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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.

Summary Background Co-morbid major depressive disorder (MDD) in individuals with posttraumatic stress disorder (PTSD) confers a more severe clinical course and is associated with distinct biologic abnormalities. Although dysregulation in the hypothalamic pituitary adrenal (HPA) axis has been well established in PTSD, the impact of commonly co-occuring MDD has received scant attention. Methods Overnight (7 p.m. to 7 a.m.) plasma cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulphate (DHEA-S) were measured at 30 min intervals in 9 participants with PTSD with MDD (PTSD + MDD), 9 with PTSD without MDD (PTSD − MDD) and 16 non-traumatized healthy controls. A low-dose dexamethasone suppression test was administered to evaluate feedback sensitivity to glucocorticoids. Linear mixed models with body mass index (BMI) and age as covariates and Bonferroni corrected post hoc tests assessed group differences. Results Compared to healthy controls, subjects with PTSD + MDD, but not those subjects with PTSD − MDD, exhibited lower basal plasma cortisol levels between 1:30 a.m. and 3:30 a.m. and at 4:30 a.m. and 6:30 a.m. (effect size d = 0.75). Despite similar plasma ACTH levels between the three groups, the ACTH/cortisol ratio was higher in PTSD + MDD patients compared to controls. We obtained similar results when the patient and control groups were re-studied 1 week later, and when men and current smokers were excluded. Basal plasma DHEA-S levels, and cortisol and ACTH response to a low-dose dexamethasone suppression test were similar in all three groups. Conclusions Lower early morning plasma cortisol levels and a high ACTH/cortisol ratio in subjects with PTSD and co-morbid MDD may not be due to enhanced peripheral sensitivity to glucocorticoids. A central abnormality in glucocorticoid regulation could explain HPA axis dysfunction in this subgroup.

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-α 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-α levels in Lewis vs Fischer inbred rats. Additionally, isoproterenol, a β adrenoreceptor agonist suppressed LPS-induced TNF-α production, with more pronounced effect in Lewis than in Fischer rats. In human monocytes, epinephrine and the β2 adrenoreceptor agonist fenoterol potently inhibited LPS-induced TNF-α 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 > = 1,25-(OH)2 vitamin D3 > 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.

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.

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.

The entrance of leptin into the central nervous system is of physiological relevance to the regulation of food intake, energy balance, and neuroendocrine function. To our knowledge, the relation between plasma and lumbar cerebrospinal fluid (CSF) leptin has not been examined across the 24-h period. To evaluate the relation between plasma and CSF leptin across the 24-h period, we studied simultaneous and continuous plasma and CSF leptin in nine subjects. We measured plasma and lumbar CSF leptin every 30 min for 24 h. All subjects had diurnal periodicity in 24-h plasma leptin levels, but not in CSF levels, as assessed by analysis of covariance and cosinor analysis. Plasma leptin had a significant 24-h pattern (P = 0.001), but CSF leptin did not. A 25-fold range of plasma leptin concentrations was reflected by a less-than-2-fold range in lumbar CSF leptin concentrations. Nocturnal increases in plasma leptin concentrations were not accompanied by commensurate changes in CSF values. It appears that leptin enters the brain by a mechanism that is highly saturable at physiological leptin concentrations and that the dynamics of plasma leptin is not accompanied by similar dynamics in CSF leptin measured at the lumbar spinal level. Therefore, it is not possible to use plasma leptin levels to predict lumbar CSF leptin concentrations. Although we acknowledge that lumbar CSF concentrations do not fully reflect the dynamics of leptin in the brain, we suggest that the nocturnal saturability of leptin transport into the central nervous system might help explain the lack of responsiveness to the central physiologic effects of leptin in states of hyperleptinemia, such as obesity.

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.

Sustained responsiveness of the hypothalamic-pituitary-adrenal (HPA) axis during chronic or repeated stress is associated with continuous activation of ascending noradrenergic neurons from the brainstem to the hypothalamic paraventricular nucleus (PVN). The fact that glucocorticoid receptor (GR) exists in the brainstem noradrenergic neurons including locus coeruleus (LC) suggests that glucocorticoids play a modulatory role in maintaining the activity of these neurons during chronic stress. To determine whether alterations in the sensitivity of noradrenergic neuronal activity to endogenous CORT occur during chronic or repeated stress, tyrosine hydroxylase (TH) and GR mRNA expressions in the LC were examined in acute (2 h) and repeated (2 h daily, 14 days) immobilization stress, using sham-operated rats and adrenalectomized rats with a moderate dose of CORT replacement (ADX+CORT group). In acute stress, TH mRNA in the LC increased in the ADX+CORT rats, but not in sham operated rats. In repeated stress, however, elevated endogenous CORT failed to inhibit TH mRNA responses in sham rats; LC TH mRNA in sham rats responded to the same extent as in ADX+CORT rats. A reduction of GR mRNA in the LC was observed in the acutely stressed and repeatedly stressed sham group, but not in the ADX+CORT groups. The decrease in LC GR mRNA levels in sham rats tended to be greater after repeated than after acute stress. LC GR mRNA levels decreased in response to systemic CORT treatment (200 mg pellet sc, for 14 days) and increased in response to adrenalectomy; neither CORT treatment nor adrenalectomy influenced TH mRNA levels in the LC. These results suggest that glucocorticoid responses to acute immobilization prevent LC TH mRNA levels from rising significantly, while glucocorticoids appear to decrease their capacity to restrain LC TH mRNA during repeated immobilization. Although the results clearly show glucocorticoid-dependent alterations in LC GR mRNA expression, the association between increased TH mRNA and decreased GR mRNA in the LC remains to be elucidated.

Stress precipitates depression and alters its natural history. Major depression and the stress response share similar phenomena, mediators and circuitries. Thus, many of the features of major depression potentially reflect dysregulations of the stress response. The stress response itself consists of alterations in levels of anxiety, a loss of cognitive and affective flexibility, activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, and inhibition of vegetative processes that are likely to impede survival during a life-threatening situation (eg sleep, sexual activity, and endocrine programs for growth and reproduction). Because depression is a heterogeneous illness, we studied two diagnostic subtypes, melancholic and atypical depression. In melancholia, the stress response seems hyperactive, and patients are anxious, dread the future, lose responsiveness to the environment, have insomnia, lose their appetite, and a diurnal variation with depression at its worst in the morning. They also have an activated CRH system and may have diminished activities of the growth hormone and reproductive axes. Patients with atypical depression present with a syndrome that seems the antithesis of melancholia. They are lethargic, fatigued, hyperphagic, hypersomnic, reactive to the environment, and show diurnal variation of depression that is at its best in the morning. In contrast to melancholia, we have advanced several lines of evidence of a down-regulated hypothalamic-pituitary adrenal axis and CRH deficiency in atypical depression, and our data show us that these are of central origin. Given the diversity of effects exerted by CRH and cortisol, the differences in melancholic and atypical depression suggest that studies of depression should examine each subtype separately. In the present paper, we shall first review the mediators and circuitries of the stress system to lay the groundwork for placing in context physiologic and structural alterations in depression that may occur as part of stress system dysfunction.

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.

Inflammation plays a critical role in atherogenesis, yet the mediators linking inflammation to specific atherogenic processes remain to be elucidated. One such mediator may be secretory sphingomyelinase (S-SMase), a product of the acid sphingomyelinase gene. The secretion of S-SMase by cultured endothelial cells is induced by inflammatory cytokines, and in vivo data have implicated S-SMase in subendothelial lipoprotein aggregation, macrophage foam cell formation, and possibly other atherogenic processes. Thus, the goal of this study was to seek evidence for S-SMase regulation in vivo during a physiologically relevant inflammatory response. First, wild-type mice were injected with saline or lipopolysaccharide (LPS) as a model of acute systemic inflammation. Serum S-SMase activity 3 h postinjection was increased 2- to 2.5-fold by LPS ( P < 0.01). To determine the role of IL-1 in the LPS response, we used IL-1 converting enzyme knockout mice, which exhibit deficient IL-1 bioactivity. The level of serum S-SMase activity in LPS-injected IL-1 converting enzyme knockout mice was ≈35% less than that in identically treated wild-type mice ( P < 0.01). In LPS-injected IL-1-receptor antagonist knockout mice, which have an enhanced response to IL-1, serum S-SMase activity was increased 1.8-fold compared with LPS-injected wild-type mice ( P < 0.01). Finally, when wild-type mice were injected directly with IL-1β, tumor necrosis factor α, or both, serum S-SMase activity increased 1.6-, 2.3-, and 2.9-fold, respectively ( P < 0.01). These data show regulation of S-SMase activity in vivo and they raise the possibility that local stimulation of S-SMase may contribute to the effects of inflammatory cytokines in atherosclerosis.

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)

In the rat, high-dose corticosterone (Cort) administration, the hypercortisolism of starvation, and adrenalectomy are all associated with decreased food intake and weight loss. We report here a study of the effects of high-dose Cort administration, starvation, and adrenalectomy on two peripheral hormones known to influence food intake and energy use, insulin and leptin. We also studied the impact of these interventions on the levels of type 2 corticotropin-releasing hormone receptor (CRHR-2) mRNA in the hypothalamic paraventricular nucleus (PVN) and ventromedial hypothalamus (VMH). The VMH is classically referred to as the satiety center because electrical stimulation of the VMH leads to inhibition of food intake, whereas CRHR-2 are thought to transduce the profound anorexogenic effects of CRH or its related peptide urocortin. Starvation and adrenalectomy each lowered plasma insulin and leptin levels and were associated with decrements in CRHR-2 mRNA levels in the VMH. Cort administration increased plasma leptin levels profoundly, as well as plasma insulin levels and the levels of VMH CRHR-2 mRNA. Under all experimental conditions, a positive correlation was seen between plasma leptin levels and VMH CRHR-2 mRNA. These data suggest that decreased food intake and weight loss after high-dose Cort administration at least partially depend on the profound impact of Cort on plasma leptin secretion in the rat; they suggest, moreover, an additional mechanism for the satiety-inducing effects of leptin, namely increasing CRHR-2 in the VMH. The concordance of a fall in plasma insulin and leptin levels with the fall in VMH CRHR-2 mRNA levels further supports the idea that compensatory responses during starvation and adrenalectomy include not only the disinhibiting effects of reduced insulin and leptin levels on appetite through already-described mechanisms but also via an effect of leptin on VMH CRHR-2. Neither Cort administration, starvation, nor adrenalectomy influenced the levels of CRHR-2 mRNA in the PVN, suggesting that these receptors are differentially regulated in different hypothalamic regions.

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.

Leptin, an adipocyte hormone, is a trophic factor for the reproductive system; however, it is still unknown whether there is a dynamic relation between fluctuations in circulating leptin and hypothalamic—pituitary–ovarian (HPO) axis hormones. To test the hypothesis that fluctuations in plasma leptin concentrations are related to the levels of luteinizing hormone (LH) and estradiol, we sampled plasma from six healthy women every 7 min for 24 h during days 8–11 of the menstrual cycle. Cross-correlation analysis throughout the 24-h cycle revealed a relation between release patterns of leptin and LH, with a lag of 42–84 min but no significant cross-correlation between LH and estradiol. The ultradian fluctuations in leptin levels showed pattern synchrony with those of both LH and estradiol as determined by cross-approximate entropy (cross-ApEn). At night, as leptin levels rose to their peak, the pulsatility profiles of LH changed significantly and became synchronous with those of leptin. LH pulses were fewer, of longer duration, higher amplitude, and larger area than during the day. Moreover, the synchronicity of LH and leptin occurred late at night, at which time estradiol and leptin also exhibited significantly stronger pattern coupling than during the day. We propose that leptin may regulate the minute-to-minute oscillations in the levels of LH and estradiol, and that the nocturnal rise in leptin may determine the change in nocturnal LH profile in the mid-to-late follicular phase that precedes ovulation. This may explain the disruption of hypothalamic—pituitary–ovarian function that is characteristic of states of low leptin release, such as anorexia nervosa and cachexia.

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)

Although we have previously shown that the integrity of inflammatory mediator-induced activation of the hypothalamic-pituitary-adrenal axis is essential for conferring resistance to inflammatory disease in susceptible Lewis rats, the role of endogenous glucocorticoid secretion in human immune function in either health or disease is less clear. To further understand the relevance of physiological variations in plasma cortisol on immune function in humans, we evaluated ex vivo lipopolysaccharide-induced interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in the whole blood of healthy volunteers studied under conditions chosen to approximate either physiological or pharmacological glucocorticoid levels. Administration of a pharmacological dose of hydrocortisone suppressed the production of all three cytokines, whereas administration of a physiological dose of hydrocortisone suppressed only TNF alpha production. Stress-induced levels of glucocorticoids, achieved during exercise at 100% maximal oxygen utilization, suppressed IL-1 beta and TNF alpha production, but were without effect on IL-6 production. In addition, circadian variations of cortisol were associated with decreased TNF alpha production, but were without effect on IL-1 beta or IL-6 production. These studies challenge the generally accepted idea that glucocorticoids consistently suppress cytokine production and indicate a hierarchy of sensitivity, with TNF alpha having the greatest sensitivity, IL-1 beta having intermediate sensitivity, and IL-6 being resistant. The resistance of IL-6 production to glucocorticoid suppression is compatible with data suggesting an antiinflammatory as well as a proinflammatory action for this cytokine.

Little is known about the effects of intentional weight loss on the function of the hypothalamic-pituitary-adrenal (HPA) axis of obese individuals. We studied the HPA axis of 34 healthy obese women (body mass index, 40.2 +/- 7.9 kg/m2) before and after a 21.0 +/- 7.9-kg weight loss induced by a 26-week weight loss program that included 12 weeks of a 3350 kJ/day (800 Cal/day) liquid formula diet, 6 weeks of gradual refeeding, and 6 weeks of caloric stabilization at 5020-6280 kJ/day (1200-1500 Cal/day). Obese subjects were evaluated twice: before caloric restriction and during the last 3 weeks of caloric stabilization with a 3-h evening 1 microg/kg ovine CRH (oCRH) stimulation test. CRH-stimulated ACTH and cortisol values were compared to those of a control group of 12 normal weight women. Before caloric restriction, both ACTH and cortisol responses to oCRH were similar in obese women and normal weight controls. Weight loss did not significantly alter the ACTH response to oCRH; however, the total plasma cortisol response to oCRH decreased significantly with weight loss (area under the curve, 96,320 +/- 21,040 nmol/L x min before weight loss; 82,450 +/- 22,460 nmol/L x min after weight loss; P < 0.001). Cortisol-binding globulin also decreased significantly after weight loss (2,270 +/- 1,050 nmol/L) compared either to values obtained before weight loss (3,590 +/- 1,360 nmol/L; P < 0.001) or to those of normal weight controls (3,910 +/- 1,400 nmol/L; P < 0.001). Assay for plasma free cortisol, either before or 180 min after oCRH treatment, showed no significant changes in cortisol responses resulting from weight loss. As plasma free cortisol was not altered by weight reduction, the decrease in the total cortisol response to oCRH after weight loss appears to be secondary to significant decreases in cortisol-binding globulin. We conclude that when obese women lose large amounts of weight with a 3350 kJ/day, very low energy diet, such weight reduction does not significantly affect the HPA axis.

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.

To examine the hypothesis that hypothalamic-pituitary-adrenal responses to stress vary across gender, contributing to gender differences in the prevalence of depression.This study examined gender differences between depressed (n = 21) and control (n = 20) adolescents in adrenocorticotropic hormone (ACTH) and cortisol response to two ovine corticotropin-releasing hormone (oCRH) tests, at baseline and following a cognitive stressor.Boys had higher (p.05) measures of ACTH than girls, regardless of depression status, whereas corresponding cortisol parameters were similar in both groups. Cortisol measures were higher (p.05) at time 1 than at time 2 in both groups, a phenomenon that might reflect the novelty of the situation.Gender differences in hormone responses may be related to differences in peripheral metabolism of ACTH, resulting in changes of immunoreactivity but not bioactivity or a different set point of the hypothalamic-pituitary-adrenal axis. The pattern of ACTH and cortisol responses to oCRH and the 24-hour excretion of free cortisol was normal in adolescents with depression, probably reflecting normal negative feedback mechanisms at this age or that most of these patients suffer from atypical rather than melancholic depression.

Studies examining the function of the hypothalamic-pituitary-adrenal (HPA) axis in anorexia nervosa are reviewed. A principal finding is that of hypercortisolism, associated with increased central corticotropin-releasing hormone levels and normal circulating levels of adrenocorticotropic hormone. Similarities between neuroendocrine findings in anorexia nervosa and in affective disorder are reviewed. The contribution of circadian rhythm disturbances and malnutrition to observed HPA axis abnormalities in anorexia nervosa is also considered. Directions for future research are discussed.

Glucocorticoids regulate the activity of the hypothalamic-pituitary-adrenal axis through both mineralocorticoid (MR) and glucocorticoid (GR) receptors in the hippocampus. In addition, glucocorticoids down-regulate hippocampal expression of MR and GR mRNA and protein, presumably decreasing their own effect. Marmosets are a New World primate characterized by extraordinarily high levels of circulating ACTH and cortisol. The relative glucocorticoid insensitivity of these animals to their massive levels of glucocorticoids was attributed to a decreased affinity of their GR for glucocorticoids, as well as a compromised ability of this receptor to transactivate glucocorticoid-responsive genes. The lack of mineralocorticoid excess, on the other hand, was attributed to a renal MR which responded poorly to cortisol, but normally to aldosterone. The purpose of this study was to examine MR and GR mRNA expression in the marmoset (Callithrix jacchus jacchus) hippocampus. Overall, steady state levels of both MR and GR mRNA were elevated in all of the hippocampal subfields of the marmoset, and this was obvious in rough comparisons with those of a typical glucocorticoid-sensitive Old World primate, the rhesus monkey (Macaca mulata). Notable were the extremely high levels of GR mRNA in the dentate gyrus and field CA3 of the marmoset. The GR mRNA density distribution of the marmoset also appeared to differ from that in the rhesus and from those previously reported in rats and humans. These findings suggest that there is a compensatory elevation of MR and GR mRNAs in the marmoset hippocampus, which appears to be the result of target tissue resistance to glucocorticoids and inappropriate down-regulation by the elevated, but ineffective, circulating cortisol.

The nucleotide sequence CTGTGCGCGCAG is a core corticotropin-releasing hormone (CRH) responsive element in the proopiomelanocortin (POMC) promoter that gives 5-7 fold stimulation of POMC transcription by CRH. This region binds a novel transacting factor, proopiomelanocortin corticotropin-releasing hormone responsive element binding protein 1 (PCRH-REB-1), recently cloned from CRH-stimulated pituitary cells. We conducted in situ hybridization histochemistry experiments, using a species-specific, antisense, 35S-labeled PCRH-REB-1 riboprobe, to determine the pattern of PCRH-REB-1 gene expression in the brain, and showed that PCRH-REB-1 mRNA is localized not only in pituitary, but it is also found in discrete brain regions such as septal nuclei, hypothalamus, cortex, hippocampus, amygdala, and cerebellum. Those regions contain CRH or CRH receptors, and respond to CRH. We hypothesize that PCRH-REB-1 may be a marker of cellular responsiveness to CRH in the brain and pituitary, and might therefore be useful in the evaluation of CRH function and in the identification of clinically effective CRH agonists and antagonists.

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.

Klotho is a hormone secreted into human cerebrospinal fluid (CSF), plasma and urine that promotes longevity and influences the onset of several premature senescent phenotypes in mice and humans, including atherosclerosis, cardiovascular disease, stroke and osteoporosis. Preliminary studies also suggest that Klotho possesses tumor suppressor properties. Klotho's roles in these phenomena were first suggested by studies demonstrating that a defect in the Klotho gene in mice results in a significant decrease in lifespan. The Klotho-deficient mouse dies prematurely at 8-9 weeks of age. At 4-5 weeks of age, a syndrome resembling human ageing emerges consisting of atherosclerosis, osteoporosis, cognitive disturbances and alterations of hippocampal architecture. Several deficits in Klotho-deficient mice are likely to contribute to these phenomena. These include an inability to defend against oxidative stress in the central nervous system and periphery, decreased capacity to generate nitric oxide to sustain normal endothelial reactivity, defective Klotho-related mediation of glycosylation and ion channel regulation, increased insulin/insulin-like growth factor signaling and a disturbed calcium and phosphate homeostasis accompanied by altered vitamin D levels and ectopic calcification. Identifying the mechanisms by which Klotho influences multiple important pathways is an emerging field in human biology that will contribute significantly to understanding basic physiologic processes and targets for the treatment of complex diseases. Because many of the phenomena seen in Klotho-deficient mice occur in depressive illness, major depression and bipolar disorder represent illnesses potentially associated with Klotho dysregulation. Klotho's presence in CSF, blood and urine should facilitate its study in clinical populations.

Corticotropin-releasing hormone (CRH), originally isolated from the hypothalamus, is widely distributed in many extrahypothalamic central nervous system sites, and in the periphery. Immunoreactive (ir)-CRH has been identified in rat and human inflammatory sites, in rat testicular Leydig cells, and in rat thecal and stromal ovarian cells. In the current study, we investigated whether aging and stress are associated with changes in ovarian ir-CRH in the rat. Healthy young (3–4 mo) and old (24 mo) female Fischer 344/N rats (6 per group) were studied in the morning, before and after being stressed by 120 min of immobilization, and were sacrificed by decapitation. Young females were all in proestrous, and old females were in constant anestrous. Pre-immobilization corticosterone (CORT) levels were similar in both age groups; immobilization produced a dramatic increase in CORT in both groups; however, the increase was smaller in the old rats, although this did not reach statistical significance (P < 0.06). Immunoreactive CRH was detected in the ovaries of all rats, and its distribution and intensity were quantified masked to the age and treatment group, in the theca, granulosa, stroma, and corpus luteum. At baseline, ir-CRH was 50% lower in old than in young rats in the theca and stroma by both distribution and intensity. Stress was associated with a decrease of ir-CRH levels in the theca in both age groups, albeit to a significantly lesser extent in old rats (old 35% versus young 70%). These data suggest a functional and, perhaps, developmental role for ovarian CRH.

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.