Elsevier

Biological Psychiatry

Volume 44, Issue 4, 15 August 1998, Pages 235-242
Biological Psychiatry

Original Articles
Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics

https://doi.org/10.1016/S0006-3223(98)00141-3Get rights and content

Abstract

Background: Impulsive violence, suicide, and depression are strongly associated with low concentrations of cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA). Increased suicide and trauma reported in some cholesterol-lowering trials may be related to altered concentrations of polyunsaturated fatty acids rather than cholesterol, a possible surrogate marker.

Methods: CSF 5-HIAA and homovanillic acid (HVA), total cholesterol, and plasma fatty acid concentrations were examined in 176 subjects, including 49 healthy volunteers, and 88 early- and 39 late-onset alcoholics.

Results: Among each group, polyunsaturated fatty acids predicted both CSF 5-HIAA and CSF HVA concentrations, but total cholesterol was unrelated to either neurotransmitter metabolite. The relationships between plasma 22:6n3 and CSF 5-HIAA were significantly different when healthy volunteers (r = .35) were compared to early-onset alcoholics (r = −.38) (p < .0002).

Conclusions: Dietary studies are indicated to determine if essential fatty acid supplementation can influence central nervous system serotonin and dopamine metabolism and modify impulsive behaviors related to these neurotransmitters.

Introduction

A well-established finding in biological psychiatry is an association between low 5-hydroxyindoleacetic acid (5-HIAA) concentrations in cerebrospinal fluid (CSF) and an increased risk of attempted and completed suicide (Roy et al 1991). Low CSF 5-HIAA concentration, an indicator of reduced serotonin turnover rate in the frontal cortex (Stanley et al 1985), has also been reported to be associated with impaired impulse control (Mann 1995), unprovoked violent and aggressive behavior (Virkkunen et al 1994a), and hostility (Linnoila et al 1983). Muldoon et al (1990) observed that mortality due to suicide, homicide, and trauma appear to increase in therapeutic trials designed to lower plasma cholesterol. These two sets of findings prompted Engelberg (1992) to propose that lowering plasma cholesterol may reduce CSF 5-HIAA concentrations. Indeed, when cholesterol plasma concentrations were lowered by reducing cholesterol intake as an isolated dietary variable, rhesus monkeys became more aggressive while CSF 5-HIAA concentrations were reduced (Kaplan et al 1994).

We postulated that plasma concentrations of polyunsaturated essential fatty acids, rather than plasma cholesterol concentrations, would predict CSF 5-HIAA concentrations. An initial report of low plasma cholesterol concentrations among violent offenders also reported a deficiency in the essential fatty acid docosahexaenoic acid (22:6n3) and replacement with 22:5n6 (Virkkunen et al 1987). Docosahexaenoic acid (22:6n3), is selectively concentrated in neuronal membranes and appears critical for proper neuronal function (Salem et al 1986). Since polyunsaturated essential fatty acids also lower plasma cholesterol measures, they may be an important variable linking drug and dietary therapies that lower plasma cholesterol with increased suicide, homicide, and trauma-related mortality (Hibbeln and Salem 1995). Essential fatty acid plasma concentrations may reach deficient levels when fat intake is reduced by National Cholesterol Education Panel Step 2 diets Meydani et al 1993, Siguel and Lerman 1994, and diets deficient in 22:6n3 can decrease human brain concentrations of docosahexaenoic acid (Farquharson et al 1992). In rats, an n-3 fatty acid deficient diet resulted in a 44% increase in serotonin2A receptor density in the frontal cortex (DeLion et al 1994). Strikingly similar observations were reported in the frontal cortex of suicide victims, a 44% increase in serotonin2A receptor density (Stanley and Mann 1983).

In this cross-sectional observational study of healthy volunteers and abstinent alcoholics, we quantified plasma total cholesterol nonessential and essential fatty acids and CSF serotonin and dopamine metabolite concentrations obtained simultaneously under stringently controlled conditions on a locked research ward. Alcoholics were selected for study because of the strong association of suicidal and aggressive behaviors with a greater genetic risk of alcohol dependence described among alcoholics with an early onset of dependence (Mann 1995). Alcoholics who begin drinking at an early age suffer disproportionately more criminal, social, and clinical consequences of their drinking (Irwin et al 1990). Among early-onset violent Finnish alcoholics, low CSF 5-HIAA concentrations have been associated with a history of suicide attempts and with impaired impulse control, which leads to severe social and criminal consequences of their drinking Virkkunen et al 1994a, Virkkunen et al 1994b. A marked genetic vulnerability to develop alcoholism associated with early onset, suicide attempts, criminal acts, and male gender has been described in replicated adoption studies (Sigvardsson et al 1996). This genetic vulnerability may be related to a reduced central serotonin turnover rate (Roy et al 1987). Because early-onset alcoholics appear to be a genetically and clinically distinct subgroup, we also postulated that the relationship between concentrations of plasma essential fatty acids and CSF 5-HIAA may distinguish early-onset alcoholics from late-onset alcoholics and healthy volunteers.

Section snippets

Subjects

All subjects were admitted to the inpatient research ward of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) at the National Institutes of Health Clinical Center in Bethesda, Maryland. Samples of cerebrospinal fluid used to quantify neurotransmitter metabolite concentrations, and fasting plasma samples used to quantify total cholesterol concentrations and total fatty acid profiles, were obtained simultaneously. Dietary fat intake was not modified. Plasma was available for lipid

Subject characteristics

Age of onset of alcoholism and years of excessive alcohol consumption were the only descriptive variables that distinguished the three groups from each other Table 1, Table 2, Table 3. Hollingshead scores of socioeconomic class differed only between healthy volunteers (3.7) and early-onset alcoholics (2.8) (p < .0001). Similar differences were found in CSF 5-HIAA (p < .05) and HVA (p < .07) comparing early- to late-onset alcoholics in a two-group comparison, with 4 fewer alcoholics than

Discussion

In this cross-sectional study of healthy volunteers and abstinent alcoholics, CSF concentrations of 5-HIAA were predicted by plasma concentrations of polyunsaturated fatty acids, and in particular by docosahexaenoic acid, an n-3 essential fatty acid selectively concentrated in the brain (Figure 1)(Salem 1989). CSF 5-HIAA is a neurotransmitter metabolite of serotonin that has been repeatedly associated with the pathophysiology of violent, suicidal, and impulsive behaviors (Mann 1995). These

Acknowledgements

The authors wish to thank Ivan Mefford, PhD (CSF metabolite assays), Gerald L. Brown, MD (psychiatric assessment), and Michael Eckardt, PhD and Susan Schoaf, PhD (critical comments).

References (45)

  • M Peet et al.

    Depletion of dososahexaenioc acid in erythrocyte membranes of depressed patients

    Biol Psychiatry

    (1998)
  • A Roy et al.

    Reduced serotonin turnover in a subgroup of alcoholics?

    Prog Neuropsychopharmacol Biol Psychiatry

    (1987)
  • N Salem et al.

    Docosahexaenoic acidMembrane function and metabolism

  • M Scheinin et al.

    Simultaneous determination of 3-methoxy-4-hydroxyphenolglycol, 5-hydroxyindolacetic acid and homovanillic acid in cerebrospinal fluid with high performance liquid chromatography using electrochemical detection

    Anal Biochem

    (1983)
  • M Stanley et al.

    Increased serotonin-2 binding in frontal cortex of suicide victims

    Lancet

    (1983)
  • M Stanley et al.

    Correlations between aminergic metabolites simultaneously obtained from human CSF and brain

    Life Sci

    (1985)
  • L.J Stevens et al.

    Essential fatty acid metabolism in boys with attention-deficit hyperactivity disorder

    Am J Clin Nutr

    (1995)
  • M.E Virkkunen et al.

    Plasma phospholipid essential fatty acids and prostaglandins in alcoholic, habitually violent, and impulsive offenders

    Biol Psychiatry

    (1987)
  • P.B Adams et al.

    Arachidonic to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression

    Lipids

    (1996)
  • L Buydens-Branchey et al.

    Age of alcoholism onsetII. Relationship to susceptibility to serotonin precursor availability

    Arch Gen Psychiatry

    (1989)
  • M.J Eckardt et al.

    Relationship between neuropsychological performance and alcohol consumption in alcoholics

    Biol Psychiatry

    (1978)
  • J Endicott et al.

    A diagnostic interviewThe Schedule for Affective Disorders and Schizophrenia

    Arch Gen Psychiatry

    (1978)
  • Cited by (0)

    Dr. Markku Linnoila is deceased.

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