Here, we show that lower serum cholesterol levels are linked with MDD and suicide attempt. Age and sex-adjusted analyses showed a clear association between serum cholesterol levels and the risk of depression and suicide attempt.

Previously, some studies have also shown an association between low cholesterol and increased risk of death due to injuries or suicide [2, 9, 26,27,28,29], but not in other reports [1, 30,31,32,33], even elevated cholesterol levels have been associated with suicide mortality in other studies [15, 33].

In Mexican subjects, there is only one research paper that has examined the possible link with hypocholesterolemia and suicide attempt in subjects with depression [34]. This study found no difference in lipid profiles between patients who had attempted suicide and those who had not. However, these authors studied only 33 patients with a major depressive episode (moderate to severe) comparing 18 subjects who had attempted suicide versus subjects who had never attempted suicide.

Although there is evidence of a link between low serum cholesterol levels and suicide in patients with depression [35, 36], the mechanism that may link serum lipids with suicidality is still unclear. It has been established that nearly all brain cholesterol is produced in situ through de novo synthesis and that adequate prevention of its uptake from the bloodstream is provided by selectivity of the blood-brain barrier [37,38,39]. Nonetheless, it is viable that decreased peripheral cholesterol in those individuals with psychiatric disorders occurs concurrently with cholesterol modifications that take place in distinct synaptic lipid rafts in neurons (by a common regulatory mechanism). This could produce the minimized activity of serotonergic communication and, consequently, give rise to instinctive responses and violent suicidal behavior [2, 40].

Cholesterol is the paramount constituent of cellular membranes in higher eukaryotes and is essential in membrane function and organization as well as dynamics and sorting. It is commonly found dispersed in a non-random form in specific areas (domains) in both biological and model membranes [41,42,43]. These areas, often denominated as ‘lipid rafts’ [43, 44], are thought to be fundamental in the preservation of the structure and function of the membrane. However, describing the spatiotemporal resolution of these domains has turned out to be a difficult task [43, 45]. It has been suggested that these formations be membrane domains in which signaling from a neurotransmitter may arise via a group of receptors, such as serotonin 1A (5-HT 1A ) receptor [46].

Previous studies demonstrated the imperative necessity of membrane cholesterol in the function and organization of the 5-HT 1A receptor [45, 47,48,49,50,51,52]. Results from additional studies showed that the fluidity of lipids considerably regulates the binding of serotonin (5-HT) in murine brain membranes. It is therefore expected that decreased levels of cholesterol would increase the fluidity of the cellular membrane. While, at the same time, minimal exposure of the 5-HT receptors would be found in the synaptic cleft [2, 53].

Reportedly, disturbance of rafts by cholesterol deficiency notably lowers agonist binding and coupling of G protein to 5-hydroxytryptamine 1A (5-HT1A) serotonin receptors in bovine hippocampal membranes [46, 47]. Serotonin 1A receptors typify one of the most formidable, evolutionarily primitive, yet largely conserved families of seven transmembrane G protein-coupled receptors (GPCRs) that span the membrane [45, 54]. Also, serotonergic signaling constitutes an important part in the formation and regulation of a multitude of functions such as behavioral, cognitive, and developmental [45]. Moreover, studies have demonstrated that there is an association between decreased 5-HT activity and suicide [2, 55].

It is noteworthy to mention that recent studies described crystal structures of GPCRs, including serotonin 1A receptor, that demonstrated structural proof of cholesterol binding sites [45, 56, 57].Currently, two conceivable pathways have been proposed by which membrane cholesterol could affect the structure and function of GPCRs: (i) by way of a direct/specific interaction with GPCRs, or (ii) via an indirect pathway by modifying the physical properties of the membrane in which the receptor is inserted, or as a result of an integration of both [45, 58].

About cholesterol levels and their relation to gender, our study showed that the decrease in total cholesterol levels occurred in both men and women. Other authors have reported a relationship between reduced cholesterol and suicidal tendencies only in males [13, 59,60,61,62]. However, it is worth noting that additional studies on the association between gender and serum cholesterol have been unconvincing.

A lack of consistency between different published reports coupled with the fact that, to date, it has not been possible to identify a cholesterol threshold level capable of precipitating a psychiatric disorder, suggests the presence of a non-linear relationship.

The existence of reports in which depression has been associated with increased cholesterol levels would support this hypothesis. A possible explanation for this, proposed the involvement of monoamine oxidase (MAO). The aforementioned model studies associated hypercholesterolemia with depression in hypercholesterolemic mice via monoaminergic metabolism. Specifically, they reported increased monoamine oxidase (MAO) A and B activity in the hippocampus of mice [63, 64]. Thus providing one possible reason why elevated levels of cholesterol are able to produce depression much like decreased levels are able to, but via independent mechanisms.

Besides total cholesterol, other studies that investigated the link between triglycerides, HDL cholesterol and LDL cholesterol, observed contrasting results between different populations. Our results showed higher levels of triglycerides in subjects with MDD and MDD associated with suicide attempt. These findings do not coincide with data previously reported in 2015 that observed decreased levels of triglycerides in subjects with suicidal attempts [65]. However, other authors report conflicting findings, even suggesting a positive association between triglyceride levels and the risk of suicidal behavior [15]. Considering LDL cholesterol levels, our results coincide with the conclusions of a meta-analysis published in 2016, which included a total of 36 different studies and found overall association between lower LDL levels and depression [66]. With respect to VLDL levels, which were significantly higher in MDD versus healthy controls, it is worth noting that few studies report VLDL levels. Taking this into consideration, our result is different from the result reported in a previous study [67] that showed significantly lower levels while our results demonstrate higher levels. With respect to HDL cholesterol levels, our results did not demonstrate significant differences when comparing subjects with MDD, subjects with MDD associated with suicide attempt and the control group. This fact contrasts with previous studies in which significant differences in HDL cholesterol between subjects with attempted suicide and healthy controls were shown [59, 68].

Lastly, we found a significant association between elevated triglyceride levels versus MDD and MDD with suicide attempt. Our finding coincides with a previous study which found a correlation between depressive symptoms and triglyceride levels [69] and suggestions by others which postulate that high triglyceride levels are associated with Type A personality traits, such as hostility, anger and domineering attitudes [70].

Several limitations of this study deserve to be mentioned. First, because our study is based on a case-control design, temporality could be not inferred with certainty. Whether hypocholesterolemia is a risk factor for developing depression and suicide attempt or merely an associated epiphenomenon can not be assured with certainty; second, we did not measure 24 S-hydroxycholesterol levels, which is a peripheral biomarker of brain cholesterol metabolism. However, it is expected that reduction of total cholesterol would reduce 24 S-hydroxycholesterol [71]. Besides, we did not evaluate dietary intake; however, because subjects in the groups of the study were enrolled from the same socio-cultural and economic background, it is expected that customary diets were similarly distributed. Finally, an additional limitation of our study is that we did not analyze the cardiovascular risk associated with serum cholesterol concentrations. In the future, it will be important to profoundly analyze the contradictory results reported with regard to cholesterol's role in depression. [63, 64]. This would help to verify if cholesterol is, in fact, a viable biomarker for neuropsychiatric disorders. It is evident that these results may be extrapolated only to a population that is similar to our own with similar exclusion criteria. Strengths of our study include the inclusion of incident cases of suicide attempt, which is a recognized tool to minimize analysis bias in the cross-sectional studies; also, the exclusion of individuals with lipid-lowering drugs allows us to control the potential source of bias.