Authors’ reply

We appreciate Dr. Terao’s comments on our review and would like to make a few concluding remarks.

First, we completely agree with Terao and Soya that cholesterol-lowering therapies do not seem to increase the risk of suicide. A meta-analysis of cholesterol-lowering therapies including more than 70,000 subjects showed no increase of mortality from suicide, accidents, and violence [9]. Statins significantly reduce cardiovascular morbidity and mortality [7] without increasing mortality from suicide or trauma [9].

Second, we do not have sufficient empirical evidence to conclude that naturally occurring low cholesterol concentrations are associated with increased risk of suicide, as suggested by Terao and Soya. Terao et al. [15] found a relationship between low cholesterol and depression, but not suicide. Some studies have found lower total serum cholesterol concentrations in suicide attempters [2] [5] [6] [10]. However, epidemiological studies on the association between cholesterol concentrations and completed suicide are controversial. Some studies reported an association between low cholesterol and suicide [11] [19]. Other studies have failed to find this association. In a large sample of 22,432 subjects, serum cholesterol concentration was not associated with mortality from suicides, accidents, and other violent deaths. Frequent use of alcohol increased mortality from these causes [18]. Iribarren et al. [3] reported a positive association between cholesterol and risk of suicide. Suicide risk increased with rising cholesterol concentrations. In a population of 37,635 persons, Tanskanen et al. [14] found that serum total cholesterol was positively related to the risk of violent suicide. Among subjects whose total serum cholesterol was in the highest category (≥ 8.0 mmol/L [309.4 mg/dl]), the adjusted relative risk of violent suicide was more than two-fold compared with the lowest category (< 5.0 mmol/L [193.3 mg/dl]).

Third, it has been postulated that reduced cholesterol concentrations in neuronal membranes may inhibit serotonergic neurotransmission. This hypothesis has been supported predominantly by animal experiments in monkeys [4] [8]. Using the cortisol response to meta-chlorophenylpiperazine (mCPP) in a small sample of young, healthy subjects, Terao et al. [16] [17] found a positive correlation between cholesterol and mCPP-induced cortisol response (double delta values) in males but not in females. With regard to the relationship between cholesterol and placebo-corrected area under the curve (cortisol), however, there was no significant correlation in either males or females. The major limitations of their study are that only young, healthy volunteers (mean age 24.7 years for females and 26.7 years for males) were investigated and that no subjects with cholesterol concentrations higher than 200 mg/dl were included. These data provide at best preliminary evidence for the assumption that low cholesterol may be associated with reduced serotonergic neurotransmission. Neither the cortisol nor the prolactin response to d-fenfluramine correlated significantly with serum cholesterol in depressed patients and suicide attempters [13]. Ringo et al. [12] found no relationship between serum cholesterol and cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations in humans. Other animal experiments [1] have found no relationship between cholesterol and parameters of central serotonergic neurotransmission.

In conclusion, at present we do not have sufficient empirical evidence that cholesterol-lowering therapies or naturally occuring low cholesterol concentrations are associated with increased risk of completed suicide or serotonergic hypoactivity. Further epidemiological and clinical studies are needed to investigate the relationship among cholesterol, essential fatty acids, depression, and suicide. Preclinical studies would be important to study possible modulatory effects of cholesterol and omega-3 fatty acids on pre- and postsynaptic serotonergic neurotransmission in vitro and in vivo.

References

• 1 Fernstrom M H, Verrico C D, Ebaugh A L, Fernstrom J D. Diet-induced changes in serum cholesterol concentrations do not alter tryptophan hydroxylation rate or serotonin concentrations in gerbil brain.  Life Sci. 1996;  58 1433-1444
• 2 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
• 3 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
• 4 Kaplan J R, Shively C A, Fontenot M B, Morgan T M, Howell S M, Manuck S B, Muldoon M F, Mann J J. Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys.  Psychosom Med. 1994;  56 479-484
• 5 Kim Y K, Lee H J, Kim J Y, Yoon D K, Choi S H, Lee M S. Low serum cholesterol is correlated to suicidality in a Korean sample.  Acta Psychiatr Scand. 2002;  105 141-148
• 6 Kunugi H, Takei N, Aoki H, Nanko S. Low serum cholesterol in suicide attempters.  Biol Psychiatry. 1997;  41 196-200
• 7 LaRosa J C, He J, Vupputuri S. Effect of statins on risk of coronary disease. A meta-analysis of randomized controlled trials.  JAMA. 1999;  282 2340-2346
• 8 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
• 9 Muldoon M F, Manuck S B, Mendelsohn A B, Kaplan J R, Belle S H. Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials.  Br Med J. 2001;  322 11-15
• 10 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
• 11 Partonen T, Haukka J, Virtamo J, Taylor P R, Lönnqvist J. Association of low serum total cholesterol with major depression and suicide.  Br J Psychiatry. 1999;  175 259-262
• 12 Ringo D L, Lindley S E, Faull K F, Faustman W O. Cholesterol and serotonin: seeking a possible link between blood cholesterol and CSF 5-HIAA.  Biol Psychiatry. 1994;  35 957-959
• 13 Sarchiapone M, Camardese G, Roy A, Della Casa S, Satta M A, Gonzales B, Berman J, De Risio S. Cholesterol and serotonin indices in depressed and suicidal patients.  J Affect Disord. 2001;  62 217-219
• 14 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
• 15 Terao T, Iwata N, Kanazawa K, Takano T, Takahashi N, Hayashi T, Sugawara Y. Low serum cholesterol levels and depressive state in human dock visitors.  Acta Psychiatr Scand. 2000;  101 231-234
• 16 Terao T, Nakamura J, Yoshimura R, Ohmori O, Takahashi N, Kjoima H, Soeda S, Shinkai T, Nakano H, Okuno T. Relationship between serum cholesterol levels and meta-chlorophenylpiperazine-induced cortisol responses in healthy men and women.  Psychiatry Res. 2000;  96 167-173
• 17 Terao T, Yoshimura R, Ohmori O, Takano T, Takahasi N, Iwata N, Suzuki T, Abe K. Effect of serum choleserol levels on meta-chlorophenylpiperazine-evoked neuroendocrine responses in healthy subjects.  Biol Psychiatry. 1997;  41 974-978
• 18 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
• 19 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