From the Editor

The puzzling relationship between cholesterol and psychopathology

Current Psychiatry. 2018 January;17(1):4-5,20

References

1. Hallahan B, Garland MR. Essential fatty acids and mental health. British J Psychiatry. 2005;186(4):275-277.
2. Papakostas GI, Ongür D, Iosifescu DV, et al. Cholesterol in mood and anxiety disorders: review of the literature and new hypotheses. Eur Neuropsychopharmacol. 2004;14(2):135-142.
3. Muldoon MF, Manuck SB, Matthews KA, et al. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ. 1990;301(647):309-314.
4. Jakovljevic´ M, Reiner Z, Milicic´ D, et al. Mental disorders, treatment response, mortality and serum cholesterol: a new holistic look at old data. Psychiatr Danub. 2007;19(4):270-281.
5. Rogers PJ. A healthy body, a healthy mind: long-term impact of diet on mood and cognitive function. Pro Nutr Soc. 2001;60(1):135-143.
6. Björkhem I. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med. 2006;260(6):493-508.
7. Tuem KB, Atey TM. Neuroactive steroids: receptor interactions and responses. Front Neurol. 2017;8:442.
8. Borroni MV, Vallés AS, Barrantes FJ. The lipid habitats of neurotransmitter receptors in the brain. Biochim Biophys Acta. 2016;1858(1):2662-2670.
9. Pfrieger FW. Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci. 2003;60(6):1158-1171.
10. Graham I, Atar D, Borch-Johnsen K, et al; European Society of Cardiology (ESC); European Association for Cardiovascular Prevention and Rehabilitation (EACPR); Council on Cardiovascular Nursing; European Association for Study of Diabetes (EASD); International Diabetes Federation Europe (IDF-Europe); European Stroke Initiative (EUSI); Society of Behavioural Medicine (ISBM); European Society of Hypertension (ESH); WONCA Europe (European Society of General Practice/Family Medicine); European Heart Network (EHN); European Atherosclerosis Society (EAS). European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of none societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2007;14(suppl 2):S1-S113.
11. 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(4):371-377.
12. Ryman A. Cholesterol, violent death, and mental disorder. BMJ. 1994;309(69525):421-422.
13. Wardle J. Cholesterol and psychological well-being. J Psychosom Res. 1995;39(5):549-562.
14. Irribarren C, Reed DM, Chen R, et al. Low serum cholesterol and mortality. Which is the cause and which is the effect? Circulation. 1995;92(9):2396-2403.
15. Stampfer MJ. Cardiovascular disease and Alzheimer’s disease: common links. J Intern Med. 2006;260(3):211-223.
16. Raffai RL, Weisgraber KH. Cholesterol: from heart attacks to Alzheimer’s disease. J Lipid Res. 2003;44(8):1423-1430.
17. Chen CC, Lu FH, Wu JS, et al. Correlation between serum lipid concentrations and psychological distress. Psychiatry Res. 2003;102(2):153-162.
18. Mössmer 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(3):141-174.
19. Papakostas GI, Petersen T, Sonawalla SB, et al. Serum cholesterol in treatment-resistant depression. Neuropsychobiology. 2003;47(3):146-151.
20. Gabriel A. Changes in plasma cholesterol in mood disorder patients: does treatment make a difference? J Affect Disord. 2007;99(1-3):273-278.

Cholesterol generally is regarded as a cardiovascular risk factor when elevated. However, numerous studies suggest that cholesterol levels—both high and low—may be associated with various psychiatric brain disorders.¹ Thus, psychiatrists should mind their patients’ cholesterol because it may affect their minds, not just their hearts.

The relationship between cholesterol and mental illness is fascinating, complex, and perplexing. Whether elevated or reduced, cholesterol’s effects can be deleterious or salutary, but the literature is riddled with conflicting reports. Physicians should measure their patients’ serum cholesterol levels not only to assess cardiovascular risk, but because cholesterol can be associated with certain neuropsychiatric disorders or may predict the lack of response to psychopharmacotherapy.²

The fact that lowering total cholesterol levels in people with hypercholesterolemia reduces the risk of coronary heart disease is indisputable. Large-scale cardiology clinical trials have shown a significant reduction in mortality from heart disease or stroke with cholesterol-lowering drugs (statins). However, the same trials found an uptick in “unnatural deaths,” mostly suicide or homicide.³ Those findings triggered numerous intriguing reports of the association between cholesterol levels and psychopathology.

Consider the following:

Low cholesterol levels have been associated with depression, antisocial personality disorder, borderline personality disorder, and dissociative disorder.⁴
High cholesterol levels have been associated with schizophrenia, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, and posttraumatic stress disorder.⁴
Some studies suggest that high cholesterol levels are associated with better mental health, mental processing speed, social skills, responsibility, self-control, and self-awareness.⁵
In the Clinical Antipsychotic Trials of Intervention Effectiveness schizophrenia study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).

The brain is only 2% of body weight, but it contains 25% of the body’s cholesterol.⁶ Cholesterol is important for brain function and neurotransmission because neuroactive steroids (NASs) are synthesized from cholesterol and they modulate brain processes and interact with γ-aminobutyric acid, N-methyl-d-aspartate, and serotonin receptors (all of which are implicated in psychiatric disorders) as well as neurotrophins such as nerve growth factor.⁷ NASs are involved in mood regulation and cognition, and regulate synaptic plasticity, apoptosis, and neuroprotection.⁷ For the brain to function normally, NASs must maintain normal levels, because low levels may lead to adverse consequences, such as depression, neuroinflammation, epilepsy, multiple sclerosis, and psychosis. On the other hand, high levels may lead to attention-deficit/hyperactivity disorder and stress. Thus, NASs—such as pregnane, androstane, and sulfated neurosteroids, all synthesized from cholesterol—are critical molecules with major neuropsychiatric activity.⁸ This may provide clues to the mechanisms of action by which cholesterol levels influence psychiatric brain functions. Cholesterol has been described as a multipurpose molecule that is a critical component of neuronal cell membranes and a precursor for many signaling molecules.⁹

Interestingly, both extremes in cholesterol levels represent a high risk for premature mortality.¹⁰ Hypercholesterolemia leads to early death from coronary artery disease. Studies that evaluated statins to lower cholesterol found increased mortality from suicide, accidents, and violence.¹¹ Even without statin treatment, among persons with naturally low cholesterol, there is a significant increase in mortality from non-medical causes.¹² However, some studies did not find an association between hypocholesterolemia and suicide.^13,14

There also is some evidence that elevated cholesterol may play a role in dementia.¹⁵ Reducing cholesterol with statins decreases beta-amyloid in mice, while the opposite occurs with elevated cholesterol.² Another possible mechanism by which high cholesterol worsens dementia is that neurodegeneration in Alzheimer’s disease (AD) breaks down neuronal cell membranes, which releases the neurotoxic metabolite of cholesterol (24-hydroxycholesterol), which leads to further neurodegeneration.¹⁶ Statins may decrease the production of 24-hydroxycholesterol in AD patients and slow down neurodegeneration.¹⁶

References

‘Self-anesthetizing’ to cope with grief

The puzzling relationship between cholesterol and psychopathology

References

Pages

Next Article: