Review articleDepression and serum low-density lipoprotein: A systematic review and meta-analysis
Introduction
In Engelberg's (1992) paper, “Low Serum Cholesterol and Suicide,” it is posited that cholesterol depletion leads to suicidality by way of serotonin-mediated mood alterations. A cross-sectional association between depression and low serum low density lipoprotein (LDL) has been noted in the literature. It has been speculated that this interplay between depression and LDL in the peripheral body system may be reflective of this aforementioned cholesterol depletion within the central nervous system. The blood-brain barrier segregates brain and body cholesterol into two distinct pools; in the body, LDL transports cholesterol to the cell membrane, whereas in the brain cholesterol is synthesized on-site (Orth and Bellosta, 2012). As such, it may be the case that the relationship between depression and low LDL in the periphery is indicative of a link between cholesterol depletion in the brain by way of a common upstream process. A study by Freemantle et al. (2013) found evidence suggesting that psychopathology may occur subsequent to elevated cholesterol turnover in the brain, which in turn may be associated with cholesterol depletion at the cell membrane. Similarly, Beasley et al. (2005) found evidence suggesting that the mechanism guiding the relationship between low cholesterol and depression pathogenesis may, at least in part, involve cholesterol-mediated alterations in nerve terminal structure and function. Additionally, Pucadyil and Chattopadhyay (2005) found evidence that cholesterol depletion impairs the ligand-binding function of the 5-HT1A receptor, which they later determined to be due to organizational changes in cholesterol-depleted membrane (Pucadyil and Chattopadhyay, 2007). The importance of membrane cholesterol in proper functioning has also been demonstrated in the serotonin receptor subclasses 5-HT2A (Dreja et al., 2002, Sommer et al., 2009) and 5-HT7 (Sjogren and Svenningsson, 2007a, Sjogren and Svenningsson, 2007b, Sjogren and Svenningsson, 2007a, Sjogren and Svenningsson, 2007b). Together, these studies suggest that one potential mechanism guiding depression pathogenesis may involve cholesterol depletion-mediated alterations in central nerve terminal structure and function that in turn influence receptor responsiveness to serotonin.
While a number of cross-sectional studies present evidence suggesting an inverse association between serum LDL and depression, conflicting findings do exist. Meta-analytic studies are an indispensable tool for bringing clarity to a disparate body of literature; however, to date there has been only one meta-analysis conducted to examine the relationship between depression and serum LDL. In 2008, Shin et al. conducted a meta-analysis of 11 observational studies (Lindberg et al., 1994, Olusi and Fido, 1996, Rutledge et al., 2001, Sevincok et al., 2001, Aijanseppa et al., 2002, Pozzi et al., 2003, Ergun et al., 2004, Huang and Chen, 2004, Karlovic et al., 2004, Elovainio et al., 2006, Roy and Roy, 2006) to evaluate the association between depression and serum LDL and determined there to be a non-significant inverse association (d =−0.17, 95% CI =−0.44, 0.10) (Shin et al., 2008). The meta-analysis conducted by Shin et al. included studies published through 2006; subsequent to 2006, there have been 23 additional studies conducted to examine the association between depression and serum LDL. This current study aimed to provide a more current meta-analysis on the relationship between depression and serum LDL in light of the growing body of literature.
Section snippets
Methods
Although this study aims to build upon the work of Shin et al. by providing a more recent meta-analysis on the association between LDL and depression, it is not intended to be an update of their 2008 manuscript and as such does not follow the selfsame meta-analytic approach. This study used PRISMA guidelines to conduct a systematic review and meta-analysis on the relationship between depression and serum LDL (Liberati et al., 2009). Papers meeting the following criteria were included:
- 1.
Results
The 42 studies identified as eligible for inclusion in this systematic review and meta-analysis employed a variety of reporting methods; for this reason, a series of meta-analyses were conducted, dividing between studies that modeled serum LDL as a continuous measure and those that modeled serum LDL as a categorical measure.
Discussion
Overall, this systematic review and meta-analysis echoes the earlier work of Shin et al. in the detection of lower mean serum LDL in depression. Interestingly, meta-analysis of studies modeling serum LDL as a categorical measure suggests a reduced odds of depression in the presence of low serum LDL relative to high serum LDL, in contrast to the findings suggested by analysis of serum LDL modeled as a continuous measure. One explanation for these contradictory findings may lie in the lack of
Conclusions
This meta-analysis demonstrates a cross-sectional link between depression and low serum LDL for studies modeling serum LDL as a continuous measure. Findings in the opposite direction, however, were noted for studies modeling serum LDL as a categorical measure, underscoring the importance of prospective analyses to assess temporality and the need for more work must be done to arrive at a commonly agreed-upon threshold by which to distinguish low LDL within a psychiatric context.
Conflicts of interest
Jane E. Persons has no conflicts of interest to declare.
Jess G. Fiedorowicz has no conflicts of interest to declare.
Author contribution
All authors have contributed materially to this body of work. JEP and JGF both participated in research and article preparation, and both authors have approved this final article for publication.
Role of funding source
JEP and JGF were funded by the National Heart, Lung, and Blood Institute (NHLBI P01HL014388). JGF is also supported by the Institute for Clinical and Translational Science at the University of Iowa, which is funded through the National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) Program, Grant U54TR001356. The CTSA program is led by the NIH's National Center for Advancing Translational Sciences (NCATS). This publication's contents are solely the responsibility of
Acknowledgments
None.
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