bolstering anti-oxidant defenses.
By framing the co-morbidity of CVD and psychiatric illness in biochemical terms, the authors have taken an important step in developing a plausible and testable model to explain how oxidative stress may impact simultaneously upon cardiac, metabolic and mental health. Moreover, by presenting the biochemical changes as protective responses to cellular damage, and not necessarily deficiencies, they propose an interesting framework for understanding why fatty acid or folate supplementation may not work in the clinic: they treat secondary symptoms, not the cause.
Predictably, this provocative issue remains unsettled. Most the studies reviewed show a correlation between CVD and psychiatric risk factors, but fall short of establishing a causal link. To prove the case, a number of areas need further exploration.
First, what is the source of the oxidative stress? The authors take the view that sedentary lifestyle and high calorie diets are the primary drivers. However, not all psychiatric patients are metabolically compromised, and historical reports suggest psychiatric illness has always been relatively common, even while obesity and diabetes were relatively rare. One alternative explanation is that psychiatric patients have defects in mitochondrial genes that may predispose them to oxidative damage [4, 5].
Second, oxidative stress is associated with many chronic diseases, and there is nothing specific about its association with psychiatric illness. So how does a process that is so pervasive lead to specific illnesses? In other words, why does one patient have major depression and diabetes, while another has schizophrenia and coronary artery disease? This issue is especially pressing at a time when genetic studies indicate that heterogeneity, even within same diagnostic category is the norm, implying a possible need for refinement, not consolidation of diagnoses.
Finally, to what extent are variables that are consequences of psychiatric illness (e.g. inactive lifestyle, smoking, and medications) the causal factors in CVD? The conventional wisdom holds that behavior affects CVD risk, not the other way around. As brain illnesses, the burden of proof remains on its proponents to incorporate oxidation, inflammation, immunity and other novel hypotheses into existing, mechanistically validated neurochemical models.
Animal and prospective clinical studies will go some way towards resolving these issues. In the interim, it seems advisable to take seriously the problems of obesity, physical inactivity and smoking, particularly in the young. As the authors reasonably speculate, interventions that curb metabolic dysfunction at early stages may avoid permanent damage to the brain, heart and endocrine organs, that takes hold to cause its well-established ill effects, and perhaps previously unrecognized psychiatric co-morbidity.
- 2Metabolic syndrome and metabolic abnormalities in patients with major depressive disorder: a meta-analysis of prevalences and moderating variables. Psychol Med 2013;21:1–12., , et al.