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Department of Adult Psychiatry, Galway University Hospital and the Clinical Sciences Institute, National University of Ireland, Galway
Department of Experimental Pharmacology, National University of Ireland, Galway
Department of Adult Psychiatry, Galway University Hospital and the Clinical Sciences Institute, National University of Ireland, Galway
Department of Clinical Biochemistry, Galway University Hospital
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Rockville, Maryland, USA
Department of Experimental Pharmacology, National University of Ireland, Galway
Department of Epidemiology and Biostatistics, The Royal College of Surgeons in Ireland, Dublin, Ireland.
Correspondence: Dr Malcolm R. Garland, St Ita’s Hospital, Portrane, County Dublin, Ireland. Email: mgarland{at}ireland.com
See pp.
118–122, this
issue. 
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONREFERENCES |
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Aims To determine whether people who self-harm also have low levels of essential fatty acids (EFAs) and to examine associations between the EFAs and serotonergic function.
Method Depression, impulsivity and suicidal intent were measured in patients with self-harm (n=40) and matched controls, together with plasma lipids and EFAs. Platelet serotonergic studies were carried out in a subgroup (n=27).
Results Patients with self-harm had significantly more pathology on all psychometric measures, lower mean total cholesterol levels (4.18 (s.d.=0.93) v. 4.87 (s.d.=0.83) mmol/l, P=0.003) and lower mean total EFA levels (89. 5 (15.6) v.103.7 (17.1) µg/ml, P=0.0001) than controls after adjustment for confounding variables. Total n-3 and n-6 EFA levels were also significantly lower. Impulsivity and depression scores were significantly inversely correlated with both n-6 EFAs and n-3 EFAs, but were not associated with total or low-density lipoprotein cholesterol levels. Platelet serotonergic measures did not differ between groups, and were not related to psychobiological measures.
Conclusions Lower plasma EFA levels combined with low cholesterol concentrations were associated with self-harm as well as impulsivity and affect. This was not related to platelet serotonergic measures.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONREFERENCES |
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Patients with self-harm exhibit a convergence of many constructs related to serotonergic dysfunction (e.g. depression, impulsivity and violence; Mann, 2003). Low concentrations of serotonin metabolites (5-hydroxyindoleacetic acid (5-HIAA)) in the cerebrospinal fluid of those who attempt suicide is a well-replicated finding and is frequently linked to impulsive and self-destructive behaviours (see Roggenbach et al, 2002). The primary aim of this study was to examine lipid and EFA levels in patients following an act of self-harm. Secondary aims were to examine associations between lipids/EFAs and two common psychopathological constructs in self-harm: impulsivity and depression. We also sought to explore, in a subgroup, any mediating influence of the serotonergic system.
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONREFERENCES |
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Assessments
In addition to demographic data, the following were documented: body mass
index (BMI); weekly alcohol intake (with cut-off points defined by the Royal
College of Psychiatrists’ guidelines
(1986) for men (
21
units/week) and women (14 units/week). In addition, all participants were
diagnosed according to ICD–10 criteria
(World Health Organization,
1993) with the relevant Axis I diagnosis. Menstrual cycle status
was recorded as being follicular, peri-ovulatory or luteal.
The psychometric measures used were as follows. The Suicide Intent Scale (SIS; Beck et al, 1974) is a 15-item scale which is rated from 0 to 2 for each item, giving a total score range of 0–30. The Beck Depression Inventory (BDI; Beck et al, 1961) is a 21-item self-rated instrument. The Barratt Impulsivity Scale–II (BIS; Barratt, 1994) is a 34-item instrument in which all items are answered on a 4-point scale. There are three sub-scales: attentional impulsivity (e.g. ‘I concentrate easily’, ‘I get easily bored when solving thought problems’), motor impulsivity (e.g. ‘I do things without thinking’, ‘I am self-controlled’) and non-planning impulsivity (e.g. ‘I plan tasks carefully’, ‘I finish what I start’).
Laboratory methods
Fasting antecubital venous blood was drawn from all participants in the
morning. All samples were immediately frozen and stored at –80°C
until use. Plasma for EFA analysis was transported on dry ice by overnight
courier to the USA (to J.R.H.). Owing to insufficient blood, serotonergic data
are missing for 13 patients (and controls). Cholesterol measures and EFA data
were available for all participants.
Cholesterol
Total plasma cholesterol was measured on a Beckman Synchron CX7 Analyser by
an enzymatic timed end-point method (Allain
et al, 1974).
Plasma EFAs
Fatty acids were extracted from plasma by adding 200 µl to 2 ml
trichloromethane (CHCl3), 1 ml BHT-MeOH and a known quantity of
23:0 methyl ester as an internal standard. After brief vortexing 1 ml of 0.2
mol/l disodium hydrogen phosphate (Na2HPO4) was added.
The samples were capped under nitrogen and vortexed again. After
centrifugation CHCl3 was removed and dried under nitrogen. Samples
were methylated under boron influoride/methanol for 60 min. Samples were kept
cold and under nitrogen throughout the analysis to prevent oxidation. Gas
chromatography was performed on a HP 5890 series II with a flame ionisation
detector, an autosampler and a FFAP capillary column. Peaks were identified
using authentic standards. Fatty acids were quantified by comparison with peak
areas of the 23:0 internal standard. When samples were subjected to thawing
and refreezing, within- and between-run coefficients of variance were less
than 0.3% and 5% respectively.
Platelet studies
Many studies support the association between platelet serotonergic measures
and psychopathology, the platelet having physiological properties in common
with the neuron (Owens & Nemeroff,
1994). This measure has the advantage of being less invasive than
other methods of assessing serotonergic function (e.g. lumbar puncture for
5-hydroxyindole acetic acid (5-HIAA) or neuroendocrine probes).
Pellets from platelet-rich plasma were frozen at –80°C for later use in the (3H)-paroxetine binding assay as described previously (Kelly et al, 1999). The data for each participant were reduced initially by using iterative curve-fitting routines (GraphPad version 2.0; http://www.graphpad.com/prism/Prism.htm) to yield dissociation equilibrium constants (Kd) and maximal binding capacity (Bmax) (saturation analyses – one-site binding hyperbolae). The Bmax reflects the number of functioning serotonin transporter molecules on the platelet membrane; the Kd is an inverse measure of the affinity of the ligand (paroxetine) for the transporter.
Statistical analysis
Data were analysed using Stata 9.2/SE Release. Linear regression was used
to estimate mean values and their confidence intervals for patients and
controls, with adjustment for confounding variables. However, because some of
the fatty acid measures were not normally distributed, statistical comparisons
between patients and controls on these measures were made using ordered
logistic regression with conversion of the fatty acid measures to deciles.
Robust variance estimation (Huber–White estimation) was used in all
regression models to compensate for the non-independence of observations
within case–control pairs. Partial correlations were calculated between
fatty acid measures and psychometric scores, adjusting for the effects of
social class, alcohol and smoking. These correlations were calculated with
both fatty acid and psychometric measures transformed to decile scores to
guard against the potential influence of outlier values.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONREFERENCES |
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Mean total n-6 EFA levels were not associated with social class (P=0.653), smoking (P=0.192), alcohol consumption (P=0.471), or regular exercise (P=0.540). Mean total n-3 EFA levels were not associated with social class (P=0.448), smoking (P=0.740), alcohol consumption (P=0.610), or regular exercise (P=0.808). Mean total cholesterol levels were not associated with social class (P=0.616), smoking (P=0.876), or regular exercise (P=0.486). They were, however, associated with alcohol consumption (P=0.037), cholesterol levels being 0.45 IU/l lower in those with excess alcohol consumption. Mean high-density lipoprotein (HDL) cholesterol levels were not associated with social class (P=0.070), smoking (P=0.906), or regular exercise (P=0.653). They were, however, associated with alcohol consumption (P=0.043), mean levels being 0.2 IU/l higher in those with excess alcohol consumption. Mean low-density lipoprotein (LDL) cholesterol levels were not associated with social class (P=0.423), smoking (P=0.640), or regular exercise (P=0.425). They were, however, associated with alcohol consumption (P<0.001), mean levels being 0.73 IU/l lower in those with excess alcohol consumption.
To examine the effect of alcohol on the estimation of differences in lipid levels between patients and controls, we performed regressions unadjusted and adjusted for alcohol consumption, followed by Wald post hoc comparisons of the coefficients associated with case–control status between the models. For total cholesterol, the coefficient associated with case–control status was unchanged when alcohol consumption was added to the model (Wald P=0.766). Although HDL levels did not differ significantly between patients and controls, the coefficient was also unchanged when alcohol was added to the model (Wald P=0.750). Likewise, the changes in the coefficients for LDL cholesterol (Wald P=0.328) and triglycerides (P=0.805) were non-significant.
Two of the patients met ICD–10 criteria for depressive disorder and a further four met criteria for adjustment disorder. Scores on the BDI were significantly higher in patients than controls. The BIS scores were also higher in patients than controls, both overall and on the three sub-scales.
Table 2 shows the lipid measures. Patients had significantly lower total cholesterol concentrations than controls and lower LDL cholesterol concentrations. However, when LDL levels were corrected for total cholesterol using the cholesterol/LDL ratio, the difference between patients and controls was not statistically significant. The other lipid indices, HDL cholesterol and triglycerides, were similar in patients and controls. Adjusting lipid comparisons for alcohol, smoking and social class did not make any substantive change to these findings. Subsequent addition of age and gender to the models was not associated with any of the variables. No consistent relationship was demonstrated between lipids and psychopathology (data not shown).
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There were no significant differences in platelet serotonergic indices between patients and controls, although Bmax for patients was lower, at 371 (s.d.=265) v. 458 (s.d.=229) fmol/mg, for controls. The Kd was 0.313 (s.d.=0.44) and 0.304 (s.d.=0.49) nM for patients and controls respectively.
Table 3 shows mean fatty acid levels in patients and controls, adjusted for social class, smoking and alcohol consumption. The levels of statistical significance are based on ordered logistic regression using deciles of fatty acids. Two comparisons between patients and controls are shown: the first compares absolute levels of fatty acids, corrected for social class, alcohol and smoking; the second also adjusts for total fatty acid level.
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Total fatty acids, total saturates and total monounsaturates did not differ significantly between patients and controls after controlling for alcohol, social class and smoking status. However, there were significant differences in levels of EFAs, total n-6 fatty acids and linoleic acid, with higher levels in controls. Total n-3 fatty acids were also higher in controls than in patients, as were eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels. There were no significant differences between patients and controls in arachidonic acid or alpha-linoleic acid levels.
When we controlled for total fatty acid level, in addition to social class, smoking and alcohol, the differences reported above remained statistically significant. In addition, patients had a significantly higher level of monounsaturates.
Table 4 shows the partial correlations between fatty acids and scores on the BIS and the BDI, adjusted for social class, alcohol consumption and smoking. There were significant negative correlations between both impulsivity and depression scores and total n-6 and n-3 fatty acids.
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We also examined the relationship of total cholesterol and LDL cholesterol to impulsivity and depression scores, using multiple regression to adjust for differences in mean score levels between patients and controls, as well as for smoking, alcohol and social class. Neither total cholesterol nor LDL cholesterol was associated with variation in impulsivity or depression scores, when adjusted in this manner. Among the patients there was no relationship between lipid parameters and degree of suicidal intent.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONREFERENCES |
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Weaknesses in this study included the small population, although it was sufficiently powered to detect the primary findings. None the less, such a small study may result in some false-negative conclusions and therefore any negative findings should be treated as absence of evidence, not evidence of absence. Likewise, for the positive findings small sample size limited the statistical power to control for possible confounding factors. The disparity in demographic variables between patients and controls was marked and potentially important; however, we were fortunate that the only confounder in the psychobiological data was an association between alcohol consumption and total, LDL and HDL cholesterol levels. Accordingly minimal adjustment was necessary prior to analysis. The loss of samples for the serotonergic studies was unfortunate and these data need to be considered with caution owing to the possibility of a false-negative result (type II error).
With such caveats in mind, our findings suggest there is a greater risk of self-harm and psychopathology predisposing to self-harm in individuals with low plasma cholesterol (both total and LDL cholesterol) and low n-3 and n-6 EFAs. Such predisposition is likely to be longstanding, as one of the two psychopathological constructs we measured, impulsivity, is a trait construct. Although cholesterol is an important component of the neuronal membrane (Engelberg, 1992), we feel it is acting as a marker or ‘bystander’ for EFA levels and is not the primary source of the deficit in the participants with self-harm. When at the lower end of the spectrum, low EFA levels (in dietary supplementation studies) are associated with low cholesterol levels (Harris et al, 1997); the brain synthesises its own cholesterol de novo (Pardridge & Mietus, 1980) and there is no relationship between peripheral and central (nervous system) levels, contrasting with the tight correlation between EFAs in plasma and cerebrospinal fluid (Yao et al, 2002). In this study, any relationship between impulsivity and depression scores and cholesterol/LDL ratio disappeared when adjusted for EFA levels. Finally, attempts to correlate cholesterol with neurotransmitter function have generally been negative, whereas there are strong data for the EFAs (although we found no such correlation in our own small sample).
Causative factors for low lipid and EFA levels
Although our estimate of EFA intake was crude, the observed differences in
EFA levels between groups are unlikely to be accounted for purely by
differences in dietary intake. Apart from socio-demographic factors that were
controlled for in regression analysis, factors accounting for the observed
lower levels of cholesterol and EFAs warrant consideration.
Perinatal factors
Levitsky & Strupp
(1995) demonstrated the
enduring effects of malnutrition in the perinatal period on learning in rats.
Lozoff et al (1991)
have shown similar effects in bottle-v. breast-fed children, and
breast milk is a richer source of EFAs. Data on perinatal nutrition were not
recorded in our study.
Stress
Several mechanisms may bring about stress-related depletion of EFAs,
although this has not been demonstrated in human models. Chronic restraint
stress in rats was associated with increased lipid peroxidation, with
resultant neuronal phospholipid depletion
(Gulyaeva et al,
1989). Reductions in membrane-protective antioxidants, such as
superoxide dismutase, in a rat immobilisation stress model
(Sosnovskii et al,
1993) have been demonstrated as another potential pathway.
Stress and diet
Periods of emotional stress, as would be a prelude to self-harm, can lead
to changes in diet, such as a switch from lipid- and protein-rich foods to
carbohydrate-rich foods (Cohen et
al, 2002). This could alter levels of both cholesterol and
EFAs. In our study, dietary history was not recorded, although there was no
difference in BMI between groups.
Genetic factors
Allelic variation in one of many genes encoding enzymes in the anabolic and
catabolic pathways of EFA and lipid metabolism could account for differences
in peripheral levels of EFAs and lipids. However, apart from the report of
polymorphism in the phospholipase A2 gene in schizophrenia
(Peet et al, 1998),
no other abnormalities have been reported in psychiatric populations.
Low cholesterol/EFA and behaviour
As proposed by Engelberg
(1992) there is a sound
theoretical basis for linking low cholesterol levels with impaired
serotonergic neurotransmission and a number of in vitro studies
support this (Heron et al,
1980; Scanlon et al,
2001). However, in accordance with this study, clinical
investigations of the cholesterol–serotonin relationship (using a
variety of measures of serotonergic activity) have, with the exception of that
of Terao et al
(2000), been negative (e.g.,
Alvarez et al,
1999).
More studies support a direct role for EFAs in neurotransmission and neuronal function in general (see Hallahan & Garland, 2005). For example, concentrations of serotonin, dopamine and their respective metabolites nearly doubled after only 18 days in piglets that were fed formulas supplemented with arachidonic acid (an n-6 EFA) and DHA (an n-3 EFA) (de la Presa Owens & Innis, 1999). In a rat model (Delion et al, 1996) of diet-induced n-3 EFA deficiency, increased 5-HT2 platelet receptor density (indicative of reduced serotonin neurotransmission) was reported. The only human studies of which we are aware (for a review see Hibbeln, 1999) reported significant positive correlations between 5-HIAA in the cerebrospinal fluid and a variety of n-3 and n-6 EFAs in 45 healthy volunteers and an effect of n-3 EFA supplementation on adenosine diphosphate (ADP)-induced serotonergic amplification in platelets of patients with schizophrenia (Yao et al, 2002). However, the results are difficult to interpret. Our sample may have been too small to detect significant relationships between EFA and platelet serotonin.
Cholesterol/EFAs and psychiatric disorder
There appears to be a J-shaped relationship between cholesterol and
mortality, cohorts with low cholesterol being at increased risk from violent
death, including suicide (reviewed in
Garland et al, 2000).
Importantly, more recent data suggest that the therapeutic lowering of
cholesterol (by diet or statins) does not increase non-cardiovascular
mortality (including suicide) (Muldoon
et al, 2001) or psychological morbidity
(Stewart et al,
2000). However, unlike the fibrates, neither of these
cholesterol-lowering methods lowers EFAs. An earlier and widely cited
meta-analysis of cholesterol-lowering trials
(Muldoon et al, 1990)
that reported the increase in suicide analysed mainly trials using fibrate.
Although there are fewer data for epidemiological links between EFAs and
mental health, they are less equivocal. Strong negative correlations were
found between national per capita fish consumption and prevalence of
post-partum depression (Hibbeln,
2002) and depression (Hibbeln,
1999). The 100-fold increase in the prevalence of depression in
North America over as many years directly correlates with the increase in
consumption of saturated fats and n-6 EFAs as part of the ‘modern’
Western diet, at the expense of n-3 EFAs
(Hibbeln, 1999).
Lipids and EFAs in clinical populations
There is now clear evidence that self-harm is associated with lowered
cholesterol (Lester, 2002).
This reflects similar deficits in EFAs reported in the only previous study of
self-harm of which we are aware (Huan
et al, 2004), in which significant diminution of n-3 EFAs
(but not n-6 EFAs) was found in 100 patients but not in 100 matched controls,
after controlling for dietary intake of fish. Two studies support an
association between low levels of n-3 EFAs and impulsive/violent behaviour
(Virkkunen et al,
1987; Stevens et al,
1995). Moreover there is mounting evidence that EFA deficits are
present in syndromal psychiatric disorders
(Hallahan & Garland,
2005). Our accompanying paper
(Hallahan et al,
2007, this issue) details a randomised controlled trial of n-3 EFA
supplementation in a similar population with self-harm.
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Received for publication November 15, 2005. Revision received August 29, 2006. Accepted for publication October 3, 2006.
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  B. HALLAHAN, J. R. HIBBELN, J. M. DAVIS, and M. R. GARLAND Omega-3 fatty acid supplementation in patients with recurrent self-harm: Single-centre double-blind randomised controlled trial The British Journal of Psychiatry, February 1, 2007; 190(2): 118 - 122. [Abstract] [Full Text] [PDF]
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