Submited on: 20 Oct 2011 02:17:30 PM GMT
Published on: 21 Oct 2011 03:41:05 PM GMT
 

1 Is the subject of the article within the scope of the subject category? Yes
2 Are the interpretations / conclusions sound and justified by the data? Partly
3 Is this a new and original contribution? Yes
4 Does this paper exemplify an awareness of other research on the topic? Yes
5 Are structure and length satisfactory? Yes
6 Can you suggest brief additions or amendments or an introductory statement that will increase the value of this paper for an international audience? Yes
7 Can you suggest any reductions in the paper, or deletions of parts? Yes
8 Is the quality of the diction satisfactory? Yes
9 Are the illustrations and tables necessary and acceptable? Yes
10 Are the references adequate and are they all necessary? Yes
11 Are the keywords and abstract or summary informative? Yes
  • Other Comments:

    The article by Sheehan and colleagues in WebMed Central, “Aberrant Cholesterol and Lipoprotein Levels in
    Aggressive Male Adolescents” extends the association of low cholesterol to violence, providing an important addition to the literature linking low cholesterol to aggression and behavior dyscontrol. I would offer several clarifications.

    There is additional prior evidence of a connection of low cholesterol to aggression that extends to youngsters: Sheehan and colleagues suggest correctly that the literature regarding low cholesterol to aggression in youngsters is sparse. But they did miss an important study, which was noted in our prior review of the low cholesterol-violence literature1: the 1984 finding by Virkkunen linking aggressive conduct disorder in children to low cholesterol2.

    It cannot be presumed that blood cholesterol is serving as a marker for brain cholesterol, and it is not true that prior studies rest on this presumption. The authors state “In all these studies, blood cholesterol levels are used as a surrogate for brain cholesterol levels.” (One of our own studies was included.3) This is not the case. In my early review of the low cholesterol-violence relationship (the first published review to assemble the evidence for this connection), I did elucidate a range of mechanisms by which brain cholesterol might have relevance to behavior (many of which mechanisms Sheehan and colleagues reprise), including delineating evidence for the serotonin hypothesis1. However we have also emphasized that peripheral phenomena can have central consequences, and no supposition is possible that relations of blood cholesterol to such outcomes are mediated by brain cholesterol.

    For instance, we not only hypothesized a potential mechanism that does not rely on a relation to central cholesterol, we experimentally tested it and found evidence to support our hypothesis. The mechanism I hypothesized involves the known competition by free fatty acids with tryptophan for binding to serum albumin4. It is only the free tryptophan that can readily cross the blood brain barrier, where it is the substrate for the rate limiting reaction in serotonin production. This would predict that conditions linked to higher free fatty acids – such as insulin resistance/metabolic syndrome factors – would lead to more central serotonin and lower propensity to violence, while the reverse of these would be associated with elevated behavioral risk. This hypothesis was experimentally tested, using the available metrics of nonillness morbidity/mortality, partnering with Helsinki Heart Study (HHS) researchers and using HHS screenee data merged with hospital data in Finland- and showing that more insulin sensitivity markers (inverse metabolic syndrome markers) were linked to increased behavioral risk4. Subsequently another group replicated the body mass index portion of this association, vis a vis suicide5, 6. In the HHS screenee study, the metrics available were hospitalizations for accidents, suicide attempts, and completed suicides (with successively stronger associations observed). Lest to a reader new to this literature these might seem unrelated to aggression, in fact, death by accident, suicide, and homicide (termed “nonillness mortality”7) track together and share many antecedents and risk factors (and indeed in many cases cannot be confidently disentangled), and this metric that has been repeatedly linked to low cholesterol1. Accidents and self-harm events were the diagnoses available for collation in Finland, among those relevant to nonillness morbidity and mortality.

    The testosterone relationship should be clarified to be in opposition to the relationship observed: Sheehan and colleagues state “Undoubtedly, steroids with neuromodulatory effects also play a role (and cholesterol, of course, is the precursor for steroid hormone synthesis). Most pertinent here are the effects of the sex steroid testosterone, which was long believed to be the main determinant of male (and female) aggression. Though more recent research has given priority to the importance of low central serotonergic activity in aggression, some research has indicated that testosterone may facilitate aggression in subjects with low 5H1AA titers (53).” However, to the degree lowering cholesterol relates positively to testosterone as its biochemical precursor, it should be clarified that the relationship suggested is opposite to that which they seek to explain. We secured direct data relating LDL change to testosterone change with statins, and testosterone to aggression, in our randomized trial of 1000 people: an abstract is available addressing a subset of results8. The primary bear in an interesting way on this issue but are still in the submission stage.

    Further mechanisms: We have elucidated additional mechanisms, again not hinging on blood cholesterol serving as a surrogate for brain cholesterol, that may be involved in behavioral effects9.

    Evidence related to lipid lowering medications might bear mention: Testosterone findings aside, Muldoon and colleagues, in meta-analysis of randomized trials in the prestatin era, found lipid reduction, relative to placebo, across a range of treatment types, was linked to nonillness mortality – particularly in men and for primary prevention10, 11.
    In men who are not elderly, our RCT findings suggest statins do not increase aggression, with the typical direction of effect the opposite with this drug class – supporting findings from meta-analyses of statin trials, again by Muldoon and colleagues, that focus particularly on middle aged men7. However our RCT data8, as well as Muldoon’s observational data,12 do suggest a “usual” association of statin use to increased aggression in women. Moreover, we have published a case reports13 and case series14 in which statin drugs have been reproducibly linked to increased aggression in select individuals, many of whom have been nonelderly men; and psychiatric adverse effects including aggression were prominent in a Norwegian adverse event database15. Clearly there are nuances: cholesterol alone cannot wholly explain this set of results, and there is need to better understand associations in both directions.

    The authors urge use of cholesterol as a screening test for aggression risk, but might want to moderate this recommendation. “Certainly, an awareness of a pediatric patient’s cholesterol level offers an important piece of data with the potential to inform predictions about a patient’s risk of self-injurious behaviors” – perhaps, but there are limited data on how well this adds to prediction, beyond past behavior;. On balance I agree that increased attention, and research, is merited for this marker. I concur, additionally, that lipids should be measured in youths as well as adults who have exhibited aggression – both because of the likely use of medications which may increase lipids, and because such assessment may hlep further knowledge about the association to violence. But I would urge clarity that testing cannot presently be advocated as a biochemical screening test for aggression. For a screening test to be useful two criteria should be satisfied:1) It should effectively segregate a group at risk (which should be accompanied by evidence of sensitivity, specificity, and positive and negative predictive value). 2) There must be an action or intervention one can take based on that test that is known to lead to more expected benefit than harm to the person. (Indeed, the USPSTF has just recommended (Oct 2011) against prostate specific antigen screening because the latter desideratum is not fulfilled.(http://www.uspreventiveservicestaskforce.org/uspstf12/prostate/prostateart.htm).) At present, more information is needed on the predictive merit of cholesterol; and it has not been shown that intervening based on the cholesterol level adds value.

    In short, I applaud this important addition to the literature. My recommendations are to add reference to the Virkkunen finding in youth (and perhaps to our review); to adjust the assumption that blood cholesterol served a surrogate for brain cholesterol (and to add reference to other mechanisms); to clarify that the testosterone association would not fall in a direction to assist as an explanation; and to perhaps modify the emphasis in the text on cholesterol as a screening test.

  • Competing interests:
    None
  • Invited by the author to review this article? :
    Yes
  • Have you previously published on this or a similar topic?:
    Yes
  • References:
    1.Golomb BA. Cholesterol and violence: Is there a connection? Annals of Internal Medicine 1998;128:478-87. 2.Golomb BA, Stattin H, Mednick S. Low cholesterol and violent crime. J Psychiatr Res 2000;34:301-9. 3.Golomb BA, Tenkanen L, Alikoski T, et al. Insulin sensitivity markers: predictors of accidents and suicides in Helsinki Heart Study screenees. J Clin Epidemiol 2002;55:767-73. 4.Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008;8:373-418. 5.Golomb BA, Kane T, Dimsdale JE. Severe irritability associated with statin cholesterol-lowering drugs. Qjm 2004;97:229-35. 6.Reilly D, CHam S, Golomb BA. First Degree Relatives with Behavioural Adverse Effects on Statins. BMJ Case Reports 2011. 7.Golomb B. Cholesterol and violence: Is there a connection? [letter]. Annals of Internal Medicine 1998;128:669-70. 8.Golomb BA. Cholesterol and violence. In: Gottesman R, Mazon M, eds. Encyclopedia of Violence in the United States. New York: Charles Scribner's Sons; 2000. 9.Golomb BA, Criqui MH, White H, Dimsdale JE. Conceptual foundations of the UCSD Statin Study: a randomized controlled trial assessing the impact of statins on cognition, behavior, and biochemistry. Arch Intern Med 2004;164:153-62. 10.Golomb BA, Criqui MH, White HL, Dimsdale JE. The UCSD Statin Study: a randomized controlled trial assessing the impact of statins on selected noncardiac outcomes. Control Clin Trials 2004;25:178-202. 11.Golomb BA, Dimsdale JE, Evans MA, Denenberg JO, White HL, Criqui MH. Effects of Statins on Aggression Differ by Gender: Results of a Double Blind Placebo Controlled Trial. Circulation supplement 2008;117:e268-9. 12.Golomb BA, Mednick SA, Tenkanen L. Suicide: a weighty matter? Arch Intern Med 2007;167:1908; author reply. 13.Golomb B. Low serum cholesterol and serotonin metabolism: Other studies have been done in humans and monkeys. BMJ 1996;312:1299. 14.Golomb BA, Kane T, Dimsdale JE. Severe irritability associated with statin cholesterol-lowering drugs. Qjm 2004;97:229-35. 15.Buajordet I, Madsen S, Olsen H. [Statins--the pattern of adverse effects with empahsis on mental reactions. Data from a national and an international database]. Tidsskr Nor Laegeforen 1997;117:3210-3.
  • Experience and credentials in the specific area of science:

    I performed the first comprehensive synthesis of this literature (Annals of Internal Medicine 1998); undertook a largescale analysis of merged longitudinal databases in Sweden; partnered with Helsinki Heart Study researchers to test a hypothesis regarding mechanism (which the evidence supported); conducted an NIH funded randomized trial to examine the influence of statin drugs on aggression (including testosterone assessment; findings submitted); conducted a patient targeted adverse event surveillance study as a Robert Wood Johnson Generalist Physician Faculty Scholar that has led to publications on this issue; and have elaborated other mechanisms by which an association of low cholesterol to aggression might be mediated.

  • How to cite:  Golomb B .Low cholesterol and Violence – Further Findings, and Evidence Serum Cholesterol Needn't be a Surrogate for Brain Cholesterol[Review of the article 'Aberrant Cholesterol and Lipoprotein Levels in Aggressive Male Adolescents ' by Du Souich C].WebmedCentral 2011;2(11):WMCRW001101
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Stimulating subject
Posted by Dr. Ennio Piantato on 28 Oct 2011 10:04:33 AM GMT

1 Is the subject of the article within the scope of the subject category? Yes
2 Are the interpretations / conclusions sound and justified by the data? Yes
3 Is this a new and original contribution? No
4 Does this paper exemplify an awareness of other research on the topic? Yes
5 Are structure and length satisfactory? Yes
6 Can you suggest brief additions or amendments or an introductory statement that will increase the value of this paper for an international audience? No
7 Can you suggest any reductions in the paper, or deletions of parts? No
8 Is the quality of the diction satisfactory? Yes
9 Are the illustrations and tables necessary and acceptable? Yes
10 Are the references adequate and are they all necessary? Yes
11 Are the keywords and abstract or summary informative? Yes
  • Other Comments:

     

    I find this paper interesting and stimulating, but I make a criticism in this way.

    Let’s not try (we the psychiatrists) to reduce symptoms and psycho(patho)logical signs to something physical forgetting how a human being lives and deals with others and himself.

    Aggressivity is such a complicated item where many elements iteract: let’s not forget all problems (psychological and social) interesting greater and greater number of world population even in the so-called developed countries.

    The new wave of biological Psychiatry worries me a bit with this trend to have a sort of the “pathologist” approach to human behaviour.

    Anyway the work – as written before – is interesting and stimulates a wide range of speeches abput different area in Psychiatry.

  • Competing interests:
    No
  • Invited by the author to review this article? :
    No
  • Have you previously published on this or a similar topic?:
    No
  • References:
    None
  • Experience and credentials in the specific area of science:

    I work in a Psychiatric Ward

  • How to cite:  Piantato E .Stimulating subject[Review of the article 'Aberrant Cholesterol and Lipoprotein Levels in Aggressive Male Adolescents ' by Du Souich C].WebmedCentral 2011;2(10):WMCRW001056
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