The kynurenine pathway and bipolar disorder: intersection of the monoaminergic and glutamatergic systems and immune response.

Dysfunction in a wide array of systems-including the immune, monoaminergic, and glutamatergic systems-is implicated in the pathophysiology of depression. One potential intersection point for these three systems is the kynurenine (KYN) pathway. This study explored the impact of the prototypic glutamatergic modulator ketamine on the endogenous KYN pathway in individuals with bipolar depression (BD), as well as the relationship between response to ketamine and depression-related behavioral and peripheral inflammatory markers. Thirty-nine participants with treatment-resistant BD (23 F, ages 18-65) received a single ketamine infusion (0.5 mg/kg) over 40 min. KYN pathway analytes-including plasma concentrations of indoleamine 2,3-dioxygenase (IDO), KYN, kynurenic acid (KynA), and quinolinic acid (QA)-were assessed at baseline (pre-infusion), 230 min, day 1, and day 3 post-ketamine. General linear models with restricted maximum likelihood estimation and robust sandwich variance estimators were implemented. A repeated effect of time was used to model the covariance of the residuals with an unstructured matrix. After controlling for age, sex, and body mass index (BMI), post-ketamine IDO levels were significantly lower than baseline at all three time points. Conversely, ketamine treatment significantly increased KYN and KynA levels at days 1 and 3 versus baseline. No change in QA levels was observed post-ketamine. A lower post-ketamine ratio of QA/KYN was observed at day 1. In addition, baseline levels of proinflammatory cytokines and behavioral measures predicted KYN pathway changes post ketamine. The results suggest that, in addition to having rapid and sustained antidepressant effects in BD participants, ketamine also impacts key components of the KYN pathway.

The PPARg System in Major Depression: Pathophysiologic and Therapeutic Implications.

To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellular stress, and functions in the CNS in glial cells, neurons, and cerebrovascular endothelial cell in multiple anti-inflammatory and neuroprotective ways. We now know that depression is associated with neurodegeneration in the subgenual prefrontal cortex and hippocampus, decreased neuroplasticity, and defective neurogenesis. Brain-derived neurotrophic factor (BDNF) is markedly depleted in these areas, and is thought to contribute to the neurodegeneration of the subgenual prefrontal cortex and the hippocampus. The PPARg system strongly increases BDNF levels and activity in these brain areas. The PPARg system promotes both neuroplasticity and neurogenesis, both via effects on BDNF, and through other mechanisms. Ample evidence exists that these brain areas transduce many of the cardinal features of depression, directly or through their projections to sites such as the amygdala and nucleus accumbens. Behaviorally, these include feelings of worthlessness, anxiety, dread of the future, and significant reductions in the capacity to anticipate and experience pleasure. Physiologically, these include activation of the CRH and noradrenergic system in brain and the sympathetic nervous system and hypothalamic-pituitary-adrenal axis in the periphery. Patients with depression are also insulin-resistant. The PPARg system influences each of these behavioral and physiological in ways that would ameliorate the manifestations of depressive illness. In addition to the cognitive and behavioral manifestations of depression, depressive illness is associated with the premature onsets of coronary artery disease, stroke, diabetes, and osteoporosis. As a consequence, patients with depressive illness lose approximately seven years of life. Inflammation and insulin resistance are two of the predominant processes that set into motion these somatic manifestations. PPARg agonists significantly ameliorate both pathological processes. In summary, PPARg augmentation can impact positively on multiple significant pathological processes in depression. These include loss of brain tissue, defective neuroplasticity and neurogenesis, widespread inflammation in the central nervous system and periphery, and insulin resistance. Thus, PPARg agonists could potentially have significant antidepressant effects.

Interparental violence and maternal mood disorders as predictors of adolescent physical aggression within the family.

Although a wealth of research has examined the effects of parental mood disorders on offspring maladjustment, studies have not identified whether elevated interparental violence (IPV) may be an exacerbating influence in this pathway. This study examined levels of physical IPV perpetration and victimization in mothers with unipolar depression or Bipolar Disorder (BD) and the processes by which maternal physical IPV moderated adolescents' physical aggression in families with maternal mood disorders. Mothers with lifetime mood disorders were predicted to have elevated IPV compared to well mothers, and maternal IPV was expected to moderate the association between lifetime mood disorders and adolescent aggression. Participants included 61 intact families with maternal depression (n = 24), BD (n = 13), or well mothers (n = 24) and two siblings (ages 10 to 18 years). Using the Conflict Tactics Scale, mothers reported on IPV perpetration and victimization, and adolescents reported on physical aggression. Mothers with BD reported significantly higher IPV perpetration, but not victimization, than depressed or well mothers. An interaction between maternal BD and IPV perpetration was a significant predictor of adolescent aggression. Main effects of maternal IPV victimization and interaction effects of maternal depression and either type of IPV on adolescent aggression were not significant. Adolescents of mothers who have BD and perpetrate IPV may be particularly vulnerable to being aggressive. Prevention and policy efforts to deter transmission of aggression in high-risk families should target families with maternal BD and intervene at the level of conflict resolution within the family. Aggr. Behav. 41:253-266, 2015. © 2014 Wiley Periodicals, Inc.

The development of thought problems: a longitudinal family risk study of offspring of bipolar, unipolar, and well parents.

There is growing evidence that many offspring of parents with bipolar disorder (BD) will develop moderate to severe forms of psychopathology during childhood and adolescence, including thought problems. The purpose of this study was to evaluate the developmental progression of thought problems within the context of a family risk study. Repeated assessments of thought problems, spanning approximately 15 years, were conducted in offspring (N = 192 from 98 families) of parents diagnosed with BD (O-BD), unipolar depression (O-UNI), or no significant psychiatric or medical problems (O-WELL). Survival analysis showed that the O-BD group had the greatest estimated probability of developing thought problems over time, followed by O-UNI, and then O-WELL and O-BD exhibiting higher levels of persistence than O-WELL. Parent-reported thought problems in childhood and adolescence predicted a range of problems in young adulthood. Disturbances in reality testing and other atypical behaviors are likely to disrupt progression through important developmental periods and to associate with poor outcomes. These findings are likely relevant to preventing the occurrence or progression of problems in offspring of bipolar parents. The study of thought problems across development represents an important area of continued research in children at risk for development of affective disorders.

Endocrine Factors in Key Structural and Intracellular Changes in Depression.

Endocrine disturbances play predominant roles in recently discovered, clinically relevant abnormalities in depression. These affect multiple sites in the prefrontal cortex, amygdala, hippocampus, nucleus accumbens, and habenula. Deficits consist of changes in volume, neuroplasticity, neural connectivity, synapse composition, and neurogenesis. Depression is associated with endocrine-related, premature systemic disease, that results in a loss of approximately 7 years of life. CRH, glucocorticoids, somatostatin, gonadal steroids, and thyroid hormones all contribute to the deficits that largely define the pathophysiologic presentation of depression. The World Health Organization ranks depression as the second greatest cause of disability worldwide. The response rate to current antidepressants is below 60%. It is important that new knowledge about the endocrine-mediated pathophysiology of depression be communicated to provide targets for new agents.

Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans?

Immunogenetic mechanisms operating within the immune system are known to influence cytokine profiles and disease susceptibility. Yet the role of the individual's neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary "defect" related to specific neurohormonal immune phenotype(s). We report that in a large subpopulation of healthy humans the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-alpha and IL-12 production but 2-fold lower IL-10 production induced by LPS ex vivo. In alternative settings, we found low baseline levels and profoundly blunted stress-induced epinephrine responses but high TNF-alpha levels in Lewis vs Fischer inbred rats. Additionally, isoproterenol, a beta adrenoreceptor agonist suppressed LPS-induced TNF-alpha production, with more pronounced effect in Lewis than in Fischer rats. In human monocytes, epinephrine and the beta(2) adrenoreceptor agonist fenoterol potently inhibited LPS-induced TNF-alpha and IL-12, but stimulated IL-10 production. The order of potency for hormones able to inhibit IL-12 production ex vivo was: epinephrine > norepinephrine > or = 1,25-(OH)(2) vitamin D(3) > hydrocortisone. This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles. Since Lewis and Fischer rats have opposite susceptibility to experimental immunological diseases, this suggests that the parallel human phenotypes could be linked to differing responsiveness and susceptibility to infections and immune/inflammatory-related conditions.

Continuity and cascade in offspring of bipolar parents: a longitudinal study of externalizing, internalizing, and thought problems.

There is growing evidence that many offspring of bipolar parents will develop moderate to severe forms of psychopathology during childhood and adolescence. The purpose of this study was to apply growth curve models to evaluate developmental progression with regard to continuity and cascades representative within the context of a family risk study of bipolar disorder (BD). Repeated assessments of externalizing, internalizing, and thought problems, spanning more than a decade, were examined in a total of 94 offspring of parents with BD (O-BD), major depressive disorder (O-UNI), or no significant psychiatric or medical problems (O-WELL). Continuity was defined by the growth curve of the O-WELL group who exhibited low levels of problems from early childhood through late adolescence. Discontinuity, as evidenced by greater complexity of growth curves relative to the O-WELL group, was exhibited in the at- risk offspring groups for internalizing problems. Different patterns of developmental cascades were supported for the at-risk group with O-UNI showing a robust cascade from self-regulatory deficits (externalizing problems) to internalizing problems. There was also support for a cascade from self-regulatory deficits to thought problems across the entire group (with some support that this pattern was accounted for primarily by O-BD). This study not only serves to advance our understanding of the risks associated with a family history of BD, but also provides a novel approach to examining developmental cascades.

A Major Role for the Lateral Habenula in Depressive Illness: Physiologic and Molecular Mechanisms.

Emerging preclinical and clinical evidence indicate that the lateral habenula plays a major role in the pathophysiology of depressive illness. Aberrant increases in neuronal activity in the lateral habenula, an anti-reward center, signals down-regulation of brainstem dopaminergic and serotonergic firing, leading to anhedonia, helplessness, excessive focus on negative experiences, and, hence, depressive symptomatology. The lateral habenula has distinctive regulatory adaptive role to stress regulation in part due to its bidirectional connectivity with the hypothalamic-pituitary-adrenal (HPA) axis. In addition, studies show that increased lateral habenula activity affects components of sleep regulation including slow wave activity and rapid eye movement (REM), both disrupted in depressive illness. Lack of perceived reward experienced during the adverse outcomes also precipitates lateral habenula firing, while outcomes that meet or exceed expectations decrease lateral habenula firing and, in turn, increase midbrain dopaminergic and serotonergic neurotransmission. The ability to update expectations of the environment based on rewards and aversive stimuli reflects a potentially important survival mechanism relevant to the capacity to adapt to changing circumstances. What if one lives in a continuously aversive and invalidating environment or under the conditions of chronic stress? If there is a propensity of the habenula to release many burst discharges over time, an individual could habitually come to perceive the world as perpetually disappointing. Conceivably, the lateral habenula could learn to expect an adverse outcome systematically and communicate it more easily. Thus, if the lateral habenula fires more frequently, it may lead to a state of continuous disappointment and hopelessness, akin to depression. Furthermore, postmortem studies reveal that the size of the lateral habenula and total number of neurons are decreased in patients who had depressive illness. Novel research in the field shows that ketamine induces rapid and sustained antidepressant effect. Intriguingly, recent preclinical animal models show that ketamine abolishes N-methyl-D-aspartate receptor (NMDAR)-dependent lateral habenula bursting activity, leading to rapid resolution of depressive symptoms.

Integration of in vivo and in vitro approaches to characterize the toxicity of Antalarmin, a corticotropin-releasing hormone receptor antagonist.

Non-clinical studies were conducted to evaluate the toxicity of Antalarmin, a corticotropin-releasing hormone type 1 receptor antagonist being developed for therapy of stress-related pathologies. Antalarmin was not genotoxic in bacterial mutagenesis assays, mammalian cell mutagenesis assays, or in vivo DNA damage assays. In a 14-day range-finding study in rats, Antalarmin doses >or=500 mg/kg/day (3,000 mg/m(2)/day) induced mortality. In a 90-day toxicity study in rats, no gross toxicity was seen at doses of 30, 100, or 300 mg/kg/day (180, 600, or 1,800 mg/m(2)/day, respectively). Antalarmin (300 mg/kg/day) induced mild anemia, increases in serum gamma-glutamyl transferase activity, and microscopic hepatic pathology (bile duct hyperplasia and epithelial necrosis, periportal inflammation). Microscopic renal changes (cortical necrosis, inflammation, hypertrophy, nephropathy) were observed in rats at all Antalarmin doses. In a 14-day range-finding study in dogs, Antalarmin doses >or=50mg/kg/day (1,000 mg/m(2)/day) induced repeated emesis and bone marrow suppression. In a 90-day toxicity study in dogs, Antalarmin (4, 8, or 16 mg/kg/day (80, 160, or 320 mg/m(2)/day, respectively)) induced bone marrow and lymphoid depletion, but no gross toxicity. Comparative in vitro studies using rat, dog, and human neutrophil progenitors demonstrated that canine bone marrow cells are highly sensitive to Antalarmin cytotoxicity, while rat and human bone marrow cells are relatively insensitive. As such, the bone marrow toxicity observed in dogs is considered likely to over-predict Antalarmin toxicity in humans. The hepatic and renal toxicities seen in rats exposed to Antalarmin identify those tissues as the most likely targets for Antalarmin toxicity in humans.

Low bone mass in premenopausal women with depression.

BACKGROUND: An increased prevalence of low bone mineral density (BMD) has been reported in patients with major depressive disorder (MDD), mostly women. METHODS: Study recruitment was conducted from July 1, 2001, to February 29, 2003. We report baseline BMD measurements in 89 premenopausal women with MDD and 44 healthy control women enrolled in a prospective study of bone turnover. The BMD was measured by dual-energy x-ray absorptiometry at the spine, hip, and forearm. Mean hourly levels of plasma 24-hour cytokines, 24-hour urinary free cortisol, and catecholamine excretion were measured in a subset of women. We defined MDD according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). RESULTS: The prevalence of low BMD, defined as a T score of less than -1, was greater in women with MDD vs controls at the femoral neck (17% vs 2%; P = .02) and total hip (15% vs 2%; P = .03) and tended to be greater at the lumbar spine (20% vs 9%; P = .14). The mean +/- SD BMD, expressed as grams per square centimeters, was lower in women with MDD at the femoral neck (0.849 +/- 0.121 vs 0.866 +/- 0.094; P = .05) and at the lumbar spine (1.024 +/- 0.117 vs 1.043 +/- 0.092; P = .05) and tended to be lower at the radius (0.696 +/- 0.049 vs 0.710 +/- 0.055; P = .07). Women with MDD had increased mean levels of 24-hour proinflammatory cytokines and decreased levels of anti-inflammatory cytokines. CONCLUSIONS: Low BMD is more prevalent in premenopausal women with MDD. The BMD deficits are of clinical significance and comparable in magnitude to those resulting from established risk factors for osteoporosis, such as smoking and reduced calcium intake. The possible contribution of immune or inflammatory imbalance to low BMD in premenopausal women with MDD remains to be clarified.

Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A.

BACKGROUND: Major depressive disorder (MDD) shows increased coronary artery disease (CAD) risk of unknown mechanism(s). MDD is more common in women than men; CAD diagnosis can be difficult in women. Elevations of the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) predict increased CAD risk in populations; few data on these markers exist in MDD, particularly in remitted patients. METHODS: We measured fasting am serum CRP (high sensitivity, CRP(hs)) and SAA in 18 unmedicated, remitted women with MDD (mean age 41 +/- (SD)12, body mass index (BMI) 25.2 +/- 4.1 kg/m(2)) and 18 BMI-matched healthy control subjects (age 36 +/- 10, BMI 25.3 +/- 3.8 kg/m(2)) on 2 separate occasions, > or = 6 days apart. RESULTS: Repeat SAA and CRP(hs) measurements strongly correlated across study days (SAA: r = .83, p < .001; CRP(hs): r = .94, p < .001). Both SAA (5.30 +/- 3.39 vs. 2.84 +/- 1.87 mg/L, p < .005) and CRP(hs) (3.23 +/- 3.17 vs. 1.12 +/- 1.45 mg/L; p < .01) were significantly elevated in MDD women versus controls. CONCLUSIONS: Elevated SAA and CRP(hs) in remitted, unmedicated women with MDD indicate a pro-inflammatory state unrelated to current depressive symptoms or pharmacotherapy. These findings suggest that inflammatory mechanisms may in part underlie findings of increased CAD risk in MDD.

Change in cytokine levels is not associated with rapid antidepressant response to ketamine in treatment-resistant depression.

Several pro-inflammatory cytokines have been implicated in depression and in antidepressant response. This exploratory analysis assessed: 1) the extent to which baseline cytokine levels predicted positive antidepressant response to ketamine; 2) whether ketamine responders experienced acute changes in cytokine levels not observed in non-responders; and 3) whether ketamine lowered levels of pro-inflammatory cytokines, analogous to the impact of other antidepressants. Data from double-blind, placebo-controlled studies of patients with major depressive disorder (MDD) or bipolar disorder (BD) who received a single infusion of sub-anesthetic dose ketamine were used (N = 80). Plasma levels of the eight cytokines were measured at baseline and at 230 min, 1 day, and 3 days post-ketamine. A significant positive correlation was observed between sTNFR1 and severity of depression at baseline. Cytokine changes did not correlate with changes in mood nor predict mood changes associated with ketamine administration. Ketamine significantly increased IL-6 levels and significantly decreased sTNFR1 levels. IL-6 and TNF-α levels were also significantly higher-and sTNFR1 levels were significantly lower-in BD compared to MDD subjects. The functional significance of this difference is unknown. Changes in cytokine levels post-ketamine were not related to antidepressant response, suggesting they are not a primary mechanism involved in ketamine's acute antidepressant effects. Taken together, the results suggest that further study of cytokine levels is warranted to assess their potential role as a surrogate outcome in the rapid antidepressant response paradigm.

Mood Therapeutics: Novel Pharmacological Approaches for Treating Depression.

INTRODUCTION: Real-world effectiveness trials suggest that antidepressant efficacy is limited in many patients with mood disorders, underscoring the urgent need for novel therapeutics to treat these disorders. Areas covered: Here, we review the clinical evidence supporting the use of novel modulators for the treatment of mood disorders, including specific glutamate modulators such as: 1) high-trapping glutamatergic modulators; 2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists; 3) NMDA receptor glycine-site partial agonists; and 4) metabotropic glutamate receptor (mGluR) modulators. We also discuss other promising, non-glutamatergic targets for potential rapid antidepressant effects in mood disorders, including the cholinergic system, the glucocorticoid system, and the inflammation pathway, as well as several additional targets of interest. Clinical evidence is emphasized, and non-pharmacological somatic treatments are not reviewed. In general, this paper only explores agents available in the United States. Expert commentary: Of these novel targets, the most promising - and the ones for whom the most evidence exists - appear to be the ionotropic glutamate receptors. However, moving forward will require us to fully embrace the goal of personalized medicine and will require health professionals to pre-emptively identify potential responders.

Depression and osteoporosis in men: association or casual link?

The longer life expectancy of women than that of men and, therefore, the longer exposure to fracture risk has, at least partially, led to neglect of osteoporosis in men. Recently, unipolar depression, which is 2 times more frequent in women than in men, has been linked to osteoporosis. However, it is quite possible that this diagnosis may escape detection in men because of a different behavioral phenotype between the genders. A potential mechanism of bone loss in depression has been proposed, involving concurrent activation of the hypothalamo-pituitary-adrenal and sympatho-adrenal axes, suppression of the gonadal and somatotrophic axes, and high interleukin-6 and low leptin levels. We suggest that similar neurohormonal changes may cause osteoporosis in men.

Neurobiological characteristics of rhesus macaque abusive mothers and their relation to social and maternal behavior.

Previous studies have reported hyperactivation of catecholaminergic systems and elevated concentrations of corticotropin-releasing-hormone (CRH) in the cerebrospinal fluid (CSF) of child maltreatment victims or combat veterans with post-traumatic stress disorder (PTSD). This study investigated the CSF concentrations of CRH and monoamine metabolites in rhesus macaque mothers that physically abused their infants and had themselves been abused as infants. Ten abusive mothers and 10 controls served as study subjects. All animals were sampled for CSF during pregnancy and the postpartum period. Focal observations of social and maternal behavior were also made. Abusive mothers had significantly higher CSF concentrations of CRH and 5-HIAA than controls. Across both subjects and controls, higher CRH, 5-HIAA and MHPG concentrations were associated with anti-social behavior patterns including a high frequency of maternal aggression, infant rejection, and a low frequency of contacts received from other individuals. These findings are consistent with those of previous primate and human studies and suggest that the neurobiological alterations associated with infant abuse may play an important role in the occurrence of maladaptive behavior in adulthood, including the perpetuation of infant abuse across generations.

Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications.

BACKGROUND: Major depressive disorder (MDD) is associated with increased risk for premature coronary heart disease and bone loss. Single time measurements of plasma IL-6, a good predictor of future risk for both cardiovascular disease and osteoporosis, revealed significant elevations in depressed patients. The objective of this study was to rigorously compare plasma IL-6 levels, measured over 24 h, in MDD patients and healthy controls. Given the activating role of IL-6 on the hypothalamic-pituitary-adrenal (HPA) axis, and the relevance of its dysregulation in MDD, we also analyzed the relations between IL-6 and cortisol levels. METHODS: We studied nine patients and nine controls, individually matched by gender, age (+/-5 yr), body mass index (+/-2 kg/m2), and menstrual cycle phase. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnostic criteria. Self-reported mood ratings were assessed by multiple visual analog scales. The rhythmicity and complexity of IL-6 and cortisol secretion were tested by cosinor analyses, approximate entropy (ApEn) and cross-ApEn algorithms. RESULTS: MDD patients had significant mean IL-6 elevations from 1000-1200 h and at 1500 h (P ranging from <0.05 to <0.01) vs. controls. In addition, in MDD, the circadian rhythm of IL-6 was shifted by 12 h, and its physiological complexity was reduced, with no difference in the cross-ApEn of IL-6 and cortisol between the two groups, and significant time-lagged correlations only in the controls. IL-6 levels correlated significantly with mood ratings. CONCLUSIONS: We report profound morning elevations of plasma IL-6 and a reversal of its circadian rhythm in MDD patients, in the absence of hypercortisolism. These findings may be relevant to the increased risk for coronary heart disease and bone loss in MDD.

Mood disorders in the medically ill: scientific review and recommendations.

OBJECTIVE: The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES: Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Experimentally-induced hyperthyroidism is associated with activation of the rat hypothalamic-pituitary-adrenal axis.

OBJECTIVE: Previous studies on the effects of altered thyroid function on the secretion and metabolism of adrenocortical hormones suggest a degree of adrenocortical hyperactivity in hyperthyroidism. We have previously shown that experimentally-induced hyperthyroidism is associated with significant alterations in pituitary-adrenal responsiveness to synthetic ovine corticotropin-releasing hormone (oCRH) that are contingent upon the duration of the altered thyroid function. The purpose of this study was to assess the time-dependent effects of hyperthyroidism on the functional integrity of the hypothalamic-pituitary-adrenal (HPA) axis by in vivo stimulation of the hypothalamic CRH neuron and adrenal cortex. METHODS: The functional integrity of the HPA axis was examined in vivo in sham-thyroidectomized male Sprague-Dawley rats given placebo or in thyroidectomized rats given 50 mug of thyroxine every day for 7 or 60 days. Responses to insulin-induced hypoglycemia and IL-1alpha stimulation were used to assess the hypothalamic CRH neuron. Adrenocortical reserve was assessed in response to low-dose adrenocorticotropic hormone (ACTH), following suppression of the HPA axis with dexamethasone. Adrenal and thymus tissue weight, in addition to basal plasma ACTH, corticosterone and thyroid indices were also determined. RESULTS: Basal plasma corticosterone and corticosterone binding globulin (CBG) concentrations were significantly increased in short- and long-term hyperthyroid rats, and by 60 days, cerebrospinal fluid (CSF) corticosterone levels were significantly increased. Basal plasma ACTH levels were similar to controls. Although plasma ACTH responses to hypoglycemic stress and IL-1alpha administration in both short- and long-term hyperthyroidism were normal, corticosterone responses to the ACTH release during the administration of these stimuli were significantly increased. The adrenal reserve was significantly elevated in short-term hyperthyroidsim. Long-term hyperthyroidism, however, was associated with a significant reduction in adrenocortical reserve. A significant increase in adrenal weights and a decrease in thymus weights were observed in both short- and long-term hyperthyroidism. CONCLUSIONS: The available data confirms that hyperthyroidism is associated with hypercorticosteronemia, although the locus that is principally affected still remains unclear. Despite the sustained hyperactivity of the HPA axis, long-term experimentally-induced hyperthyroidism is associated with diminished adrenal functional reserve. The alterations in HPA function in states of disturbed thyroid function were found to be somewhat more pronounced as the duration of thyroid dysfunction increased.