How lipids may affect risk for suicidal behavior

Abstract

Suicide and nonfatal suicidal behaviors are major causes of mortality and morbidity worldwide. Variability in rates of suicide and suicidal behaviors within and between countries has been attributed to population and individual risk factors, including economic status and cultural differences, both of which can have suicide risk effects mediated through a variety of factors, of which perhaps the least understood is the role of diet. We therefore review the scientific literature concerning two major dietary lipid classes, cholesterol and polyunsaturated fatty acids (PUFAs), that have been associated with higher risk of suicide attempts and suicide. We consider potential mechanistic intermediates including serotonin transporters and receptors, toll-like receptors (TLRs), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and peroxisome proliferator activated receptors (PPARs). Based on this review, we describe a theoretical model linking cholesterol and PUFA status to suicide risk, taking into account the effects of cholesterol-lowering interventions on PUFA balance, membrane lipid microdomains (rafts) as a nexus of interaction between cholesterol and omega-3 PUFAs, and downstream effects on serotonergic neurotransmission and specific inflammatory pathways.

Figure 1.. Theoretical schematic of pathways through which an elevated n-6 to n-3 PUFA ratio could affect suicide risk.

Treatment with (1) diet, (2) fibrates and (3) statins that lower (4) cholesterol can cause (5) disruption of lipid rafts with functional consequences, due to lipid raft regulation of serotonin transporters and receptors, resulting in (6) decreased serotonergic neurotransmission, which has been shown to increase (12) suicide risk. (1) Diets replacing saturated fats with polyunsaturated oils high in n-6 PUFAs and (2) fibrates also can cause an increase in (7) the ratio of n-6 to n-3 PUFAs. This is, effectively, a lowering of n-3 that also is expected to contribute to (5) destabilization of lipid rafts, although directional effects of PUFAs on lipid rafts are complex and incompletely understood. More clearly, a higher n-6 to n-3 PUFA ratio directly promotes (10) inflammation, which is associated with (12) suicide risk. Also, lower n-3 PUFAs can indirectly result in increased inflammation by lowering DHA-mediated inhibition of (8) TLR dimerization and activation, resulting in downstream increased activation of (9) NF-KB, a (10) pro-inflammatory molecule. Either (1) decreased n-3 intake or (2) fibrate competition with EPA can reduce EPA binding to PPARs. Since (11) the EPA*PPARs complex acts as a brake on (9) NF-KB, interference with the EPA*PPARs complex via both mechanisms also contributes to activation (disinhibition) of (9) NF-KB. Counter to these pro-inflammatory forces, (5) decreased lipid raft functioning could decrease (8) TLR recruitment into lipid rafts and activation; and (3) statins may have lesser effects on (7) the n-6 to n-3 ratio and they also exert pleiotropic (10) anti-inflammatory effects that may mitigate (12) suicide risk. See text for all references substantiating these relationships.