The puzzling relationship between cholesterol and psychopathology

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study, better cognitive scores were found in patients with higher fasting cholesterol and triglyceride levels (H.A.N., unpublished data, 2017).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