McEwen 2003 - MOOD DISORDERS AND MEDICAL ILLNESS Mood...

Info iconThis preview shows pages 1–8. Sign up to view the full content.

View Full Document Right Arrow Icon
Background image of page 1

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Background image of page 2
Background image of page 3

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Background image of page 4
Background image of page 5

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Background image of page 6
Background image of page 7

Info iconThis preview has intentionally blurred sections. Sign up to view the full version.

View Full DocumentRight Arrow Icon
Background image of page 8
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: MOOD DISORDERS AND MEDICAL ILLNESS Mood Disorders and Allostatic Load Bruce S. McEwen The brain controls both the physiologic and the behavioral coping responses to daily events as well as mayor stressors, and the nervous system is itself a target of the mediators of those responses through circulating hormones. The amyg— dala and hippocampus interpret what is stressful and regu- late appropriate responses. The am ygdala becomes ln’perac- tive in posttraumatic stress disorder (PTSD) and depressive illness, and hypertrophy of amygdala nerve cells is reported after repeated stress in an animal model. The hippocampns expresses adrenal steroid receptors. it undergoes atrophy in several psychiatric disorders and responds to repeated stres- sors with decreased dendritic branching and reduction in number of neurons in the dentate gyrus. Stress promotes adaptation ("allostasis ”), but a perturbed diurnal rhythm or failed shutoff of mediators afler stress (“allostatic state’) leads, over time, to wear and tear on the bony ("allostatic load "J. Neural changes mirror the pattern seen in the cardiovascular, metabolic, and immune systems. that is, short-term adaptation versus long-term damage. Allostatic load leads to impaired immunity, atherosclerosis, obesint. bone demineralization, and atrophy of nerve cells in brain. A llostatic load is seen in major depressive illness and may also be expressed in other chronic anxiety disorders such as PTSD and should be documented. Biol Psychiatry 2003;54: 200~20ir © 2003 Society of Biological Psychiatry Key Words: Allostasis, stress, HPA axis, hippocampus, amygdala Introduction hat do stressors do to the brain? We have known for some time that stress hormones such as cortisol are involved in psychopathology, reflecting emotional arousal and psychic disorganization rather than the specific disor- der per se (Sachar et al 1970). We now know that adrenocortical hormones enter the brain and produce effects ranging from steroid psychosis that can be blocked by a glucocorticoid antagonist (mefipristone; Belanoff et al 2001; Chu ct al 2001) to a wide range of effects on the normal brain that I review here. In Cushing’s disease, From the Harold and Margaret Millikcn Hatch Laboratory of Neurocndocrinology, The Rockefeller University. New York. New York. Address reprint requests to Bruce 8. McEwcn, Phil. The Rockefeller University, Box I65. 1230 York Avenue. New York NY IDOZI. Received November 18. 2002; revised January 23, 1003: accepted January 27. 2003. D 2003 Society of Biological Psychiatry depressive symptoms exist that can be relieved with surgical correction of the hypercortisolemia. Both major depression and Cushing‘s disease are asso- ciated with chronic elevation of cortisol that results in gradual loss of minerals from bone and abdominal obesity. In major depressive illness, as well as in Coshing’s disease, the duration of the illness and not the age of the subjects predicts a progressive reduction in volume of the hippocam- pus, determined by structural magnetic resonance imaging (Sheline et al 1999; Starkman et at 1999). Moreover, there are a variety of other anxiety-related disorders, such as posttraumatic stress disorder (PTSD), in which atrophy of the hippocampus has been reported, suggesting that this is a common process reflecting chronic imbalance in the activity of adaptive systems, such as the hypothalamic- pituitary-adrenal (HPA) axis, but also including endoge- nous neurotransmitters, such as glutamate. There is another side to the story, however: the role of stress hormones and other mediators in allostasis (main- taining stability, or homeostasis, through change), that is, the process of adaptation to events in daily life. When mediators of allostasis, such as cortisol and adrenalin (but also neurotransmitters and other tissue and hormonal mediators), are released in response to stressors or lifestyle factors such as diet, sleep—wake cycles, and exercise, they promote adaptation and are generally beneficial. When they are not turned off when no longer needed, or are not turned on when they are needed, or are overused by excessive challenge, cumulative changes lead to a wear and tear, called “allostatic load,” on the body and brain. This article is about allostasis and allostatic load as organizing concepts for understanding, on one hand, the short-term adaptation of the brain and body to acute stressors or to the daily rhythm of sleep and activity, and, on the other hand, the pathophysiology that is evident in major depression and other chronic anxiety-related disorders when the media- tors of allostasis are dysregulated or either over- or underac~ tive over many months and years. After describing these concepts, I briefly review the role of the biological mediators of stress in the protective and damaging aspects of stress on the brain and body. I then consider the dynamics of the HPA axis in relation to both normal adaptive effects and the pathophysiology associated with depressive illness; I also suggest that other anxiety-related disorders also fit the model of allostasis and allostatic load and should be studied for their systemic manifestations. ooosszzvosnsono doi:io.loiasoooa-3zzs(os)oom.x Depression, Anxiety, and Allostatic Load Protective and Damaging Effects of the Mediators of Adaptation Individual differences in the progression of a number of disorders that accumulate with time can be conceptualized as an accumulation of wear and tear of daily experiences, lifestyle, and major life stressors that interact with the genetic constitution and predisposing early life experiences (Geroni- mus 1992). The neuroendocrine system, autonomic ner- vous system, and immune system are mediators of adap- tation to challenges of daily life, referred to as “allostasis” (Sterling and Eyer 1988). Physiologic mediators, such as adrenalin, glucocorticoids, and cytokines, act on receptors in various tissues and organs to produce effects that are adaptive in the short run but can be damaging if the mediators are not shut off when no longer needed. A state of heightened activity of mediators, such as a chronic elevation of glucocorticoids in a flattened diurnal rhythm or as a result of chronic stress, is referred to as an “allostatic state." As a result, their effects on target cells are prolonged, leading to other consequences that may include receptor desensitization and tissue damage. This is “allostatic load" (MeEwen 1998; MeEwen 20003,b; Me- Ewen and Stellar 1993), which refers to the “cost” of adaptation. The brain is the master controller of the three systems noted above and is also a target of these systems, subject to both protection and damage (MeEwen 1998). Neuro- transmitters, like hormones, are usually released during a discrete period of activation and are then shutoff, and the mediators themselves are removed from the intracellular space by reuptake or metabolism so as not to prolong their effects. When this does not happen, however, there is allostatic load, and the brain is at increased risk for damage (Lowy et a1 1995; Moghaddam et al 1994). Roles of Stress-Related Hormones in Adaptation and Structural Plasticity I now look at some of the positive, adaptive effects that one mediator of allostasis, glueocorticoids, produces in the brain. The amygdala and hippocampus are both involved in contextual fear conditioning and in passive avoidance learning. In fear conditioning, glucocorticoids enhance leamed fear (Corodimas et a1 1994) and modulate infor- mation flow through the lateral amygdala, and they play an important role in forming the memory of context in contextual fear conditioning (Stutzmann et a1 1998) but not of the actual effect of footshock in rats that are already familiar with the context in which the shock is adminis- tered (Pugh et al 1992a, 1992b). This suggests that the hippocampal role in contextual fear conditioning is en- hanced by moderate levels of glucocorticoids, but that fear Bret. PSYCHIATRY 20] 2003;54:200—20? conditioning is either not so dependent on glucocorticoids or is so strong that glucocorticoid influences are difficult to demonstrate. Moreover, in passive avoidance, both catecholamines and glucocorticoids play a role in facili- tating the learning (Cahill et al 1994; Roozendaal 2000). Adrenal steroids also play a supporting role in the leaming ofa spatial navigation task in mice (Oitzl et a1 2001). Other evidence for glucocorticoid actions supports an inverted U-shaped dose-response curve in which low to moderate levels of adrenal steroids enhance acquisition of tasks that involve the hippocampus, whereas high levels of glucocorticoids disrupt task acquisition (Conrad et al 1999a; Diamond ct al 1992, 1999; Pugh et al 1997b). Adrenal steroids have biphasic effects upon excitability of hippocampal neurons that may underlie their biphasic actions on memory and recall (Diamond ct a1 1992; Pavlides et al 1994, 1995; Pavlides and McBwen 1999). One of the ways that stress hormones modulate function within the brain is by changing the structure of neurons. There is structural plasticity within the dentate gyms comu ammonis 3 (DG—CA3) system, in that new neurons continue to be produced in the dentate gyrus throughout adult life (Gould et al 2000) and CA3 pyramidal cells undergo remodeling of their dendrites (MeEwen 1999; MeEwen and Magarinos 2001). The subgranular layer of the dentate gyrus contains cells that have properties of astrocytes (e.g., expression of glial fibrillary acidic pro- tein) that give rise to granule neurons (Seri et a1 2001). There are many hormonal and neurochemical facilitators of neurogenesis and cell survival in the dentate gyrus, including insulin-like growth factor (lGF)-l. serotonin, and estradiol (Aberg et al 2000; Czeh et al 2001; Gould ct al 2000; Malberg et al 2000; Trejo et a1 2001). Neurogenesis or survival of newly born cells is in- creased by putting mice in a complex (“enriched”) envi- ronment (Kempennann et al 199?). Moreover, a form of classical conditioning that activates the hippocampus (“trace conditioning") leads to prolongation of the survival of newly born dentate gyrus neurons (Gould et al 1999; Shors et al 2001). Certain types of acute stress and many chronic stressors suppress neurogenesis or cell survival in the dentate gyrus, and the mediators of these inhibitory effects include excitatory amino acids acting via N- methyl-D-aspartate receptors and endogenous opioids (Cameron et a1 1998; Eisch et al 2000; Gould and Tanapat 1999; MeEwen 1999). Another form of structural plasticity is the remodeling of dendrites in the CA3 region of the hippocampus (MeEwen and Magarinos 2001). CA3 pyramidal neurons in hip— pocampus receive mossy fiber input from the granule neurons that are undergoing replacement, and the mossy fiber input is a powerful excitatory amino acid input that is responsible for remodeling of the length and branching of 202 [nor PSYCHIATRY 2003;54:200—20? dendrites. Such remodeling is seen in animals living in a dominance hierarchy (Blanchard et a1 2001; McKittrick et a1 2000). in hibernating hamsters, it occurs in a matter of hours and reverses itself just as quickly when the animals are aroused from torpor (Magarinos et al, unpublished). Along with suppressed neurogcnesis, this remodeling is an important target of allostatic load in chronic stress. Repeated Stress and Structural Changes in the Hippocampus and Amygdala Dendritic remodeling and suppression of neurogcnesis occurs in models of repeated stress in rodents. Repeated restraint stress for 6 hours per day for 21 days suppresses neurogcn- esis; continuing daily restraint out to 6 weeks results in decreased dentate gyros neuron number and volume and reduction by half in the survival of cells born during the period of daily stress (Pham et al, unpublished}. Besides suppressing neurogcnesis, 21 days of daily restraint stress reduces branching and total length of apical dendrites of CA3 neurons (Magarinos and McEwen 19953, 1995b). Re- peated stress has also been reported to decrease the length and branching of dentate gyms granule neurons and CA1 pyramidal neurons (Sousa et a1 2000). Dendritic remodel- ing is also produced by daily exposure to elevated corti- costerone (Magarinos et a1 1999; McEwen 1999; Sousa et a1 2000), and both stress- and glucocorticoiddnduced remodeling are reversible (Conrad et al 1999b; Magarinos et al 1999). Glucocorticoids are not acting alone, and their effects can be blocked by agents that interfere with glutamate and serotonin actions (McEwen I999). Exeitatory amino acids appear to be largely responsible for suppressing neurogcn- esis in the dentate gyms, as well as participating in the remodeling of dendrites (Gould and Tanapat 1999; McEwen 1999). During restraint stress, extracellular lev- els of glutamate are elevated in the hippocampus, as shown by microdialysis (Lowy et a1 1993; Moghaddam et a1 1994). Adrenalectomy prevents the increased levels of extracellular glutamate during restraint stress (Lowy et a1 1993), implying that adrenal secretions modulate the extracellular levels of glutamate. Repeated restraint stress has a number of effects on behavior after 21 days or longer. These include cognitive impairment on spatial recognition memory and increased anxiety in an open field, as well as increased fear condition- ing (Conrad et al 1999a, 1999b; Luine et a1 I994) and increased aggression toward animals in the same cage that is manifested progressively during the dark period follow- ing the daily restraint stress (Wood et al, unpublished). The cognitive impairment is likely to be related to the structural changes in the hippocampus described earlier, whereas the anxiety, fear, and aggression may be due to 3.8. McEwen changes in the amygdala. A neural correlate of the increased anxiety, fear, and aggression is the recently reported hypertrophy of neurons in the amygdala (Chat- tarji et a1 2000). An animal model of chronic psychosocial stress has been influential and informative in showing that the hippocampal structural plasticity after chronic restraint stress can be generalized to another species and to a stressful situation that has consequences that are reminiscent of depressive illness (Czch et al 2001). Repeated psychosocial stress for 28 days causes remodeling of dendrites of CA3 neurons, and the remodeling of CA3 dendrites can be prevented by daily treatment of intruder tree shrews with phenytoin, a drug that blocks the actions of excitatory amino acids (Magarinos et al 1996). Chronic psychosocial stress also causes reduced neurogcnesis in the dentate gyms (Czeh et a1 2001; Gould et al 199?). The effects of psychosocial stress to suppress neurogcnesis can be prevented by daily treatment with the antidepressant tianeptine (Czeh et a1 2001). Other antidepressants have been reported to in- crease neurogenesis in the dentate gyrus (Malberg et a1 2000), but so far the recent study on the tree shrew is the only animal study thus far to use an antidepressant to counteract the effects of an ongoing stress {Czeh et al 2001). Tree shrews show behavioral alterations—anhedo- nia and reduced exploratory aetivity—-that are prevented by treatment with antidepressants (Van Kampcn et a1 2002). Therefore, these results have some relevance to what antidepressants may be doing in depressive illness. Allostatic States in Depressive Illness Stress hormones are elevated in major depressive illness. In particular, the diurnal rhythm is distorted (Sachar et a1 191’0). Normally low evening levels of cortisol are in~ creased in depression (Deuschle et a1 1998; Young et a] 1994) and the stress hormone axis in major depression is resistant to suppression by the synthetic glucocorticoid dexamethasone (Carroll et a1 1968). it is also noteworthy that androgen levels are elevated in women with major depression, which undoubtedly reflects adrenal hyperac~ tivity (Weber et a] 2000). IGF-l levels are also reported to be elevated in major depression, and this may reflect elevated growth hormone release as a result of the hyper- cortisolemia (Deuschle 1997). Each of these patterns of elevation constitute an “allostatic state,” as defined earlier, and they represent a pathway for the development of allostatic load in the brain and other organs throughout the body. I now examine some of these changes, focusing on the hypercortisolemia. Regarding the brain, I noted earlier the studies showing that hippocampal volume loss in major depressive illness is related to duration of the depression rather than to age Depression, Anxiety, and Allostatic Load per se of the patients (Bremner et al 2000; Sheline et a] 1996, 1999). Not all studies report such changes (e.g., Rusch et a1 2001; Vakili et a1 2000), and the reasons for these different results are beyond the scope of this discus- sion, but they may be explained by differences in the duration of depression, as well as gender and age. (See the article by Sheline in this issue.) It should be noted that hippocampal size in elderly twins shows only 40% genetic contribution, with the predomi- nant influence being environmental (Sullivan et al 2001). This emphasizes the importance of experiential factors and allostatic load in determining hippoeampal volume. in relation to geriatric depression, hippocampal atrophy has been reported in relation to depression in the elderly (Steffens et al 2000), with an association detected with presence of the apolipoprotein E4 genotype that is linked to Alzheimer‘s disease risk (Kim et a1 2002). Sheline and colleagues described in their magnetic resonance imaging study evidence for discontinuities that might represent sites of damage (Sheline et a1 1996). Although some recent postmortem studies on brains from depressed individuals did not show neuron loss in hip- pocampus (Lucassen et a1 2001; Muller et a1 2001), the duration of the depression and the subtype of depression were not carefillly controlled. Thus the possibility that neural damage may ultimately occur in major depression cannot be disregarded, particularly when depression lasts a long time. Moreover, in a recent study in young depressed subjects, hippocampal volume was not smaller in first episode depres- sion but declined rapidly over several years even while treatment was underway (MacQueen et al 2003). If permanent damage occurs, how might it come about? There are specific situations in which damage to the hippocampus is known to occur that is exacerbated by glueocorticoids. The hippoeampus is vulnerable to isch- emic damage (Sapolslcy and Pulsinelli 1985) and to damage from kainic acid induced seizures (Roozendaal et al 2001). The former involves the CA1 and subiculum to a greater extent and the latter, the CA3 region, as dis- cussed earlier. Based on the discussion earlier in this article about excitatory amino acids and structural remod- eling, there may be a fine line between the conditions that lead to reversible remodeling of neurons and the circum- stances that can cause permanent damage (for further discussion, see McEwen 2000a,b). It is important to note that other brain regions besides hippocampus are affected in depressive illness and un- dergo structural changes. One region is the prefrontal cortex, and structural imaging (Drevets et a] 199?) showed loss of volume in familial pure depressive disorder, whereas autopsy studies (Rajkowska 2000; Rajkowska et a] 1999, 2001) have shown loss of volume and glial cells as well as neuronal density in both unipolar and bipolar BIOL PSYCHIATRY 203 2003;54:200-207 disorder. There is one animal study showing that chronic glucocorticoid treatment induces loss of dendrites in the rat prefrontal cortex (Wellman 2001); however, much more work needs to be done on this brain region. Depressive illness is associated with a hyperactivation of the amygdala (Drevets et al 1992; Sheline et a1 2001) and more recently with an actual enlargement of the amygdala in first episode major depression (Frodl et al 2002), although shrinkage of the amygdala has also been reported with increased duration of depression (Sheline et a1 1999). The amygdala hypertrophy is reminiscent of the increased dendritie branching reported in rats after re~ pcated immoblization stress (described earlier; see also Chattarji et a1 2000). Because the amygdala integrates information related to fear and strong emotions and also sends outputs via the central nucleus for autonomic arousal and via the basal nucleus for more active aspects of coping (LeDoux l996), the elevation of amygdala activity may be a first step that leads to overactivation of systems involved in physiologic and behavioral coping. The long-term consequences ofthis may well be a wear and tear on the body that results in a number of patho- physiologie consequences, because the amygdala regulates both autonomic nervous system activity and corticotropin and cortisol production through outputs of its central nucleus (Schulkin et a1 1994). There are reports that in recurrent major depression of long duration. the amygdala may undergo shrinkage (Sheline et a1 1998, 1999). It is thus possible that initial hypertrophy gives way to atrophy in this important brain structure. Whether or not there is brain damage in depressive illness of long duration, there certainly appears to be altered brain structural changes that may or may not be reversible if suitable pharmacologic agents and behavioral and psychotherapies can be found. Besides the brain changes in major depression, there are other changes in the body that reflect dysregulated HPA and autonomic activity and are slow in developing. These constitute allostatic load that produces cumulative pathos physiology that may also be reversible if caught in time. Such cumulative, long-term effects include bone mineral loss (Cizza et a1 2001; Michelson et a1 1996; Schweiger et al 2000) and abdominal fat deposition (Thakore et a1 1997; Mann and Thakore 1999; Weber-Hamann et a1 2002). Sleep disruption may be a key feature that leads to these consequences, because even short periods of sleep depriva- tion in otherwise normal individuals elevate evening cortisol and glucose levels and increase insulin levels and insulin resistance (Plat et a] 1999; Spiegel et al 1999). This combination of long-term allostatic load, together with dysregulation of the autonomic nervous system in major depression (Thayer ct al 1998), is associated with in- 204 13101. PSYCHIATRY 2003;54:200-20? creased blood platelet reactivity (Lederbogen et al 2001a; Musselman et al 1996; Walsh et al 2002) and increased risk for cardiovascular disease (Ballcnger et a1 2001; Heuser 2002; Musselman et al 1998; Perlmutter et al 2000). There are parallels between the story for major depression and what is known about psychiatric and somatic features of Cushing’s disease involving melancholia, depression, ab- dominal obesity, bone mineral loss, and increased risk for cardiovascular disease (Condren and Thakore 2001; Gold et a1 1936; Starkman and Schteingart 1981; Starkman et a] 1981). In addition, there is evidence for hippocampal atrophy in Cushing‘s disease along with memory impair- ments (Forget et al 2000; Mauri et a1 1993; Starkman et a1 1992}. Interestingly, hippocampal volume loss in Cush- ing’s disease is at least partially reversible over several years after correction of the hypercortisolemia (Bourdcau et al 2002; Heinz et al 1927; Starkman et a1 1999). Finally, a largely unexplored area concerns the effects of antidepressant medication on the brain and body changes associated with depressive illness. On one hand, certain antidepressants may contribute to some of the associated pathophysiology, such as cardiovascular instability (Leder- bogen et al 2001b). On the other hand, withdrawal from antidepressant treatment may cause imbalances in neuro- transmitter systems, with elevations of cxcitatory amino acid tone (Harvey et a1 2002), and contribute to the allostatic load that occurs as the depressive state continues. Conclusions In the ease of depressive illness, and likely in other anxiety- related disorders, there appears to be a pattem of systemic pathophysiology that reflects allostatic states leading to allo- static load and producing cumulative changes in both brain and body. The hippocampus appears to play an important role, because it is involved in cognitive functions related to contextual, episodic, and spatial memory, and it is also a key structure in shutting off the HPA axis after psychological stressors (Jacobson and Sapolsky I991). Dysfunction of the hippocampus can then lead to elevated cortisol levels in the aftermath of stress and also to an inability to associate context with fearw—that is, discriminate situations that are fear-producing from those that are not. A key issue, then, is whether stress and allostatic load damage the brain, and particularly, the hippocampus. Yes, perhaps they do, but the brain has a huge capacity for adaptive plasticity, and the animal studies raise the question whether the atrophy is reversible. We have also seen that there is damage to the brain in stroke and seizures that is caused by excessive excitatory amino acids, aided by glucocorticoids. insofar as the same combination operates in long-term depressive illness and other psychiatric disorders of long duration, the question is when and how to intervene to prevent such damage. B.S. McEwcn Finally, it is possible to suggest a sequence of changes in depressive illness: I Amygdala hyperactivity; I HPA dysregulation resulting, at least in part, from disruption of nomtal sleep patterns; I Delayed atrophy of hippocampus, prefrontal cortex, along with bone mineral loss and abdominal obesity; 0 Increased risk of cardiovascular disease. It is important to document whether other anxiety disorders also cause the dysregulation of the HPA axis and other mediators of allostasis. If so, a similar comorbidity of systemic and neural pathophysiology may also occur to that seen in long-term depressive illness. Such a pattern of allostatic load needs to be evaluated in other anxiety disorders such as PTSD, bipolar illness, and borderline personality disorder to see if there is a common pattern that arises from the physiologic dysregulation that Edward Sachar originally recognized in his pioneering studies. Some of the material in this report has grown out of activities ofthe John D. and Catherine T. MacArthur Foundation lleallh Program and its Network on Socioeconomic Status and Health (Nancy Adler, PII.D.. Chair). Research support has come from the National Institute of Mental Health Grant Nos. MH4l256 and M1i589l1. Aspects of this work were presented at the conference, “The Diagnosis and Treatment of Mood Disorders in the Medically [11,“ November 12—13, 2002 in Washington DC. The conference was sponsored by the Depression and Bipolar Support Alliance through unrestricted educa- tional grants provided by Abbott Laboratories, Bristol-Myers Squibb Company, Cyberonies, lnc., Eli Lilly and Company, Forest Laboratories, lnc., GlaxoSmithKline, Janssen Pharmaceutica Products, Organon lnc., Pfizer Inc, and Wyeth Pharmaceuticals. References Aberg MA, Aberg ND, Hedbacker H, Oscarsson J, Eriksson PS (2000): Peripheral infitsion of IGF-I selectively induces neuro» genesis in the adult rat hippocampus. J Neurosci 2028964903. Ballenger JC, Davidson JRT, Lecrubier Y. Nutt DJ, Roosc SP, Sheps DS, International Consensus Group on Depression and Anxiety (2001}: Consensus statement on depression, anxiety, and cardiovascular disease. J Clin Psychiatry 62:24—27. Belanoff JK, Flores BH, Kalezhan M, Sund B, Schatzberg AF (2001): Rapid reversal of psychotic depression using mife- pristone. J Clin Psychopharm 21:516—521. Blanchard RJ, McKittrick CR, Blanchard DC (2001}: Animal models of social stress: Effects on behavior and brain neuro— chemical systems. Physioi Behav 73:261—271. Bourdcau I, Bard C, Noel B. Leclerc I, Cordeau M-P, Belair M, et al (2002): Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercorti— solism. J Clin Endocrine! Metal) 8?:1949—1954. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller 11L, Chamey DS (2000): Hippocampal volume reduction in major depression. Am J Psychiatry 157:1 lS—-l 17. Depression, Anxiety. and Allostatic Load Cahill L, Prins B, Weber M, McGaugh JL (I994): Beta~ adrenergic activation and memory for emotional events. Nature 37 l :702—1’04. Cameron HA, Tanapat P, Gould E (1998): Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogen- esis in the dentate gyrus of adult rats through a common pathway. Neuroscience 82:349—354. Carroll B, Martin F, Davies B (1968): Resistance to suppression by dexamethasone of plasma ll-O.H.C.S. levels in severe depressive illness. Br MedJ 25:285—287. Chattarji S, Vyas A, Mitra R, Rao 338 (2000): Effects of chronic unpredictable and immobilization stress on neuronal plastic- ity in the rat amygdala and hippocampus. Soc Neorosei Abs 26(571.9):1533. Chu JW, Matthias DF, Belanof‘f .1, Schatzberg A, Hoffman AR, Feldman D (2001): Successful long-term treatment of refrac- tory Cushing’s disease with high-dose mifepristone (RU 486). J Ciin Enal'ocrinolr Metab 36:1—6. Cizza G, Ravn P, Chrousos GP, Gold PW (2001): Depression: A major, unrecognized risk factor for osteoporosis? Trends Endocrine! Metab 12:198 —203. Condren RM, Thakorc JH (200 I }: Cushing‘s disease and melan- cholia. Stress 4:91—119. Conrad CD, Galea LAM, Kuroda Y, McEwen BS {1996): Chronic stress impairs rat spatial memory on the Y-Maze and this effect is blocked by tianeptine pre-treatment. Benav Nertroscr' 110:1321—1334. Conrad CD, Lupien SJ, McEwen BS (1999a): Support for a bimodal role for type It adrenal steroid receptors in spatial memory. Neorobiot Learn Mem 72:39-46. Conrad CD, Magarinos AM, LeDoux JE, McEwen BS (1999b): Repeated restraint stress facilitates fear conditioning indepen- dently of causing hippocampal CA3 dendritie atrophy. Betrav Neorosci 113:902—913. Corodimas KP, LeDoux JE, Gold PW, Schulkin J (1994): Corticosterone potentiation of learned fear. Ann N YAead Sci 746:392. Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van Kampen M, et al (2001): Stress-induced changes in cerebral metabolites, hippocampal volume and cell proliferation are prevented by antidepressant treatment with tianeptine. Prat: Nari Acad Sci U S A 98:12796—12301. Deuschle M, Blurn WF, Strasburger Cl, Schweiger U, Weber B, Korner A, et al (199?): lnsulin-iike growth factor—I (IGF-l) plasma concentrations are increased in depressed patients. Psycnonetiroendoerinalagy 22:493—503. Deuschle M, Weber B, Colla M, Depner M. Ileuser I (1998): Effects of major depression, aging and gender upon calcu- lated diurnal l'ree plasma cortisol concentrations: A re- evaluation study. Stress 2:281—28't'. Diamond DM, Bennett MC, Fleshner M, Rose GM (1992): Inverted-U relationship between the level of peripheral cor- ticosterone arid the magnitude of hippocampal primed burst potentiation. Hippocampns 21421—430. Diamond DM, Park CR, Heman KL, Rose GM (1999): Exposing rats to a predator impairs spatial working memory in the radial arm water maze. Hippocampns 9:542—552. Drevets WC, Price J]... Simpson JR Jr, Todd RD, Reich T, Vannier M, Raichle ME (199?): Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386:324—827. BIOL PSYCHIATRY 205 2003;54:200 207 Drevets WC, Videen T0, Price J L, Preskom SH, Carmichael ST, Raichle ME (1992): A filnctional anatomical study of unipo- lar depression. J Neiirosci 12:3628—3641. Eisch AJ. Barrot M, Schad CA, Self DW, Nestler EJ (2000): Opiates inhibit neurogenesis in the adult rat hippocampus. Proc Natl Acad Sci U S A 917579—7584. Forget H, Lacroix A, Somma M, Cohen H (2000): Cognitive decline in patients with Cushing‘s syndrome. J int Neiiropsy- ehot' Soc 6:20—29. Frodl T, Meisenzahl E, Zetzsche T, Bottlender R, Born C, Groll C, et a1 (2002): Enlargement of the amygdala in patients with a first episode of major depression. Bio! thiatry 51 :708 —'t'14. Geronimus AT (1992): The weathering hypothesis and the health of African-American women and infants: Evidence and spec— ulations. Elfin Dis 2:207—221. Gold PW, Loriaux DL, Roy A, Kling MA, Calabrese JR, Kellner CH, et al (1986}: Responses to corticotropin—reteasing hor- mone in the hypercortisolism of depression and Cushing‘s disease. New Engi' J Med 314:13294335. Goald E, Beylin A, Tanapat P, Reeves A, SllOl'S TJ [1999): Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2:260—265. Gould E, McEwen BS, Tanapat P, Galea LAM, Fuchs E (199?): Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activa- tion. J Nearesci 17:2492—2498. Gould E, Tanapat P (1999): Stress and hippocampal neurogen- esis. Biol Psychiatry 46:1472—14't'9. Gould E, Tanapat P, Rydel T, Hastings N (2000): Regulation of hippocampal neurogenesis in adulthood. Biol Psychiatni 48:715-720. Harvey BH, Jonker LP, Brand L, Heenop M, Stein D] (2002): NMDA receptor involvement in imipramine withdrawal- associated effects on swim stress, GABA levels and NM DA receptor binding in rat hippocampus. Life Sci "it :43-54. Heinz RE, Martinez J, Haenggeli A [19?7): Reversibility of cerebral atrophy in anorexia nervosa and Cushing‘s syn~ drome. J Comp Assisted Taniogr 1:415—418. Heuser I (2002}: Depression, cndocrinologically a syndrome of premature aging? Maturiras 41(suppl l}:Sl9—823. Jacobson L, Sapolsky R (1991): The role of the hippocampus in feedback regulation of the hypothalamie—pituitary-adrenocor— tical axis. Endocr Rev 12:118—I34. Kempermann G, Kuhn HG, Gage FH {1997): More hippocampal neurons in adult mice living in an enriched environment. Nature 586:493—495. Kim DH, Payne ME, Levy RM, MacFalI JR, Steffens DC (2002): APOE genotype and hippocampal volume change in geriatric depression. Biol Psychiatry 51:426—429. Lederbogen F, Gilles M, Maras A, Hamann B, Colla M, Heuser I, Deuschle M (2001a): Increased platelet aggregability in major depression. Psychiatr Res 102:255—261. Lederbogen F, Weber B, Colla M, Heuser I, Dreuschle M, Demptle CE (2001b): Antidepressant treatment and global tests of coag— ulation and fibrinolysis. J Clin Psychiatry 62:130. LeDoux JE (1996): The Emotional Brain. New York: Simon and Schustcr. 206 BIUL PSYCHIATRY 200354200207 Lawy MT, Gault L, Yamamoto BK (1993): Adrenalectomy atten- uates stress—induced elevations in extracellular glutamate con- centrations in the hippocampus. J Netiracltem 6l:l957—l960. Lowy MT, Wittenberg L, Yamamoto BK (I995): Effect of acute stress on hippocampal glutamate levels and spectrin proteol- ysis in young and aged rats. J Netti-ache»: 65:268 —274. Lucassen P], Muller MB, Holsboer F, Bauer J, Holtrop A. Wouda .I. et al (200]): Hippocampal apoptosis in major depression is a minor event and absent from subareas at risk for glucorcorticoid overexposure. Am J Partial 58:453-468. Luine V, Villegas M, Martinez C, McEwen BS (1994): Repeated stress causes reversible impairments of spatial memory per~ formance. Brain Res 639:167—l't'0. MacQueen GM, Campbell S, Macdortald K, Amano S. J offe R'I‘, Nahmias C, Young LT (2003): Course of illnessI hippocam- pal function and hippocampal volume in major depression. Proc Natl Acod Sci USA 100: 13875-1 392. Magarinos AM, Deslandes A, McEwen BS (1999): Effects of antidepressants and benzodiazepine treatments on the den- dritic structure ofCAS pyramidal neurons after chronic stress. Eur J Pltarm 371:113—122. Magarirtos AM, McEwen BS ( I995a}: Stress-induced atrophy of apical dendrites of hippocampal CA3e neurons: Comparison of stressors. Neuroscience 69:83—83. Magarinos AM, McEwen BS ( 1995b): Stress—induced atrophy of apical dendrites of hippocampal CA3e neurons: Involvement of glucocorticoid secretion and exeitatory atnino acid recep- tors. Neorosciettce 69:89 ~98. Magarinos AM, McEwen BS, Flugge G, Fuchs E (I996): Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrevvs. J Neurosci l6:3534 —3540. Malberg JE, Eisch A], Nestler EJ, Duman RS (2000): Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Nettrosci 20:9104—9l 10. Mann JN, Thakore JH (1999}: Melancholic depression and abdominal fat distribution: A mini~review. Stress 3:1—15. Mauri M, Sinforiani E. Bono G, Vignati F, Berselli ME. Attanasio R, Nappi G (1993): Memory impairment in Cush- ing‘s disease. Acra Neural Scattd 87:52—55. McEwen B (20003): Allostasis and allostatic load: Implications for neuropsychopltarmacology. Nettropsycliopltarmacology 22:108—124. McEwen BS (1998): Protective and damaging effects of stress mediators. New Engl J Med 338: 171-179. McEtven BS (1999): Stress and hippocampal plasticity. Atmtt Rev Netirosct' 22: 105—122. McEwen BS (2000b): Allostasis. allostatic load, and the aging nervous system: Role of excitatory amino acids and excito- toxicity. Nettrocltem Res 25:1219—1231. McEwen BS, Magarinos AM (2001): Stress and hippocampal plasticity: Implications for the pathophysiology of affective disorders. Hum Psychophamocol 16:57—319. McEwen BS, Stellar E 0993): Stress and the individual: Mech- anisms leading to disease. Arch int Med l53:2093—2l01. McKittricl-z CR, Magarinos AM, Blanchard DC, Blanchard RJ, Mel-Ewen BS, Sakai RR (2000}: Chronic social stress reduces BS. McEwen dendritic arbors in CA3 of hippocampus artd decreases binding to serotonin transporter sites. Synapse 36:85—94. Michelson D. Stratakis C, I'Iill L. Reynolds J, Galliven E, Chrousos G, Gold P (I996): Bone mineral density in women with depression. New Eng! J Med 335:1176—1181. Moghaddam B, Boliano ML, Stein—Behrcns B, Sapolsky R {1994): Glucoconicoids mediate the stress-induced extracel— lular accumulation of glutamate. Brain Res 655:251—254. Muller MB. Lucassen PJ, Yassouridis A, Hoogendijk WJG, Holsboer F, Swaab DF (2001): Neither major depression nor glucocorticoid treatment affects the cellular integrity of the human hippocampus. Ettt'J Neurascl 14:1603—1612. Musselman DL, Evans DL, Nemerot‘f CB (1998}: The relation— ship of depression to cardiovascular disease. Arclt Gen Psychiat 55:580—692. Musselman DL, Tomer A, Manattmga AK, Knight BT, Porter MR, Kasey S, et a] (I996): Exaggerated platelet reactivity in major depression. Am J Psychiatry lS3:l3l3—-l3l7. Oitzl MS, Reichardt HM, Joels M, de Kloet ER (2001): Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory, Proc Natl Acad Sci U S A 98:12790—12795. Pavlides C, Kimura A, Magarinos AM, McEwen BS {I994}: Type I adrenal steroid receptors prolong hippocampal long- tenn potentiation. Neuroreport 52673—2677. Pavlides C, McEwen BS (1999): Effects of mineralocorticoid and glucocortieoid receptors on long—term potentiation in the CA3 hippocampal field. Brain Res 351:204—214. Pavlides C, Watanabe Y, Magarinos AM, MeEvven BS (1995): Opposing role of adrenal steroid type I and Type 11 receptors in hippocampal long—tom] potentiation. Neuroscience 68:38?—394. Perlmutter JB, Frishman WH, Feinstein RE (2000): Major depression as a risk factor for cardiovascular disease: Thera- peutic implications. Heart Dis 2:75-32. Plat L, Leproult R, L’l-len'nite-Baleriaux M, Fery F, Mockel .I, Polonsky KS, Van Cauter E {I999}: Metabolic effects of short-term elevations of plasma cortisol are more pronounced in the evening than in the morning. J Clin Endocrinol Metal) 843032—3092. Pugh CR, Fleshner M, Rudy J W (1997a): Type II glucocorticoid receptor antagonists impair contextual but not auditory-cue fear conditioning in juvenile rats. Netirobt'ol Learn Mem 67:75—79. Pugh CR, Tremblay D, Fleshner M, Rudy .IW (1997b): A selective role for eorticosterone in contextual~fear condition— ing. Beltav Nertrosei 111:503—511. Rajkowska G (2000): Postmortem studies in mood disorders indicate altered numbers of neurons and gliai cells. Biol Psychiatry 48:766 47?. Rajkowska G. Halaris A, Selemon LD (200]): Reductions in neuronal and glial density characterize the dorsolateral pret-‘rontal cortex in bipolar disorder. Biol Psychiatry 49:741—752. Rajkowska G, Miguel-Hidalgo JJ, Wei J, Dilley G. Pittman SD, Meltzer HY, et a] (1999): Morphometric evidence for neurow nal and glial prefrontal cell pathology in major depression. Biol Psychiatry 45: 1085—1098. Roozendaal B (2000): Glueocorticoids and the regulation of mem— ory consolidation. Psycltortettroendocrinology 25:213—238. Depression, Anxiety, and Allostatic Load Roozendaal 13, Phillips RC}, Power AE, Brooke SM. Sapolsky RM, McGaugh JL, (2001): Memory retrieval impairment induced by hippocampal CA3 lesions is blocked by adreno- cortical suppression. Nat Nettrosci 4:1 169—1171. Rowe JW, Kahn RL {1998): Successful Aging. Pantheon Books. Rusch BD, Abercrombie HC, Oakes TRI Schaefer SM. Davidson R] (2001): Hippocampal morphometry in depressed patients and control subjects: Relations to anxiety symptoms. Biol Psychiatry 50:960—964. Sachar BJ, Hellman .l, Fukushima DK, Gallagher TF (1970): Cortisol production in depressive illness. Arch Gen Psychia- try 23:289—298. Sapolsky R, Pulsinelli W (1985): Glucocorticoids potentiate ischemic injury to neurons: Therapeutic implications. Science 229:1397—1399. Schulkin J, McEwen BS, Gold PW (1994): Allostasis, amygdala, and anticipatory angst. Nettrosci Biobeitav Rev 18:385—396. Schwciger U, Weber B, Deuschle M, Heuscr l (2000): Lumbar bone mineral density in patients with major depression: Evidence of increased bone loss at follow-up. Am J Psychi- atry 157:118—120. Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A (200]): Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21:7153—7160. Sheline ‘1’], Batch DM, Donnelly IM, Ollinger JM, Snyder AZ, Mintun MA (2001): Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepres~ sant treatment: An {MRI study. Bioi Psychiatry 50:651—658. Sheline Yl, Gado MH, Price JL (1998): Amygdala core nuclei volumes are decreased in recurrent major depression. Neuro- rcport 92023—2028. Sheline Y1, Sanghavi M, Mintun MA, Gado MH (1999): De» pression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depres- sion. J Nettrosci 19:5034—5043. Sheline Yl, Wang PW, Gado MH, Csernansky JC, Vannier MW (1996): Hippocampal atrophy in recurrent major depression. Proc Natlr Acad Sci U S A 933903—3913. Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001): Neurogenesis in the adult is involved in the formation of trace memories. Nature 410:3?2—376. Sousa N, Lukoyanov NV, Madeira MD, Almeida OFX, Paula- Barbosa MM (2000): Reorganization of the morphology of hippocampal neurites and synapses after stress-induced dam- age correlates with behavioral improvement. Neuroscience 97:253—266. Spiegel K. Leproult R, Van Canter B (1999): Impact of sleep debt on metabolic and endocrine filnction. Tire Lancet 354:1435—1439. Starkman MN, Gebarski SS, Berent S, Sehteingart DE (1992): Hippocampal formation volume, memory dysfiinction, and cortisol levels in patients with Cushing’s syndrome. Bioi Psychiatry 32:756. —765. Starkman MN, Giordani B, Gebrski SS, Berent S, Schork MA, Schteingart DE (1999): Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing‘s dis- ease. Bioi Psychiatry 46:1595—1602. BIOL PSYCHIATRY 20? 2003;54:200—207 Starkman MN, Scliteingart DE (1981): Neurcpsychiatric mani- festations of patients with Cushing’s syndrome. Arch totem Med 141:215—219. Starkman MN, Schteingart DE, Schork MA {1981}: Depressed mood and other psychiatric manifestations of Cushing’s syndrome: Relationship to hormone levels. Psycirosom Med 43:3—18. Stefl‘ens DC, Byrum CE, McQuoid DR, Greenberg DL, Payne ME, Blitchington TF (2000): Hippocampal volume in geriat- ric depression. Biol Psychiatry 48:301—309. Sterling P, EyerJ (1938): Allostasis: A new paradigm to explain arousal pathology. In: Fisher S, Reason J, editors. Handbook othfe Stress, Cognition and Health. New York: John Wiley & Sons, 629—649. Stutzntann GE, McEwen BS, LcDoux J E (1998): Serotonin modulation of sensory inputs to the lateral amygdala: Depen— dency on corticosterone. J Netirosct‘ 18:9529—9538. Sullivan EV, Pfef‘ferbaum A, Swan GE, Cannelli D (2001): Heritability of hippocampal size in elderly twin men: Equiv— alent influence from genes and environment. Hippocamptts 11:254-762. Thakore JH, Richards P], Reznek RH, Martin A, Dinan TO {1997): Increased intra-abdominal fat deposition in patients with major depressive illness as measured by computed tomography. Biol Psychiatry 41:] 140—1142. Thayer JF, Smith M, Rossy LA, Sellers .lJ, Friedman BH (1998): Heart period variability and depressive symptoms: Gender differences. Bio! Psychiatry 44:304—306. Trejo JL, Carro E, Torres-Aleman l (2001): Circulating insulin- like growth factor I mediates exercise—induced increases in the number of new neurons in the adult hippocampus. J Nettrosci 21:1628 —1634. Vakili K, Pillay SS, Lafer B, Fava M, Renshaw PF. Bonello- Cintron CM, et al (2000): Hippocampal volume in primary unipolar major depression: A magnetic resonance imaging study. Biol Psychiatry 4?:1087—1090. Van Kampen M, Kramer M, Hietnke C, Flugge G, Fuchs E (2002): The chronic psychosocial stress paradigm in male tree shrews: Evaluation of a novel animal model for depressive disorders. Stress 5:3?46. Walsh MT, Dinan TG, Condren RM, Ryan M, Kenny D (2002): Depression is associated with an increase in the expression of the platelet adhesion receptor glyeoprotein Ib. Ltfi' Sci 70:3l55—3165. Weber B, Lewicka S, Deuschle M, Calla M, Heuser l {2000): Testosterone, androstenedione and dihydrotestosterone con- centrations are elevated in female patients with major depres- sion. Psycitooertrocrtdocrinoiogy 25 :765—771 . Weber-l lamann B, Hentschel F, Kniest A, Deuschle M, Colla M, Lederbogen F, Heuser I {2002): Hypercortisolemic depres- sion is associated with increased intra-abdominal fat. Psycho- scm Med 64:224—227. Wellman CL (200”: Dendritic reorganization in pyramidal neurons in medial prefrontal cortex afler chronic corticoste- rone administration. J Neurobioi 49:245—253. Young EA, Haskett RF, Grunhaus L, Pande A. Weinberg M, Watson SJ, Akil H ( l 994}: increased evening activation ofthe hypothalamic-pituitary-adrenai axis in depressed patients. Arch Gert Psychiatry 51:701-707. ...
View Full Document

This note was uploaded on 09/08/2010 for the course PSYC 230 at San Jose State University .

Page1 / 8

McEwen 2003 - MOOD DISORDERS AND MEDICAL ILLNESS Mood...

This preview shows document pages 1 - 8. Sign up to view the full document.

View Full Document Right Arrow Icon
Ask a homework question - tutors are online