Cholesterol, essential fatty acids, and suicide

Epidemiological and clinical studies have described an association between lower serum cholesterol concentrations and increased suicide risk that is not entirely attributable to depression-related malnutrition and weight loss. Recent epidemiological studies with greater samples and longer follow-up periods, however, have even shown a positive correlation between cholesterol concentrations and suicide risk after controlling for potential confounding variables. A meta-analysis of earlier intervention trials suggested that cholesterol lowering could cause or worsen depressive symptoms and increase the risk of suicide. Large trials of statins (simvastatin, lovastatin, and pravastatin) did not show an increase of suicide mortality. The aim of this selective review is to critically discuss the current evidence for a potential link between cholesterol, essential fatty acids, depression, suicide, impulsivity, and aggression. Preclinical data support the hypothesis that cholesterol reduction may contribute to the serotonergic abnormalities that have been postulated in suicidal subjects. Recently, it was hypothesised that a decreased consumption of polyunsaturated fatty acids, especially omega-3 fatty acids, may be a risk factor for depression and suicide. Currently, we do not have sufficient evidence that cholesterol-lowering therapies increase the risk of depression and suicide. Increasing the dietary intake of omega-3 fatty acids may increase central serotonergic activity and reduce impulsive and aggressive behaviours.

References

• 1 Adams P B, Lawson S, Sanigorski A, Sinclair A J. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression.  Lipids. 1996;  31 (suppl) 157-161
• 2 Alvarez J C, Cremniter D, Lesieur P, Gregoire A, Gilton A, Macquin-Mavier I. et al . Low blood cholesterol and low platelet serotonin levels in violent suicide attempters.  Biol Psychiatry. 1999;  45 1066-1069
• 3 Block E R, Edwards D. Effect of plasma membrane fluidity on serotonin transport by endothelial cells.  Am J Physiology. 1987;  253 C672-C678
• 4 Bronisch T. The relationship between suicidality and depression.  Archives of Suicide Research. 1996;  2 235-254
• 5 Brown D W, Ketter T A, Crumlish J, Post R M. Carbamazepine-induced increases in total serum cholesterol: clinical and theoretical implications.  J Clin Psychopharmacol. 1992;  12 431-437
• 6 Brunner J, Bronisch T. Neurobiologische Korrelate suizidalen Verhaltens.  Fortschr Neurol Psychiat. 1999;  67 391-412
• 7 Delion S, Chalton S, Hérault J, Guilloteau D, Besnard J C, Durand G. Chronic dietary α-linolenic acid deficiency alters dopaminergic and serotoninergic neurotransmission in rats.  J Nutr. 1994;  124 2466-2476
• 8 Delva N J, Matthews D R, Cowen P J. Brain serotonin (5-HT) neuroendocrine function in patients taking cholesterol-lowering drugs.  Biol Psychiatry. 1996;  39 100-106
• 9 Downs J R, Clearfield M, Weis S, Whitney E, Shapiro D R, Beere P A. et al . Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels.  JAMA. 1998;  279 1615-1622
• 10 Duits N, Bos F M. Depressive symptoms and cholesterol-lowering drugs.  Lancet. 1993;  341 114
• 11 Engelberg H. Low serum cholesterol and suicide.  Lancet. 1992;  339 727-729
• 12 Fawcett J, Busch K A, Jacobs D, Kravitz H M, Fogg L. Suicide: a four-pathway clinical-biochemical model.  Ann NY Acad Sci. 1997;  836 288-301
• 13 Freedman D S, Byers T, Barrett D H, Stroup N E, Eaker E, Monroe-Blum H. Plasma lipid levels and psychologic characteristics in men.  Am J Epidemiol. 1995;  141 507-517
• 14 Gallerani M, Manfredini R, Caracciolo S, Scapoli C, Molinari S, Fersini C. Serum cholesterol concentrations in parasuicide.  Br Med J. 1995;  310 1632-1636
• 15 Glueck C J, Tieger M, Kunkel R, Hamer T, Tracy T, Speirs J. Hypocholesterolemia and affective disorders.  Am J Med Sci. 1994;  308 (4) 218-225
• 16 Golier J A, Marzuk P M, Leon A C, Weiner C, Tardiff K. Low serum cholesterol level and attempted suicide.  Am J Psychiatry. 1995;  152 419-423
• 17 Golomb B A, Stattin H, Mednick S. Low cholesterol and violent crime.  Journal of Psychiatric Research. 2000;  34 301-309
• 18 Hamazaki T, Sawazaki M, Asaoka E, Nagao Y, Nishimura N, Yazawa K. et al . The effect of docosahexaenoic acid on aggression in young adults. A placebo-controlled double-blind study.  J Clin Invest. 1996;  97 1129-1133
• 19 Hawton K, Cowen P, Owens D, Bond A, Elliott M. Low serum cholesterol and suicide.  Br J Psychiatry. 1993;  162 818-825
• 20 Heron D S, Shinitzky M, Hershkowitz M, Samuel D. Lipid fluidity markedly modulates the binding of serotonin to mouse brain membranes.  Proc Natl Acad Sci USA. 1980;  77 (12) 7463-7467
• 21 Hibbeln J R, Linnoila M, Umhau J C, Rawlings R, George D T, Salem  N. Essential fatty acids predict metabolites of serotonin and dopamine in cerebrospinal fluid among healthy control subjects, and early- and late-onset alcoholics.  Biol Psychiatry. 1998;  44 235-242
• 22 Hibbeln J R, Salem N. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy.  Am J Clin Nutr. 1995;  62 1-9
• 23 Hibbeln J R, Umhau J C, Linnoila M, George D T, Ragan P W, Shoaf S E. et al . A replication study of violent and nonviolent subjects: cerebrospinal fluid metabolites of serotonin and dopamine are predicted by plasma essential fatty acids.  Biol Psychiatry. 1998;  44 243-249
• 24 Horsten M, Wamala S P, Vingerhoets A, Orth-Gomer K. Depressive symptoms, social support, and lipid profile in healthy middle-aged women.  Psychosomatic Medicine. 1997;  59 521-528
• 25 Iribarren C, Reed D M, Wergowske G, Burchfiel C M, Dwyer J H. Serum cholesterol level and mortality due to suicide and trauma in the Honolulu heart program.  Arch Int Med. 1995;  155 695-700
• 26 Kaplan J R, Muldoon M F, Manuck S B, Mann J J. Assessing the observed relationship between low cholesterol and violence-related mortaility. Implications for suicide risk.  Ann NY Acad Sci. 1997;  836 57-80
• 27 Kaplan J R, Shively C A, Fontenot M B, Morgan T M, Howell S M, Manuck S B. et al . Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys.  Psychosomatic Medicine. 1994;  56 479-484
• 28 Kunugi H, Takei N, Aoki H, Nanko S. Low serum cholesterol in suicide attempters.  Biol Psychiatry. 1997;  41 196-200
• 29 LaRosa J C, He J, Vupputuri S. Effects of statins on risk of coronary heart disease. A meta-analysis of randomized controlled trials.  JAMA. 1999;  282 2340-2346
• 30 LaRosa J C. Cholesterol lowering and morbidity and mortality.  Current Opinion in Lipidology. 1995;  6 62-65
• 31 Lechleitner M, Hoopichler F, Konwalinka G, Patsch J R, Braunsteiner H. Depressive symptoms in hypercholesterolaemic patients treated with pravastatin.  Lancet. 1992;  340 910
• 32 Lester D. The cencentration of neurotransmitter matabolites in the cerebrospinal fluid of suicidal individuals: a meta-analysis.  Pharmacopsychiat. 1995;  28 45-50
• 33 Maes M, Christophe A, Delanghe J, Altamura C, Neels H, Meltzer H Y. Lowered ω3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients.  Psychiatry Res. 1999;  85 275-291
• 34 Maes M, Smith R, Christophe A, Cosyns P, Desnyder R, Meltzer H. Fatty acid composition in major depression: decreased ω3 fractions in cholesteryl esters and increased C20 : 4ω6/C20 : 5ω3 ratio in cholesteryl esters and phospholipids.  Journal of Affective Disorders. 1996;  38 35-46
• 35 Maes M, Smith R, Christophe A, Vandoolaeghe E, Van Gastel V, Neels H. et al . Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicidal attempts: relationship with immune-inflammatory markers.  Acta Psychiatr Scand. 1997;  95 212-221
• 36 Maguire P A, Druse M J. The influence of cholesterol on synaptic fluidity, dopamine D1 binding and dopamine-stimulated adenylate cyclase.  Brain Res Bull. 1989;  23 69-74
• 37 Mann J J. The neurobiology of suicide.  Nature Medicine. 1998;  4 25-30
• 38 Modai I, Valevski A, Dror S, Weizman A. Serum cholesterol levels and suicidal tendencies in psychiatric inpatients.  J Clin Psychiatry. 1994;  55 252-254
• 39 Morgan R E, Palinkas L A, Barrett-Connor E L, Wingard D L. Plasma cholesterol and depressive symptoms in older men.  Lancet. 1993;  341 75-79
• 40 Muldoon M, Manuck S B, Matthews K A. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials.  Br Med J. 1990;  301 309-314
• 41 Muldoon M, Rossouw J E, Manuck S E, Glueck C J, Kaplan J R, Kaufmann P G. Low or lowered cholesterol and risk of death from suicide and trauma.  Metabolism. 1993;  42 (9 Suppl 1) 45-56
• 42 Muldoon M F, Kaplan J R, Manuck S B, Mann J J. Effects of a low-fat diet on brain serotonergic responsivity in cynomolgus monkeys.  Biol Psychiatry. 1992;  31 739-742
• 43 New A S, Sevin E M, Mitropoulou V, Reynolds D, Novotny S L, Callahan A. et al . Serum cholesterol and impulsivity in personality disorders.  Psychiatry Res. 1999;  85 145-150
• 44 Papaphilis A, Deliconstantinos G. Modulation of serotonergic receptors by exogenous cholesterol in the dog synaptosomal plasma membrane.  Biochemical Pharmacology. 1980;  29 3325-3327
• 45 Papassotiropoulos A, Hawellek B, Frahnert C, Rao G S, Rao M L. The risk of acute suicidality in psychiatric inpatients increases with low plasma cholesterol.  Pharmacopsychiat. 1999;  32 1-4
• 46 Partonen T, Haukka J, Virtamo J, Taylor P R, Lönnqvist J. Association of low serum total cholesterol with major depression and suicide.  British Journal of Psychiatry. 1999;  175 259-262
• 47 Ringo D L, Lindley S E, Faull K F, Faustman W O. Cholesterol and serotonin: seeking a possible links between blood cholesterol and CSF 5-HIAA.  Biol Psychiatry. 1994;  35 957-959
• 48 Rubins B H, Robins S J, Collins D, Fye C L, Anderson J W, Elam M B. et al . Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.  N Engl J Med. 1999;  341 410-418
• 49 Sacks F M, Pfeffer M A, Moye L A, Rouleau J L, Rutherford J D, Cole T G. et al . The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med. 1996;  335 101-109
• 50 Salter M. Low serum cholesterol and suicide.  Lancet. 1992;  339 1169
• 51 Scandinavian Simvastatin Survival Study Group.  Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian simvastatin survival study (4S). Lancet 1994 344: 1383-1389
• 52 Severus W E, Ahrens B. Omega-3 fatty acids in psychiatry.  Nervenarzt. 2000;  71 58-62
• 53 Shepherd J, Cobbe S M, Ford I, Isles C G, Lorimer A R, MacFarlane P W. et al . Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.  N Engl J Med. 1995;  333 (20) 1301-1307
• 54 Shih J C, Ohsawa R. Differential effect of cholesterol on two types of 5-hydroxytryptamine binding sites.  Neurochemical Research. 1983;  8 (6) 701-710
• 55 Spivak B, Lamschtein C, Talmon Y, Guy N, Mester R, Feinberg I. et al . The impact of clozapine treatment on serum lipids in chronic schizophrenic patients.  Clinical Neuropharmacology. 1999;  22 (2) 98-101
• 56 Steegmans P HA, Fekkes D, Hoes A W, Bak A AA, van der Does E, Grobbee D E. Low serum cholesterol concentrations and serotonin metabolism in men.  Br Med J. 1996;  312 221
• 57 Steinert T, Woelfle M, Gebhardt R P. No correlation of serum cholesterol levels with measures of violence in patients with schizophrenia and non-psychotic disorders.  Eur Psychiatry. 1999;  14 346-348
• 58 Stoll A L, Severus E, Freeman M P, Rueter S, Zboyan H A, Diamond E. et al . Omega 3 fatty acids in bipolar disorder. A preliminary double-blind, placebo-controlled trial.  Arch Gen Psychiatry. 1999;  56 407-412
• 59 Strandberg T E, Räikkönen K, Partinen M, Pihl S, Vanhanen H, Miettinen T A. Associations of cholesterol lowering by statins with anger and hostility in hypercholesterolemic men.  Biol Psychiatry. 1994;  35 575-577
• 60 Tanskanen A, Vartiainen E, Tuomilehto J, Viinamäki H, Lehtonen J, Puska P. High serum cholesterol and risk of suicide.  Am J Psychiatry. 2000;  157 648-650
• 61 The long-term intervention with pravastatin in ischaemic disease (LIPID) study group . Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.  N Engl J Med. 1998;  339 1349-1357
• 62 Vartiainen E, Puska P, Pekkanen J, Tuomilehto J, Lönnqvist J, Ehnholm C. Serum cholesterol concentrations and mortality from accidents, suicide, and other violent causes.  Br Med J. 1994;  13 445-447
• 63 Virkkunen M. Serum cholesterol levels in homicidal offenders.  Neuropsychobiology. 1983;  10 65-69
• 64 Virkkunen M E, Horrobin D F, Jenkins D K, Manku M S. Plasma phospholipid essential fatty acids and prostaglandins in alcoholic, habitually violent, and impulsive offenders.  Biol Psychiatry. 1987;  22 1087-1096
• 65 Yeragani V K, Balon R, Pohl R, Ramesh C. Imipramine treatment and increased serum cholesterol levels.  Canadian Journal of Psychiatry. 1989;  34 (8) 845
• 66 Zureik M, Courbon D, Ducimetière P. Serum cholesterol concentration and death from suicide in men: Paris prospective study I.  Br Med J. 1996;  313 649-651