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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 (23F, ages 18–65) received a single ketamine infusion (0.5mg/kg) over 40 minutes. 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 minutes, 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 pro-inflammatory 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.

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.

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.

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.

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.

We previously found that body mass index (BMI) strongly predicted response to ketamine. Adipokines have a key role in metabolism (including BMI). They directly regulate inflammation and neuroplasticity pathways and also influence insulin sensitivity, bone metabolism and sympathetic outflow; all of these have been implicated in mood disorders. Here, we sought to examine the role of three key adipokines—adiponectin, resistin and leptin—as potential predictors of response to ketamine or as possible transducers of its therapeutic effects. Eighty treatment-resistant subjects who met DSM-IV criteria for either major depressive disorder (MDD) or bipolar disorder I/II and who were currently experiencing a major depressive episode received a single ketamine infusion (0.5 mg kg −1 for 40 min). Plasma adipokine levels were measured at three time points (pre-infusion baseline, 230 min post infusion and day 1 post infusion). Overall improvement and response were assessed using percent change from baseline on the Montgomery–Asberg Depression Rating Scale and the Hamilton Depression Rating Scale. Lower baseline levels of adiponectin significantly predicted ketamine’s antidepressant efficacy, suggesting an adverse metabolic state. Because adiponectin significantly improves insulin sensitivity and has potent anti-inflammatory effects, this finding suggests that specific systemic abnormalities might predict positive response to ketamine. A ketamine-induced decrease in resistin was also observed; because resistin is a potent pro-inflammatory compound, this decrease suggests that ketamine’s anti-inflammatory effects may be transduced, in part, by its impact on resistin. Overall, the findings suggest that adipokines may either predict response to ketamine or have a role in its possible therapeutic effects.

Objective: Serum cortisol concentrations fluctuate in a circadian fashion, and glucocorticoids exert strong effects on adipose tissue and induce obesity through the glucocorticoid receptor. Design and Methods: To examine the impact of physiologic levels of circulating cortisol on subcutaneous adipose tissue, 25 overweight and obese subjects were employed, and their serum levels of morning (AM) and evening (PM) cortisol, AM/PM cortisol ratios, and 24-h urinary-free cortisol (UFC) were compared with their clinical parameters, serum cytokine levels, and mRNA expression of 93 receptor action-regulating and 93 glucocorticoid-responsive genes in abdominal subcutaneous fat. Results and Conclusions: AM cortisol levels did not correlate with mRNA expression of the all genes examined, whereas PM cortisol levels, AM/PM cortisol ratios, and 24-h UFC were associated with distinct sets of these genes. Body mass index did not significantly correlate with the four cortisol parameters employed. These results suggest that physiologic levels of AM serum cortisol do not solely represent biological effects of circulating cortisol on the expression of glucocorticoid-related genes in subcutaneous adipose tissue, whereas PM levels, amplitude, and net amounts of the diurnally fluctuating serum cortisol have distinct effects. Through the genes identified in this study, glucocorticoids appear to influence intermediary metabolism, energy balance, inflammation, and local circadian rythmicity in subcutaneous fat. Our results may also explain in part the development of metabolic abnormality and obesity in subjects under stress or patients with melancholic/atypical depression who demonstrate elevated levels of PM serum cortisol.

Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230 min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness.

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.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.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.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.

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 μg of thyroxine every day for 7 or 60 days. Responses to insulin-induced hypoglycemia and IL-1α 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-1α 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.

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.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.MDD patients had significant mean IL-6 elevations from 1000-1200 h and at 1500 h (P ranging from0.05 to0.01) 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.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.

CRH is a main regulator of the stress response. This neuropeptide and its specific receptors, CRHR-1 and CRHR-2, are disseminated throughout the central nervous system. There is a significant interspecies difference in the distribution of CRHR within the central nervous system. CRH-R1 antagonists may attenuate stress-related behavior in rats without compromising adrenal function, but few studies have addressed the same question in higher mammals. Antalarmin (AA) is a specific CRHR-1 antagonist suitable for oral administration. Social separation is a potent stressor for rhesus monkeys. Therefore, we sought to investigate the hormonal responses to chronic administration of AA using a primate stress model. Eight preadolescent (4-6 kg) male rhesus monkeys received AA (20 mg/kg.d) or placebo (PBO) orally. All animals were on a regular day/light cycle and were fed with standard monkey chow daily. The study (114 d) was comprised of the following consecutive phases: adaptation, baseline, separation (stress), recovery, and cross-over. During social separation, solid panels separated the individuals. Cerebrospinal fluid (CSF) and femoral venous blood samples were obtained once a week on the fourth day of separation under ketamine anesthesia. Serum samples were also obtained 1 and 2 h after separation. CSF samples were assayed for CRH, AA, norepinephrine (NE) and epinephrine (EPI). Plasma was assayed for ACTH, cortisol, NE, and EPI. AA was detected in the plasma of each monkey while they were taking the active drug and in none of the animals on PBO. Among the behaviors assessed, environmental exploration, a behavior inhibited by stress, was increased during AA administration. However, AA at this dose did not affect other anxiety-related behavioral end points, including self-directed behavior, vocalization, or locomotion. We also observed that: 1) ACTH decreased between adaptation and baseline, indicating that the animals had adjusted to the novel environment; 2) ACTH and cortisol increased significantly after social separation, indicating that social separation was an adequate model for acute stress; 3) NE and EPI increased significantly during acute stress in the AA and PBO groups (P0.005, NE; P0.001, EPI); 4) after chronic stress, by d 4 of separation, ACTH levels were no longer significantly different from baseline, and NE and EPI remained slightly elevated when compared with baseline (P0.05, NE; P0.01, EPI); and 5) all the animals remained healthy and gained the expected weight during the study. In summary, oral chronic administration of a specific CRH-R1 antagonist to rhesus monkeys does not blunt the sympathoadrenal response to stress while increasing environmental exploration, a behavior that is normally suppressed during stressful events. Taken together, these findings suggest that CRHR-1 antagonists may be a valid treatment for stress-related disorders.

Studies have shown that ghrelin plays a major role in energy homeostasis and modulation of feeding behavior. However, little is known about the influence of food consumption on plasma ghrelin levels in humans. Therefore, we investigated responses of plasma ghrelin to food intake, meal volume and meal nutritional value in healthy volunteers and women with anorexia nervosa (AN). After overnight fasting, all subjects received either a standardized breakfast or fiber. Plasma ghrelin levels were measured before and after the meal. Fasting plasma ghrelin was significantly higher in AN patients than in controls (1,800.6 +/- 47.0 vs. 795.9 +/- 24.3 pg/ml, P0.001) (606.8 +/- 15.8 vs. 268.2 +/- 8.2 pmol/l, P0.001), and correlated negatively with percentage of body fat in both groups. Ghrelin levels markedly fell after consumption of either a standardized meal or fiber in controls, but not in anorexic women. Thus, we concluded that the acute plasma ghrelin response to food intake, which in healthy individuals is independent of meal caloric value, is impaired in women with AN. This abnormality may be part of a chronic adaptation to prolonged food restriction, which attempts to restore a normal feeding conduct by maintaining the drive to eat.

Circulating thyroid autoantibodies are more prevalent in patients with mood disorders than in the general population, but longitudinal clinical data that establish a relationship between thyroid antibody status and the course of any psychiatric syndrome have been lacking. In addition, scant attention has been paid to thyroid hormones and autoimmunity in borderline personality disorder (BPD). We report a case of a patient with classic BPD whose fluctuating mood and, especially, psychotic symptoms-rated using a double-blind method-were directly linked to antithyroglobulin antibody titers serially determined over an inpatient period of 275 d. Significantly lower psychosis and depression ratings were seen during a 4-wk period of relatively low antithyroid antibody titers, during blinded treatment with carbamazepine, than were observed during two high autoantibody epochs. The significant positive correlations between nurse- and patient-rated depression and thyroid autoantibodies over the entire period of inpatient study were similar to those also observed between urinary free cortisol levels and depression; the positive correlation between antithyroglubulin antibody titers and psychotic symptoms was stronger (r = +0.544; p < 0.002). Although this patient had biochemical indices of primary hypothyroidism, she showed only marginal improvement to triiodothyronine (T3) and no apparent clinical response to sustained levorotatory thyroxine (T4) administration; neither were antithyroid antibody titers significantly associated with changes in T3, free T4, or thyroid-stimulating hormone concentrations. She clinically deteriorated during a 50-d fluoxetine trial. The present data demonstrate a clinically significant, longitudinal correlation between fluctuating antithyroid antibody titers and symptoms of borderline psychopathology in our patient. It will be of interest to determine the prevalence, pathophysiologic mechanisms, and treatment implications of this putative autoimmune- BPD link.

Major depression and bipolar disorder are associated with decreased bone mineral density (BMD). Antidepressants such as imipramine (IMIP) and specific serotonin reuptake inhibitors (SSRIs) have been implicated in reduced BMD and/or fracture in older depressed patients. Moreover, anticonvulsants such as valproate (VAL) and carbamazepine (CBZ) are also known to increase fracture rates. Although BMD is a predictor of susceptibility to fracture, bone strength is a more sensitive predictor. We measured mechanical and geometrical properties of bone in 68 male Sprague Dawley rats on IMIP, fluoxetine (FLX), VAL, CBZ, CBZ vehicle and saline (SAL), given intraperitoneally daily for 8 weeks. Distinct regions were tested to failure by four-point bending, whereas load displacement was used to determine stiffness. The left femurs were scanned in a MicroCT system to calculate mid-diaphyseal moments of inertia. None of these parameters were affected by antidepressants. However, VAL resulted in a significant decrease in stiffness and a reduction in yield, and CBZ induced a decrease in stiffness. Only CBZ induced alterations in mechanical properties that were accompanied by significant geometrical changes. These data reveal that chronic antidepressant treatment does not reduce bone strength, in contrast to chronic anticonvulsant treatment. Thus, decreased BMD and increased fracture rates in older patients on antidepressants are more likely to represent factors intrinsic to depression that weaken bone rather than antidepressants per se. Patients with affective illness on anticonvulsants may be at particularly high risk for fracture, especially as they grow older, as bone strength falls progressively with age.

Existing studies of the relationship between depression and osteoporosis have been heterogeneous in their design and use of diagnostic instruments for depression, which might have contributed to the different results on the comorbidity of these two conditions. Nevertheless, these studies reveal a strong association between depression and osteoporosis. Endocrine factors such as depression-induced hypersecretion of corticotropin-releasing hormone and hypercortisolism, hypogonadism, growth hormone deficiency and increased concentration of circulating interleukin 6, might play a crucial role in the bone loss observed in subjects suffering from major depression.

We evaluated the effects of the lipophilic nonpeptide corticotropin-releasing hormone (CRH) type 1 receptor antagonist antalarmin on the behavioral, neuroendocrine, and autonomic components of the stress response in adult male rhesus macaques. After oral administration, significant antalarmin concentrations were detected in the systemic circulation and the cerebrospinal fluid by a mass spectrometry-gas chromatography assay developed specifically for this purpose. Pharmacokinetic and dose-response studies suggested that an oral dose of 20 mg/kg was optimal for behavioral and endocrine effects. We then administered this dose in a double-blind, placebo-controlled fashion to monkeys exposed to an intense social stressor: namely, placement of two unfamiliar males in adjacent cages separated only by a transparent Plexiglas screen. Antalarmin significantly inhibited a repertoire of behaviors associated with anxiety and fear such as body tremors, grimacing, teeth gnashing, urination, and defecation. In contrast, antalarmin increased exploratory and sexual behaviors that are normally suppressed during stress. Moreover, antalarmin significantly diminished the increases in cerebrospinal fluid CRH as well as the pituitary-adrenal, sympathetic, and adrenal medullary responses to stress. We conclude that CRH plays a broad role in the physiological responses to psychological stress in primates and that a CRH type 1 receptor antagonist may be of therapeutic value in human psychiatric, reproductive, and cardiovascular disorders associated with CRH system hyperactivity.

Both stress-system activation and melancholic depression are characterized by fear, constricted affect, stereotyped thinking, and similar changes in autonomic and neuroendocrine function. Because norepinephrine (NE) and corticotropin-releasing hormone (CRH) can produce these physiological and behavioral changes, we measured the cerebrospinal fluid (CSF) levels each hour for 30 consecutive hours in controls and in patients with melancholic depression. Plasma adrenocorticotropic hormone (ACTH) and cortisol levels were obtained every 30 min. Depressed patients had significantly higher CSF NE and plasma cortisol levels that were increased around the clock. Diurnal variations in CSF NE and plasma cortisol levels were virtually superimposable and positively correlated with each other in both patients and controls. Despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and CSF CRH. However, plasma ACTH and CSF CRH levels in depressed patients were inappropriately high, considering the degree of their hypercortisolism. In contrast to the significant negative correlation between plasma cortisol and CSF CRH levels seen in controls, patients with depression showed no statistical relationship between these parameters. These data indicate that persistent stress-system dysfunction in melancholic depression is independent of the conscious stress of the disorder. These data also suggest mutually reinforcing bidirectional links between a central hypernoradrenergic state and the hyperfunctioning of specific central CRH pathways that each are driven and sustained by hypercortisolism. We postulate that α-noradrenergic blockade, CRH antagonists, and treatment with antiglucocorticoids may act at different loci, alone or in combination, in the treatment of major depression with melancholic features.

OBJECTIVES Although several studies have shown that sleep deprivation is associated with increased slow wave sleep during the recovery night, the effects of sleep deprivation on cortisol and growth hormone (GH) secretion the next day and recovery night have not been assessed systematically. We hypothesized that increased slow wave sleep postsleep deprivation is associated with decreased cortisol levels and that the enhanced GH secretion is driven by the decreased activity of the HPA axis. DESIGN AND SUBJECTS After four consecutive nights in the Sleep Laboratory, 10 healthy young men were totally deprived of sleep during the fifth night, and then allowed to sleep again on nights six and seven. Twenty-four hour blood sampling was performed serially every 30 minutes on the fourth day, immediately following the previous night of sleep and on the sixth day, immediately after sleep deprivation. MEASUREMENT Eight-hour sleep laboratory recording, including electroencephologram, electro-oculogram and electromyogram. Plasma cortisol and GH levels using specific immunoassay techniques. RESULTS Mean plasma and time-integrated (AUC) cortisol levels were lower during the postdeprivation nighttime period than on the fourth night (P

Patients with pathologically increased daytime sleepiness and fatigue have elevated levels of circulating interleukin-6 (IL-6). The latter is an inflammatory cytokine, which causes sickness manifestations, including somnolence and fatigue, and activation of the hypothalamic-pituitary-adrenal axis. In this study, we examined: 1) the relation between serial measurements of plasma IL-6 and quantity and depth of sleep, evaluated by polysomnography; and 2) the effects of sleep deprivation on the nyctohemeral pattern of IL-6 secretion. Eight healthy young male volunteers were sampled for 24 h twice, at the baseline state, after a normal night's sleep and after total overnight sleep deprivation. At the baseline state, IL-6 was secreted in a biphasic circadian pattern with two nadirs at 0800 and 2100 and two zeniths at 1900 and 0500 (P < 0.01). The baseline amount of sleep correlated negatively with the overall daytime secretion of the cytokine (P < 0.05). Also, depth of sleep at baseline correlated negatively with the postdeprivation increase of daytime secretion of IL-6 (P < 0.05). Sleep deprivation changed the temporal pattern of circadian IL-6 secretion but not the overall amount. Indeed, during the post-deprivation period, the mean daytime (0800-2200 h) levels of IL-6 were significantly higher (P < 0.05), whereas the nighttime (2200-0600 h) levels were lower than the predeprivation values. Thus, sleep-deprived subjects had daytime oversecretion and nighttime under-secretion of IL-6; the former might be responsible for their daylong somnolence and fatigue, the latter for the better quality (depth) of their sleep. These data suggest that a good night's sleep is associated with decreased daytime secretion of IL-6 and a good sense of well-being and that good sleep is associated with decreased exposure of tissues to the proinflammatory and potentially detrimental actions of IL-6. Sleep deprivation increases daytime IL-6 and causes somnolence and fatigue during the next day, whereas postdeprivation decreases nighttime IL-6 and is associated with deeper sleep.

Healthy men exhibit a differential hypothalamic-pituitary-adrenal axis (HPA) response to exercise stress and fall into two groups: high responders (HR) and low responders (LR). The present study examined whether HR to physical stress also exhibit higher HPA reactivity to psychological stress than LR. We examined 14 HR and 13 LR classified based on their ACTH responses to high intensity exercise after pretreatment with dexamethasone. Both groups were of similar age, height, weight, and fitness level. Trait anxiety scores on the Spielberger Trait Anxiety Scale were not different. Subjects underwent a psychological stress test consisting of an interview and mental arithmetic. This test raised heart rate, blood pressure, and plasma ACTH and cortisol levels in both HR and LR. HR tended to have higher heart rates and blood pressures in anticipation of the psychological stress test than LR. ACTH responses of HR were higher, although not significantly, throughout the psychological stress test than LR. HR had a significantly (P < 0.05) greater net integrated cortisol response to the psychological stress than LR. This suggests that the adrenal cortexes of the HR are hypertropic and/or hypersensitive to ACTH. We conclude that men who are highly responsive to exercise stress are also highly responsive to psychological stress.

The nonpeptide CRH antagonist antalarmin has been shown to block both behavioral and endocrine responses to CRH. However, it's potential activity in blunting behavioral and endocrine sequelae of stressor exposure has not been assessed. Because antagonism of central CRH by alpha-helical CRH attenuates conditioned fear responses, we sought to test antalarmin in this regard. In addition, it remains unclear as to whether this is a result of receptor blockade during conditioning or during testing. Thus, we explored whether CRH mediates the induction or expression of conditioned fear (freezing in a context previously associated with 2 footshocks; 1.0 mA, 5 sec each). Furthermore, because rats previously exposed to inescapable shock (IS; 100 shocks, 1.6 mA, 5 sec each), demonstrate enhanced fear conditioning, we investigated whether this effect would be blocked by antalarmin. Antalarmin (20 mg/kg x 2 ml i.p.) impaired both the induction and expression of conditioned fear. In addition, antalarmin blocked the enhancement of fear conditioning produced by prior exposure to IS. Despite the marked behavioral effects observed in antalarmin-treated rats, antalarmin had no effect on IS-induced rises in ACTH or corticosterone. However, antalarmin did block the ACTH response produced by exposure to 2 footshocks.

Leptin, a product of fat cells, provides a signal of nutritional status to the central nervous system. Leptin concentrations have ultradian and diurnal fluctuations. We conducted this study to assess sex differences in the levels of organization of frequently sampled leptin concentrations in healthy, normal weight women and men. Leptin levels were sampled every 7 min for 24 h in 14 healthy, normal weight individuals (6 women and 8 men). The 14 leptin time series containing a total of 2898 leptin measurements were assessed by 1) algorithms that characterize statistically significant pulsatility, 2) Spectral (Fourier) analysis, 3) analysis of time intervals and variability, and 4) approximate entropy. We found that frequently sampled plasma leptin concentrations have a 24-h profile that is numerically more than twice as high in women as in men, and leptin pulse amplitude is likewise more than twice as high in women. However, healthy men and women have nearly identical concentration-independent and frequency-related 24-h and ultradian patterns. Leptin concentrations have nonrandom fluctuations over 24 h, independent of their absolute value and underlying 24-h periodicity, that are similar in men and women. Ultradian periodicities detected by Fourier time series have similar values in men and women. The strongest distinction between the sexes in the level of organization of leptin concentration is not at the level of pulse organization or oscillation frequency, but, rather, in the mass or amount of leptin released (or removed) per unit time, indicating that women might be more resistant to the effects of leptin than men. Because leptin is clinically relevant to the regulation of body weight, future studies should examine whether the relative leptin resistance exhibited by women might contribute to their increased susceptibility to disorders whose pathophysiology involves dysregulation of food intake and body weight. (J Clin Endocrinol Metab 83: 4140 ‐ 4147, 1998)

Exercise promotes escape of ACTH and cortisol from suppression by dexamethasone (DEX) in some healthy men and women. To determine whether stimulus strength, diurnal rhythmicity, or gender influences neuroendocrine escape during DEX suppression, we studied men (n = 5) and women (n = 5) during high intensity exercise tests after taking 4 mg DEX: two tests (one at 90% and one at 100% of maximal aerobic capacity) were conducted in the morning and two were performed in the afternoon on nonconsecutive days. Plasma ACTH and cortisol showed significantly greater increases with the 100% compared to the 90% intensity exercise (ACTH: 90%, 2 +/- 0.4; 100%, 3 +/- 0.5 pmol/L; cortisol: 90%, 53 +/- 5.3; 100% 93 +/- 23.6 nmol/L). Plasma cortisol responses were significantly higher in women than in men (P < 0.01). Plasma arginine vasopressin (AVP) exhibited significant intensity-dependent increases, with higher responses in women than men (P < 0.01). In conclusion, despite high dose glucocorticoid pretreatment, intense exercise can override the glucocorticoid negative feedback of hypothalamic-pituitary-adrenal activation in most normal men and women. This ability to override cortisol negative feedback inhibition may relate to the magnitude of the AVP response, the potency/specificity of the stressor to elicit a CRH/AVP response, and/or the sensitivity of the glucocorticoid negative feedback system at the time of the stress.

α-klotho, a protein with anti-aging properties, has been involved in important biological processes, such as calcium/phosphate metabolism, resistance to oxidative stress, and nitric oxide production in the endothelium. Recent studies have suggested a role of α-klotho in endocrine regulation of mineral metabolism and postnatal growth in infants. Yet, the role of α-klotho during pregnancy remains largely unknown. The aim of this study was to determine whether maternal plasma concentration of α-klotho changes during pregnancy and evaluate its expression in pregnancies complicated by small for gestational age (SGA) and/or preeclampsia (PE).This cross-sectional study included patients in the following groups: (1) non pregnant women (n = 37); (2) uncomplicated pregnancy (n = 130); (3) PE without an SGA neonate (PE; n = 58); (4) PE with an SGA neonate (PE and SGA; n = 52); and (5) SGA neonate without PE (SGA; n = 52). Plasma concentrations of α-klotho were determined by ELISA.The median plasma α-klotho concentration was higher in pregnant than in non-pregnant women. Among women with an uncomplicated pregnancy, the median plasma concentration of α-klotho increased as a function of gestational age (Spearman Rho = 0.2; p = 0.006). The median (interquartile range) plasma concentration of α-klotho in women with PE and SGA [947.6 (762-2013) pg/mL] and SGA without PE [1000 (585-1567) pg/mL] were 21% and 17% lower than that observed in women with an uncomplicated pregnancy [1206.6 (894-2012) pg/mL], (p = 0.005 and p = 0.02), respectively. Additionally, there were no significant differences in the median plasma concentration of α-klotho between uncomplicated pregnancies and women with PE without an SGA neonate (p = 0.5).Maternal plasma concentration of α-klotho was higher during pregnancy than in a non-pregnant state. Moreover, the median maternal plasma concentration of α-klotho was lower in mothers who delivered an SGA neonate than in those with an uncomplicated pregnancy regardless of the presence or absence of PE.

The hypercortisolism of melancholic depression is thought to reflect hypothalamic hypersecretion of CRH and may be related to the hyperarousal associated with this syndrome. Although chronic administration of imipramine to experimental animals significantly decreases CRH messenger RNA levels in the paraventricular nucleus, it is generally thought that resolution of hypercortisolism following recovery from depression is related to the improvement in mood and decrease in anxiety that accompanies recovery rather than an intrinsic effect of imipramine. The present study was designed to explore whether chronic imipramine administration to healthy, nondepressed volunteers is associated with effects on hypothalamic-pituitary-adrenal (HPA) axis function. We studied basal and provocative measures of HPA axis function in 14 healthy volunteers before and after 6 weeks of imipramine treatment at therapeutic doses. Imipramine was associated with decreased responses in peak ACTH and cortisol to ovine CRH and in peak ACTH to arginine vasopressin (P 5 0.02, P 5 0.003, and P 5 0.02, respectively) without changes in indices of basal HPA axis function. These data are consistent with preclinical findings and support the hypothesis that imipramine has an intrinsic effect on central components of HPA axis function, potentially related to its therapeutic effects. (J Clin Endocrinol Metab 82: 2601‐2606, 1997)

Petrides, John S., Philip W. Gold, Gregory P. Mueller, Anita Singh, Costas Stratakis, George P. Chrousos, and Patricia A. Deuster.Marked differences in functioning of the hypothalamic-pituitary-adrenal axis between groups of men. J. Appl. Physiol. 82(6): 1979–1988, 1997.—To compare profiles of hypothalamic-pituitary-adrenal (HPA) responsiveness, healthy, moderately trained men ( n = 15) were classified as high ( n = 7) or low responders ( n = 8) on the basis of plasma adrenocorticotropic hormone (ACTH) responses to strenuous treadmill exercise 4 h after 4 mg of dexamethasone (Dex). These groups were then evaluated to compare 1) HPA and growth hormone responses to exercise at 90% maximal oxygen uptake 4 h after placebo, Dex (4 mg), and hydrocortisone (100 mg); 2) pituitary-adrenal responses to infusion of arginine vasopressin (AVP); 3) plasma cortisol after a Dex suppression test (1 mg); and 4) behavioral characteristics. In comparison to low responders, high responders exhibited significantly 1) higher plasma ACTH responses to exercise after placebo and Dex; 2) higher plasma AVP secretion with exercise after placebo and marked Dex- and hydrocortisone-induced enhancement of exercise-induced AVP secretion; 3) lower Dex-induced increases in basal and stimulated growth hormone secretion; 4) higher plasma ACTH responses to infusion of AVP; and 5) a trend ( P = 0.09) for higher trait anxiety ratings. Similar suppression of plasma cortisol was noted after 1 mg Dex. We conclude that subgroups of healthy male volunteers exhibit unique profiles of HPA responsiveness. We also believe that glucocorticoid pretreatment combined with strenuous exercise allows functional HPA responsiveness to be distinguished between subgroups of healthy controls and may be useful in the determination of susceptibility to disorders characterized by hyper- and hypo-HPA activation.

This study applied the corticotropin-releasing hormone (CRH) stimulation test to patients with panic disorder, before and during treatment with alprazolam, and to control subjects. In contrast to some, but not all prior studies, untreated, nondepressed panic disorder patients failed to show blunted adrenocorticotropic hormone or cortisol responses to CRH. In fact, the responses were subtly enhanced in that they were more rapid than those of controls. After 12 weeks of alprazolam treatment, repeat testing gave results that were indistinguishable from those of controls. Inconsistency among reports of CRH testing in panic disorder may be related to interactions among illness mechanisms, concurrent subthreshold depressive symptoms, the chronic stress of the illness, and hyperresponsiveness of panic patients to the acute stress of experimental manipulations. Pretreatment abnormalities in hypothalamic-pituitary-adrenal axis function appear to resolve with alprazolam treatment. Preliminary observations suggest that pretreatment dysregulation of the hypothalamic-pituitary-adrenal system may predict a more difficult or less satisfactory treatment.

Lithium, a first line treatment for bipolar disorder (BD), has been associated with significant weight gain, but the mechanisms underlying this phenomenon are still unclear. It has been suggested that changes in production/release of adipokines – molecules secreted by adipose tissue presenting anti-inflammatory (adiponectin) and pro-inflammatory (leptin, resistin) properties – might be implicated. Adiponectin, resistin and leptin were assessed in 25 acutely depressed BD individuals (88% medication-free and 68% treatment-naive) at baseline and after 6 weeks of lithium therapy, and in 23 healthy controls matched by age. The 21-item Hamilton Depression Rating Scale was used to assess depression severity. Levels of adiponectin significantly decreased after lithium monotherapy, while the levels of resistin and leptin remained stable after the follow-up period. Adipokine levels during depressive episodes in BD did not differ compared to controls. Pretreatment levels of leptin were higher in remitters and changes in resistin levels were negatively correlated to improvement of depressive symptoms with lithium. Our findings shed light in this pathophysiological process, which might be associated with metabolic syndrome, inflammation and other medical comorbidities in BD.

Depression is associated with alterations in behavior and neuroendocrine systems that are risk factors for decreased bone mineral density. This study was undertaken to determine whether women with past or current major depression have demonstrable decreases in bone density.We measured bone mineral density at the hip, spine, and radius in 24 women with past or current major depression and 24 normal women matched for age, body-mass index, menopausal status, and race, using dual-energy x-ray absorptiometry. We also evaluated cortisol and growth hormone secretion, bone metabolism, and vitamin D-receptor alleles.As compared with the normal women, the mean (+/-SD) bone density in the women with past or current depression was 6.5 percent lower at the spine (1.00+/-0.15 vs. 1.07+/-0.09 g per square centimeter, P=0.02), 13.6 percent lower at the femoral neck (0.76+/-0.11 vs. 0.88+/-0.11 g per square centimeter, P0.001), 13.6 percent lower at Ward's triangle (0.70+/-0.14 vs. 0.81+/-0.13 g per square centimeter, P0.001), and 10.8 percent lower at the trochanter (0.66+/-0.11 vs. 0.74+/-0.08 g per square centimeter, P0.001). In addition, women with past or current depression had higher urinary cortisol excretion (71+/-29 vs. 51+/-19 micrograms per day [196+/-80 vs. 141+/-52 nmol per day], P=0.006), lower serum osteocalcin concentration (P=0.04), and lower urinary excretion of deoxypyridinoline (P=0.02).Past or current depression in women is associated with decreased bone mineral density.

Adrenocorticotropic hormone (ACTH) and cortisol secretion have been shown to be abnormal in approximately half of depressed patients. Information from pituitary and adrenal studies suggests that the locus of this dysregulation is at or above the level of the hypothalamus; however, direct evidence from provocative studies of the hypothalamic corticotropin releasing hormone (CRH) neuron does not exist. The current study was designed to stimulate hypothalamic CRH release using the opiate antagonist naloxone in patients with depression and elevated urinary-free cortisols as well as healthy and psychiatric controls. All subjects received naloxone and placebo on separate days in a double-blinded, randomized fashion at a dose determined previously to reliably induce significant increases in ACTH and cortisol secretion. No significant differences were noted among groups. We conclude that although naloxone is an effective central stimulant of the hypothalamic CRH neuron, stimulation of the hypothalamic CRH neuron with naloxone does not provide evidence of dysregulation of the HPA axis in depression.

It is well established that in vivo changes in ratios of lymphocyte phenotype subsets is altered by glucocorticoid administration. To determine whether the lymphocyte response would be further affected by strenuous exercise, since glucocorticoids are released during exercise, 14 physically fit men were randomly given placebo (P), 4 mg of dexamethasone (DEX), or 100 mg of hydrocortisone (HCO) 4 h before high-intensity treadmill running. Blood was drawn pre- and immediately post-exercise ; lymphocyte subsets (CD3, CD4, CD8, CD19, and CD56) were determined by flow cytometry. Pre-exercise CD3 and CD4 percentages were lower, whereas CD8 and CD56 were higher with DEX and HCO as compared to P. Exercise induced a lymphocytosis after all treatments, but subsets did not change proportionally. With P, DEX, and HCO, the magnitudes of change were comparable : CD3 and CD4 decreased and CD8 and CD56 increased. Notably, for all treatments exercise induced an approximately 2-fold increase in the percentage of cells expressing CD56 (natural killer cells). Thus, a single oral dose of DEX or HCO did not alter the direction or magnitude of immediate post-exercise changes in lymphocyte subset expression. Whether glucocorticoid pretreatment influences lymphocyte responses during recovery from strenuous exercise remains to be determined.

Corticotropin-releasing hormone (CRH) antagonism has neuroprotective effects in models of ischemia. We examined CRH mRNA by in situ hybridization in a well-established rat model of focal cerebral ischemia caused by permanent middle cerebral artery occlusion (MCAo). In ischemic cortex CRH mRNA levels were elevated 2.6-fold 60 min after MCAo, compared with sham operated animals. CRH mRNA was also induced in the amygdala, 60 min following ischemia, in a pattern which was qualitatively different from that of sham operated animals. This rapid and profound increase in CRH mRNA levels during focal cerebral ischemia is likely to be associated with neurotoxicity, as CRH antagonism has been reported to cause a significant reduction in neuronal loss during ischemia.

A stressor above a threshold magnitude, or multiple stressors applied simultaneously, cause an organism to alter its behaviour and physiology, with the aim of maintaining homeostasis. The adaptive changes that occur are coordinated and mediated by the stress system in the central nervous system (which includes corticotrophin-releasing hormone and noradrenergic neurons in the hypothalamus and brainstem, respectively), and its peripheral limbs, the hypothalamic-pituitary-adrenal axis and the autonomic (sympathetic) system. Controlled or self-driven challenges to homeostasis and a normally functioning stress system are crucial for normal development and preservation of self and species. In childhood and adolescence, appropriately functioning neuroendocrine responses to stressors are necessary to allow growth and psychosexual maturation to progress normally. Maladaptive neuroendocrine responses, i.e. dysregulation of the stress system, may lead to disturbances in growth and development and cause psychiatric, endocrine/metabolic and/or autoimmune diseases or vulnerability to such diseases, not only during childhood and adolescence, but also in adulthood.

Aging is associated with a progressive decrement in the basal activity of the hypothalamic-pituitary-thyroid axis in male Fischer 344/N rats. The aim of this study was to determine whether stress influences the activity of this axis in young and old rats. As prolactin and growth hormone share some regulatory mechanisms with thyrotropin-releasing and thyroid-stimulating hormones, which are influenced by stress, the plasma levels of these two hormones were also determined during immobilization (Immo). To accomplish this, young (3-month-old) and old (23-month-old) male 344/N Fischer rats were immobilized for 2 h; blood was collected by cannulation from the tail artery at different intervals during Immo (0, 5, 30, 60, and 120 min), and brains were removed at the end of Immo. The basal plasma levels of thyroid-stimulating hormone were similar in both groups, but were significantly and progressively inhibited by Immo in young, but not in old rats. The baseline plasma levels of total triiodothyronine were slightly lower in old than in young rats; Immo caused a significant decrease of total triiodothyronine levels only in the young animals. The baseline plasma levels of free triiodothyronine were similar and were not altered by Immo in either age group. The paraventricular nucleus thyrotropin-releasing hormone mRNA levels were lower in old than in young rats under basal conditions; under stress they were significantly inhibited in young, but remained unchanged in old rats. The basal thyroid-stimulating hormone beta mRNA levels in the anterior pituitary were significantly lower in old than in young rats, but were not affected by Immo in either age group. The plasma prolactin levels were similar at baseline and were significantly increased by Immo in both age groups, but significantly more in old than in young rats. The plasma growth hormone levels were also similar at baseline; they were significantly decreased by Immo to a similar extent in both age groups. In summary, these data indicate that the stress-induced decrease in plasma thyroid-stimulating hormone is in part mediated at the level of the hypothalamic thyrotrophin-releasing hormone neuron and that this phenomenon is attenuated in the aged rat.

We previously found that, following intravenous administration of ovine corticotropin-releasing hormone (CRH), the plasma ACTH concentrations of Black women were approximately twice as high as those of White women; however, there were no corresponding differences in cortisol response. To determine whether this difference in ACTH secretion is also present in men, we studied the hypothalamic-pituitary-adrenal axis of 10 Black and 10 White weight-, age-, and education-matched men. Waist-to-hip ratio, 24-hour urine free cortisol excretion, and ACTH and cortisol responses to 1 microgram/kg ovine CRH were determined. There were no racial differences in waist-to-hip ratio, 24-hour urine free cortisol excretion, baseline free or total plasma cortisol and ACTH concentrations, or plasma cortisol response to CRH. However, CRH-stimulated plasma ACTH concentrations, measured in an extraction polyclonal radioimmunoassay, were significantly greater in Blacks than in Whites at all time points between 30 and 180 min after administration of CRH (area under curve (AUC) 1,796 +/- 245 pmol/l.min in Blacks vs. 1,278 +/- 121 pmol/l.min in Whites, p < 0.001). Neither cortisol nor ACTH AUCs were significantly correlated with Body Mass Index in Black or White men. We conclude that there are differences in the HPA axis of Black and White men similar to those found previously in women. The physiology underlying these differences remains to be understood.

Background An inverse relationship between major depressive disorder (MDD) and bone mineral density (BMD) has been suggested, but prospective evaluation in premenopausal women is lacking. Methods Participants of this prospective study were 21 to 45 year-old premenopausal women with MDD (n = 92) and healthy controls (n = 44). We measured BMD at the anteroposterior lumbar spine, femoral neck, total hip, mid-distal radius, trochanter, and Ward's triangle, as well as serum intact parathyroid hormone (iPTH), ionized calcium, plasma adrenocorticotropic hormone (ACTH), serum cortisol, and 24-hour urinary-free cortisol levels at 0, 6, 12, 24, and 36 months. 25-hydroxyvitamin D was measured at baseline. Results At baseline, BMD tended to be lower in women with MDD compared to controls and BMD remained stable over time in both groups. At baseline, 6, 12, and 24 months intact PTH levels were significantly higher in women with MDD vs. controls. At baseline, ionized calcium and 25-hydroxyvitamin D levels were significantly lower in women with MDD compared to controls. At baseline and 12 months, bone-specific alkaline phosphatase, a marker of bone formation, was significantly higher in women with MDD vs. controls. Plasma ACTH was also higher in women with MDD at baseline and 6 months. Serum osteocalcin, urinary N-telopeptide, serum cortisol, and urinary free cortisol levels were not different between the two groups throughout the study. Conclusion Women with MDD tended to have lower BMD than controls over time. Larger and longer studies are necessary to extend these observations with the possibility of prophylactic therapy for osteoporosis. Trial Registration ClinicalTrials.gov NCT 00006180

Background Major depressive disorder (MDD) has been associated with adverse medical consequences, including cardiovascular disease and osteoporosis. Patients with MDD may be classified as having melancholic, atypical, or undifferentiated features. The goal of the present study was to assess whether these clinical subtypes of depression have different endocrine and metabolic features and consequently, varying medical outcomes. Methods Premenopausal women, ages 21 to 45 years, with MDD (N = 89) and healthy controls (N = 44) were recruited for a prospective study of bone turnover. Women with MDD were classified as having melancholic (N = 51), atypical (N = 16), or undifferentiated (N = 22) features. Outcome measures included: metabolic parameters, body composition, bone mineral density (BMD), and 24 hourly sampling of plasma adrenocorticotropin (ACTH), cortisol, and leptin. Results Compared with control subjects, women with undifferentiated and atypical features of MDD exhibited greater BMI, waist/hip ratio, and whole body and abdominal fat mass. Women with undifferentiated MDD characteristics also had higher lipid and fasting glucose levels in addition to a greater prevalence of low BMD at the femoral neck compared to controls. Elevated ACTH levels were demonstrated in women with atypical features of depression, whereas higher mean 24-hour leptin levels were observed in the melancholic subgroup. Conclusions Pre-menopausal women with various features of MDD exhibit metabolic, endocrine, and BMD features that may be associated with different health consequences. Trial Registration ClinicalTrials.gov NCT00006180

Imipramine was administered chronically to LEW/N, outbred and F344/N rats which were then exposed to the aseptic irritant carrageenin in order to determine whether the decreased hypothalamic expression of CRH m-RNA previously shown to be associated with imipramine affects peripheral immune processes. Both LEW/N and outbred but not F344/N rats had vigorous inflammatory responses to carrageenin, and imipramine was associated with significant decreases in the local cellular inflammatory response to carrageenin. Imipramine was also associated with changes in the expression of peripheral blood cell MHC class II expression in LEW/N and outbred rats. These results suggest that at doses comparable to those used clinically imipramine has significant effects on response to an inflammatory stimulus.

The L -tryptophan eosinophilia myalgia syndrome ( L -Trp-EMS), related to ingestion of impure L -Trp, occurred in epidemic proportions in the Unite

Even though it is widely known that interleukin (IL)-1 alpha acts at the local level, it is still uncertain whether IL-1 alpha is secreted into the circulation and acts at distant sites. We have tried to elucidate this by measuring 24-hour levels of total IL-1 alpha in six healthy female volunteers. Subjects had detectable and pulsatile levels of IL-1 alpha throughout the 24-hour period. The integrated 24-hour IL-1 alpha concentration was 2,367 +/- 753 min x micrograms/l (mean +/- SD), and the integrated pulsatile IL-1 alpha concentration was 553 +/- 260 (25 +/- 10% ot total integrated IL-1 alpha). The mean IL-1 alpha concentration was 1.63 +/- 0.53 micrograms/l, mean pulse frequency/24 h was 12.8 +/- 0.8, mean pulse height was 2.31 +/- 0.52 micrograms/l; mean pulse width was 80.4 +/- 2.3 min, and mean interpulse interval was 105.3 +/- 2.8 min. Total IL-1 alpha levels significantly correlated with those previously reported for IL-2 in the same samples, and IL-1 alpha pulse parameters which are concentration independent were significantly similar to those of IL-2. Furthermore, cross-correlation analysis indicated that in 83% of our subjects (5/6) there was synchronicity of IL-1 alpha and IL-2 levels. IL-1 alpha pulse parameters were in the range reported for hormones which have well-characterized pulsatility, such as growth hormone, luteinizing hormone, follicle-stimulating hormone, cortisol, beta-endorphin, and progesterone. Based on these data we speculate that a pulsatile cytokine cascade may exist in the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE: Because the central administration of somatostatin to experimental animals produces behaviors with some similarities to the compulsions of patients with obsessive-compulsive disorder and because serotonin reuptake inhibitors have been reported to reduce brain content of somatostatin, the authors examined central somatostatin activity in patients with obsessive-compulsive disorder. METHOD: CSF for measurement of somatostatin was obtained from 15 drug-free outpatients with obsessive-compulsive disorder and 27 normal volunteers. RESULTS: The mean CSF somatostatin level was significantly higher in the patients with obsessive-compulsive disorder than in the normal subjects. CONCLUSIONS: Although the functional significance of this finding is unknown, these data are consistent with a role for somatostatin in the clinical symptomatology of obsessive-compulsive disorder and its response to neuropharmacological agents. The high levels of CSF somatostatin reported here in a patient subgroup whose predominant symptoms consisted of overly focused, perseverative thought processes are in contrast to the consistently low levels of CSF somatostatin seen in patients with a spectrum of disorders characterized by substantial cognitive deficits.