10.1192/bjp.162.6.818Access the most recent version at doi: 1993 162: 818-825 The British Journal of Psychiatry

  K Hawthon, P Cowen, D Owens, A Bond and M Elliott  

Low serum cholesterol and suicide  

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British Journal of Psychiatry (1993), 162, 8 18—825

The summary quoted above is from an article byEngelberg (1992). The present authors were invitedto comment upon the study.

Keith Hawton & Philip Cowen

The paper in which this summary appeared was atheoretical one, prompted by a meta-analysis byMuldoon et al (1990) of six randomised, controlledtrials of cholesterol-lowering drugs. The paradoxicalresult - that while there was evidence that cholesterollowering drugs were associated with reduced mortalityfrom coronary heart disease in men, total mortalitywas unaffected - appeared to be due to a significantexcess of deaths from suicide, accidents, or violence.Other evidence quoted by Engelberg in support ofhis hypothesis relating low serum cholesterol tosuicide and aggressive behaviour concerns findingsof relatively low cholesterol levels in offenders withantisocial personality disorder (Virkkunen, 1979), inhomicidal offenders with antisocial personalities oran intermittent explosive disorder with a habituallyviolent tendency (Virkkunen, 1983),and in adolescentboys with aggressive conduct disorder (Virkkunen& Penttinen, 1984). He acknowledged that twonaturalistic follow-up studies of men had not showna relationship between serum cholesterol and violentdeaths or suicide (Pekkanen et al, 1989; Davey Smithet al, 1990), but since then, Lindberg et al (1992)from Sweden have reported a strong negativeassociation between original serum cholesterol levelsand suicide in men (but not women), during the firstseven years of a follow-up study of more than 20years. This association persisted when the resultswere corrected for cancer present at the time ofsuicide (there being a relationship between low serum

cholesterol concentration and the incidence ofcancer). Subsequent commentators, however, havepointed out that since depression is usually associatedwith reduced appetite and weight (hence lowercholesterol), the association could have resulted fromsuicides in men who, at the original assessment, weredepressed (and hence at increased risk of subsequentsuicide) but also had lowered serum cholesterol levelsfor this reason.

The association of lowered serum cholesterol withdecreased activity of brain serotonin pathways, alsopostulated by Engelberg, stems partly from theconsiderable although not absolutely consistentevidence for an association between reduced serotoninactivity and aggressive and suicidal behaviour. Thusdecreased concentrations in cerebrospinal fluid (CSF)of the metabolite of 5-hydroxytryptamine (5-HT),5-hydroxyindoleaceticacid(5-HIAA), have beenfound in patients who have made suicide attempts,particularly of a violent nature, and in convictedmurderers, especially those in whom the crime wascommitted impulsively (Brown & Linnoila, 1990).Furthermoresome, though not all,post-mortemligand-binding studies have indicated increasednumbers of 5-HT2 receptors in the prefrontal corticalarea of brains of suicide victims, especially those whoused violent means (Mann et a!, 1989). It has beensuggested that violent suicides (and perhaps otherkinds of violent behaviour) are associated withimpaired presynaptic release of 5-HT, the increasein numbers of 5-HT2 receptors being interpreted asan attempt by post-synaptic neurones to compensatefor the decrease in 5-HT availability at post-synapticreceptor sites. It has also been postulated that theassociation between lowered brain 5-HT function andcomplex behaviour such as violence towards the self

818

The Current Literature

Low Serum Cholesterol and Suicide

KEITH HAWTON & PHILIPCOWEN, DAVID OWENS, ALYSON BOND and MARTIN ELLIOTT

“¿�Primaryprevention trials which have shown that the lowering of serum cholesterolconcentrations in middle-aged subjects by diet, drugs, or both leads to a decrease in coronaryheart diseasehave alsoreportedan increasein deathsdue to suicideor violence.There hasbeen no adequateexplanationfor this association.I have reviewed the relevant publishedwork and describea physiologicalmechanismthat might account for this curiousfinding.Oneof the functionsof serotonininthe centralnervoussystemisthe suppressionof harmfulbehaviourimpulses.When mousebrainsynaptosomalmembranecholesterolisincreasedthereis a pronounced increase in the number of serotonin receptors. Low membrane cholesteroldecreases the number of serotonin receptors. Since membrane cholesterol exchanges freelywith cholesterol in the surrounding medium, a lowered serum cholesterol concentration maycontributeto a decreasein brainserotonin,with poorersuppressionof aggressivebehaviour.―

LOW SERUM CHOLESTEROL AND SUICIDE 819

or others might be explicable in terms of 5-Hi'pathways functioning as a behavioural restraintsystem which inhibits impulsive behaviour (Depue& Spoont, 1986).Thus, reduced 5-HT function mightmake such behaviour more likely in the face ofpersonal or social adversity.

Engelberg has attempted to link such a postulatedfunction of brain 5-HI pathways with the apparentassociation of cholesterol-loweringdrugs with increasesin suicidal and other kinds of violent behaviour. Hequotes evidence that mouse brain synaptic membraneviscosity is increased by cholesterol, and that this isassociated with increased binding of serotonin,indicating raised uptake of serotonin from the bloodand entry into brain cells (Heron et al, 1980).Engelberg postulated, therefore, that reducingcholesterol could impair serotonin uptake from theblood by decreasing the number of 5-HI receptorsthat are available on the cell membrane to interactwith 5-HI, thus reducing the amount of 5-HIentering brain cells. However, there seems to be someconfusion in his article between 5-HI receptors and5-HI uptake sites, and as noted earlier, currentevidence implicates increased rather than decreasedbrain 5-HI receptor density in suicide victims.

While it is clear that cholesterol is an importantconstituent of neuronal membranes, and it is quitepossible that reduced cholesterol, whether throughmedication or other reasons, could modify theprocess of signalling in various ways, there is no firmevidence that cholesterol-lowering drugs alter brain5-HI transmission. Nevertheless, the possible linkbetween changes in serum cholesterol levels andviolent behaviour is intriguing and deserving offurther study.

Fatal violent acts, however, represent a rather insensitive outcome measure. As Engelberg and othershave suggested, it would seem important that carefulpsychiatric assessments should be incorporated infuture clinical trials of cholesterol-lowering drugs.Ihus, regular assessments should be made of, forexample, mood, irritability, feelings of aggression,pessimism, and suicidal ideas. Another relevant lineof study would be of possible changes in brain 5-HIfunction in people taking cholesterol-lowering drugs.Currently, the most appropriate non-invasive methodis to use neuroendocrine tests in which 5-HI pathwaysare challenged by a selective drug, and the hormonaloutput is measured. For example, Coccaro et al(1989) have found that patients with a history ofaggressive and suicidal behaviour have a decreasedprolactin response to the 5-HI releasing agentfenfluramine, suggesting a lowering of brain 5-HIneurotransmission in these patients. Such investigationsof cholesterol-lowering drugs could usefully also

include standardised psychiatric assessments, in orderthat relationships between any changes in 5-HIfunction and alterations in psychiatric and psychological status, especially those likely to increase riskof suicide, could be examined.

David Owens

Engelberg's article proposes a biological hypothesisto explain why lowering of cholesterol might leadto excess deaths due to accidents, suicide orviolence. I will concentrate on whether he wasjustified in asserting that, “¿�Sinceresults were similarin all six trials, I thought it unlikely that thosefindings were merely due to chance alone―.Each ofthe six trials found an excess of deaths due toaccident, suicide or violence in the cholesterollowering intervention group. On the other hand,none of the trials found a significant excess of suchdeaths (actual numbers of excess deaths were 2, 3,4, 6, 7 and 7).

The conclusion about excess deaths arose from ameta-analysis of the six intervention studies (Muldoonet al, 1990). Meta-analysis is a procedure in whichdata from separate investigations are amalgamatedin one review. Sample size is increased, so firmfmdings may be reported where previous results wereeither inconclusive or conflicting. Consensus has notbeen reached on how to combine data in metaanalyses. The epidemiologist Feinstein (1985) put itwell: “¿�Apragmatist might argue that when no otheranswers are available, the results of the pooledanalyses are better than nothing; a fastidious reviewermight insist that no answer is better than one thatis probably misleading―. Before accepting theconclusions of any meta-analytic review, readersshould ask several questions about how it was carriedout. Four such questions are considered below (someof these questions, and others, are set out in simpleand direct terms in the excellent book by Sackett etal(1991)).

Firstly, were the studies in the meta-analysisselected correctly? We are told that all six randomised,primary prevention trials which achieved significantlygreater lowering of cholesterol in the active treatmentgroup were included (Muldoon et al, 1990).However,in the published responses to this meta-analysis,commentators argue that several of the studiesincluded do not match the authors' own criteria, andthat further studies with much lower mortalitiesmight equally well have been included —¿�probablyleading to different conclusions (Canter, 1990;DaveySmith & Pekkanen, 1992). Although the originaltrials were randomised to eliminate bias, choice ofstudies for a meta-analysis cannot be random, and

820 HAWTON ET AL

can estimate and minimise the play of chance. Inepidemiological practice, the more perilous enemiesare the systematic errors of bias and confounding.In a single investigation it will often be possible to‘¿�controlfor' potentially confounding factors. Forexample, it seems feasible that alcohol intake bearsa relation both to cholesterol-lowering and tomortality due to accidents, suicide or violence. Areport of an excess of such deaths should examinewhether alcohol intake was influencing the findings,even in a randomised trial.

However, in none of the studies was the excess ofdeaths due to accident, suicide or violence adjustedfor exposure to other risk factors —¿�presumablybecause no one study found a significant excess. The‘¿�unplannedobservation' (Davey Smith & Phillips,1992) which led to the Lancet article arose from thepooled data in the meta-analysis, and is proneto confounding effects which cannot easily beexamined, because of differences between the studiesin their patients and methods.

If we think the observation unlikely to have arisenby chance, perhaps there is a systematic reasoninstead. If so, we may be misled by the apparentbenefit of the increased sample size which resultsfrom the amalgamation of data. Larger samples,such as those generated by meta-analysis, do noteliminate systematic errors; instead they may renderthem more likely to be reported. “¿�Sophisticatedstatistics will not improve poor data but could leadto an unwarranted comfort with one's conclusions―(Ihacker, 1988).

Engelberg has proposed a hypothesis whichmight explain the apparent excess in mortality.A fourth question which a reader might thereforeask is whether a fmding is more likely to beauthentic if a biologically plausible explanationcan be applied to it. Unfortunately, a credibleinterpretation must carry little weight. Scientistsgenerate numerous theories as they devise theirresearch projects. They also become adept atthinking of explanations for their own resultsand those of others; there are many examples ofdiametrically opposed findings, each explainedby equally plausible hypotheses. Epidemiologicalfmdings are at least as prone to inventive explanationas any other medical research results, and “¿�itisthe exceptional epidemiological association forwhich no mechanism can be proposed― (DaveySmith & Phillips, 1992).

Ihis hypothesis about why there should be anexcess of deaths from accidents, suicide and violenceis interesting, but perhaps rather hasty; when we readany research study we should critically examine themethod before perusing the discussion.

two reviewers may select different papers, therebyproducing opposite results.

Secondly, were the data which were pooled derivedfrom similar studies? Even when trials are apparentlysimilar there will be differences in the sort of patientsincluded and excluded, differing severity of thecondition in question, variation in the treatment andcontrol interventions, and so on. There will also bevarying quality of design and precision in measurement (Detsky et al, 1992). Of the six trials ofcholesterol-lowering interventions, two involveddiets, two used drugs, and two combined drugs anddiet. No two studies used the same drug. Subjectsin four of the trials were included only if baselinecholesterol was over a certain level; in the other twotrials, subjects were selected independently ofcholesterol concentrations. These differences in studydesign are considerable. In the end, only the readercan decide whether the trials are sufficiently similarfor it to make clinical sense to combine them; viewson this issue will differ. It has been suggested, forexample, that an alternative meta-analysis of thosecholesterol-lowering trials which used only dietaryinterventions does not suggest a significant excess ofdeaths due to accident, suicide or violence; if thereis cause for concern perhaps it should be about theuse of cholesterol lowering drugs in primaryprevention (Davey Smith & Pekkanen, 1992).

Thirdly, are the conclusions of the pooled analysisconfined to those outcomes which the original studiesset out to examine? Authors of research projectsoften report on results, and draw conclusions, whichgo beyond the questions posed by the study hypothesis. However, statistical test results have clinicalmeaning only when they determine the precision ofa finding which was intended to be tested from theoutset of the investigation (Bradford Hill, 1953). Wetake a risk every time we believe that an unplanned,low probability (P) value tells us that “¿�somethingis going on―.All six of these studies were set up toexamine cardiovascular events. None proposed thehypothesis that there would be an excess of mortalitydue to accidents, suicide or violence, and nonereported a ‘¿�significant'excess of such deaths. Wewould be rash to accept from the pooled data theconclusion that something really is going on —¿�concerning mortality from a cause not proposed byany of the trials.

Even if we are sceptical about excess mortalityfrom these causes, we are left with the uneasyrecollection that it did occur in all six trials (albeitwith only a tiny effect in each); perhaps, as Engelbergsays, that fmding is unlikely to have arisen by chancealone. It is not chance, however, which poses thegreatest danger, because appropriate statistical tests

821LOW SERUM CHOLESTEROL AND SUICIDE

Alyson Bond

The relationship between brain serotonin and oneform of behaviour - suicide - is controversial, but theunderlying hypothesis has currently moved from anassociation with impulsive, violent suicide to one ofstrength to commit the act. The relationship betweenserotonin and several forms of behaviour which leadto an increase in mortality rates is still moredebatable. In this paper, that very proposition isadvanced via an association with serum cholesterol,a substance only marginally related to serotonin, andthis is suggested to the exclusion of all otherbiological, psychological, or environmental factors.Such an incredulous leap does no justice to thecomplexities inherent in biological psychiatry.

There is considerable debate as to whether generalpractitioners should screen and treat asymptomatichypercholesterolaemia, and at what level they shoulddo so (Royal College of General Practitioners, 1993;Davey Smith & Pekkanen, 1992). A meta-analysis ofsixprimary prevention trials has suggestedthat loweringcholesterol by diet, drugs, or both leads to a decreasein deaths due to coronary heart disease (CHD) butto an increase in those due to accidents, suicide, orviolence (Muldoon et a!, 1990). However, to makesuch a decision purely on the grounds of mortalitystatistics seems unwise. Ihe reduction in non-fatalcoronary events and a possible improvement inquality of life is surely equally important, but hasnot been considered. Neither has any potentialmorbidity from an increased risk of depression,irritability, or suicidal intent been reported orevaluated. Randomisation does not automaticallyguarantee that groups of subjects are matched onpsychiatric psychopathology. Engelberg presents ahypothesis to explain the increase in violence-relateddeaths by linking lowered serum cholesterol concentrations with decreased brain serotonin, but therelationship is unlikely to be a simple linear one.Even the work linking low levels of serotoninneurotransmission with increased impulsivity andimpulsive aggression is based on association ratherthan hard evidence; although the question of whetherabnormalities of serotonin metabolism are a trait ora state marker has not been answered, the evidenceindicating a link with history or personality ratherthan with a current form of behaviour supports atrait theory.

The evidence for an inhibitory role of centralserotonin in impulsive behaviour in humans comesfrom two major sources: CSF analysis and neuroendocrine challenge tests. Studies of CSF analysishave been conducted both post-mortem from thebrains of suicide victims and ante-mortem from

people who have recently attempted suicide or animpulsive act such as homicide/arson, or who havea history of such behaviour. Only one small studyhas been conducted in normal volunteers (Roy et a!,1988) but this confirmed the trend: in 17 subjects,a negative correlation was found between 5-HIAAconcentrations and scores on the “¿�urgeto act outhostility―subscale of the Hostility & Direction ofHostility Questionnaire (Foulds, 1965). The othermethod of studying serotonin in the brain has beenby examining the response of a hormone (e.g.prolactin) to a challenge with a serotonin probe.Patients with various disorders, including borderlineor antisocial personality disorder, a history of suicideattempts, or episodic alcohol abuse have exhibitedreduced responses to such a challenge (Coccaro eta!,1989),and thisrelationshiphas been foundirrespective of behavioural disturbance at the time(O'Keane eta!, 1992). Thus, the work showing a linkbetween reduced indices of serotonin function andan irritable, aggressive behaviour pattern seems toreveal a biological marker for a psychological traitof dysregulated impulsivity or aggression (Apter eta!,1990).

Engelberg also presents some evidence relatingserum cholesterol concentrations to personality traits.Generally, clinical populations with a propensity foraggression had lower mean serum cholesterolconcentrations than control groups (Virkkunen,1979, 1983; Virkkunen & Pentinnen, 1984), but nodifference in concentrations of triglycerides. Theseresults are from small samples of disturbed offenders,and it may be that these individuals have a numberof biological abnormalities. Large cohort studies ofgeneral populations have not shown a relationshipbetween serum cholesterol concentrations and eitherviolent death or hostility as a personality trait (DaveySmith eta!, 1990; Pekkanen eta!, 1989). Low serumcholesterol does not, therefore, seem to be abiological marker for a psychological trait in thenormal population, but naturally low concentrationsmay differ biologically from those lowered bymanipulations. Thus, these associations are limitedto trials which set out to lower (raised) serumcholesterol levels deliberately by diet, drugs, or acombination. A purposeful intervention of this kindis reputed to be associated with decreased deathsfrom CHD, but also with increased mortality fromaccidents, suicide, or violence; such an increase mayinvolve a number of factors, but does not seem tobe related to an enduring biological characteristic.

Aggressive behaviour may be due to numerousfactors, both internal and external. The role of serotonin, and by implication serum cholesterol, accordingto Engelberg's hypothesis, focuses on internal

822 HAWTON ET AL

or biological factors, but the data showing thatabnormalities in the neurotransmission of serotoninare associated with individuals committing impulsiveaggressive acts against themselves or others do notprovide evidence of a causal link. However, it maybe that changes in this system may either increaseor decrease the predisposition to aggression oracting impulsively: it may be possible to change thelikelihood of this behaviour by manipulating levelsof central serotonin. Some preliminary work hasbeen done using specific serotonergic agonists to treatpatients with high levels of aggression and self-injury(Ratey et a!, 1991), and a diet rich in serotonin hasalso been advocated (Gedye, 1991). These interventions have had some success, but there is a needfor further investigation; for instance, there may bea rebound increase in feelings of irritability oraggression on cessation of treatment with 5-HIreuptake inhibitors (Szabadi, 1992).

Since intervention trials may alter numerousfactors in both the individual and the environment,careful controls are necessary to try and keep thesebalanced across the groups. The discovery that anindividual has a high level of serum cholesterol, andthus an increased risk of CHD, may itself lead tobehavioural changes. Even if no direct encouragement is given to alter such other related factors asdiet, smoking, alcohol, exercise —¿�as there has beenin some trials (Lipid Research Clinics Program, 1984;Frick eta!, 1987;Watts eta!, 1992)—individuals maylearn more about their problem and make changesof their own volition. Clinicians are ethically boundnot to withhold requested information on preventivehealth issues. Changes in lifestyle, such as cyclingto work or giving up smoking, increase the risk ofaccident or irritability respectively. However, thesewould not be expected to differ systematically acrossgroups and cannot account for increased violentdeaths only in the experimental groups. Loweringof serum cholesterol may also interact with personalityfactors. There has been a wealth of research showingthat patients with CHD are more likely to have acoronary-prone (type A) behaviour pattern, whichis characterised by intense competitiveness, a senseof being under time-pressure, and easily provokedhostility. Modifying this behaviour has been shownto reduce myocardial infarction (Friedman et a!,1986). Perhaps interventions to lower serumcholesterol in patients with this type of personality,without any attempt to alter the behaviour, puts themmore at risk of violent or accidental death.

The drugs used in intervention studies are notspecific to lowering cholesterol, and it may be someother action of their's which is responsible for anincrease in deaths not related to physical illness. Since

the studies included in the meta-analysis cited byEngelberg (Muldoon et a!, 1990) used variouscompounds, there may well be a difference betweendrugs with different modes of action, for exampleclofibrate and cholestyramine, as indeed has beensuggested with cancer-related deaths. Ihe meanduration of treatment was only 4.8 years, and noindication is given in the paper of factors suchas initial level of serum cholesterol, success ofmanipulation, or whether those dying violently hadindeed shown a significant reduction. It is, therefore,impossible to say if such an effect is a risk at thebeginning of treatment asthe patient adjusts to newlevels, whether the risk occurs when treatment isintroduced too rapidly, whether it becomes greateras treatment continues, or if it only occurs whenlevels become too low. The advent of new drugs, suchas the 3-hydroxymethylglutaryl coenzyme A (HMGCoA) reductase inhibitors, is important in elucidatingthese factors. As these drugs are much more efficientat lowering serum cholesterol (an average of 30°lo,ascompared with l0°lo),primary intervention trialswith these compounds may show an increased riskof violent death. Ihe first year of follow-up of theEXCEL trial of lovastatin (Bradford eta!, 1991) doesshow an excess of deaths in drug groups, comparedwith placebo, but the figures refer to mortality fromall causes, and are not divided as to cause of death.

The argument that the lowering of serum cholesterolconcentrations is the key factor in an excess of deathsdue to accidents, suicide, or violence is reinforcedby a parallel effect found in studies only manipulatingdiet (Muldoon et a!, 1990). However, a change indiet, which has been shown to be beneficial inreducing both the progression of atherosclerosis(Watts et a!, 1992) and the number of coronaryevents, may lead to changes in substances other thancholesterol. It is not clear to what extent changes innutritional status alone, in particular weight loss,may account for changes in morbidity, thus increasingrisk (Anderson eta!, 1990). A more recent comparisonof lowering cholesterol levels by diet or drugs, whichhas included more data from newer and crossovertrials (Davey Smith & Pekkanen, 1992),has concludedthat there is a difference: drugs but not diet increasemortality from non-cardiovascular causes. It may notbe the actual lowering of cholesterol which is criticalin increasing mortality, but the method, extent, andspeed of the process —¿�or indeed, some other drugeffect. The concomitant intake of other drugs or ofsubstances such as alcohol (Shaper & Cook, 1990)may also have behavioural consequences.

It is also important to remember that otherdrugs and illnesses may affect serum cholesterol.Myxoedema has been shown to be associated with

823LOW SERUM CHOLESTEROLAND SUICIDE

abnormal plasma lipids (Fowler, 1977), and in acommunity screening study, Ball et a! (1991) foundthat l2% of subjects with plasma cholesterolconcentrations of more than 8 mmol/l had impairedthyroid function. As patients with myxoedema arelikely to have lower activity levels than normalcontrols, if the hypercholesterolaemia is correctedby thyroxine supplementation, does the consequentlowered cholesterol concentration or the increasedactivity result in more risk of accident-related death?There are no data detailing such a risk, but it isinteresting that maintenance therapy is introducedslowly. Beta-blockers also adversely affect the lipidprofile, and so it may be profitable to monitorpatients on these treatments.

No one can argue with Engelberg's conclusion that“¿�weneed to know more about the relation of braincell-membrane cholesterol and microviscosity withexpression of serotonin receptors on the membranesurface in man.― However, his statement that“¿�interventionsto reduce cholesterol concentrationson a large scale could lead to a population shift toa more violent pattern of behaviour― and hissuggestion that this is due to a direct relationship withbrain serotonin are unsubstantiated. Our knowledgeof central serotonin, especially as regards manipulation, is still unrefined and we know little of itscorrelates in the general population. Much moreresearch needs to be done to elucidate the elementswhich are important in the clinical manipulation ofcholesterol itself. We need to know which factorsmay cause increased risk —¿�initial level of serumcholesterol, drug type or administration, diet, weightloss, and personality —¿�so that we can controlthem in future treatment. Such an effect is likely tobe multifactorial.

Martin Elliott

Engelberg's hypothesis has drawn attention to thereported associations between aggression/suicide andbrain/CSF levels of serotonin (5-HI) and 5-HIAA onthe one hand and blood cholesterol on the other. Hisattempt to relate these two biochemical measures basedon the action of cholesterol to alter membrane fluidityand thence brain serotonin content is, however,flawed. Ihe experimental basis for the hypothesisderives from a study of [3H] 5-HI binding insynaptic membranes from mouse brain (Heron et a!,1980). Addition of cholesterol to the membranes invitro increased membrane microviscosity, and correspondingly increased specific binding of [3H] 5-HI,whereas reducing the lipid viscosity caused a smallbut significant decrease in binding. The precisenature of the site labelled by [3H] 5-HI was not

defined, but potent inhibition of binding by compounds such as methysergide and metergoline,compared with the weak effect of imipramine,indicated that this site was more likely to be a 5-HIreceptor than the 5-HI uptake site.

Engelberg interpreted these data as indicating thatincreased cholesterol would lead to “¿�enhanceduptake of serotonin from the blood and a consequentincreased entry of serotonin into brain cells―.Hetherefore suggested that a reduction in serumcholesterol, caused by drug treatment in man, maylead to a decrease in membrane lipid viscosity andhence to a reduction in serotonin uptake from bloodand ultimately to decreased brain serotomn content.As pointed out, however, the 5-HI site labelled byHeron et a! (1980) was clearly not the uptake site,and therefore changes in brain serotonin contentwould not be anticipated on the basis of their data.Furthermore, the serotomn stored within brain cellsis not accumulated from blood, where most serotomnis stored within platelets rather than free in plasma,but is synthesised in situ from the precursor aminoacid L-tryptophan. Indeed, the limiting factor inserotonin synthesis within the brain is the availabilityof L-tryptophan.

Although the original mechanism proposed mayhave to be discounted, there are substantial datasuggesting that the neurotransmitter function ofserotonin within the brain may in fact be compromised by changes in cholesterol content. Theeffects of cholesterol on [3H] 5-HI bindingdescribed by Heron eta! (1980) have been replicatedby Shih & Ohsawa (1983) in membranes of ratcerebral cortex where, again, changes in lipidviscosity correlated with changes in binding. However,since these experiments were carried out, there hasbeen substantial progress in the classification of 5-HIreceptors, which are now divided into four majorcategories, with further subtypes within each. Thesites identified in both binding studies describedabove were probably 5-HI1 receptors, since theywere labelled with high affinity by [3H] 5-HI.Within the 5-HI1 class of receptors, however, thereare at least four subtypes; therefore further investigation using selective ligands will be necessaryto confirm the identity of the receptor(s) involvedin this mechanism. Modification of binding parameters should not then be automatically translatedinto changes in receptor function, since cholesterolloading in the rabbit has been shown to increase @3-adrenoceptor binding in aortic membranes (Isutsumiet a!, 1988), but decreased stimulation of adenylylcyclase via j3-adrenoceptor activation in rat prostaticepitheial cells (Prieto eta!, 1990). Functional studiesof 5-HI receptors following cholesterol modification

824 HAWTON ET AL

could be carried out at the biochemical level,measuring second-messenger changes, or at thebehavioural level in animal models and in man, usingthe neuroendocrine challenge test.

Besides changes in 5-HI receptors, there isevidence that the active transport of serotonininto cells via the 5-HT uptake pump is sensitiveto changes in membrane fluidity, but that additionof cholesterol reduces serotonin uptake (Block &Edwards, 1987)rather than increasing it as suggestedby Engelberg. In patients with essential hypertension,an inverse correlation was observed between totalplasma cholesterol and both platelet serotonincontent and maximal rate of uptake, whereas no suchassociation was seen in normotensive controls(Guicheney et a!, 1988). It may therefore beanticipated that drug treatment to reduce cholesterollevels would enhance serotonin uptake and so,within the neuronal synapse, reduce the effectiveconcentration of serotonin available to activate5-Hi' receptors. The overall result of cholesterol

depletion might therefore be to reduce serotoninneuronal activity by actions at both presynaptic(increased serotonin reuptake) and postsynapticsites (decreased receptor number and/or function).Hence, it is plausible that a lowered serum cholesterolconcentration might contribute to a decrease inbrain serotonin function. This is a modificationof the conclusion proposed by Engelberg, althoughsubstantial work is needed to demonstrate the actualbiochemical and behavioural mechanisms underlyingthis proposal.

References

ANDERSON, I. M., PARRY-BILLINGS, M. & NEWSHOLME, E. A. (1990)

Dieting reduces plasma tryptophan and alters brain 5-HTfunction in women. Psychological Medicine, 20, 785—791.

AFTER, A., VAN PRAAG, H. M., PLUTCHIK, R., et a! (1990)Interrelationships among anxiety, aggression, impulsivity, andmood: a serotonergically linked cluster? Psychiatry Research,32,191—199.

BALL, M. J., GRImTHS, D. & THOR0000D, M. (1991) Asymptomatic

hypothyroidism and hypercholesterolaemia. Journal of the Royal

Society of Medicine, 84, 527—529.BLOCK, E. R. & EDWARDS, D. (1987) Effect of plasma membrane

fluidity on serotonin transport by endothelial cells. AmericanJournal of Physiology, 253, 672—678.

BRADFORD HILL, A. (1953) Observation and experiment. New

England Journal of Medicine, 248, 995—1001.BRADFORD, R. H., SHEAR, C. L., CHREMOS, A. N., et al (1991)

Expanded clinical evaluation of lovastatin (EXCEL) studyresults. 1. Efficacy in modifying plasma lipoproteins and adverseevent profile in 8245patients with moderate hypercholesterolemia.Archives of Internal Medicine, 151, 43—49.

BROWN, C. L. & LINNOILA, M. I. (1990) CSF serotonin metabolite

(5-HIAA) studies in depression, impulsivity, and violence.Journal of Clinical Psychiatry, 51, 31—41.

CANTER, D. (1990) Lowering cholesterol concentrations andmortality. British Medical Journal, 301, 814.

COCCARO, E. F., SIEVER, L. J., KLAR, H. M., et a! (1989)

Serotonergic studies in patients with affective and personalitydisorders. Archives of Genera! Psychiatry, 46, 587—599.

DAVEY SMITH, C. , SHIPLEY, M. J., MARMOT, M. 0., et a! (1990)Lowering cholesterol concentrations and mortality. British

MedicalJournal,301, 552.& PEKKANEN,J. (1992)Should there be a moratorium on

the use of cholesterol lowering drugs? British Medical Journal,304, 431—434.

& PHILLIPS,A. N. (1992)Confounding in epidemiologicalstudies: why “¿�independent―effects may not be all they seem.British Medical Journal, 305, 757-759.

DEPUE, R. A. & Spoowr, M. R. (1986) Conceptualizing a serotonintrait: a behavioral dimension of constraint. Annals ofthe NewYork Academy of Science, 487, 47-62.

DETSKY,A. S., NAYLOR, C. 0. , O'RoUR@, K. , et a! (1992)Incorporating variations in the quality of individual randomizedtrials into meta-analysis. Journal of Clinical Epidemiology, 45,255—265.

ENGELRERG, H. (1992) Low serum cholesterol and suicide. Lancet,338, 727—729.

FEINSTEIN,A. R. (1985) Clinical Epidemiology: The Architectureof Clinical Research.Philadelphia: W.B. Saunders.

FOULDS,G. (1965) Personality and Personal Illness. London:Tavistock.

FOWLER, P. B. 5. (1977) Premyxoedema —¿�a cause of preventable

coronary heart disease.Proceedingsof the Royal Society ofMedicine,70, 297—299.

FRICK, M. H., ELO, 0., HAAPA, K., et al (1987) Helsinki heartstudy: primary prevention trial with gemfibrozil in middle-agedmen withdyslipidemia.New EnglandJournalofMedicine,317,1237—1245.

FRIEDMAN, M., THORESEN, C. D., GILL, J. J., et al (1986)Alteration of type A behaviour and its effect on cardiacrecurrences in postmyocardial infarction patients: summaryresults of the recurrent coronary prevention project. AmericanHeart Journal, 112, 653—665.

GEDYE, A. (1991) Buspirone alone or with serotonergic diet reducedaggression in a developmentally disabled adult. BiologicalPsychiatry, 30, 88—91.

GUICHENEY, P., Daitmcx, M. A., CLOLX, J. F., et a! (1988) Platelet5-HT content and uptake in essential hypertension: role ofendogenousdigitalis-likefactorsandplasmacholesterol.Journalof Hypertension, 6, 873—879.

HERON, D. S., SHINITZKY, M., HERSHKOWITZ,M., et a! (1980) Lipidfluiditymarkedlymodulatesthebindingofserotonintomousebrain membranes.Proceedingsof the National Academy ofScience,USA, 77, 7463-7467.

LINDBERG, C., R@srAM, L., GULLBERG, B., et a! (1992) Low serum

cholesterol concentration and short term mortality from injuriesin men and women. British Medical Journal, 305, 277—279.

LIPIDRESEARCHCLINICSPRoow@ (1984) The lipid research clinicscoronary primary prevention trial results. Journal of theAmerican Medical Association, 251, 351—374.

MANN, J. 3., ARANGO, A., MARZUK, P. M., eta! (1989) Evidencefor the 5-HT hypothesis of suicide: a review of post-mortemstudies. British Journal of Psychiatry, 155, 7—14.

MULDOON, M. F., MANUCK, S. B. & MATrHEWS, K. A. (1990)

Loweringcholesterolconcentrationsand mortality:a quantitativereview of primary prevention trials. British Medical Journal, 301,309—314.

O'KEANE, V., MOLONEY, E., O'NEILL, H., et a! (1992) Blunted

prolactin responses to d-fenfluramine in sociopathy. Evidencefor subsensitivity of central serotonergic function. British Journalof Psychiatry, 160, 643-646.

PEKKANEN, J., NISSINEN, A., PUNSAR, S., et a! (1989) Serumcholesterolandriskofaccidentalorviolentdeathina 25-yearfollow-up: the Finnish cohorts of the seven countries study.Archives of Internal Medicine, 149, 1589—1591.

825LOW SERUM CHOLESTEROL AND SUICIDE

SZABADI,E. (1992) Fluvoxamine withdrawal syndrome. BritishJournal of Psychiatry, 160, 283-284.

THACKER, S. B. (1988) Meta-analysis: a quantitative approach to

research integration. Journal of the American MedicalAssociation, 259, 1685—1689.

TSUTSUMI,S., TswI, K., OGAWA,K., et a! (1988) Effect of dietarysalt and cholesterol loading on vascular adrenergic receptors.Blood Vessels,25, 209-216.

VIRKKUNEN,M. (1979) Serum cholesterol in antisocial personality.Neuropsychobiology, 5, 27-30.

(1983)Serumcholesterollevelsin homicidaloffenders.A lowcholesterol level is connected with a habitually violent tendencyunder the influence of alcohol. Neuropsychobiology, 10,65—69.

& PENTINNEN,H. (1984) Cholesterol in aggressive conductdisorder: a preliminary study. Biological Psychiatry, 19,435—439.

WAn'S, C. F., LEWIS, B., BRUNT, 3. N. H., et a! (1992)Effects on coronary artery disease of lipid-lowering diet,or diet plus cholestyramine, in the St Thomas' Artherosclerosis Regression Study (STARS). Lancet, 339, 563—569.

PRIETO, 3. C., HuItso, C. & CARMENA, M. J. (1990) Modulation

of the @1-adrenergicstimulation of cyclic AMP accumulation inrat prostatic epithelial cells by membrane fluidity. GeneralPharmacology, 21, 931—933.

RATEY,J., SOvNER,R., PAJtKS,A., et a! (1991) Buspirone treatmentof aggression and anxiety in mentally retarded patients: amultiple-baseline, placebo lead-in study. Journal of ClinicalPsychiatry,52, 159—162.

ROY, A., ADINOFF, B., LINNOILA,M., et a! (1988) Acting outhostility in normal volunteers: negative correlation with levels of5HIAA in cerebrospinal fluid. Psychiatry Research, 24, 187-194.

ROYALCOLLEGEOFGENERALPRAcrrnormlts (1993) Guidelines forthe Management of Hyperlipidaemia in Genera! Practice.London:RoyalCollegeofGeneralPractitioners.

SAaat-rr, D. L., HAYNES,R. B., GUYAi-r,C. H., et a! (1991)Clinical Epidemiology: A BasicSciencefor Clinical Medicine.Boston: Little, Brown & Company.

SHAPER, A. C. & COOK, D. C. (1990) Lowering cholesterolconcentrationsand mortality. BritishMedicalJournal, 301.553.

SHIH, J. C. & OHSAWA,R. (1983) Differential effect of cholesterolon two typesof 5-hydroxytryptaminebindingsites.NeurochemicalResearch,8, 701—710.

Keith Hawton, DM, FRCPsych, Consultant and Clinical Lecturer, University Department of Psychiatry andWarneford Hospital, Oxford 0X3 7JX; Philip Cowen, MD, FRCPsych,MRC Clinical Scientist and HonoraryConsultant Psychiatry, ResearchUnit, Littlemore Hospital, Oxford 0X4 4XN; David Owens, BSc,MD,MRCPsych, Senior Lecturer in Psychiatry, University of Leeds, Academic Unit of Psychiatry, 15 HydeTerrace, Leeds LS2 9LT; Alyson J. Bond, BA, MSc,PhD,Senior Lecturer, Department of Psychiatry,Institute of Psychiatry, De Crespigny Park, London SE5 8AF; Martin Elliott, MA, DPhil, SeniorPharmacologist,Oxford UniversitySmithKlineBeechamCentrefor Applied Neuropsychobiology,UniversityDepartment of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE