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Omic sciences coupled with novel computational approaches such as machine intelligence offer completely new approaches to major depressive disorder (MDD) research. The complexity of MDD's pathophysiology is being integrated into studies examining MDD's biology within the omic fields. Lipidomics, as a late-comer among other omic fields, is increasin...
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Context 1
... will describe the systematic search process for studies applying lipidomic approaches in MDD or rodent models of depression (see Figure 1). Subsequently, we will review the identified studies with regard to their biological interpretation and discriminative power for MDD classification (see Table 1) and compare identified lipid species between studies (see Supplementary Table 1). ...Context 2
... a final step, studies (v) with a special focus on bio-technologies (n = 3) were eliminated. Figure 1 shows the sample development throughout the selection process, reaching the final set of 12 studies for review including 7 human and 5 rodent studies (see Table 1). The study selection and eligibility screening were conducted according to the PRISMA guidelines (47). ...Similar publications
The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various preclinical epilepsy research disciplines. The aim of the CDEs is to improve the standardization of experimental designs across a range of epilepsy resea...
The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force established the TASK3 working groups to create common data elements (CDEs) for various preclinical epilepsy research disciplines. This is the second in a two-part series of omics papers, with the other including genomics, transcriptomics an...
Citations
... In the field of depression research, Andreas Walther et al. proposed their model of lipid involvement in the pathogenesis of depression [35]. This model is based on the chronic stress effects. ...
... This model is based on the chronic stress effects. Chronic stress has been thought to trigger two main pathways: the hypothalamic-pituitary-adrenal axis (HPA) and neuroinflammation [35]. ...
... Chronic stress leads to HPA hyperactivity. Elevated glucocorticoid levels increase phospholipase D activity [35]. Increased phospholipase D activity enhances the conversion of PC and PE into phosphatidic acid, as well as lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). ...
Background: Lipids are a crucial component of the human brain, serving important structural and functional roles. They are involved in cell function, myelination of neuronal projections, neurotransmission, neural plasticity, energy metabolism, and neuroinflammation. Despite their significance, the role of lipids in the development of mental disorders has not been well understood. Results: This review focused on the potential use of lipids as blood biomarkers for common mental illnesses, such as major depressive disorder, anxiety disorders, bipolar disorder, and schizophrenia. This review also discussed the impact of commonly used psychiatric medications, such as neuroleptics and antidepressants, on lipid metabolism. Conclusion: The obtained data suggested that lipid biomarkers could be useful for diagnosing psychiatric diseases, but further research is needed to better understand the associations between blood lipids and mental disorders and to identify specific biomarker combinations for each disease.
... Recently, lipidomic approaches by liquid chromatography coupled to MS (LC-MS) and tandem MS (LC-MS/MS) have studied the lipidome from the brain and its subregions [20,21] in mice [22], as well as body fluids (e.g., plasma, serum, cerebrospinal fluid), to identify characteristic markers for the diagnosis of brain conditions and disorders such as MDD [23]. Previous studies have reported changes in the lipidome of the brain or the plasma of animal models of disease as well as in plasma and serum from patients with MDD [24]. ...
Complete animal welfare evaluation in intensive farming is challenging. With this study, we investigate new biomarkers for animal physical and mental health by comparing plasma expression of biochemical indicators in dairy cows reared in three different systems: (A) semi-intensive free-stall, (B) non-intensive tie-stall, and (C) intensive free-stall. Additionally, protein levels of mature brain-derived neurotrophic factor (mBDNF) and its precursor form (proBDNF) and indoleamine 2,3-dioxygenase (IDO1) specific activity were evaluated in brain samples collected from 12 cattle culled between 73 and 138 months of age. Alterations in plasma lipid composition and in the kynurenine pathway of tryptophan metabolism were observed in the tie-stall-reared animals. The total plasma BDNF concentration was higher in tie-stall group compared to the two free-housing groups. Brain analysis of the tie-stall animals revealed a different mBDNF/proBDNF ratio, with a higher level of proBDNF (p < 0.001). Our data are similar to previous studies on animal models of depression, which reported that inhibition of the conversion of proBDNF in its mature form and/or elevated peripheral kynurenine pathway activation may underlie cerebral biochemical changes and induce depressive-like state behavior in animals.
... Epidemiological studies have reported that depressive patients had lower levels of total cholesterol [9,10] and low-density lipoprotein (LDL) cholesterol [11] compared to healthy controls, although results are mixed [12][13][14][15][16][17][18]. Together, these findings strongly suggest that metabolic dysregulation may underlie depression and its related phenotypes [19,20]. However, as routine blood lipids provide only a narrow snapshot of lipid metabolism, it fails to capture the complexity of the blood lipidome that includes hundreds to thousands of individual lipid species (both endogenous and exogenous) in a blood sample. ...
... The observed associations between changes in phosphatidylcholines, phosphatidylethanolamines, and lysophosphatidylethanolamines and changes in psychosomatic traits could be attributed to their effects on inflammation and oxidized stress [21,22,30]. Altered triacylglycerols may contribute to depression through affecting energy storage in lipid droplets or membrane formation [19,23]. ...
Dyslipidemia has been associated with depression, but individual lipid species associated with depression remain largely unknown. The temporal relationship between lipid metabolism and the development of depression also remains to be determined. We studied 3721 fasting plasma samples from 1978 American Indians attending two exams (2001–2003, 2006–2009, mean ~5.5 years apart) in the Strong Heart Family Study. Plasma lipids were repeatedly measured by untargeted liquid chromatography-mass spectrometry (LC-MS). Depressive symptoms were assessed using the 20-item Center for Epidemiologic Studies for Depression (CES-D). Participants at risk for depression were defined as total CES-D score ≥16. Generalized estimating equation (GEE) was used to examine the associations of lipid species with incident or prevalent depression, adjusting for covariates. The associations between changes in lipids and changes in depressive symptoms were additionally adjusted for baseline lipids. We found that lower levels of sphingomyelins and glycerophospholipids and higher level of lysophospholipids were significantly associated with incident and/or prevalent depression. Changes in sphingomyelins, glycerophospholipids, acylcarnitines, fatty acids and triacylglycerols were associated with changes in depressive symptoms and other psychosomatic traits. We also identified differential lipid networks associated with risk of depression. The observed alterations in lipid metabolism may affect depression through increasing the activities of acid sphingomyelinase and phospholipase A2, disturbing neurotransmitters and membrane signaling, enhancing inflammation, oxidative stress, and lipid peroxidation, and/or affecting energy storage in lipid droplets or membrane formation. These findings illuminate the mechanisms through which dyslipidemia may contribute to depression and provide initial evidence for targeting lipid metabolism in developing preventive and therapeutic interventions for depression.
... Therefore, the investigation of objective molecular markers will provide assistance for the differential diagnosis of mental diseases. Recently, alternations in lipid composition in patients with mental diseases, such as bipolar disorder, SCZ, and MDD have been reported [28][29][30]. A direct comparison of the lipid compositions in patients with SCZ and MDD is particularly valuable for understanding the common and unique lipid characteristics of these two diseases and identifying lipid markers that might differentiate SCZ, MDD, and HC subjects. ...
Background and Objectives: Lipidomics is a pivotal tool for investigating the pathogenesis of mental disorders. However, studies qualitatively and quantitatively analyzing peripheral lipids in adult patients with schizophrenia (SCZ) and major depressive disorder (MDD) are limited. Moreover, there are no studies comparing the lipid profiles in these patient populations. Materials and Method: Lipidomic data for plasma samples from sex- and age-matched patients with SCZ or MDD and healthy controls (HC) were obtained and analyzed by liquid chromatography-mass spectrometry (LC-MS). Results: We observed changes in lipid composition in patients with MDD and SCZ, with more significant alterations in those with SCZ. In addition, a potential diagnostic panel comprising 103 lipid species and another diagnostic panel comprising 111 lipid species could distinguish SCZ from HC (AUC = 0.953) or SCZ from MDD (AUC = 0.920) were identified, respectively. Conclusions: This study provides an increased understanding of dysfunctional lipid composition in the plasma of adult patients with SCZ or MDD, which may lay the foundation for identifying novel clinical diagnostic methods for these disorders.
... Their ability to traverse the blood-brain barrier (BBB) into the periphery in various forms makes them attractive physiological biomarkers for disease and depending on the species may reflect pathways that have gone awry in the depressed patient. As such, comparative shotgun, or non-targeted lipidomics measurements of circulating lipids from MDD plasma versus controls, or tissue taken directly from brain have identified a variety of lipid species that track with MDD (Liu et al., 2016;Pinto et al., 2022;Walther et al., 2018). It is already well-established that the prostaglandins factor into depression as mentioned earlier (Furuyashiki et al., 2019). ...
Patients with cancer are at greater risk of developing depression in comparison to the general population and this is associated with serious adverse effects, such as poorer quality of life, worse prognosis and higher mortality. Although the relationship between depression and cancer is now well established, a common underlying patho-physiological mechanism between the two conditions is yet to be elucidated. Existing theories of depression, based on monoamine neurotransmitter system dysfunction, are insufficient as explanations of the disorder. Recent advances have implicated neuroinflammatory mechanisms in the etiology of depression and it has been demonstrated that inflammation at a peripheral level may be mirrored centrally in astrocytes and microglia serving to promote chronic levels of inflammation in the brain.
Three major routes to depression in cancer, in which proinflammatory mediators are implicated, seem likely. Activation of the kynurenine pathway, involving cytokines, increased tryptophan catabolism, resulting in diminished levels of serotonin, which is widely acknowledged as being the hallmark of depression. It also results in neurotoxic effects on brain regions thought to be involved in the evolution of major depression. Proinflammatory mediators also play a crucial role in impairing regulatory glucocorticoid mediated feedback of the hypothalamic-pituitary-adrenal axis, which is activated by stress and considered to be involved in both depression and cancer. The third route is via the glutamatergic pathway, whereby glutamate excitotoxicity may lead to depression associated with cancer. A better understanding of the mechanisms underlying these dysregulated and newly emerging pathways may provide a rationale for therapeutic targeting, serving to improve the care of cancer patients.
... Research increasingly recognizes that key pathophysiological processes occur directly at the cellular level and that DD can impair peripheral blood cell function via disturbed glucocorticoid secretion by the hypothalamus-pituitary-adrenal (HPA) axis or via inflammation (Lopez-Vilchez et al., 2016;Moylan et al., 2013;Pariante, 2017;Rodrigues et al., 2014;Walther et al., 2018;Wolkowitz et al., 2010). Blood cells fulfill multiple functions from primary immune response, over metabolite transport to overall blood flow. ...
... It is suggested that the underlying mechanism leading to increased immune cell counts in depressed individuals is rooted in the effect of elevated glucocorticoid levels remodeling the actin cytoskeleton of blood cells and thereby softening leukocytes and enabling them to demarginate from the vessel wall (Fay et al., 2016). Not only starts the actin cytoskeleton to be remodeled with continuously elevated levels of glucocorticoids, but also are lipid metabolism and composition crucially affected resulting in increased softening and bending of blood cells (Demirkan et al., 2013;Knowles et al., 2017;Liu et al., 2016;Ravetto et al., 2014;Walther et al., 2018). This cascade of processes ultimately impairs blood cell function and may be an underlying cause of symptoms of fatigue and exhaustion in DD. ...
... Immune cells might respond to increased glucocorticoid concentrations by reorganizing the cytoskeleton, which affects cell deformability directly as previous studies showed using dexamethasone administration (Fay et al., 2016;Ronchetti et al., 2018). Moreover, elevated glucocorticoid concentrations can cause increased permeation through the cell membrane affecting the lipidome and the cell structure leading to membrane destabilization and bending (Walther et al., 2018), and hence to increased cell deformability. Alterations in membrane-forming lipids in the central nervous system have already been linked to DD (Müller et al., 2015). ...
Background: Cell deformability of all major blood cell types is increased in depressive disorders (DD). Furthermore, impaired glucocorticoid secretion is causally related to DD. Nevertheless, there are no longitudinal studies examining changes in glucocorticoid output and depressive symptoms regarding cell deformability in DD. Aim: To investigate, whether changes in depressive symptoms or hair glucocorticoids predict cell deformability in DD.
Methods: In 136 individuals, depressive symptoms (PHQ-9) and hair glucocorticoids (cortisol and cortisone) were measured at timepoint one (T1), while one year later (T2) depressive symptoms and hair glucocorticoids were remeasured and additionally cell deformability of peripheral blood cells was assessed and DD status was determined by clinical interview.
Results: Depression severity at T1 predicted higher cell deformability in monocytes and lymphocytes over the entire sample. Subjects with continuously high depressive symptoms at T1 and T2 showed elevated monocyte deformability as compared to subjects with low depressive symptoms. Depression severity at T1 of subjects with a lifetime persistent depressive disorder (PDD) was associated with elevated monocyte, neutrophil, and granulo- monocyte deformability. Depression severity at T1 of subjects with a 12-month PDD was positively associated with monocyte deformability. Furthermore, increases in glucocorticoid concentrations from T1 to T2 tended to be associated with higher immune cell deformability, while strongest associations emerged for the increase in cortisone with elevated neutrophil and granulo-monocyte deformability in the 12-month PDD group.
Conclusion: Continuously elevated depressive symptomatology as well as an increase in glucocorticoid levels over one year are associated with higher immune cell deformability, particularly in PDD. These findings suggest, that persistent depressive symptomatology associated with increased glucocorticoid secretion may lead to increased immune cell deformability thereby compromising immune cell function and likely contributing to the perpetuation of PDD.
... There is increasing evidence that lipid dysregulation in the brain might represent a key event in the pathophysiology of neurological diseases such as depression and Alzheimer's disease (1)(2)(3)(4)(5)(6)(7). Importantly, early-life stress (ELS) and dietary fatty acids (FA), have been shown to greatly contribute to the risk of developing such psychopathologies (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and Alzheimer's disease (20)(21)(22)(23)(24)(25)(26)(27). ...
Brain lipid dysregulation is a hallmark of depression and Alzheimer’s disease, also marked by chronic inflammation. Early-life stress (ELS) and dietary intake of polyunsaturated fatty acids (PUFAs) are risk factors for these pathologies and are known to impact inflammatory processes. However, if these early-life factors alter brain lipid homeostasis on the long-term and thereby contribute to this risk remains to be elucidated. We have recently shown that an early diet enriched in omega(ω)-3 PUFAs protected against the long-term negative effects of ELS on cognition and neuroinflammation. Here, we aim to understand if modulation of brain lipid and oxylipin profiles contributes to the detrimental effects of ELS and the protective ones of the diet. We therefore studied if and how ELS and early dietary PUFAs modulate the brain lipid and oxylipin profile, basally as well as in response to an inflammatory challenge, to unmask possible latent effects. Male mice were exposed to ELS via the limited bedding and nesting paradigm, received an early diet with high or low ω6/ω3 ratio (HRD and LRD) and were injected with saline or lipopolysaccharide (LPS) in adulthood. Twenty-four hours later plasma cytokines (Multiplex) and hypothalamic lipids and oxylipins (liquid chromatography tandem mass spectrometry) were measured. ELS exacerbated the LPS-induced increase in IL-6, CXCL1 and CCL2. Both ELS and diet affected the lipid/oxylipin profile long-term. For example, ELS increased diacylglycerol and LRD reduced triacylglycerol, free fatty acids and ceramides. Importantly, the ELS-induced alterations were strongly influenced by the early diet. For example, the ELS-induced decrease in eicosapentaenoic acid was reversed when fed LRD. Similarly, the majority of the LPS-induced alterations were distinct for control and ELS exposed mice and unique for mice fed with LRD or HRD. LPS decreased ceramides and lysophosphotidylcholine, increased hexosylceramides and prostaglandin E2, reduced triacylglycerol species and ω6-derived oxylipins only in mice fed LRD and ELS reduced the LPS-induced increase in phosphatidylcholine. These data give further insights into the alterations in brain lipids and oxylipins that might contribute to the detrimental effects of ELS, to the protective ones of LRD and the possible early-origin of brain lipid dyshomeostasis characterizing ELS-related psychopathologies.
... For statins, participants' baseline lipid and inflammatory profile should be taken into account when interpreting their effects on both neuropsychological markers and depressive scales. Statins' chief activity is enacted on lipid metabolism and inflammation (Jain and Ridker 2005); both have been linked to depression (Miller et al. 2017;Walther et al. 2018) as well as the interaction between these two elements have (van Diepen et al. 2013). In line with these observations, a recent study in healthy volunteers has shown that minocycline, an antibiotic with putative antidepressant action, reduces negative affective bias and CRP levels while also increasing cholesterol (Chan et al. 2020). ...
Rationale
Clinical studies suggest that the highly lipophilic, anti-inflammatory molecule, simvastatin, might be an ideal candidate for drug repurposing in the treatment of depression. The neuropsychological effects of simvastatin are not known, but their ascertainment would have significant translational value about simvastatin’s influence on mood and cognition.
Objectives
We aimed to investigate the effects of simvastatin on a battery of psychological tests and inflammatory markers in healthy volunteers.
Methods
Fifty-three healthy subjects were randomly assigned to 7 days of either simvastatin ( N = 27) or sucrose-based placebo ( N = 26) given in a double-blind fashion. Then, participants were administered questionnaires measuring subjective rates of mood and anxiety, and a battery of tasks assessing emotional processing, reward learning, and verbal memory. Blood samples for C-reactive protein were also collected.
Results
Compared to placebo, participants on simvastatin showed a higher number of positively valenced intrusions in the emotional recall task ( F 1,51 = 4.99, p = 0.03), but also an increase in anxiety scores ( F 1,51 = 5.37, p = 0.02). An exploratory analysis of the females’ subgroup ( N = 27) showed lower number of misclassifications as sad facial expression in the simvastatin arm ( F 1,25 = 6.60, p = 0.02). No further statistically significant changes could be observed on any of the other outcomes measured.
Conclusions
We found limited evidence that 7-day simvastatin use in healthy volunteer induces a positive emotional bias while also being associated with an increase in anxiety, potentially reflecting the early effects of antidepressants in clinical practice. Such effect might be more evident in female subjects. Different drug dosages, treatment lengths, and sample selection need consideration in further experimental medicine and clinical studies.
Trial registration
Clinicaltrials.gov: NCT04652089.
... Based on our findings that specific HN markers are associated with depression, we next sought to determine whether nutritional, metabolomic and/or lipidomic biomarkers could be modulating these outcomes, given the association between diet and neurogenesis [16,17]. Interestingly, not only did we find that both metabolite butyrylcarnitine (a member of the acylcarnitines) and glycerophospholipid, PC35:1(16:0/19:1), were associated with depressive symptomology -findings that have previously been reported in clinical populations [78,79] but that they also specifically modulated neuronal differentiation within our sample. For example, we show that reduced levels of PC35:1 (16:0/19:1) were associated with increased differentiation, which in turn increased the risk of late-life depressive symptoms. ...
... Moreover, we found a negative association between cell death during proliferation and (PE0)34:3(16:1/18:2)an ether phospholipid that forms a key component of the lipid membrane and lipid rafts [93]. Ether phospholipids, together with cell death, not only plays a critical role in neurotransmission and synaptic plasticity [80], but has also been implicated in the pathogenesis of depression [79]. However, the precise mechanisms involved in how these nutritional factors influence HN outcomes remain to be elucidated, falling outside the scope of this study. ...
Environmental factors like diet have been linked to depression and/or relapse risk in later life. This could be partially driven by the food metabolome, which communicates with the brain via the circulatory system and interacts with hippocampal neurogenesis (HN), a form of brain plasticity implicated in depression aetiology. Despite the associations between HN, diet and depression, human data further substantiating this hypothesis are largely missing. Here, we used an in vitro model of HN to test the effects of serum samples from a longitudinal ageing cohort of 373 participants, with or without depressive symptomology. 1% participant serum was applied to human fetal hippocampal progenitor cells, and changes in HN markers were related to the occurrence of depressive symptoms across a 12-year period. Key nutritional, metabolomic and lipidomic biomarkers (extracted from participant plasma and serum) were subsequently tested for their ability to modulate HN. In our assay, we found that reduced cell death and increased neuronal differentiation were associated with later life depressive symptomatology. Additionally, we found impairments in neuronal cell morphology in cells treated with serum from participants experiencing recurrent depressive symptoms across the 12-year period. Interestingly, we found that increased neuronal differentiation was modulated by increased serum levels of metabolite butyrylcarnitine and decreased glycerophospholipid, PC35:1(16:0/19:1), levels – both of which are closely linked to diet – all in the context of depressive symptomology. These findings potentially suggest that diet and altered HN could subsequently shape the trajectory of late-life depressive symptomology.
... Interestingly, cholesterol and other lipids like phosphatidylglycerol and sphingomyelin modulate the function of P2X7R (311). Our lab and others have found altered brain lipids in psychopathology (312) and depression (313)(314)(315) suggesting lipid control of P2X7R should be further investigated. Generally, lipids in the cell membrane organize position and function of proteins. ...
Increasing evidence supports the notion that neuroinflammation plays a critical role in the etiology of major depressive disorder (MDD), at least in a subset of patients. By virtue of their capacity to transform into reactive states in response to inflammatory insults, microglia, the brain’s resident immune cells, play a pivotal role in the induction of neuroinflammation. Experimental studies have demonstrated the ability of microglia to recognize pathogens or damaged cells, leading to the activation of a cytotoxic response that exacerbates damage to brain cells. However, microglia display a wide range of responses to injury and may also promote resolution stages of inflammation and tissue regeneration. MDD has been associated with chronic priming of microglia. Recent studies suggest that altered microglial morphology and function, caused either by intense inflammatory activation or by senescence, may contribute to depression and associated impairments in neuroplasticity. In this context, modifying microglia phenotype by tuning inflammatory pathways might have important translational relevance to harness neuroinflammation in MDD. Interestingly, it was recently shown that different microglial phenotypes are associated with distinct metabolic pathways and analysis of the underlying molecular mechanisms points to an instrumental role for energy metabolism in shaping microglial functions. Here, we review various canonical pro-inflammatory, anti-inflammatory and metabolic pathways in microglia that may provide new therapeutic opportunities to control neuroinflammation in brain disorders, with a strong focus on MDD.
