Search

The exact pathophysiology of major depressive disorder (MDD) remains elusive. The monoamine theory, which hypothesizes that MDD emerges as a result of dysfunctional serotonergic, dopaminergic and noradrenergic pathways, has guided the therapy of this illness for several decades. More recently, the involvement of activated immune, oxidative and nitrosative stress pathways and of decreased levels of neurotrophic factors has provided emerging insights regarding the pathophysiology of MDD, leading to integrated theories emphasizing the complex interplay of these mechanisms that could lead to neuroprogression. In this review, we propose an integrative model suggesting that T helper 17 (Th17) cells play a pivotal role in the pathophysiology of MDD through (i) microglial activation, (ii) interactions with oxidative and nitrosative stress, (iii) increases of autoantibody production and the propensity for autoimmunity, (iv) disruption of the blood–brain barrier, and (v) dysregulation of the gut mucosa and microbiota. The clinical and research implications of this model are discussed. [ABSTRACT FROM AUTHOR]

Abstract: This paper reviews that cell-mediated-immune (CMI) activation and inflammation contribute to depressive symptoms, including anhedonia; anxiety-like behaviors; fatigue and somatic symptoms, e.g. illness behavior or malaise; and mild cognitive impairment (MCI). These effects are in part mediated by increased levels of pro-inflammatory cytokines (PICs), e.g. interleukin-1 (IL-1), IL-6 and tumor necrosis factor (TNF)α, and Th-1-derived cytokines, such as IL-2 and interferon (IFN)γ. Moreover, new pathways, i.e. concomitants and sequels of CMI activation and inflammation, were detected in depression: (1) Induction of indoleamine 2,3-dioxygenase (IDO) by IFNγ and some PICs is associated with depleted plasma tryptophan, which may interfere with brain 5-HT synthesis, and increased production of anxiogenic and depressogenic tryptophan catabolites. (2) Increased bacterial translocation may cause depression-like behaviors by activating the cytokine network, oxidative and nitrosative stress (O&NS) pathways and IDO. (3) Induction of O&NS causes damage to membrane ω3 PUFAs, functional proteins, DNA and mitochondria, and autoimmune responses directed against intracellular molecules that may cause dysfunctions in intracellular signaling. (4) Decreased levels of ω3 PUFAs and antioxidants, such as coenzyme Q10, glutathione peroxidase or zinc, are associated with an increased inflammatory potential; more oxidative damage; the onset of specific symptoms; and changes in the expression or functions of brain 5-HT and N-methyl-d-aspartate receptors. (5) All abovementioned factors cause neuroprogression, that is a combination of neurodegeneration, neuronal apoptosis, and lowered neurogenesis and neuroplasticity. It is concluded that depression may be the consequence of a complex interplay between CMI activation and inflammation and their sequels/concomitants which all together cause neuroprogression that further shapes the depression phenotype. Future research should employ high throughput technologies to collect genetic and gene expression and protein data from patients with depression and analyze these data by means of systems biology methods to define the dynamic interactions between the different cell signaling networks and O&NS pathways that cause depression. [Copyright &y& Elsevier]

• Mood disorders can feature disturbances in lipid metabolism, oxidative stress and inflammation. • Statins are extensively prescribed for cardiovascular disease for their lipid-lowering properties. • Pleiotropic effects of statins include anti-inflammatory and anti-oxidative action. • Growing evidence suggests statins may have potential as adjunctive psychotropic agents. • Larger scale clinical trials are needed to better assess the utility of statins in mood disorders. Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) treat dyslipidaemia and cardiovascular disease by inhibiting cholesterol biosynthesis. They also have immunomodulatory and anti-inflammatory properties. Beyond cardiovascular disease, cholesterol and inflammation appear to be components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Statins may therefore afford some therapeutic benefit in mood disorders. In this paper, we review the pathophysiology of mood disorders with a focus on pharmacologically relevant pathways, using major depressive disorder and bipolar disorder as exemplars. Statins are discussed in the context of these disorders, with particular focus on the putative mechanisms involved in their anti-inflammatory and immunomodulatory effects. Recent clinical data suggest that statins may have antidepressant properties, however given their interactions with many known biological pathways, it has not been fully elucidated which of these are the major determinants of clinical outcomes in mood disorders. Moreover, it remains unclear what the appropriate dose, or appropriate patient phenotype for adjunctive treatment may be. High quality randomised control trials in concert with complementary biological investigations are needed if the potential clinical effects of statins on mood disorders, as well as their biological correlates, are to be better understood. [ABSTRACT FROM AUTHOR]

• Chronic systemic inflammation is associated with increased cardiovascular disease. • It is also associated with the pathophysiology of neuroprogressive disorders. • Both can occur with low LDL and low cholesterol: a lipid paradox. • Inflammatory molecules released by activated neutrophils play a crucial role. • The associated molecular mechanisms suggest potential therapeutic targets. Chronic systemic inflammation is associated with an increased risk of cardiovascular disease in an environment of low low-density lipoprotein (LDL) and low total cholesterol and with the pathophysiology of neuroprogressive disorders. The causes and consequences of this lipid paradox are explored. Circulating activated neutrophils can release inflammatory molecules such as myeloperoxidase and the pro-inflammatory cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha. Since activated neutrophils are associated with atherosclerosis and cardiovascular disease and with major depressive disorder, bipolar disorder and schizophrenia, it seems reasonable to hypothesise that the inflammatory molecules released by them may act as mediators of the link between systemic inflammation and the development of atherosclerosis in neuroprogressive disorders. This hypothesis is tested by considering the association at a molecular level of systemic inflammation with increased LDL oxidation; increased small dense LDL levels; increased lipoprotein (a) concentration; secretory phospholipase A 2 activation; cytosolic phospholipase A 2 activation; increased platelet activation; decreased apolipoprotein A1 levels and function; decreased paroxonase-1 activity; hyperhomocysteinaemia; and metabolic endotoxaemia. These molecular mechanisms suggest potential therapeutic targets. [ABSTRACT FROM AUTHOR]

• HDL, ApoA1 and PON1 are related to inflammation and lipid peroxidation in psychiatry. • Reduced HDL contributes both localised and systemic inflammation. • Homocysteine contributes to inflammation, oxidative stress and mitochondrial dysfunction. Lowered high-density lipoprotein (HDL) cholesterol has been reported in major depressive disorder, bipolar disorder, first episode of psychosis, and schizophrenia. HDL, its major apolipoprotein component, ApoA1, and the antioxidant enzyme paraoxonase (PON)1 (which is normally bound to ApoA1) all have anti-atherogenic, antioxidant, anti-inflammatory, and immunomodulatory roles, which are discussed in this paper. The paper details the pathways mediating the anti-inflammatory effects of HDL, ApoA1 and PON1 and describes the mechanisms leading to compromised HDL and PON1 levels and function in an environment of chronic inflammation. The molecular mechanisms by which changes in HDL, ApoA1 and PON1 might contribute to the pathophysiology of the neuroprogressive disorders are explained. Moreover, the anti-inflammatory actions of ApoM-mediated sphingosine 1-phosphate (S1P) signalling are reviewed as well as the deleterious effects of chronic inflammation and oxidative stress on ApoM/S1P signalling. Finally, therapeutic interventions specifically aimed at improving the levels and function of HDL and PON1 while reducing levels of inflammation and oxidative stress are considered. These include the so-called Mediterranean diet, extra virgin olive oil, polyphenols, flavonoids, isoflavones, pomegranate juice, melatonin and the Mediterranean diet combined with the ketogenic diet. [ABSTRACT FROM AUTHOR]

• Neuropsychiatric diseases predispose individuals to obesity and vice versa. • Pathophysiological processes are similar in obesity and neuropsychiatric disease. • Processes observed in neuropsychiatric disease contribute to developing obesity. • Processes observed in obesity contribute to developing neuropsychiatric disease. • Adjunctive agents can target these processes, with possibly ameliorative effects. Activated immune-inflammatory, oxidative and nitrosative stress (IO&NS) pathways and consequent mitochondrial aberrations are involved in the pathophysiology of psychiatric disorders including major depression, bipolar disorder and schizophrenia. They offer independent and shared contributions to pathways underpinning medical comorbidities including insulin resistance, metabolic syndrome, obesity and cardiovascular disease - herein conceptualized as somatoprogression. This narrative review of human studies aims to summarize relationships between IO&NS pathways, neuroprogression and somatoprogression. Activated IO&NS pathways, implicated in the neuroprogression of psychiatric disorders, affect the pathogenesis of comorbidities including insulin resistance, dyslipidaemia, obesity and hypertension, and by inference, metabolic syndrome. These conditions activate IO&NS pathways, exacerbating neuroprogression in psychiatric disorders. The processes whereby proinflammatory cytokines, nitrosative and endoplasmic reticulum stress, NADPH oxidase isoforms, PPARγ inactivation, SIRT1 deficiency and intracellular signalling pathways impact lipid metabolism and storage are considered. Through associations between body mass index, chronic neuroinflammation and FTO expression, activation of IO&NS pathways arising from somatoprogression may contribute to neuroprogression. Early evidence highlights the potential of adjuvants targeting IO&NS pathways for treating somatoprogression and neuroprogression. [ABSTRACT FROM AUTHOR]

Background Bipolar disorder phenomenologically is a biphasic disorder of energy availability; increased in mania and decreased in depression. In consort, there is accumulating evidence indicating increased mitochondrial respiration and ATP production in bipolar mania which contrasts with decreased mitochondrial function in patients in the euthymic or depressive phase of the illness. Consequently, the central thesis of this paper is that bipolar disorder is due to a phasic dysregulation of mitochondrial biogenergetics. The elements responsible for this dysregulation may thus represent critical treatment targets for mood disorders, and are the subject of this paper. Discussion There are many potential mediators of mitochondrial function which collectively are implicated in bipolar disorder. Levels of oxidative stress, pro-inflammatory cytokines and intracellular calcium ions are all higher in bipolar mania than in the euthymic and depressive phases of the illness. Increased levels of calcium ions can partly account for increased oxidative phosphorylation via well documented pathways such as the modulation of the F 1 –F O elements of ATP synthase. Likewise, increased levels of oxidative stress and pro-inflammatory cytokines lead to the upregulation of AMPK, SIRT-1, SIRT-3 and NAD + which directly stimulate oxidative phosphorylation. Uric acid and melatonin are also differentially elevated in bipolar mania and both molecules stimulate the production of ATP. The pro-apoptotic, neurotoxic and mitotoxic effects of elevated glutamate, dopamine and GSK-3 in bipolar mania may be counterbalanced by higher basal levels and activity of p53, Bcl-2, PI3K and Akt in an environment of elevated uric acid and decreased BDNF. Summary Details of these pathways are discussed as an explanatory model for the existence of increased ATP generation in mania. We also offer a model explaining the biphasic nature of mitochondrial respiration in bipolar disorder and the transition between mania and depression based on increasing levels of TNFα, ROS, NO, AMPK and SIRT-1 together with the antagonistic relationship between p53 and NF-κB. [ABSTRACT FROM AUTHOR]

Many studies support a crucial role for oxidative & nitrosative stress (O&NS) in the pathophysiology of unipolar and bipolar depression. These disorders are characterized inter alia by lowered antioxidant defenses, including: lower levels of zinc, coenzyme Q10, vitamin E and glutathione; increased lipid peroxidation; damage to proteins, DNA and mitochondria; secondary autoimmune responses directed against redox modified nitrosylated proteins and oxidative specific epitopes. This review examines and details a model through which a complex series of environmental factors and biological pathways contribute to increased redox signaling and consequently increased O&NS in mood disorders. This multi-step process highlights the potential for future interventions that encompass a diverse range of environmental and molecular targets in the treatment of depression. [ABSTRACT FROM AUTHOR]