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Depression results in excess Oxidative stress in the body. Clearly reversing depression may alleviate this stress. Oxidative stress results in excess aging and further diseases of aging in humans. This is a good reason to consider Ketamine as a rapid reversal agent for depression.

Serum 4-Hydroxynonenal Linked to Depression in Coronary Artery Disease

For patients with coronary artery disease, 4-hydroxynonenal may be an important marker of depression and may be involved in the progression of the depressive disorder, according to a study published in Psychiatry Research.

Assuming oxidative stress as a possible mechanism underlying depression, researchers in the current study examined the relationship between depression and markers of early lipid peroxidation, measured by lipid hydroperoxides and lipid-polymer hybrid (LPH), and late lipid peroxidation, measured by 4-hydroxynonenal and 8-isoprotane. Serum levels of lipid peroxidation markers were measured in patients with coronary artery disease (N=120) undergoing cardiac rehabilitation at the UHN Toronto Rehabilitation Institute from 2012 to 2015. Investigators used the Structured Clinical Interview for DSM Axis I Disorders- Depression Module (SCID) to diagnose baseline levels of depression, and they calculated the severity of depressive symptoms using the Center for Epidemiological Studies Depression Scale (CES-D).

The researchers used multivariate mixed models to compare the trajectories of serum 4-hydroxynonenal, LPH, and 8-isoprotane between participants with and without depression who were undergoing 6 months of cardiac rehabilitation. Similar models were used to evaluate the associations between CES-D scores and serum 4-hydroxynonenal, LPH, and 8-isoprotane over the 6-month rehabilitation. Participants with depression (n=18) showed significantly higher serum 4-hydroxynonenal concentrations than participants without depression (n=102) at baseline, but no significant between-group difference was seen in serum LPH or 8-isoprotane. Furthermore, participants without depression showed a greater decrease in serum 4-hydroxynonenal than participants with depression. Increases in 4-hydoxynonenal serum concentrations over the course of 6 months were significantly associated with increased depression severity, as measured by decreases in CES-D scores during that same time period.

Study investigators conclude that these findings indicate that 4-hydoxynonenal may play a significant role in depression development and progression and could be an important marker of depression for patients with coronary artery disease. They note that “[f]uture studies should emphasize assessment of the oxidative balance by including markers of exogenous and endogenous antioxidants as well as a greater number of depressed patients.”

Reference

Rosen M, Chan P, Saleem M, et al. Longitudinal associations between 4-hydroxynonenal and depression in coronary artery disease patientsPsychiatry Res. 2018; 270:219-224.

Longitudinal associations between 4-hydroxynonenal and depression in coronary artery disease patients

Depressive symptoms in patients with coronary artery disease (CAD) attenuate the cardiovascular benefits of
cardiac rehabilitation (CR). Given that oxidative stress may be an important mechanism underlying depression,
this study aimed to understand the longitudinal relationship between lipid peroxidation markers and depression
in CAD. Serum levels of early (lipid hydroperoxides, LPH) and late (4‑hydroxy‑2-nonenal, 4-HNE; 8-isoprotane,
8-ISO) lipid peroxidation markers were measured in 120 CAD patients undergoing CR. The Structured Clinical
Interview for DSM Axis I Disorders – Depression Module (SCID) was used to diagnose depression at baseline and
the Center for Epidemiological Studies Depression Scale (CES-D) was used to measure depressive symptom
severity. Multivariate mixed models compared the trajectories of serum LPH, 4-HNE, and 8-ISO between depressed
and non-depressed CAD patients undergoing 6 months of CR. Similar models evaluated the associations
between serum LPH, 4-HNE, and 8-ISO and CES-D score over the course of CR. Serum 4-HNE decreased less in
CAD patients with depression compared to those without. In addition, a decrease in 4-HNE concentrations was
significantly associated with a decrease in CES-D scores over 6 months. These findings suggest that 4-HNE may
be an important marker of depressive symptoms in CAD and may be involved in its progression.

Highlights

Depression is an independent predictor of poorer outcomes in patients with CAD.

Antidepressants are modestly effective; oxidative stress (OS) may be a novel target.

4-HNE, an OS marker, was increased in CAD patients with depression despite exercise.

A decrease in 4-HNE was associated with an improvement in depressive symptoms.

4-HNE may predict depression in CAD; 4-HNE activity may be a future drug target.

This study assessed the relationships between depression and serum markers of lipid peroxidation over a 6-month CR program in participants with CAD. Over 6 months, those who were depressed had a significant increase in serum 4-HNE relative to those who were not depressed. Additionally, a decrease in serum 4-HNE in the overall study group was significantly associated with an improvement in depressive symptoms over the course of CR.

1. Discussion

This study assessed the relationships between depression and serum markers of lipid peroxidation over a 6-month CR program in participants with CAD. Over 6 months, those who were depressed had a significant increase in serum 4-HNE relative to those who were not depressed. Additionally, a decrease in serum 4-HNE in the overall study group was significantly associated with an improvement in depressive symptoms over the course of CR.

At baseline, depressed participants had significantly elevated 4-HNE levels compared to non-depressed participants, suggesting that depression in CAD may be associated with a pro-oxidative state. Longitudinally, there was a significant increase in 4-HNE in depressed CAD patients compared to non-depressed patients despite exercise. Additionally, a decrease in 4-HNE overall was associated with an improvement in depressive symptom severity over the course of 6 months. However, the same trend was not observed with LPH and 8-ISO levels. While previous cross-sectional studies report that levels of LPH and 8-ISO are elevated in depressed populations (Selley, 2004Vargas et al., 2013), the lack of association between LPH and depression may be due to depleted antioxidant defenses. Antioxidants such as glutathione (GSH) have been shown to be reduced in the brain of depressed patients compared to non-depressed controls in a post-mortem study (Gawryluk et al., 2011). GSH depletion may lead to a pro-oxidative state resulting in conversion of LPH to 8-ISO and 4-HNE and accumulation of these late-stage lipid peroxidation products. In addition, 8-ISO levels in the present study population may have been confounded by health and lifestyle factors (Black et al., 2016) and use of statins(Sinzinger and Oguogho, 2003).

Several mechanisms link 4-HNE and depression. First, the high degree of 4-HNE cytotoxicity stems from its ability to react with various biomolecules including DNA, lipids, and proteins. In proteins, 4-HNE can form Michael adducts with amino acids, thus impairing the function of proteins critical to mood regulation (Barrera et al., 2015). For example, in a rat model of bipolar depression, 4-HNE formed adducts with vesicular monoamine transporter 2 (VMAT2), which is responsible for packaging monoamine neurotransmitters, including serotonin into synaptic vesicles (Tan et al., 2012). Given that certain VMAT2haplotypes have been previously associated with depressive symptoms (Christiansen et al., 2007), the connection between 4-HNE and depressive symptoms may involve modulation of serotonin neurotransmission.

Another potential linkage between 4-HNE and depression involves the reduced bioavailability of the vasodilatornitric oxide (NO), which plays an important role in both CAD and depression etiology (Sherwood et al., 2005). In CAD, reduced NO levels result in impaired vasodilation, while its reduced bioavailability is suggested to alter neurotransmission involved in depression (Dhir and Kulkarni, 2011). Specifically, evidence suggests that 4-HNE modulates NO levels through increasing levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase. 4-HNE levels have been shown to positively correlate with levels of ADMA and negatively correlate with NO levels in depression (Selley, 2004). Furthermore, 4-HNE can inhibit the activity of dimethylarginine dimethylaminohydrolase-1, an enzyme responsible for catabolizing ADMA (Forbes et al., 2008).

Lastly, 4-HNE accumulation could elicit depressive symptoms through induction of apoptosis, leading to neuronal cell death (Kruman et al., 1997). Depression is associated with decreased hippocampal volume and exhibits high comorbidity with neurodegenerative diseases (Hurley and Tizabi, 2013). CAD subjects also have 13–15% reductions in hippocampal volume compared to healthy controls (Koschack and Irle, 2005). Long-term exposure to increased oxidative stress in CAD could result in accumulation of 4-HNE, leading to subsequent neurodegeneration and depression.

The biochemical mechanisms described outline an important potential role of 4-HNE in depression etiology, which may be particularly relevant in CAD patients, who likely have oxidative stress. As such, modulation of 4-HNE activity may hold important implications for future antidepressant development. For example, mitochondrial aldehyde dehydrogenase(ALDH2) plays a key role in detoxification of aldehydes produced during oxidative stress. A recent study in a rat model of depression showed that administration of ALDH2 activator 1, 3-benzodioxol-5-ylmethyl-2-6-dichlorobenzamide decreased both depressive-like behaviors and plasma levels of 4-HNE adducts (Stachowicz et al., 2016).

While a decrease in oxidative stress markers has been previously reported during CR programs (Fukuda et al., 2013), the decrease in 4-HNE was not associated with cardiopulmonary fitness in this study. This may be due to several reasons. First, the CR program at UHN Toronto Rehabilitation consisted of both aerobic exercise and resistance training, which is consistently associated with reduced oxidative stress (Cakir-Atabek et al., 2010). However, resistance training could not be assessed as a predictor of change in oxidative stress markers due to the lack of documentation. Healthy dietary changes were also encouraged during the CR program and may have contributed to the decrease in lipid peroxidation markers. For example, high antioxidant diets such as the traditional Mediterranean diet have previously been shown to reduce plasma oxidative stress markers (Fito et al., 2007). Moreover, cardiovascular medications like statins may also have antioxidant properties (Kruman et al., 1997). Thus, differences in medications and dosing may also confound the relationship between cardiopulmonary fitness and oxidative stress in the present study.

Strengths of the present study include adjustment for clinical and demographic confounders, including age, sex, BMI, cardiopulmonary fitness, history of depression and completion of the CR program. The measurement of multiple lipid peroxidation markers allowed for comprehensive profiling of lipid peroxidation that is relevant in CAD. Also, this study assessed the relationship of lipid peroxidation markers with both depression and depressive symptomology, providing an in-depth analysis of the relationship between lipid peroxidation and depression.

This study was limited by the small sample size of depressed patients compared to the non-depressed group. However, the proportion of patients who met criteria for MDD in the present study is representative of the prevalence of depression in CAD patients (Huffman et al., 2013). Another limitation of this study was that it assessed peripheral markers as indicators of brain physiology. However, it has been shown previously that peripheral lipid peroxidation markers correlate with neuropathy in psychiatric disorders (Versace et al., 2014). In addition, we have previously shown associations between peripheral oxidative stress markers and antidepressant response in patients with CAD (Mazereeuw et al., 2017), further validating peripheral markers of lipid peroxidation as predictors of depression outcomes.

In summary, we showed that in a sample of patients with CAD, 4-HNE was increased significantly in those who were depressed compared to those who were not. Additionally, a decrease in 4-HNE was correlated with a decrease in depressive symptoms over a 6-month period of CR. These findings suggest 4-HNE may be an important marker of depressive symptoms in CAD and suggest a specific role of 4-HNE in the development and progression of depression. Despite a lack of association with cardiopulmonary fitness, a decrease in 4-HNE over CR indicates that lifestyle changes and pharmacotherapy could play an important role in modulating oxidative stress. Future studies should emphasize assessment of the oxidative balance by including markers of exogenous and endogenous antioxidants as well as a greater number of depressed patients.

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