Role Of Metabolic Dysfunction In Treatment Resistance Of .
ReviewRole of metabolic dysfunction intreatment resistance of major depressive disorderMarisa S Toups1 & Madhukar H Trivedi†1Practice points Major depressive disorder (MDD) and metabolic syndrome (MetS) are both disorders that causeserious morbidity.– We model both disorders as arising when environmental factors act on intrinsic patient risk factors. Epidemiological overlap of MDD and MetS: patients with either disorder have approximately doubledincidence of the other. MetS and MDD cause overlapping inflammatory, endocrine and neurobiological pathology.– MDD and MetS share a systemic profile of inflammatory cytokines and cortisol resistance.– Inflammation leads to insulin resistance, cardiovascular disease and diabetes.– MetS and MDD are associated with atrophy and dysfunction of several common brain regions.– MetS and MDD are both associated with decreased brain-derived neurotrophic factor.– Insulin resistance and chronic inflammation impair hypothalamic regulation of metabolism andhippocampal function.– MDD and MetS are both associated with changes in tryptophan metabolism that may contribute tomedication failure in MDD. Clinical research findings that support the treatment of MetS in MDD patients: the direct treatment ofmetabolic dysfunction or inflammation is very likely to improve depressive symptoms. Clinical relevance of the pathophysiological links: we believe that in some patient with treatment-resistantdepression, MetS in an unrecognized cause. Clinical recommendations: an algorithm for diagnosis and treatment of MetS with patients with depression. Future research should focus on validating the importance of MetS in MDD treatment: we suggest studiesvalidating metabolic parameters as predictors of treatment outcome.Department of Psychiatry, UT Southwestern Medical Center, Dallas TX 75235, USAAuthor for correspondence: .11.49 2011 Future Medicine LtdNeuropsychiatry (2011) 1(5), 441–455ISSN 1758-2008441
Review Toups & TrivediSummaryMajor depressive disorder (MDD) and metabolic syndrome (MetS) are bothwidespread and cause enormous morbidity. The presence of one syndrome approximatelydoubles the risk of the other. Standard antidepressant treatments lead to remission in lessthan a third of the patients; a majority of patients experience treatment resistance at somepoint during their illness. Research focusing on clinical and biological markers has yet toprovide evidence for the cause(s) of treatment resistance. MDD and MetS share endocrineand immune abnormalities that account for their overlap and suggest potential mechanismsfor treatment resistance for a subgroup of patients with MDD. Cortisol resistance and positiveenergy balance work together to create inflammation. Chronic inflammation leads to insulinresistance. In the brain, inflammation and insulin resistance cause changes in metaboliccontrol, decreases in serotonin synthesis, decreased hedonic drive and lower hippocampalneurogenesis, all of which are consistent with the neurobiology of MDD. We hypothesizethat treatment-resistant MDD may result when MetS reinforces the pathophysiology ofMDD, making it harder to reverse.Major depressive disorder (MDD) is the fourthleading cause of disability and is expected tobecome the second leading cause of disabilityworldwide by 2020 [1] . MDD affects an estimated2.5% of the population at any given time [1] , witha lifetime prevalence of approximately 20% [2] .Although many different treatments – pharmacologic, behavioral and neurostimulatory – have beendeveloped, MDD remains difficult to manage.Indeed, resistance to treatment is a major problem in contemporary psychiatric practice. Onlyapproximately a third of patients will remit fullywith any given trial of medication [3] , and the rateof remission drops as the number of medicationtrials increase [4] . Although definitions of treatment resistance vary [5] in the number and typeof failed treatment trials required, approximately30% of patients with MDD remain resistant totreatment even following several well-documentedtreatment trials [6] . Much of the confusion overthe ‘right’ definition is related to the lack of knowledge – other than some demographic and clinicalcharacteristics [7] – about the differences betweenthose patients who have good outcomes and thosewho do not. What is known is that patients withtreatment-resistant depression (TRD) have higherlifetime illness burden and mortality, as well as alower quality of life than patients without treatment resistance [8,9] . Understanding the biologicalmechanisms of TRD would be useful not onlyin developing a concrete definition, but wouldalso make a large impact on patient outcomes byproviding new avenues of research and treatment.Similarly, metabolic syndrome (MetS) andType 2 diabetes mellitus (DM2) are commonin developed countries, particularly the USA.MetS is defined as a combination of abnormallyelevated triglycerides, blood pressure, fasting glucose, increased waist circumference and decreased442Neuropsychiatry (2011) 1(5)high-density lipoprotein, with or without adirect or indirect measure of insulin resistance(IR) [10] . MetS has high clinical utility becauseall of its components, with the exception of IR,can quickly and easily be assessed by cliniciansin most practice areas, and because its presence ishighly predictive of serious morbidity via stroke,heart attack or other vascular disease [11] . Thedefinition of MetS has evolved over time, andseveral national and international organizationshave developed definitions [12] that differ in clinical feasibility of diagnostic criteria and whetherMetS is viewed as simply epidemiological (i.e.,predictive of risk) or as a discrete syndrome. Theassessed rate of MetS in the USA varies between23 and 40% depending on the definition used [13] .The term ‘metabolic dysfunction’ may refer to anyor all of the aspects of MetS, without referenceto specific abnormal values – although less precise, it is used here as a rough synonym for MetS.On the other hand, DM2 is a natural sequelaof MetS, resulting when IR progresses such thatfasting blood sugar is outside the normal range,affecting 18% of North Americans [14] . In thisarticle, we have chosen to use the term MetS asinclusive of DM2 since all of the pathophysiological features we discuss later are shared betweenthem. We attempted to find experimental resultsin human studies that applied specifically to MetSpopulations; however, in those instances whenwe were unable to do so, we have used studiesof DM2 patients but have specifically noted thisfact in the text.At first glance, a biological link between depression and metabolic dysfunction may seem implausible, since they appear to have differing causesas well as symptoms. To make the link as clearas possible, we start with a model of MDD as adisorder that occurs when intrinsic genetic andfuture science group
Role of metabolic dysfunction in treatment resistance of major depressive disorderepigenetic susceptibilities of an individual areacted upon by the individual’s environment; wealso have a similar model of MetS. In this article,we will deal almost exclusively with extrinsic factors and present evidence that these cause similarpathology in patients. We will also discuss how webelieve that the common pathology may lead totreatment resistance. We hypothesize that in casesin which both syndromes are present, they exertadditive physiological effects that lead to a lowerprobability of positive outcomes for treatment foreither syndrome. To support our hypothesis thatMetS is likely an underappreciated cause of TRD,we will focus on mechanisms – both peripheraland central – by which MetS may reinforce depression symptoms and pathology, as well as interferewith the action of antidepressant treatment.Simplifying somewhat, we will take the primary exogenous factor in MetS to be chronicpositive energy balance (PEB), a state in whichmore calories are consumed than expended.For MDD, the primary environmental influence appears to be chronic or severe stress. Wewill begin by reviewing epidemiological studiesthat demonstrate high comorbidity of MetS andMDD. Next, we will discuss significant similarities in how the endocrine and immune systemsrespond to the two environmental factors, stressand PEB, and how this leads to similar profilesof cytokine and hormone abnormalities in thosewith MDD and MetS. Following the examination of systemic dysfunction, we will look at common structural and functional changes that occurin the brains of those with MDD and MetS. Wewill also discuss some of the pathophysiologicalmechanisms underlying these abnormalities in aneffort to demonstrate that the presence of one ofthese disorders creates positive feedback that maymake the other more difficult to reverse.Epidemiological overlap of MDD & MetSMajor depressive disorder and MetS share manyqualities: both are chronic, cause high morbidityand require sustained, coordinated treatment thatmanages rather than cures. However, beyond thesuperficial similarities, there is a significant epidemiological overlap between them. Both crosssectional and longitudinal studies have found thathaving depression approximately doubles the rateof MetS [15–18] and vice versa [19,20] , although someauthors have found an elevated, but not doubled,risk of MDD in DM2 [21,22] . Several studiesfound that subjects reporting high levels of stresswith or without MDD had similarly elevatedfuture science groupReviewMetS rates [18,23] . Rates of TRD in patients withMetS have not accurately been determined – fewplacebo-controlled studies of treatments exist,and those that do have small sample sizes [24,25] .Shared systemic profile of inflammatorycytokines & cortisol resistance in MetS& MDDInflammation has emerged as a major, if not theprimary, pathophysiological link between MDDand MetS [26] . An inflammatory model of MetSthat begins with changes in metabolic activity ofadipose tissue as it increases in volume has becomeincreasingly validated with ongoing research. Inresponse to chronic PEB, adipocytes produce factors that recruit macrophages and decrease thenumber and/or function of anti-inflammatoryTregs [27,28] . Adipocytes also begin to produce theproinflammatory cytokines IL-1b and TNF‑a.These attract macrophages and incline them toswitch from an anti-inflammatory M2 state to aproinflammatory M1 state, in which they produce the same cytokines, as well as IL-6 [27] . Itappears that these inflammatory processes areenhanced by leptin, an ‘adipokine’, which is animmunologically and metabolically active factorproduced by adipocytes. Leptin serves as a signalof energy balance, and is high when energy balance is positive [29] . In ongoing PEB, high leptin directly activates macrophages and inducestheir expression of inflammatory cytokines [30] .This cascade in turn recruits more macrophages,which stimulate further cytokine production ina feed-forward manner, setting up a chronicinflammatory state. Clinically, this is reflectedin elevations of circulating TNF-a, IL-1b andIL-6 in the blood of MetS patients [31–34] .This same cascade of macrophage-associatedinflammation occurs in MDD. It has beenhypothesized that MDD itself is an inflammatory illness [35] ; certainly, inflammation causedby autoimmune disease or administration ofcytokines (such as IFN-g for the treatment ofhepatitis C) induces depression in a sizable minority (30–50%) of patients [36,37] . Even depressedpatients without known autoimmune or infectious processes have elevated levels of M1 inflammatory cytokines, with IL-6 and TNF-a having the most consistent evidence [38] . Althoughcortisol is acutely anti-inflammatory, MDD- orchronic stress-associated cortisol resistance, asmanifested by glucocorticoid receptor (GR)insensitivity, leads to activation of proinflammatory pathways that are normally suppressedwww.futuremedicine.com443
Review Toups & Trivediby cortisol [39,40] . Once activated, macrophagescan also support chronic stress induced hypercortisolemia; exposure to IL-1b can activateexpression of adrenocorticotropic hormone frommacrophages themselves [41] , as well as via thehypothalamus [42] . Thus the effects of stress aresynergistic with PEB-associated inflammation;the two feed forward to create a chronic state ofinflammation and high systemic cortisol and/orcortisol resistance. The changes in inflammatory factors that are in common with MetS andMDD are listed in Table 1.While it is clear that chronic elevations of cortisol can cause IR – this is the basis of high ratesof diabetes in patients with Cushing’s disease [43]– the role of cortisol and GR insensitivity in mostcases of MetS is less straightforward. Basal levelsof cortisol may be normal in MetS; however, ifcorticosteroid suppression testing is performed,GR insensitivity is often found [44,45] – the variability in cortisol levels is likely accounted forby increased cortisol clearance in obesity [46] .Inflammation leads to IRIf this chronic inflammatory and cortisol resistant state persists, it leads to IR, which occursby several mechanisms. First, cortisol decreasesinsulin-mediated expression of the GLUT4 glucose transporter – the primary systemic transporter of glucose into cells – by decreasing insulinreceptor activity [47] . Similarly, cortisol promotesrelease of free fatty acids from lipoproteins [48] ,leading to an increase in circulating lipids. Freefatty acids also cause decreased sensitivity of theinsulin receptor, particularly on muscle cells [49] .Chronic elevations of inflammatory cytokines,particularly TNF-a, cause similar, additionalsuppression of insulin receptor signaling [50] . Anadditional mechanism of IR is a PEB-associateddecrease in the expression of adiponectin,Table 1. Shared inflammatory changes in major depressive disorder andmetabolic syndrome.FactorChange in MetSChange in sol– (resistance) (resistance)– (resistance) (resistance)CRP: C-reactive protein; MDD: Major depressive disorder; MetS: Metabolic syndrome.444Neuropsychiatry (2011) 1(5)another adipokine. Unlike leptin, adiponectinlevels are inversely related to body weight, andit appears to promote insulin sensitivity [51,52]and oppose the MetS-associated inflammatorycascade [53] . Adiponectin-knockout mice are notdiabetic at baseline but develop IR more easilywhen fed diets that induce PEB [54] . Cytokines,particularly TNF‑a, can also act to decreaseexpression of adiponectin [55] , such that lowerlevels are found in MDD patients independent ofweight [56,57] . The overlap in these mechanismssuggests that weight-independent IR may befound in patients with MDD. In fact, outside ofthe population of patients with comorbid MetSand MDD, a significant minority of patientswith MDD alone show IR when given oral glucose tolerance testing [58] . Figure 1 summarizesthe peripheral inflammatory changes associatedwith MetS and MDD.Chronic inflammation leads to morbidityfrom cardiovascular disease & DM2Over time, if the environmental influences ofstress and PEB continue, inflammation leads tovascular disease – the major cause of morbidityassociated with MetS. Patients with MDD alsohave higher rates of morbidity/mortality fromcardiovascular disease [59] . The general inflammatory marker C-reactive protein is also consistently increased in MDD [60] and MetS [61,62] .This increase in C-reactive protein is associatedwith elevation in a wide variety of factors thatcontribute to the development of arteriosclerosis [63] . Cardiovascular disease risk is elevatedthreefold in patients with MetS [14] , makingthis the primary cause of serious morbidity andmortality in MetS. When there is systemic IR,the pancreas compensates by increasing insulin output, but over time diabetes developsbecause blood glucose can no longer be keptwithin the normal range. Feed-forward IL-1bsignaling occurs within the pancreas and sets upchronic, local islet inflammation, which leads toislet cell death, and eventually patients requiresupplementary insulin [64] .MetS & MDD are associated with atrophy& dysfunction of several commonbrain regionsAlthough we have so far focused on systemicpathology, MDD at least is thought of as a braindisease, and has been characterized by bothstructural and functional changes in the brain.While MetS may have its roots in adipose tissue,future science group
Role of metabolic dysfunction in treatment resistance of major depressive itytinHPA axis hyperactivityepdleasreIncCortisol resistancedaseacreodipnctineDeIDO ardiseaseInflammationIL-6Low serotoninReviewLow insulin productionInsulin resistanceNeuropsychiatry Future Science Group (2011)Figure 1. Network showing the links between metabolic syndrome and depression via inflammation.HPA: Hypothalamic–pituitary–adrenal; IDO: Indoleamine-2,3-dioxygenase.it also causes brain changes that overlap anatomically to a large extent with those associated withdepression. Perhaps the most consistently identified structural abnormality in MDD is hippocampal atrophy [65] . Some studies also have foundthinning of the prefrontal cortices [66] . It hasbeen debated whether this atrophy represents anunderlying vulnerability to MDD [67] or an effectof the illness [68] , but these areas are clearly partof the biological substrate on MDD. A similarpattern of hippocampal and prefrontal atrophyis seen in MetS and DM2 [69,70] . BMI itself ispositively correlated with decreased hippocampalvolume and frontal cortex thickness [71] .The consequence of brain atrophy is reducedcognitive function in patients with MDD andMetS. MDD is associated with decreased attention and verbal working memory [72] . MetS isfound to correlate with similar deficits [73,74] . Bothsyndromes have been associated with an increasedrisk of dementia [75,76] . At least some authors havefound that comorbid MDD and MetS is associated with more impairment than either alone [77] .IR has been isolated from the other components offuture science groupMetS as the most associated with cognitive declineand is correlated with decreases in bloodflow in frontal cortical areas [79] . Hippocampalatrophy and impaired hippocampal learningare both associated with normal aging [80] , andsome authors have proposed that inflammationplays a significant role in the accelerated cognitive decline associated with MDD and MetS [81] .Figure 2 shows the putative relationships leadingto hippocampal dysfunction.Changes in growth factor expression (see later)and accumulation of microvascular damage overthe lifespan may contribute to these structuralabnormalities, but clearly some common factorsin MDD and MetS that we have already discussed play a role by acting in the brain muchas they do systemically. For example, inflammatory cytokines appear to increase the activity ofthe serotonin transporter [82] , possibly impairing serotonin neurotransmission and decreasing the efficacy of selective serotonin-reuptakeinhibitors (SSRIs). However, perhaps the mostimportant of these is central IR, which developsin association with peripheral resistance. Insulin[74,78]www.futuremedicine.com445
Review Toups & TrivediPositive energy d nctionand atrophyNeuropsychiatry Future Science Group (2011)Figure 2. Model of the effects of stress and positive energy balance on the hippocampus.BDNF: Brain-derived neurotrophic factor.is important in the hippocampus because insulinreceptors mediate changes in glutamate neurotransmission – a form of long-term depressionthat plays a role in memory and cognitive function – and promote growth of synaptic architecture and dendritic spines [83] . In fact, intranasalinsulin administration improves cog
Role of metabolic dysfunction in treatment resistance of major depressive disorder Practice points Major depressive disorder (MDD) and metabolic syndrome (MetS) are both disorders that cause serious morbidity. – We model both disorders as arising when environmental factors act on intrinsic patient risk factors.
A third type of stroke, known as metabolic stroke, begins with metabolic dys-function and leads to a rapid onset of lasting focal brain lesions in the absence of large vessel rupture or occlu-sion [3-5]. The mechanism by which global metabolic dysfunction leads to focal brain injury in metabolic stroke is not well understood. Pure metabolic .
Metabolism influences brain activity, and metabolic dysfunction is associated with a wide variety of neurological disorders. The cause-and-effect relationship between metabolic and neuronal dysfunction is often unclear,though not in the case of epilepsy and diet. Historical observations noted the therapeutic benefits of fast-
latent metabolic syndrome that warrants clinic al evaluation and risk factor modification. Though intricate and still incompletely understood, the gradual expansion of knowledge about inter-relationships between the metabolic syndrome, GDM and T2DM may provide us with opportunities to screen for and detect metabolic dysfunction at various stages of
relation between nut consumption and metabolic syndrome (MetS). Metabolic Syndrome is a group of cardio-metabolic risk factors, which comprise of type 2 diabetes, high fasting plasma glucose, hyperglycemia, hyper-triglycerides, low HDL cholesterol and abdominal obesity [21]. Metabolic syndrome raises the risk of diabetes by 5 times and that of
ment of the metabolic syndrome (Table 1) [10]. Prevalence of the Metabolic Syndrome and Risk for Cardiovascular Events It is estimated that approximately one fifth of the US population has the metabolic syndrome, and prevalence increases with age. The prevalence of the metabolic syndrome in a healthy American population is approxi-mately 24% [11].
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F52.21 Male erectile disorder N52.01 Erectile dysfunction due to arterial insufficiency N52.02 Corporo-venous occlusive erectile dysfunction N52.03 Combined arterial insufficiency and corporo-venous occlusive erectile dysfunction N52.2 Drug-induced erectile dysfunction N52.31 Erec
pile bending stiffness, the modulus of subgrade reaction (i.e. the py curve) assessed based on the SW model is a function of the pile bending - stiffness. In addition, the ultimate value of soil-pile reaction on the py curve is governed by either the flow around failure of soil or the plastic hinge - formation in the pile. The SW model analysis for a pile group has been modified in this study .
