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Low Serum Cholesterol Levels, Depression, and Violence in Adolescents: a pilot study in rural Minnesota
William Sheehan, M.D., Rice Memorial Hospital, 301 Becker Avenue SW, Willmar, Minnesota, USA, 56201
Steven Thurber, Ph.D., ABPP, Woodland Centers, 1125 SE Sixth Street, Willmar, Minnesota, USA, 56201
The present study is an attempt to investigate the relation between mood disorders, aggression, and suicide and low serum cholesterol levels in adolescent patients. A number of studies have already documented such a relation in adults. There are, however, few studies looking at this problem in younger people – a serious omission given that young males constitute the group at highest risk for aggression and violence, and youth suicide is the second leading cause of death among this population. There are even fewer studies looking at these variables in a rural population. The present study confirms that low cholesterol levels are associated with increased risk for mixed disorders of mood and conduct and associated with increased placement in residential treatment programs.
A number of investigations have shown that naturally occurring low cholesterol concentrations (<160 mg/dl) are associated with excess mortality. When first reported, this was an unexpected result of large epidemiologic studies examining risk factors for cardiovascular disease and cancer which showed this mortality to be related to suicides and accidental deaths (Jacobs, e. al., 1992, Muldoon, et. al., 1992, Neaton, et. al., 1992). Consistent with other studies of this kind, deaths from suicide, in particular, were found to rise with lower cholesterol concentrations (Muldoon, et. al., 1993). For instance, in one of the most methodologically impressive studies, involving a Swedish cohort of 27,000 men during seven years of follow-up, the risk of suicide was four times higher among men in the lowest quartile of total cholesterol as compared with those in the highest quartile (Lindberg, et. al., 1992), while a recent Canadian study showed a six-fold increase in suicide risk (Ellison and Morrison, 2001).
Most, though not all (Iribarren, et. al., 1995), epidemiologic studies have found an association between death due to suicide. Despite remaining controversial, it has become one of the most robust associations in medical epidemiology. In addition to epidemiologic studies, a number of primary prevention trials have cooroborated the association between lowered plasma cholesterol and violent death (especially suicide), and there have been many studies in both humans and primates demonstrating that physical aggression and impulsivity are negatively correlated with the lowest serum cholesterol levels (Freedman, et. al., 1995; Hillbrand, et. al., 1995). At least for adult males (women and younger subjects have been insufficiently studied), the relation between cholesterol and violence has been shown, in a recent meta-analysis of several studies, to meet criteria for causal association (Golomb B, 1998). The largest cohort studies, with 350,000 (Neaton, et. al., 1992) and 55,000 subjects (Lindberg, et. al., 1992) have found significantly more violent deaths in men with low cholesterol. Most impressively, impressively a prospective study involving a cohort of nearly 80,000 Swedish adults in 1962-1965 showed that men with below-average cholesterol levels had an increased likelihood of committing violent crime, with violent offenders being more likely than non-offenders to have had below-median cholesterol levels at baseline (Golomb, et. al., 2000).
Several mechanisms have been proposed to account for the relation of serum cholesterol level and proclivities to aggression, violence, or suicide. Cholesterol may be a marker for central serotonergic activity, which is low in violent offenders and suicide completers (Roy, et. al., 1989; Virkkunen, et. al., 1989). A possible evolutionary explanation for this relationship, based in part on primate studies, has been proposed (Kaplan, et. al., 1997). Cholesterol may directly modulate serotonin receptor function, as has been demonstrated with other G protein-coupled receptors (Gimpl, et. al., 1997). Because cholesterol is an important component of cell membranes, it may also influence cell membrane fluidity with indirect effects on neurotransmitters or their membrane-bound receptors – and serotonin in particular, whose binding can be increased or decreased in vitro by the addition or removal of cholesterol from brain synaptic membranes (Heron, et. al., 1980). Yet another possibility is that dietary changes related to cholesterol intake – i.e., reduced fatty acid intake -- could decrease brain serotonergic activity by reducing the amount of tryptophan available to the brain, tryptophan being the chemical precursor of serotonin. Cholesterol is the precursor of the steroid hormones, so the relationship of serum cholesterol to the activity of these hormones or their receptors may be modulated through complex feedbacks at various levels of the neuroendocrine system.
Despite the robustness of these findings, the existence of plausible explanations as to the basis for this association, and the ready availability and considerable public awareness of the importance of high serum cholesterol levels, rather surprisingly, the possible implications of low cholesterol levels have attracted relatively little attention among medical practitioners in the United States. The authors have found that most of their medical colleagues are completely unaware of this literature and are actually quite shocked that a laboratory value like cholesterol level can possibly have any behavioral implications. This neglect is also surprising given that youth violence and suicide have been major problems identified by policy experts for attention (e.g., the widely discussed and generally helpful Surgeon General’s Report on Youth Violence, 2003, fails to mention it at all). The authors have found that coordinators of NIMH and NIH research programs were uniformly unaware of these associations and some of them found them implausible (personal correspondence with NIH and NIMH project coordinators). Undoubtedly the preoccupation of public health and medical officials with heart disease has resulted in an overly narrow focus on cholesterol lowering to the exclusion of consideration of morbidity and mortality at the other end of the spectrum, though there also seems to be an inherent difficulty in conceptualizing complex behaviors – and presumably “choices” – being made in response to variations in a laboratory value. Though the association between elevated plasma low-density lipoprotein cholesterol (LDL-C) and atherogenesis is well-known and now widely accepted, leading to a population-wide preoccupation with lowering cholesterol by means of diet or medication or both, the idea that there might be adverse behavioral consequences to excessively low cholesterol has not so far captured the imagination of public health authorities, medical practioners, pharmaceutical companies, or the general public. Moreover, because elevated cholesterol levels even for young people have been associated with early changes related to atherogenesis (fatty streaks) and there has been a widely publicized obesity epidemic among youth, recommendations for cholesterol lowering have now been extended to young people.
There are at least tentative indications that even medication response for patients with depression may be partly mediated through changes in cholesterol level. Individuals with elevated cholesterol levels seem to be less responsive to SSRI treatment, presumably because the increase in cholesterol level, however mediated, is proportionately less; while low serum cholesterol appears to be associated with low mood and thus to predict its serious consequences (Partonen, et. al., 1999). It is possible that response of depressive symptoms to medications may be predicted by elevations in cholesterol level, and a number of medications known to have antidepressant effects also elevate cholesterol levels. If so, it may be especially important to evaluate whether this connection also exists in children and adolescents, where controversy has existed as to the appropriateness of using SSRI medications for depression because of possible increases in suicidal ideation. Unfortunately, the literature on behavioral implications of low cholesterol levels in children and adolescents is virtually non-existent.
Total serum cholesterol levels were obtained on 21 adolescents (16 boys; 5 girls; mean age = 14.3) in an outpatient community mental health setting. The cholesterol levels were obtained through coordination with their primary care physicians. In addition, seven total serum cholesterol levels were obtained for a normal age-matched samples (5 boys; 2 girls) at a public health fair.
Subsequently, psychiatric records for all patients were obtained and assessed by a reviewer blinded to the laboratory results. All of the psychiatric diagnoses were made using DSM-IV criteria by the same child psychiatrist, but because of the small sample size and concerns about validity and comorbidity of commonly encountered DSM diagnoses (ADHD, ODD or CD, depressive or anxiety disorder or bipolar disorder), the participants of the study were aggregated into the following three groups for purposes of this investigation:
1) Disruptive or externalizing disorders (ADHD, ODD, or CD), without evidence of a comorbid mood disorder.
2) Mood or anxiety disorder primary; no significant symptoms of comorbid conduct disorder
3) Mixed disorders of mood and conduct.
The third group included all individuals in the study who were in out-of-home placements (n = 4; either hospital, shelter, group home, or correctional facility). Typically, these patients had been described by psychiatrists as “bipolar” or “rule out bipolar.” The patients included in the study were in these settings because of aggressive or assaultive behaviors.
The mean total serum cholesterol level was 147.8 (S.D. 38.5). The values ranged from a low of 87 to a high of 228. The mean total serum cholesterol of the male participants was 145.8 (S.D. 39.3). For females, the mean total serum cholesterol was 154.4 (S.D. 39.3).
For controls (n=7) were juniors and seniors in high school, 5 males and 2 females, with a mean total serum cholesterol level of 161. The values ranged from 132 to 200.
The results by diagnostic category were significant, F(2,18)=5.85, p<.02, as follows:
Disruptive disorders (n = 7). Mean total serum cholesterol = 174.3 (S.D. 34.6)
Mood or anxiety disorders (n=8). Mean total serum cholesterol = 149.8 (S.D. 35.7)
Mixed disorder of mood and conduct (n=6). Mean total serum cholesterol = 114.2 (S.D. 19.3)
The results by placement vs. non-placement were highly significant, F(1,19)=8.66, p<0.08 (placement, mean total serum cholesterol = 104.5, S.D. = 15.3; non-placement, mean total serum cholesterol = 158.0, S.D. = 35.3).
When presented in histogram form, the results were suggestive of a bimodal distribution. There was a long tail which seemed to reflect a normal Gaussian distribution of total serum cholesterol across the general population. The other – lower-cholesterol – distribution represented a skewed distribution consisting of patients with mood disorders and with comorbid mood and conduct disorders.
The strongest association, which was highly significant, was of low total serum cholesterol and patients being in residential placement. For patients with depression or anxiety disorders but without comorbid conduct disorders, there was a weak positive correlation; for patients with disruptive disorders, a weak negative correlation. This suggests that for adolescents results may prove to be similar to those found in incarcerated or aggressive and violent adults.
Within the limitations of the small sample size, the results appear to be consistent with a continuum model of mental disorders and with the cholesterol-serotonin hypothesis. It appears that low total serum cholesterol levels might be potentially useful in predicting risk for aggression or suicide in adolescents. This study is also consistent with a recently published study, based on a large epidemiologic survey by the Center for Disease Control, showing a three-fold increase of risk of school suspension and expulsion among Caucasian youth with cholesterols in the lowest quartile. They failed to identify such a risk in African-American students. (Zhang J, et. al., 2005).
A number of other study questions are also suggested for further investigation. We propose to do a larger study of incarcerated youngsters or to look at total serum cholesterol levels. Moreover, it would be important to know whether those involved in the most serious aggressive acts – such as school shootings – have significantly low total serum cholesterol levels, which would be consistent with the hypothesis based on the results of our pilot study. It would be appropriate to investigate whether similar relationships held for non-whites (e.g, Latino or African-American individuals), and if not, why not. (All the patients in the current study were Caucasians.) Are there rural/urban differences?
As neurotransmitter systems are still developing during childhood and adolescence, it would be useful to look at different ages of children and youth – presumably in terms of their developmental stage (e.g., Tanner scores) – to determine at what point total serum cholesterol levels begin to show a statistically significant correlation with aggression and violence. Would this information help to predict responsiveness to medications that would alter serotonergic activity, such as SSRIs, where currently there are serious questions about predicting response and reports of increased agitation or suicidal ideation are a matter of concern?
Apart from medications, what other approaches would have potential use in mitigating risk of aggression or violence in younger patients? Would tryptophan or 5-HTP be more helpful than SSRIs? Would omega-3 supplements be useful, as might be expected given that one effect of cholesterol is to increase fluidity of the cell membrane, and yet another is to alter the function of the serotonin receptor? Would the degree of response to treatment be predictable based on the relative change in the cholesterol level? Do circannual variations in total serum cholesterol levels occur in children and adolescents as have been documented in adults? Might parasuicidal behaviors, such as cutting or self-injurious behaviors, which are more common in girls, correlate with low total serum cholesterol levels?
What about special populations – like autistic-spectrum disorders or Asperger’s disorder – with high brain serotonergic activity, rather than low activity? What are total serum cholesterol levels of these patients and how do they compare with those of the population as a whole? What about developmentally disabled youngsters? Do self-injurious behaviors or “intermittent explosive disorders” correlate with cholesterol levels?
Would greater predictive reliability for aggression, violence, and suicide be obtained by combining cholesterol screening data together with psychological instruments (and if so, which ones?) or other established indirect measures of central serotonergic activity, such as fenfluramine stimulation challenges evaluating prolactin or cortisol response?
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