This is the first analysis to report unfavorable changes in biomarkers for atherogenic dyslipidemia in healthy male participants in the context of weight loss following a seven-day administration of 30 mg/d mirtazapine. This observation is remarkable and provides insights into the short-term effects of mirtazapine on lipid metabolism that are independent of weight gain.
While weight gain and metabolic derangement are a well-described side effect of mirtazapine treatment in individuals with psychiatric disorders,  the effect of mirtazapine on lipid metabolism in healthy participants is less investigated. In healthy individuals, there is only one comparable study that investigated changes in lipid metabolism related to mirtazapine treatment. Nicholas and colleagues found that a four-week treatment with mirtazapine 15 mg per day, which was increased to 30 mg per day at the beginning of week two, resulted in a significant rise in plasma triglycerides and weight gain in 50 healthy individuals using a placebo-controlled study design.  Aligning with the observation of Nicholas et al., in our study, we observed a significant rise in triglycerides. However, contrary to their findings, triglycerides increased in our participants in the absence of weight gain. We observed a small but systematic weight loss in all participants. The reasons for the slight weight loss observed under dietary clamping and unchanged energy expenditure remains unclear. The expected effect of weight loss and loss of intrahepatic fat content in particular on the lipid profile, would be a decrease in serum triglyceride levels/triglyceride-rich lipoproteins. [22,23] However, despite a slight weight loss, triglycerides significantly increased in our study participants. While none of the healthy study participants met criteria for dyslipidemia after exposure to mirtazapine, these findings are of potential clinical importance for two major reasons. First, the changes became evident after a very short period on mirtazapine, raising concerns about long-term effects on lipid metabolism. This question about long-term effects of mirtazapine on blood lipid levels in the context of stable weight or weight loss cannot be addressed with this study but warrants further research. Second, and importantly, biomarkers of atherogenic dyslipidemia worsened in our study in the context of weight loss. It appears that effects of short-term exposure to mirtazapine outweigh the lipid changes that would be expected in the context of weight loss. [22,23] Taken together, our findings suggest potential effects of mirtazapine on hepatic lipid metabolism independent of weight gain.
The effects we observed in healthy individuals with short term exposure to mirtazapine may be more pronounced and of higher clinical relevance in individuals with depressive disorders with an elevated risk for metabolic disorders [24,25] and/or individuals with pre-existing metabolic conditions or prolonged treatment with mirtazapine. In addition, mirtazapine induced increases in appetite and cravings for sweet foods as reported previously  might result in weight gain under normal dietary conditions and add to drug-induced dyslipidemia. [26,27] This may overall contribute to elevation of cardiovascular risk in addition to cardiovascular risk already associated with psychiatric conditions such as major depression. 
Mechanistically, the effect of mirtazapine on triglyceride levels may in part be explained by disinhibition of insulin secretion by mirtazapine due to inhibition of pancreatic ß-cell α2-adrenoceptors.  As reported previously, as expected in the context of disinhibition of insulin secretion, we observed increased insulin release with mirtazapine in our study.  This aligns with the observed triglyceride increase since insulin stimulates hepatic de novo lipogenesis and VLDL-secretion [serum triglycerides can be considered as a surrogate for VLDL in this study (VLDL=triglycerides/5)]. [27,29,30] Furthermore, increased insulin and triglyceride levels and decreased HDL-C might account for our observation of a decrease in LDL-C after mirtazapine exposure potentially explained by this mechanism: a rise in TG/HDL-C ratio, as we observed in our analysis, implies compositional changes of LDL-particles due to a metabolic shift which renders LDL particles cholesterol-depleted and triglyceride-enriched.  This results in a decrease in LDL-C (i.e. lower LDL-cholesterol content).  TG/HDL-C ratio is a metabolic index that serves as a surrogate for atherogenic dyslipidemia, which encompasses a constellation of lipoprotein abnormalities including high serum triglycerides, low HDL-C and an atherogenic lipoprotein phenotype, including a predominance of small, cholesterol-depleted LDL-P, and an accumulation of triglyceride-rich lipoproteins.  Higher TG/HDL-C ratio (i.e. high triglycerides and low HDL-C) is associated with both insulin resistance and measures of atherogenic dyslipidemia, which includes a smaller LDL-P diameter, higher remnant lipoprotein particle cholesterol and further traits that render low density lipoproteins more atherogenic such as increased ApoC3. [27,31] In patients with coronary artery disease, the the TG/HDL-C ratio was significantly higher in patients with thin-cap fibroatheromas than in those without, and it was non-significantly higher in patients with multiple recurrent acute coronary syndromes than in those with long-standing stable angina. [32-34]
Overall, although our study included healthy individuals neither meeting the criteria for atherogenic dyslipidemia or hypertriglyceridemia, nor carrying any common vascular risk factors as documented by a thorough clinical assessment, we observed significant adverse short-term changes in lipoprotein pattern which may in part be explained by increased drug-induced insulin release as shown in our prior analysis.  Extrapolating these changes that occurred in a short period in healthy individuals, and considering the effects of mirtazapine on weight gain without caloric restriction, it is likely possible that these effects are clinically significant in the long run, i.e., under longer term antidepressant treatment and/or in the context of pre-existing metabolic conditions. [12,27] These alterations associated with mirtazapine exposure may have the potential to contribute to elevated cardiovascular risk with longer administration of the drug as it is common in treatment of individuals with depressive or anxiety disorders. Of note, in the context of pre-existing metabolic disorders as frequently observed as a comorbidity in psychiatric patients and in the absence of dietary restriction as in this study,  mirtazapine-related changes in lipid metabolism are likely even more pronounced. Additionally, mirtazapine induced appetite, and cravings for sweet foods in particular in our participants  that would have exacerbated drug-induced dyslipidemia mediated by weight gain and/or increased intrahepatic fat content under free-running conditions. [26,27]
Limitations and Strengths
Our analysis is limited to short-term effects of mirtazapine on lipid metabolism and additional research investigating long-term effects is warranted. Further, the small sample size and the lack of a placebo group limit interpretation and generalizability, and our results should be regarded as explorative and hypothesis-generating. Nevertheless, the highly standardized conditions and the use of an ‘extremely’ healthy and homogenous study population may be a first step towards disentangling the direct, weight-independent pharmacological effects of mirtazapine on lipid metabolism.