The Role of Anxiety in Metabolic Syndrome

Endocannabinoid System Mediation

In biological terms, the association between MS and increased cardiovascular risk seems to be mediated by the endocannabinoid system (ECS). The mechanism functions through binding of endocannabinoids at the cannabinoid receptors (CB1), which regulate appetite and energy homeostasis, emotions such as anxiety and fear, and behaviors such as food and water intake.^[51] CB1 receptors are also found in peripheral tissues such as liver, pancreas, skeletal muscle and adipose tissues, where they play an important role in lipid and glucose metabolism. Metabolic alterations such as dyslipidemia, insulin resistance, lipogenesis, excessive weight gain and increasing intra-abdominal obesity have been associated with overactivation of the ECS.^[51] Recent data suggest that the ECS is overactivated in the presence of abdominal obesity and/or diabetes, which contributes to further disturbances of energy balance and metabolism. In addition to regulating the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, the ECS also intervenes in transport, metabolism and deposition of nutrients in the digestive tract, liver, adipose tissue, skeletal muscle and possibly the pancreas. Thus, activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes.^[18]

Recently, the medical community has shown great interest in the CB1 receptor antagonists, which were expected to advance the treatment of obesity and MS. This class of drugs has been shown to reduce bodyweight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels and to increase HDL-cholesterol and adiponectin concentrations in both nondiabetic and diabetic overweight/obese patients.^[18] However, rimonabant, the first clinically available member of this class of drugs, has been linked to an increased risk of anxiety, depression and suicidality, and was thus withdrawn from the market in 2008.^[52]

In behavioral terms, psychological conditions closely related to chronic stress, such as anxiety and depression, can lead to overeating, co-elevation of cortisol and insulin levels, and suppression of certain anabolic hormones. This state of metabolic stress, in turn, promotes abdominal adiposity. This biochemical environment appears to be conducive to several cell aging mechanisms and to influence a variety of diseases through a biochemical cascade leading to immune cell senescence.^[41]

Table 1. Current evidence on the association of anxiety and depression and metabolic syndrome.
Study (year)	Sample	Outcome	Ref.
Cohen et al. (2010)	1024 stable CAD outpatients	Higher levels of depression were significantly associated with increased prevalence of MS	[16]
Holt et al. (2009)	2997 subjects	Depression increases risk for diabetes	[17]
Engum (2007)	37291 subjects	Diabetes could not be considered a predictor of depression or anxiety. The presence of depression and anxiety represented a significant risk for onset of Type 2 diabetes	[20]
Takeuchi et al. (2009)	1183 men	MS can predict the development of depression	[24]
Hildrum et al. (2009)	9571 subjects	No association of anxiety and depression with MS	[25]
Raikkonen et al. (2002)	425 women	Psychological risk factors, particularly anger, predicted the development of MS	[26]
Dunbar et al. (2008)	1690 subjects	Participants with MS with or without diabetes presented higher scores on depression scales than individuals without MS. No association was found with psychological distress or anxiety	[28]
Petrlova et al. (2004)	116 subjects	In MS patients, depression was approximately four-times more prevalent than in the general population	[29]
Bonnet et al. (2009)	840 hypertensive subjects with MS	In hypertensive subjects with MS, depressive symptoms were independently associated with unhealthy lifestyles	[30]
Skilton et al. (2007)	1598 subjects	MS was related to an increased prevalence of depression but not anxiety	[31]
Toker et al. (2008)	2355 men and 1525 women	Depression among women, but not men, was associated with a twofold increased risk of MS and elevated glucose levels	[32]
Nishnia et al. (2011)	1613 subjects	Depression was associated with MS and glucose abnormality in men	[33]
Vogelzangs et al. (2007)	2917 elderly patients	An association between depressive and MS symptoms was found in white but not in black participants. Anxiety symptoms were significantly associated with MS in men, but not in women	[34]
Herva et al. (2006)	5698 subjects	No clear association of MS with depression or anxiety	[45]
van Reedt Dortland et al. (2010)	1217 anxious and depressive patients	MS was associated with severity of depression and with tricyclic antidepressant use, but not with anxiety	[47]
Carroll et al. (2009)	4256 men	Generalized anxiety disorder, but not major depressive disorder, was associated with MS	[50]

Table 1. Current evidence on the association of anxiety and depression and metabolic syndrome.

Study (year)

Sample

Outcome

Ref.

Cohen et al. (2010)

1024 stable CAD outpatients

Higher levels of depression were significantly associated with increased prevalence of MS

[16]

Holt et al. (2009)

2997 subjects

Depression increases risk for diabetes

[17]

Engum (2007)

37291 subjects

Diabetes could not be considered a predictor of depression or anxiety. The presence of depression and anxiety represented a significant risk for onset of Type 2 diabetes

[20]

Takeuchi et al. (2009)

1183 men

MS can predict the development of depression

[24]

Hildrum et al. (2009)

9571 subjects

No association of anxiety and depression with MS

[25]

Raikkonen et al. (2002)

425 women

Psychological risk factors, particularly anger, predicted the development of MS

[26]

Dunbar et al. (2008)

1690 subjects

Participants with MS with or without diabetes presented higher scores on depression scales than individuals without MS. No association was found with psychological distress or anxiety

[28]

Petrlova et al. (2004)

116 subjects

In MS patients, depression was approximately four-times more prevalent than in the general population

[29]

Bonnet et al. (2009)

840 hypertensive subjects with MS

In hypertensive subjects with MS, depressive symptoms were independently associated with unhealthy lifestyles

[30]

Skilton et al. (2007)

1598 subjects

MS was related to an increased prevalence of depression but not anxiety

[31]

Toker et al. (2008)

2355 men and 1525 women

Depression among women, but not men, was associated with a twofold increased risk of MS and elevated glucose levels

[32]

Nishnia et al. (2011)

1613 subjects

Depression was associated with MS and glucose abnormality in men

[33]

Vogelzangs et al. (2007)

2917 elderly patients

An association between depressive and MS symptoms was found in white but not in black participants. Anxiety symptoms were significantly associated with MS in men, but not in women

[34]

Herva et al. (2006)

5698 subjects

No clear association of MS with depression or anxiety

[45]

van Reedt Dortland et al. (2010)

1217 anxious and depressive patients

MS was associated with severity of depression and with tricyclic antidepressant use, but not with anxiety

[47]

Carroll et al. (2009)

4256 men

Generalized anxiety disorder, but not major depressive disorder, was associated with MS