Many authors have dealt with the attempt to understand the relationship between depressive disorder and cardiovascular disease, as well as the role of cholesterol as a risk factor in the respective diseases.
Recently, Cocchi et al. (2016) in a letter to the Editor of the BMJ Open, demonstrate the lack of importance of cholesterol in cardiovascular risk and that the assessment made by an Artificial Neural Network (Self-Organizing Map/SOM) and by a biochemical index (Stearic/Oleic ratio) for the classification of patients with a coronary plaque, was perfectly overlapping the physiological risk for age of the Framingham study, corresponding, at least, to 5000 cases. This shows the strong power of the Artificial Neural Network when the biological relationships are complex (Cocchi & Tonello, 2010) .
In this direction, it becomes important to clarify the relationship between serotonin and cholesterol, and also, in the light of experimental data, try to give a possible and plausible contribute to this intriguing problem.
2. Cholesterol and Serotonin
Acute coronary syndrome is characterized by a substantial decrease in total cho- lesterol (Balci, 2011) , as well as an aberrant lipid metabolism has been reported in coronary patients with and without depression (de Jonge et al., 2010; Stapelberg et al., 2011) .
There are also many evidences linking a low level of cholesterol to depression and suicide risk (Partonen et al., 1999; De Berardis et al., 2012; Rabe-Jablonska & Poprawska, 2000; Boston et al., 1996; Kaplan et al., 1997) .
It was suggested, also, that cholesterol in synaptic membranes may determine the number of serotonin receptors (Engelberg, 1992) and that cholesterol abnormalities may be involved with alterations of serotonergic mechanisms. Cholesterol, in addition, participate, substantially to the functional homeostasis of the membranes to regulate, together with the phospholipid fraction, their mobility (Cocchi et al., 2011; Cocchi et al., 2010) . More the cell membrane is viscous, more serotonin receptors are exposed, more is fluid, the serotonin receptors internalize and the uptake of serotonin does not occur (Tonello & Cocchi, 2010) .
Other studies have demonstrated the role of cholesterol in the organization and function of the 5-HT1A receptors (Payla et al., 2008) , furthermore chronic cholesterol depletion reduces the coupling of G protein of the 5-HT1A receptors (Shrivastava et al., 2010) .
Literature further investigates the total cholesterol levels in depressed patients to assess the risk of suicide (Kim et al., 2014) .
In this long-standing dispute between those who find high or low cholesterol in mood disorders, an interesting paper (Payla et al., 2008) shows how it is fundamental the brain region in which cholesterol levels are reduced and this area is the medial pre- frontal cortex, which is also the area of the decision-making ability. Cholesterol is not the main responsible for the ischemic heart disease and of the combined risk of depression and ischemic heart disease. In fact, we will see how novel markers identified by the SOM [some platelet fatty acids: Oleic, Linoleic and Arachidonic Acid for ischemic heart disease and Palmitic, Linoleic and Arachidonic Acid for depression] can explain, in a biochemical key, the interactions between depression and ischemia.
Before addressing this part, we try to clarify, in the light of recent acquisitions, the interdependence of the two phenomena (Depression and Cardiovascular Disease).
3. Depression and Cardiovascular Disease
Depression is a prevalent manifestation in patients with heart disease [stable CAD (Coronary Artery Disease), unstable angina, myocardial infarction]. In CAD, it is detected an incidence of Major Depression (MD) of at least three times higher than the general population (Kessler et al., 2003) and similar to that seen in chronic renal disease (Hedayati et al., 2006) .
Even those who undergo cardioinversion-defibrillation, patients with heart failure and atrial fibrillation are at serious risk of onset of the depressive phenomenon, mostly considered as Major Depression (Magyar-Russell et al., 2011; McCabe, 2010) .
A meta-analysis of patients with Heart Failure found an incidence of about 40% of dysthymia, Bipolar Disorder (BD), or MD, which represents the 15% of the total (Tully & Baker, 2012) . However, these data are reported with diagnostic questionnaires, with subjective evaluations and not with biological objective data. In fact, it is known, that there is a diagnostic misinterpretation which ranges from 40% (Bowden, 2001) to 70% (Tenth World Day forth Prevention of Suicide, 2012) .
Another recent paper (Hoffman et al., 2011) details a little better the relation depression- heart disease.
The prevalence of unrecognized depression in cardiac patients has been known for over 40 years.
In a survey conducted in 1967 (Wynn, 1967) in Australia, on heart patients, the perception of a depressive tendency has been estimated in 40% of the sample and, for many of the subjects, not previously recognized. In 1972 (Cay et al., 1972) , symptoms of anxiety and depression were detected in 2/3 of patients after cardiac event.
Because depression is a common occurrence in the CVD (Cardiovascular Disease), Hare et al. (2014) wonder if the CVD leads to depression or vice versa, and they point out that there are no arguments that depression is a marker for an increased incidence of CVD (Colquhoun et al., 2013; Nicholson et al., 2006) .
Regarding the causality of the relationship between depression and CVD, about the incidence and prognosis, it should be demonstrated that depression is a risk factor rather than a marker.
1. A longitudinal adjustment of patients that includes objective and perspective measurements of CVD.
2. That there is a strong, consistent and gradual relationship.
3. That the association cannot be explained by known covariates.
4. That there is the presence of potential and plausible biological mechanisms.
5. That there is evidence that altering the risk factors the prognosis changes.
An experimental design is practically impossible.
4. Ischemic Heart Disease and “Depression” or Depression and Ischemic Heart Disease
The summary of the work by Cocchi et al. (2011) describes the steps of the research that led to the classification of patients with ischemia and depression, using platelet fatty acids and a SOM. All pathological subjects were accurately identified (Major Depression (MD), Bipolar Disorder (BD) and Coronary plaque).
Each case has been recognized by the SOM providing a comprehensive picture of gravity with respect to the CAD and the recognition of cases of MD and BD. Within these two pathologies the SOM has further recognized cases of Obsessive Compulsive Disorder, severe psychosis and suicide attempt (Benedetti et al., 2014) . Out of the descriptive phase of research and because of the conflictual hypothesis of the scientific literature on the controversial interdependence of depression and coronary heart disease (Hare et al., 2014) , we have considered the subjects studied by evaluating crosswise the “depressed patients” within the SOM of ischemia and the ischemic patients within the SOM of depression. Below the results which are reported visually through the maps built by the SOM for Ischemic Heart Disease (CAIN) and Mood Disorders (ADAM) in the first experimental phase (Figures 1-4).
After having recognized the MD subjects and the BD subjects, it was made the same assessment (Figures 7-9).
Figure 1. Classification of ischemic patients in CAIN (red area).
Figure 2. Classification of normal subjects in CAIN (green area).
Figure 3. Distribution of patients with mood disorders in ADAM (green = normal; red, yellow and orange = pathologic).
Figure 4. Distribution of normal subjects in ADAM (green = normal; red, yellow and orange = pathologic).
Figure 5. Distribution of the Depressive patients (first experiment) in CAIN (green = normal; red = pathologic).
Figure 6. Distribution of the Ischemic patients (first experiment) in ADAM (green = normal; red, yellow and orange = pathologic).
Figure 7. Patients with MD in CAIN.
Figure 8. Patients with BD in CAIN.
Figure 9. Subjects with severe ischemia (second trial) in ADAM.
On the contrary, the subjects with severe ischemia are mainly concentrated in the classification of the most severe bipolars with a significant impact in the position 14:1, the area in which the suicide attempts have been classified. In the assessment made by the SOM, the Ischaemic subjects in the suicide risk area, are 17 over 83 patients studied. The percentage of suicidal risk is not far from that reported in the literature as suicidal risk among Ischaemic (Dou et al., 2015; Larsen et al., 2010) . We must remember, also, that the answer of the SOM is given on biological basis and not on subjective assessments. In the light of the results obtained, we can hypothesize that the ischemia, with its cell membrane molecular characteristic, could be responsible of the induction of a “depressive” state, a condition shared by the majority of subjects with ischemic heart disease.
In conclusion, it can be observed that it is very likely that cardiovascular disease can induce a “depressive” condition, probably due to the particular characteristics of the platelet membrane.
Cholesterol, Linoleic Acid and Serotonin (Cocchi & Minuto, 2015; Cocchi et al., 2015; Tonello et al., 2015) have proved to be important factors in determining the molecular aspects of the membrane that can affect both cardiovascular and psychiatric responses to this phenomenon.
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