by Randy A. Sansone, MD, and Lori A. Sansone, MD
Dr. R. Sansone is a professor in the Departments of Psychiatry and Internal Medicine at Wright State University School of Medicine in Dayton, Ohio, and Director of Psychiatry Education at Kettering Medical Center in Kettering, Ohio; Dr. L. Sansone is a family medicine physician in practice (government service) and Medical Director, Primary Care Clinic at Wright-Patterson Air Force Base. The views and opinions expressed in this column are those of the authors and do not reflect the official policy or the position of the United States Air Force, Department of Defense, or US government.
A number of investigators have found a possible relationship between low serum cholesterol levels and mood disorders. In addition, low serum cholesterol levels have been associated with suicidal ideation and suicide attempts. While the pathophysiology of this association remains unknown, some researchers have postulated that there may be a relationship between altered lipid metabolism and changes in serotonin functioning. In addition, some researchers have found that the pharmacological treatment of depression results in increased serum cholesterol levels. While controversies and inconsistencies characterize this area of study, it appears reasonable to conclude the following: (a) alterations in lipid metabolism may be one of several risk factors for the subsequent development of depression and/or suicidal ideation/suicide attempts (i.e., a non-specific contributory variable) and/or (b) low serum cholesterol levels are an inconsistent but possible biological marker for the manifestation of these phenomena in some individuals.
Low Cholesterol and Depression
A number of studies in various types of populations have found an association between low serum cholesterol levels and depressive symptoms and/or mood disorders.
General population studies. In a Finnish community sample of nearly 30,000 participants, investigators found that low serum cholesterol levels were associated with depressed mood and a heightened risk of hospitalization for depression.
Outpatient samples. In addition to general population studies, the relationship between low serum cholesterol levels and depression has been explored in outpatient samples. For example, in an Irish study of primary care patients, Rafter found that participants with low serum cholesterol levels scored significantly higher on depression assessments.
Inpatient samples. A relationship between low serum cholesterol levels and depressed mood has also been examined among various types of psychiatric inpatient samples. For example, in an Italian study, Borgherini and colleagues found that lower serum cholesterol levels correlated with higher scores on the depression assessment that was used in this study. In a US study, Ghaemi and colleagues examined consecutive admissions to an affective disorders unit and found, compared with the bipolar subsample, lower cholesterol levels among those with unipolar depression.5 Glueck and colleagues examined hospitalized patients with affective disorders and, in comparison with controls, found a relationship between low serum cholesterol levels and affective disorders. These findings have been replicated in other studies, as well.[7–9]
Cholesterol and depression in special populations. In addition to the association between low serum cholesterol levels and depressive symptoms/mood disorders in community and general patient samples, investigators have examined this relationship in somewhat unique types of populations. For example, Pjrek and colleagues confirmed this relationship in a controlled study of patients with seasonal affective disorder. Dimopoulos and colleagues substantiated this relationship in a sample of elderly Greek patients. Their findings among elderly patients were echoed in a sample of Finnish males as well as a US sample of patients over the age of 70 years. A relationship between low serum cholesterol and depressive symptoms has also been found among women during the post-partum period.[14–16]
Studies with negative findings. While a substantial number of studies indicate an association between low serum cholesterol levels and depressive symptoms and diagnoses, not all studies have found support for such a relationship. For example, in a nonclinical sample of Japanese males, investigators found that higher serum cholesterol levels were associated with depression. Negative findings have been reported in several other clinical studies of depressed individuals as well.[18–25] To augment the preceding findings, among a large retrospective sample of patients suffering from affective psychoses, Fritze and colleagues found no association between low serum cholesterol levels and depressive symptoms. Findings have also been negative in several studies of post-partum women.[27,28]
Low Cholesterol and Suicidal Ideation/Suicide Attempts/parasuicide
Cholesterol and suicidal ideation. In addition to studies on the relationship between cholesterol and depressive symptoms/disorders, investigators have also examined the relationship between low serum cholesterol levels and suicidal ideation. For example, in a controlled study from South Korea, Kim and Myint examined depressed patients admitted to an emergency department and developed subsamples according to the presence or not of suicidal ideation. Compared to those without such ideation, those with suicidal ideation evidenced lower serum cholesterol levels. These findings were replicated in a Polish study by Rabe-Jablonska and Poprawska, in which low serum cholesterol levels statistically correlated with suicidal ideation.
Cholesterol and suicide attempts. In addition to suicidal ideation, low serum cholesterol levels have been associated with bonafide suicide attempts. For example, in a controlled study from the UK, Kunugi and colleagues examined patients who were admitted from the emergency department following a suicide attempt; compared with non-attempting psychiatric inpatients and normal controls, those with suicide attempts evidenced lower serum cholesterol levels. Sarchiapone and colleagues examined patients who were admitted to hospital following an intentional overdose. Compared with controls, the cohort of patients’ status-post overdose had significantly lower serum cholesterol levels. In an Israeli sample, Modai and colleagues found that compared with non-suicidal depressed patients, suicide attempters evidenced significantly lower serum cholesterol levels.
In keeping with these data, researchers from New Zealand examined the relationship between low serum cholesterol levels and the degree of the suicidal process. Using three levels of status (i.e., no suicidal thoughts, suicidal thoughts, suicide attempt), Sullivan and colleagues found that there was a significant association between lower serum cholesterol levels and increasing degrees of suicidal experience.
Finally, Garland and colleagues examined cholesterol abnormalities among a consecutive sample of patients with self-harm behavior, but not genuine suicide attempts (i.e., parasuicidal patients). In this population, investigators also found a significantly lower mean serum cholesterol level.
Studies with negative findings. As expected, several studies have found no association between low serum cholesterol levels and suicidal ideation.[20,26] There are also studies that indicate no relationship between low serum cholesterol levels and bonafide suicide attempts[36–40] or parasuicidal behavior. Finally, among a cohort of schizophrenic patients, there was no association between low serum cholesterol levels and completed suicide.
Interpretation of Available Data
Given these conflicting data, we suggest the following tentative conclusions. Despite the noted inconsistencies in empirical findings, there are a substantial number of studies that support a relationship between low serum cholesterol levels and depressive symptoms/disorders and suicidal ideation/suicide attempts. In affected individuals, this relationship appears most often to be an inverse one (i.e., that low serum cholesterol levels correlate with these various psychiatric phenomena). That the relationship is an inconsistent one does not necessarily imply that it is an invalid one. Rather, the inconsistency suggests that the relationship is probably a variable or a partial one (i.e., low serum cholesterol levels variably or partially contribute to or manifest with these psychiatric phenomena) that may only be relevant in some individuals. Given the role of variable or partial contribution, whether this relationship is genuinely causal (i.e., that low serum cholesterol levels contribute to the generation of psychopathology) or secondary (psychopathology results in low serum cholesterol levels) remains unknown.
If low serum cholesterol levels are genuinely associated with the described psychopathologies, what might be the pathophysiology of such a relationship? The pragmatic answer is that no one knows. Papakostas and colleagues offer some in-depth and complex hypotheses that might explain the relationship between low serum cholesterol levels and the discussed psychopathologies. These explanations relate to cholesterol levels in cell membranes, inhibited neuronal growth, and attenuated serotonergic function. Other authors discuss the possible roles of serotonin transporters, decreased serotonin receptors, inter-relationships with leptin, dietary intake, decreased serotonin turnover, interleukin-2, and genetics. Given the plethora of tentative possibilities, there is likely to be a very complex and/or an elusive psychobiological interface.
Medications and Effects on Cholesterol
Given that the preceding data is inconsistent, we suggest that the relationship between low serum cholesterol and depressive symptoms/disorders and suicidal ideation/attempts is not a strictly predictable one. Rather, it appears to be only partially and moderately specific. Given this tentative conclusion, is there any evidence that medications can cause simultaneous changes in serum cholesterol levels and mood?
Cholesterol-lowering medications and psychopathology. As expected, the literature on the psychiatric effects of cholesterol-lowering medications is controversial. For example, Boston, Dursun, and Reveley indicate that there is substantial evidence that lowering cholesterol levels with medications is associated with an increase in various psychiatric disorders (e.g., depression) and violent deaths—findings that emerged in cardiovascular primary prevention studies. However, other investigators indicate that no such relationship is evident in their empirical studies.[52,53]
Psychotropic medications and cholesterol effects. In samples of depressed patients, several studies indicate that effective mood-disorder treatment results in an increase in serum cholesterol levels. These findings have been reported with various antidepressants and mood stabilizers, doxepin, imipramine, paroxetine, and even following treatment with electroconvulsive therapy. However, in future studies, the explicit duration of drug treatment as well as weight status throughout the study of participants would have to be meticulously clarified.
As expected, there are also studies indicating that antidepressant treatment does not affect cholesterol levels. For example, there is a six-week study of trazodone and a six-month study of bupropion—both with negative findings.
Given the inconsistencies in the data, it appears that only some individuals with low serum cholesterol levels evidence depressive symptoms, mood disorders, suicidal ideation, and/or suicide attempts. Whether this metabolic peculiarity is causal or secondary to these psychopathologies is unknown. In addition, we do not know if this particular subgroup consistently responds to antidepressant treatment with an elevation in serum cholesterol levels. However, this area of investigation appears potentially fertile. Indeed, future investigations need to examine whether some individuals have a predisposition to depressive symptoms/mood disorders and suicidal ideation/suicide attempts that is presaged by low serum cholesterol levels; whether cholesterol assessment, in conjunction with the measurement of other metabolic or neurohormonal parameters, might suffice as a biological marker in some susceptible individuals; and whether in affected individuals, cholesterol elevation with treatment signifies a consistently good response to medications. Only further investigation will clarify these intriguing cholesterol quandaries.
1. Mossner R, Mikova O, Koutsilieri E, et al. Consensus paper of the WFSBP Task Force on Biological Markers: Biological markers in depression. World J Biol Psychiatry 2007;8:141–74.
2. Partonen T, Haukka J, Virtamo J, et al. Association of low serum total cholesterol with major depression and suicide. Br J Psychiatry 1999;175:259–62.
3. Rafter D. Biochemical markers of anxiety and depression. Psychiatry Res 2001;103:93–6.
4. Borgherini G, Dorz S, Conforti D, et al. Serum cholesterol and psychological distress in hospitalized depressed patients. Acta Psychiatr Scand 2002;105:149–52.
5. Ghaemi SN, Shields GS, Hegarty JD, Goodwin FK. Cholesterol levels in mood disorders: High or low? Bipolar Disord 2000;2:60–4.
6. Glueck CJ, Tieger M, Kunkel R, et al. Hypocholesterolemia and affective disorders. Am J Med Sci 1994;308:218–25.
7. Maes M, Delanghe J, Meltzer HY, et al. Lower degree of esterification of serum cholesterol in depression: Relevance for depression and suicide research. Acta Psychiatr Scand 1994;90:252–8.
8. Maes, M, Smith R, Christophe A, et al. Lower serum high-density lipoprotein cholesterol (HDL-C) in major depression and in depressed men with serious suicide attempts: Relationship with immune-inflammatory markers. Acta Psychiatr Scand 1997;95:212–21.
9. Jow GM, Yang TT, Chen CL. Leptin and cholesterol levels are low in major depressive disorder, but high in schizophrenia. J Affect Disord 2006;90:21–7.
10. Pjrek E, Winkler D, Abramson DW, et al. Serum lipid levels in seasonal affective disorder. Eur Arch Psychiatry Clin Neurosci 2007;257:197–202.
11. Dimopoulos N, Piperi C, Salonicioti A, et al. Characterization of the lipid profile in dementia and depression in the elderly. J Geriatr Psychiatry Neurol 2007;20:138–44.
12. Aijanseppa S, Kivinen P, Helkala EL, et al. Serum cholesterol and depressive symptoms in elderly Finnish men. Int J Geriatr Psychiatry 2002;17:629–34.
13. Brown SL, Salive ME, Harris TB, et al. Low cholesterol concentrations and severe depressive symptoms in elderly people. BMJ 1994;308:1328–32.
14. Nasta MT, Grussu P, Quatraro RM, et al. Cholesterol and mood states at 3 days after delivery. J Psychosom Res 2002;52:61–3.
15. Troisi A, Moles A, Panepuccia L, et al. Serum cholesterol levels and mood symptoms in the postpartum period. Psychiatry Res 2002;109:213–19.
16. Beasley CL, Honer WG, Bergmann K, et al. Reductions in cholesterol and synaptic markers in association cortex in mood disorders. Bipolar Disord 2005;7:449–55.
17. Nakao M, Yano E. Relationship between major depression and high serum cholesterol in Japanese men. Tohoku J Exp Med 2004;204:273–87.
18. Oxenkrug GF, Branconnier RJ, Harto-Truax N, Cole JO. Is serum cholesterol a biological marker for major depressive disorder? Am J Psychiatry 1983:140:920–1.
19. Chung KH, Tsai SY, Lee HC. Mood symptoms and serum lipids in acute phase of bipolar disorder in Taiwan. Psychiatry Clin Neurosci 2007;61:428–33.
20. Huang TL. Serum cholesterol levels in mood disorders associated with physical violence or suicide attempts in Taiwanese. Chang Gung Med J 2001;24:563–8.
21. Sevincok L, Buyukozturk A, Dereboy F. Serum lipid concentrations in patients with comorbid generalized anxiety disorder and major depressive disorder. Can J Psychiatry 2001;46:68–71.
22. Chen CC, Huang TL. Association of serum lipid profiles with depressive and anxiety disorders in menopausal women. Chang Gung Med J 2006;29:325–30.
23. Ledochowski M, Murr C, Sperner-Unterweger B, et al. Association between increased serum cholesterol and signs of depressive mood. Clin Chem Lab Med 2003;41:821–4.
24. Kemp BJ, Spungen AM, Adkins RH, et al. The relationships among serum lipid levels, adiposity, and depressive symptomatology in persons aging with spinal cord injury. J Spinal Cord Med 2000;23:216–20.
25. Roy A, Roy M. No relationship between serum cholesterol and suicidal ideation and depression in African-American diabetics. Arch Suicide Res 2006;10:11–14.
26. Fritze J, Schneider B, Lanczik M. Autoaggressive behaviour and cholesterol. Neuropsychobiology 1992;26:180–1.
27. van Dam RM, Schuit AJ, Schouten EG, et al. Serum cholesterol decline and depression in the postpartum period. J Psychosom Res 1999;46:385–90.
28. Grussu P, Nasta MT, Quatraro RM. Serum cholesterol concentration and distress in the initial days after childbirth. Psychiatry Res 2007;151:159–62.
29. Kim YK, Myint AM. Clinical application of low serum cholesterol as an indicator for suicide risk in major depression. J Affect Disord 2004;81:161–6.
30. Rabe-Jablonska J, Poprawska I. Levels of serum total cholesterol and LDL-cholesterol in patients with major depression in acute period and remission. Med Sci Monit 2000;6:539–47.
31. Kunugi H, Takei N, Aoki H, Nanko S. Low serum cholesterol in suicide attempters. Biol Psychiatry 1997;41:196–200.
32. Sarchiapone M, Roy A, Camardese G, De Risio S. Further evidence for low serum cholesterol and suicidal behaviour. J Affect Disord 2000;61:69–71.
33. Modai I, Valevski A, Dror S, Weizman A. Serum cholesterol levels and suicidal tendencies in psychiatric inpatients. J Clin Psychiatry 1994;55:252–4.
34. Sullivan PF, Joyce PR, Bulik CM, et al. Total cholesterol and suicidality in depression. Biol Psychiatry 1994;36:472–7.
35. Garland M, Hickey D, Corvin A, et al. Total serum cholesterol in relation to psychological correlates in parasuicide. Br J Psychiatry 2000;177:77–83.
36. Engstrom G, Alsen M, Regnell G, Traskman-Bendz L. Serum lipids in suicide attempters. Suicide Life Threat Behav 1995;25:393–400.
37. Deisenhammer EA, Kramer-Reinstadler K, Liensberger D, et al. No evidence for an association between serum cholesterol and the course of depression and suicidality. Psychiatry Res 2004;121:253–61.
38. Fiedorowicz JG, Coryell WH. Cholesterol and suicide attempts: A prospective study of depressed inpatients. Psychiatry Res 2007;152:11–20.
39. Almeida-Montes LG, Valles-Sanchez V, Moreno-Aguilar J, et al. Relation of serum cholesterol, lipid, serotonin and tryptophan levels to severity of depression and to suicide attempts. J Psychiatry Neurosci 2000;25:371–7.
40. Brunner J, Bronisch T, Pfister H, et al. High cholesterol, triglycerides, and body-mass index in suicide attempters. Arch Suicide Res 2006;10:1–9.
41. Ryan M, Murray FE. Serum cholesterol concentrations in parasuicide. Scottish study does not replicate findings. BMJ 1995;311:807.
42. Kuo CJ, Tsai SY, Lo CH, et al. Risk factors for completed suicide in schizophrenia. J Clin Psychiatry 2005;66:579–85.
43. Papakostas GI, Ongur D, Iosifescu DV, et al. Cholesterol in mood and anxiety disorders: Review of the literature and new hypotheses. Eur Neuropsychopharmacol 2004;14:135–42.
44. Vevera J, Fisar Z, Kvasnicka T, et al. Cholesterol-lowering therapy evokes time-limited changes in serotonergic transmission. Psychiatry Res 2005;133:197–203.
45. Ergun UG, Uguz S, Bozdemir N, et al. The relationship between cholesterol levels and depression in the elderly. Int J Geriatr Psychiatry 2004;19:291–6.
46. Atmaca M, Kuloglu M, Tezcan E, et al. Serum leptin and cholesterol values in suicide attempters. Neuropsychobiology 2002;45:124–7.
47. Hillbrand M, Waite BM, Miller DS, et al. Serum cholesterol concentrations and mood states in violent psychiatric patients: An experience sampling study. J Behav Med 2000;23:519–29.
48. Fawcett J, Busch KA, Jacobs D, et al. Suicide: A four-pathway clinical-biochemical model. Ann NY Acad Sci 1997;836:288–301.
49. Penttinen J. Hypothesis: Low serum cholesterol, suicide, and interleukin-2. Am J Epidemiol 1995;141:716–18.
50. Rujescu D, Thalmeier A, Moller HJ, et al. Molecular genetic findings in suicidal behavior: What is beyond the serotonergic system? Arch Suicide Res 2007;11:17–40.
51. Boston PF, Dursun SM, Reveley MA. Cholesterol and mental disorder. Br J Psychiatry 1996;169:682–9.
52. Huffman JC, Stern TA. Neuropsychiatric consequences of cardiovascular medications. Dialogues Clin Neurosci 2007;9:29–45.
53. Wardle J, Armitage J, Collins R, et al. Randomised placebo controlled trial of effect on mood of lowering cholesterol concentration. Oxford Cholesterol Study Group. BMJ 1996;313:75–8.
54. Gabriel A. Changes in plasma cholesterol in mood disorder patients: Does treatment make a difference? J Affect Disord 2007;99:273–8.
55. Roessner V, Demling J, Bleich S. Doxepin increases serum cholesterol levels. Can J Psychiatry 2004;49:74-75.
56. Yeragani VK, Pohl R, Balon R, et al. Increased serum total cholesterol to HDL-cholesterol ratio after imipramine. Psychiatry Res 1990;32:207–9.
57. Lara N, Baker GB, Archer SL, Melledo JM. Increased cholesterol levels during paroxetine administration in healthy men. J Clin Psychiatry 2003;64:1455–9.
58. Kurt E, Guler O, Serteser M, et al. The effects of electroconvulsive therapy on ghrelin, leptin and cholesterol levels in patients with mood disorders. Neurosci Lett 2007;426:49–53.
59. Perry PJ, Garvey MJ, Dunner DL, et al. A report of trazodone-associated laboratory abnormalities. Ther Drug Monit 1990;12:517–9.
60. Othmer E, Othmer SC, Stern WC, Van Wyck Fleet J. Long-term efficacy and safety of bupropion. J Clin Psychiatry 1983;44:153–6.
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