Most of the data that examined depressive symptoms and lipid profile levels have been from the community studies performed in different countries by the self-related depression scales. Most of these studies were performed by psychiatrists according to specifically clinical criteria in psychiatric inpatients or outpatients or in patients admitted for general health screening.
2.1.1. Depressive Symptoms and Lipid Profile Levels in the Community
Lower cholesterol levels have been found in some patients with depressive symptoms [21, 22], but not in others [23-26]. Troisi et al. also found no significant association in the younger age group (<50 years of age) . In contrast, in a subgroup of older women, serum cholesterol was negatively and significantly correlated to negative mood with the self-rated scales. Restricting analysis to the subjects in the highest quartile of the age distribution (>60 years of age) yielded a much stronger correlation between cholesterol and mood. This result was not, however, compatible with those reported previously . McCallum et al. examined the relationship between low serum cholesterol and depressive symptoms in the elderly and found that low serum cholesterol was not associated with depressive symptoms in older men or women from the cross-sectional data in a community . However, they did point out the significance of financial status, low self esteem, adequacy of practical help and emotional support, and recent widowhood in depression. Hu et al. found that hypocholesterolemia was not an independent risk factor for increased overall mortality in older men and women . The association between low total cholesterol and high mortality is mainly confounded by common cardiovascular risk factors, rather than underlying inflammation or lack of adequate nutrition .
In addition, Nakao et al. have examined the effects of mood states on "persistent" versus "temporary" hypercholesterolemia in students entering a university . They found that depressive mood appeared to relate to hypercholesterolemia when the university students were screened with tension-anxiety, depression, anger-hostility, vigor, fatigue, and confusion scales . In children, after covariance adjustment for age, race, and sex, Glueck et al. pointed out that children having adjustment disorders with depression had much lower covariance-adjusted TC values than control schoolchildren, whereas those with disruptive behavior with oppositional defiant disorder had much higher adjusted TC value .
In addition to total cholesterol, Lindberg et al. tried to explore the relationship between other lipids and depressive symptoms . They found that total cholesterol and LDL cholesterol values were lower in men, but serum triglyceride concentration was not. In women, however, the serum triglyceride value, but not the total cholesterol or LDL cholesterol, was lower in those who reported low mood, depression, or anxiety during the last 6 months . Chen et al. examined the correlation between serum lipid levels and psychological distress . They found that women with an HDL-C level lower than 35 mg/dL scored significantly higher on depression, interpersonal sensitivity, phobia, anxiety, somatization, and aggressive hostility, whereas subjects with a total cholesterol concentration lower than 160 mg/dL scored significantly higher on anxiety, aggressive hostility, phobia, and psychosis . Huang et al. also investigated the correlation between serum lipid, lipoprotein concentrations, and anxious state, depressive state, or major depressive disorder . A total of207 patients admitted for general health screening were recruited in this study during a 1-year period. When the patients were not associated with systemic diseases (n = 162), the researchers found that HDL and the ratio of TC/HDL displayed significant differences among anxious state, depressive state, and normal groups in men after age adjustment. However, the ratios of TC/HDL and LDL/HDL showed significant differences between patients with major depressive disorder and normal controls in women .
2.1.2. Depressive Disorders and Lipid Profile Levels in Psychiatric Inpatients
The relationships between cholesterol, lipids, and depressive symptoms have been investigated but require further study. Lower cholesterol levels have been found in patients with major depression [34-38], but not in others .
Glueck et al. assessed hypocholesterolemia in 203 patients hospitalized with affective disorders (depression, bipolar disorder, and schizoaffective disorder), 1595 self-referred subjects in an urban supermarket screening, and 11,864 subjects in the National Health and Nutrition Examination Survey II (a national probability sample) . Low plasma cholesterol concentration (<160 mg/dL) was much more common in patients with affective disorders than in those found in urban supermarket screening subjects or in the National Health and Nutrition Examination Survey II subjects. When paired with supermarket screening subjects by age and sex, patients with affective disorders had much lower TC, LDL, HDL, and higher TG concentrations. However, there was no evidence that low plasma cholesterol could cause or worsen affective disorders .
Apter et al. investigated the relationship between serum cholesterol levels and suicidal behaviors in adolescent psychiatric inpatients . They found that serum cholesterol levels were significantly higher in adolescent patients who were currently suicidal than in nonsuicidal adolescents. Within the suicidal group, but not in the total inpatient group, serum cholesterol correlated negatively with the degree of suicidal behavior. No correlation between serum cholesterol levels and depression, violence, and impulsivity was detected. No significant differences were found in serum cholesterol levels between diagnoses or between suicidal and nonsuicidal patients within each diagnostic group .
In Taiwan, Huang et al. investigated the correlation between serum lipid, lipoprotein concentrations and major depressive disorder in patients admitted for general health screening . They found that the ratios of TC/HDL and LDL/HDL showed significant differences between patients with major depressive disorder and normal controls in women. Huang and Chen also pointed out that no significant differences were found in lipid concentrations of TC, TG, HDL, VLDL, LDL, TC/HDL, and LDL/HDL between patients with dysthymia and normal controls .
Depressive symptoms are common in patients with physical illness, including cardiovascular disease, diabetes mellitus, end-stage renal disease, and women in pregnancy, delivery, or menopause. The depressive symptoms in patients with physical illness include apathy, anorexia, sleep disorder, fatigue, and cognitive deficits .
18.104.22.168. Depression, Cardiovascular Disease, and Cognitive Impairment. The effect of depression on patients with heart disease has been mentioned and is strongly associated with increased morbidity and mortality [43-45]. Coelho et al. showed that there were significant differences according to gender regarding almost every psychometric dimension assessed . After adjusting for the presence of different biomedical risk factors, significant decreasing mean behavior pattern scores were found with increasing age. Mean depression scores were significantly higher in women and in individuals with lower educational level .
In a previous study, van Doornen and van Blokland pointed out that type A behavior and a vital exhaustion/depression cluster appeared to be the most crucial elements of the psychological "coronary risk profile'' . The authors found that type A behavior was related to a stronger response of adrenaline and diastolic blood pressure to the stressor. Vital exhaustion was also positively correlated with the adrenaline reaction and, moreover, with cholesterol base level, stress-induced cholesterol change, and noradrenaline and cholesterol stress levels . Recently, Rutledge et al. investigated associations between atherosclerosis risk factors (smoking behavior, serum cholesterol, hypertension, body mass index, and functional capacity) and psychological characteristics with suspected linkages to coronary disease (depression, hostility, and anger expression) in an exclusively female cohort . High depression scores were associated with a nearly threefold risk of smoking after covariate adjustment, and women reporting higher depression symptoms were approximately four times more likely to describe themselves in the lowest category of functional capacity. High anger-out scores were associated with a fourfold or greater risk of low HDL concentration (<50 mg/dL) and high LDL concentration (>160mg/dL). In conclusion, these results demonstrate consistent and clinically relevant relationships between psychosocial factors and atherosclerosis risk factors among women and may aid our understanding of the increased mortality risk among women reporting high levels of psychological distress .
Although cholesterol is a major cardiovascular risk factor, its association with stroke remains controversial. In Taiwan, Su investigated the relation between job strain status and cardiovascular risk factors (high serum total cholesterol, low serum HDL cholesterol, and high plasma fibrinogen) . The author found that plasma fibrinogen is a possible intermediate factor linking occupational stress to elevated cardiovascular risk . Engstrom et al. also explored whether the cholesterol-related incidence of stroke and myocardial infarction is modified by plasma markers of inflammation, using a large, population-based cohort with a long follow-up . The researchers found that hypercholesterolemia is associated with high plasma levels of inflammation-sensitive plasma proteins (fibrinogen, arantitrypsin, haptoglobin, ceruloplasmin, and orosomucoid). These proteins increase the cholesterol-related incidence of cardiovascular diseases . In addition, C-reactive protein (CRP) is a prototypic marker of inflammation. Numerous prospective studies in healthy volunteers have confirmed that high-sensitivity CRP predicts cardiovascular events, and high-sensitivity CRP seems additive to an elevated total cholesterol level and a TC/HDL ratio in men and women in predicting risk .
Further, certain dietary risk factors for physical ill health are also risk factors for depression and cognitive impairment. For example, cognitive impairment is associated with atherosclerosis, type 2 diabetes, and hypertension, and findings from a broad range of studies show significant relationships between cognitive function and intakes of various nutrients, including long-chain polyunsaturated fatty acids, antioxidant vitamins, and folate and vitamin B12. Further support is provided by data on nutrient status and cognitive function [52-54].
Alzheimer disease (AD) is characterized by the presence of senile plaques, neurofibrillary tangles, and neuronal cell loss associated with membrane cholesterol release. 24S-hydroxycholesterol (24S-OH-Chol) is an enzy-matically oxidized product of cholesterol mainly synthesized in the brain. Lutjohann et al. found that the concentration of 24S-OH-Chol in AD and non-AD demented patients was significantly higher than in healthy controls and in depressed patients . However, there was not a significant difference in the concentrations of 24S-OH-Chol between depressed patients and healthy controls, or between AD and non-AD demented patients. The researchers speculated that 24S-OH-Chol plasma levels may potentially be used as an early biochemical marker for an altered cholesterol homeostasis in the central nervous system . Even though it is known that apolipoprotein E is deeply involved in major age-related disorders such as atherosclerosis or AD , the control of cell-specific apolipoprotein E expression is still poorly understood. The response of KYN-2 cells to both cytokines and cholesterol differs from that found in astrocytoma cells . Brahimi et al. suggested that blood variation of apolipoprotein E concentrations in AD does not reflect the lack of regulation taking place in the brain . In addition, glial fibrillary acidic protein autoantibody level may be a late marker for neurodegeneration . To date, serum arantichymotrypsin concentration is the most convincing marker for CNS inflammation. Increased serum homocysteine concentrations have also been consistently reported in AD .
Kaysen et al. have shown that serum cholesterol concentration was dependent only on the renal clearance of albumin, and changes in serum cholesterol concentration were dependent only on changes in the renal clearance of albumin. Serum cholesterol concentration was completely independent of the rate of albumin synthesis . Nihei et al. suggested that resveratrol, a polyphenolic compound, is a potent anti-glomerulonephritic food factor capable of suppressing proteinuria, hypoalbuminemia, and hyperlipidemia concurrently . In addition, endothelin 1 (ET-1) is able to determine functional and structural renal alterations in diabetic patients. In a select group of type 2 normotensive diabetic patients with microalbuminuria, Bruno et al. showed that circulating ET-1 values were increased and correlated with albumin excretion rate . These findings confirm that endothelial dysfunction, as expressed by ET-1 levels, occurs early in these patients, and it supports the hypothesis of a potential role for this peptide in development of microalbuminuria in diabetic nephropathy . Using clinical data, Huang and Lee also showed that hemodialysis patients with major depression had lower serum albumin and higher ferritin levels than the hemodialysis patients without major depression .
Mild depressive symptoms ("postpartum blues'') are a common complication of the puerperium and affect 30%-85% of women in the early postpar-tum period. on the basis of these observations, it has been suggested that the sudden fall in cholesterol levels after delivery could serve as a ''natural model'' to test the suggested association between cholesterol and mood . Troisi et al. expanded the database concerning the association between cholesterol levels and mood in the postpartum period . They found significant relationships between serum cholesterol levels and mood symptoms in the postpartum period that were not present during late pregnancy. Lower postpartum levels of total cholesterol were associated with symptoms of anxiety, anger-hostility, and depression, and lower postpartum levels of HDL cholesterol were associated with symptoms of anxiety . The study confirmed that the physiological fall in blood lipids in the postpartum period provided a useful model to test the relationship between serum cholesterol levels and mood .
Nasta et al. also tried to investigate the relationship between cholesterol and mood states in the initial puerperal period. Their results showed that reduced plasma cholesterol concentration was associated with major feelings of fatigue and depressed mood . In addition, West et al. compared the effects of transdermal versus oral estrogens on the vascular resistance index, mean arterial pressure, serum lipid concentrations, norepinephrine, and left ventricular structure in 10 postmenopausal women. The results showed that oral and transdermal estrogen significantly decreased the vascular resistance index, mean arterial pressure, norepinephrine, and total and low-density lipoprotein cholesterol to a similar extent .
2.2. Suicide Attempt, Aggression, or Violence
Because depression is a major factor in most suicides, investigating the association between low serum cholesterol levels and suicide may be important. Some studies have shown an association between low cholesterol and increased risk of death resulting from injuries or suicide [81-85]. Other studies have shown no such association [40, 86-89].
Fawcett et al. proposed four hypothetical pathways leading to suicide in clinical depression: an acute pathway involving severe anxiety/agitation associated with high brain corticotrophin-releasing factor levels, trait baseline and reactivity hopelessness, severe anhedonia, and trait impulsiveness associated with low brain serotonin turnover, with low total cholesterol as a possible peripheral correlate . Future possibilities and the applications of these findings are discussed.
2.2.1. Depression, Cholesterol-Serotonin Theory, and Suicide
Both suicidal behavior and impulsive aggression have been associated with low levels of brain serotonergic activity [91, 92]. Engelberg suggested that a reduction in serum cholesterol may decrease brain-cell-membrane cholesterol, lower lipid microviscosity, and decrease exposure of protein serotonin receptors on the membrane surface, thus resulting in a poorer uptake of serotonin from the blood and less serotonin entry into brain cells . Other reports have discussed the relationships between cholesterol, serotonin, and depression [6, 93-96].
In clinical studies, Steegmans et al. found that middle-aged men with chronically low serum cholesterol levels (<4.5 mmol/L or 172 mg/dL) have a higher risk of having depressive symptoms, according to scores on the Beck Depression Inventory, when compared with a reference group of men with cholesterol levels between 6 and 7 mmol/L . These data may be important in the ongoing debate on the putative association between low cholesterol levels and violent death in the future.
Epidemiological and clinical studies have described an association between lower serum cholesterol concentrations and increased suicide risk that is not entirely attributable to depression-related malnutrition and weight loss. Recent epidemiological studies with greater samples and longer follow-up periods, however, have even shown a positive correlation between cholesterol concentrations and suicide risk after controlling for potential confounding variables [97, 98]. A meta-analysis of earlier intervention trials indicated that cholesterol lowering could cause or worsen depressive symptoms and increase the risk of suicide. However, some large trials of statins (simvastatin, lovastatin, and pravastatin) did not show an increase of suicide mortality [98, 99]. Recently, it was hypothesized that a decreased consumption of polyunsaturated fatty acids, especially omega-3 fatty acids, may be a risk factor for depression and suicide .
2.2.2. Depression, Poor Social Support, and Suicide
Horsten et al. examined the inverse relationship between cholesterol levels and death from violent causes, including suicide, in a group of 300 middle-aged healthy Swedish women . The authors also investigated the association between cholesterol and other psychosocial factors (social support, vital exhaustion, and stressful life events), which are known to be related to depression. The results showed that women with low serum cholesterol, defined as the lowest tenth of the cholesterol distribution (<4.7 mmol/L or 180 mg/dL), reported significantly more depressive symptoms. In addition, low cholesterol was found to be strongly associated with lack of social support . The findings may constitute a possible mechanism for the association found between low cholesterol and increased mortality, particularly suicide.
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