Department of Psychiatry, St Vincent's University Hospital, Dublin
St Patrick's Hospital, Dublin
Department of Psychiatry, St Vincent's University Hospital, Dublin
Department of Public Health Medicine and Epidemiology, University College, Dublin
Department of Biochemistry, St Vincent's Hospital, Dublin
Department of Psychiatry, St Vincent's University Hospital, Dublin, Ireland
Correspondence: Malcolm Garland, Department of Psychiatry, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland. Tel. : 00 353 1 2094471 ; fax : 00353 1 2837556 ; e-mail : mgarland{at}svherc.ucd.ie
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ABSTRACT |
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Aims To examine the relationship between total serum cholesterol and psychological parameters in parasuicide.
Method Total serum cholesterol and self-rated scores for impulsivity, depression and suicidal intent were measured in 100 consecutive patients following parasuicide, pair-matched with normal and psychiatric control groups.
Results Backward, stepwise multiple regression analysis revealed a significantly lower mean cholesterol in the parasuicide population (P<0.01). Across all groups there was an independent significant (P<0.01) negative correlation between cholesterol and self-reported scores of impulsivity. No correlation existed between cholesterol and scores for depression or suicidal intent.
Conclusions The data confirm previous reports of low cholesterol in parasuicide. This is the first reported investigation of the construct of impulsivity in relation to cholesterol. We hypothesise that the reported increased mortality in populations with low cholesterol may derive from increased suicide and accident rates consequent on increased tendencies to impulsivity in these populations.
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INTRODUCTION |
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METHOD |
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Two control populations were recruited : normal (n=100) and psychiatric (n=100). These were pair-matched for age and gender with the index cases. The same relevant exclusion criteria were applied. The normal controls were recruited from the medical day ward on the morning of their elective admission for minor diagnostic or therapeutic procedures. The psychiatric controls were recruited from the out-patient psychiatric department. Patients with a prior history of DSH were excluded from these groups.
Assessments
Patients (DSH and psychiatric) were diagnosed according to ICD-10 research
diagnostic criteria (World Health
Organization, 1993) with the relevant Axis I and II diagnoses. In
addition to standard demographic data, the following were documented : weekly
alcohol intake, with cut-off points as defined by the Royal College of
Psychiatrists' guidelines
(1986) : 21 units per week
for men and
14 units per week for women ; violence of the attempted DSH,
classified as high (e.g. self-hanging) or low (e.g. self-poisoning) ;
intoxication at the time of DSH ; and the presence of a clear, acute (within
the previous 24 hours) precipitating event for the DSH.
The following self-rated instruments were administered :
All of the above have documented satisfactory psychometric properties.
Cholesterol estimation
Total serum cholesterol was measured on a Beckman Synchron CX7 analyser by
an enzymatic timed end-point method (Allain
et al, 1974). In this method, serum specimens are diluted
1:100 with reagents. The cholesterol esters are hydrolysed by the enzyme
cholesterol esterase to yield free cholesterol and fatty acids. The free
cholesterol is oxidised to cholesten-3-one and hydrogen pyroxide by another
enzyme, cholesterol oxidase. Peroxidase then catalyses the reaction of
hydrogen pyroxide with 4-aminoantipyrine and phenol to produce a colored
quinoneimine product (Trinder's reaction). The change in absorbence at 520 nm
is proportional to the cholesterol concentration in the specimen. The fasting
status of subjects was not recorded because the cholesterol level is not
altered significantly by this (Cohn et
al, 1988). Venous blood was drawn in the morning.
Statistical analysis
Comparisons between continuous variables in the three matched groups were
made using analysis of variance (ANOVA) for paired samples. Variables were
then entered into backward, stepwise multiple regression analysis ; where
necessary, continuous psychometric variables were subdivided into tertiles.
The second principal analysis was within groups. Within each group, the
association of cholesterol as a continuous variable with variables of interest
was estimated using Pearson's correlation coefficient for continuous variables
and the two-sided t-test for categorical variables. Factors
significant on univariate analysis were entered into a backward, stepwise
multiple regression model to determine independent factors. To facilitate
analysis, axis I and II psychiatric diagnoses were both split into two groups
: axis I disorders into depressive- (including adjustment disorder) and
non-depressive-spectrum illnesses ; axis II into impulsive- (dissocial and
emotionally unstable) and non-impulsive-spectrum personality disorders.
We next examined the index population with each control group separately, using backward stepwise logistic regression. Finally, we examined the association with variables of interest within male and female groups separately, with factors significant on univariate analysis entered into a backward, stepwise multiple regression model.
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RESULTS |
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Table 3 displays the results of the multiple regression analysis of categorical and continuous data to determine independent factors associated with cholesterol across the three groups. Group type (DSH, normal or psychiatric), older age, social class IV, being married, lower non-planning and motor scores on the BIS-11 and having a desperate diagnosis remained independently significantly positively associated with the level of cholesterol across the three groups (n=300). A prior history of DSH, a medium or high motor sub-scale score on the BIS-11, a non-depressive diagnosis, being single and being from social classes II or III remained independently significantly negatively associated with the cholesterol level.
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Intra-group analysis
The data were then analysed within each group. The association of
cholesterol as a continuous variable with variables of interest was estimated
for continuous variables (Table
4) and for categorical variables
(Table 5). Factors significant
on univariate analysis were entered into a multiple regression model to
determine independent factors (Table
6).
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In the correlational analysis (Table 4), age remained strongly positively related to cholesterol level in all three groups. In the DSH group, the BDI score just failed to reach statistical significance (positive correlation), whereas motor impulsivity in the psychiatric controls was significantly negatively related to cholesterol level. No relationship was observed between cholesterol and self-reported suicidal intent in the DSH group.
The results in Table 5 reveal a significantly lower mean cholesterol level in those who used a violent means of DSH, had a non-depressive-spectrum illness and a non-impulsive-spectrum personality disorder. None of the other categorical variables was related to cholesterol.
The multivariate analysis of individual groups in Table 6 again confirms the independent association between age and cholesterol. Less highly significant associations existed between Axis II spectrum personality disorder (positive association for impulsive-spectrum disorders) in the DSH group and motor impulsivity in the psychiatric controls (negative association).
Comparison of DSH group with each control group
The DSH group was then compared with each control group individually. After
backward stepwise logistic regression, the cholesterol level remained
independently associated with group type when compared with the psychiatric
control after adjusting for age and gender (odds ratio=0.48,
P<0.01). Similar analysis of the normal control group after
adjustment failed to show a significant difference in cholesterol between the
two groups.
Analysis by gender
Finally, the level of cholesterol was examined within each gender group.
For males (n=90), total BDI score (P=0.04) and attentional
(P=0.01) and non-planning (P=0.004) sub-scales of the BIS-11
were each negatively associated with cholesterol levels, whereas being
unemployed and older were positively associated. After multivariate analysis,
only non-planning impulsivity (negative association, P=0.007) and age
(positive association, P=0.0001) were associated independently. A
similar analysis in the female group (n=210) revealed an independent
(positive) association for increasing age only.
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DISCUSSION |
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However, one needs to bear in mind the very large populations used in the epidemiological studies in this area (see below) in considering the findings of this more modestly sized study. The finding of a lower mean cholesterol in parasuicide accords with other published studies. By systematically examining cholesterol in relation to psychological correlates, our study has taken a further step in examining the relevance of this lipid to mental health.
Low cholesterol and mortality
Epidemiological evidence strongly suggests the existence of a J-shaped
curve in relation to total cholesterol and mortality, and that the principal
causes of mortality in the low cholesterol populations are trauma (road
traffic accidents, homicide, etc.) and suicide. The largest study examining
low cholesterol and mortality was that of Jacobs et al
(1992), who pooled the results
of 20 naturalistic cohort studies (total population over 600 000) and found an
excess mortality, in adults with lower cholesterol levels, from deaths due to
non-cancer, non-cardiovascular causes and trauma (including suicide,
P <0.001). This effect persisted after controlling for age, race,
smoking, income and blood pressure. In
1990, Muldoon et al
published a meta-analysis of six large cholesterol-lowering primary prevention
trials that found no overall reduction in mortality between treatment and
non-treatment groups (n=27 847, P=0.004). It was found that
an excess of violent and non-accidental deaths, including suicide, in the
treatment groups compensated for the reduced cardiac mortality. On the basis
of these results, it appears reasonable to hypothesise that low cholesterol as
a trait, or as the desired result of cholesterol-lowering treatment, may in
some way influence CNS function or act as a peripheral marker for factors
governing predisposition to death by trauma and suicide.
Cholesterol and the CNS
Enkelberg (1992), aware
that peripheral cholesterol exchanges freely with that in the CNS, proposed
that, as a principal component of neuronal membranes, the concentration of
cholesterol could determine the availability of the serotonin receptor and its
transporter by inducing changes in their quaternary structure. He refers to
in vitro work that has demonstrated just this : cholesterol, by
increasing the microviscosity of mouse synaptosomal membranes, greatly
enhanced serotonin uptake intracellularly
(Heron et al, 1980).
This hypothesis provides a model to address not only the phenomenon of excess
suicides in those with low cholesterol, but also the increased mortality from
accidents and trauma. Hyposerotonergic function is not just linked to
depression, parasuicide and completed suicide, but it is also linked to
aggression and impulsivity (Coccaro,
1989), which are crucial antecedents to accidents, trauma,
parasuicide and suicide (Romanov et
al, 1994).
Cholesterol in psychiatric populations
The results of studies examining cholesterol in different psychiatric
disorders have often been conflicting. For depressive disorders the findings
have been inconclusive and possibly confounded by weight loss secondary to
depression (Law et al,
1994). The literature on cholesterol and disorders of impulsivity
and aggression is also equivocal. Virkkunen
(1983) did, however, find
lower mean cholesterol levels in a population of homicidal offenders and, in
later studies, arsonists and those with antisocial personality disorder and
aggressive conduct disorder. As reviewed by Wardle
(1995), cholesterol-lowering
drugs in five prospective studies showed no effects on depression or
aggression. However, all of the parasuicide studies have revealed
significantly lower total cholesterol concentrations in their study
populations. Of these studies, Kunugi et al
(1997) (n=99), Golier
et al (1995)
(n=650) and our own all controlled for potential confounders such as
weight loss.
Cholesterol and serotonin
The evidence to support a cholesterolserotonin link is also divided, but
somewhat less so. Anderson et al
(1990) found that a 3-week
low-calorie diet reduced plasma tryptophan and increased prolactin secretion
in response to a tryptophan challenge. Streegmans et al
(1996) reported a significant
correlation between plasma serotonin and cholesterol level in a population of
100 men with low cholesterol but not in a reference population with normal
cholesterol. Terao et al
(1997) found a significant
positive correlation between serum cholesterol and prolactin response to the
serotonin agonist m-chlorophenylpiperazine in ten healthy volunteers.
However, Delva et al
(1996) found no relationship
between cholesterol, plasma tryptophan and d-fenfluramine-induced
prolactin release (a probe of central serotonergic function) in 40 subjects,
20 of whom were on cholesterol-lowering treatment. Similarly, Ringo et
al (1994) examined the
cholesterolserotonin relationship in 84 humans and found only an
insignificant correlation between total serum cholesterol and cerebrospinal
fluid (CSF) 5-hydroxy-indoleacetic acid (5-HIAA). With animal studies, Kaplan
et al (1994) found
lower 5-HIAA concentrations and more aggressive and less affiliative behaviour
in 17 cynomolgus monkeys fed a low-cholesterol diet compared with animals on
normal rations.
Other lipids and the CNS
The focus of recent research on lipids has not limited itself to
cholesterol. Studies are now finding important correlates between another
lipid fraction obtained exclusively from diet - the essential fatty acids
(EFAs) - and the same psychological parameters associated with cholesterol and
serotonin (i.e. depression, impulsivity, hostility, etc.) (see
Horrobin, 1998, for review).
Although cholesterol is an important component of neuronal membrane
phospholipid, so too are the EFAs. The two most common cerebral EFAs,
arachidonic acid and docosohexaenoic acid (DHA), make up 15% of the dry weight
of the brain. Small changes in membrane EFA composition can produce large
quaternary conformational changes in proteins, which include receptors and ion
channels. Large variations in behaviour due to differing dietary EFA intake
are therefore possible. One illustration is the strong correlation that has
been described recently between fish consumption and the incidence of major
depression across the world (r=-0.84 ; P <0.005)
(Hibbeln, 1998). Fish is a
principal source of DHA. Hibbeln et al
(1998) found a strong
correlation between CSF serotonin metabolites and EFAs, particularly DHA
(P <0.0002), in a population of alcoholics. This finding also
applied to normal controls. It may be that cholesterol, in previous studies,
was acting as a surrogate marker for EFAs. This possibility is currently
being examined.
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CLINICAL IMPLICATIONS AND LIMIATIONS |
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LIMITATIONS
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Received for publication June 30, 1999. Revision received December 16, 1999. Accepted for publication December 16, 1999.