Extracellular levels of glucose in the hippocampus and striatum during maze training for food or water reward in male rats.

Glucose potently enhances cognitive functions whether given systemically or directly to the brain. The present experiments examined changes in brain extracellular glucose levels while rats were trained to solve hippocampus-sensitive place or striatum-sensitive response learning tasks for food or water reward. Because there were no task-related differences in glucose responses, the glucose results were pooled across tasks to form combined trained groups. During the first 1-3 min of training for food reward, glucose levels in extracellular fluid (ECF) declined significantly in the hippocampus and striatum; the declines were not seen in untrained, rewarded rats. When trained for water reward, similar decreases were observed in both brain areas, but these findings were less consistent than those seen with food rewards. After the initial declines in ECF glucose levels, glucose increased in most groups, approaching asymptotic levels ∼15-30 min into training. Compared to untrained food controls, training with food reward resulted in significant glucose increases in the hippocampus but not striatum; striatal glucose levels exhibited large increases to food intake in both trained and untrained groups. In rats trained to find water, glucose levels increased significantly above the values seen in untrained rats in both hippocampus and striatum. The decreases in glucose early in training might reflect an increase in brain glucose consumption, perhaps triggering increased brain uptake of glucose from blood, as evident in the increases in glucose later in training. The increased brain uptake of glucose may provide additional neuronal metabolic substrate for metabolism or provide astrocytic substrate for production of glycogen and lactate.

Does conventional early life academic excellence predict later life scientific discovery? An assessment of the lives of great medical innovators.

BACKGROUND: Perhaps, as never before, we need innovators. With our growing population numbers, and with increasing pressures on our education systems, are we in danger of becoming more rigid and formulaic and increasingly inhibiting innovation? When young can we predict who will become the great innovators? For example, in medicine, who will change clinical practice? AIMS: We therefore determined to assess whether the current academic excellence approach to medical school entrance would have captured previous great innovators in medicine, assuming that they should all have well fulfilled current entrance requirements. METHODS: The authors assembled a list of 100 great medical innovators which was then approved, rejected or added to by a jury of 12 MD fellows of the Royal Society of Canada. Two reviewers, who had taken both the past and present Medical College Admission Test as part of North American medical school entrance requirements, independently assessed each innovator's early life educational history in order to predict the innovator's likely success at medical school entry, assuming excellence in all entrance requirements. RESULTS: Thirty-one percent of the great medical innovators possessed no medical degree and 24% would likely be denied entry to medical school by today's standards (e.g. had a history of poor performance, failure, dropout or expulsion) with only 24% being guaranteed entry. Even if excellence in only one topic was required, the figure would only rise to 41% certain of medical school entry. CONCLUSION: These data show that today's medical school entry standards would have barred many great innovators and raise questions about whether we are losing medical innovators as a consequence. Our findings have important implications for promoting flexibility and innovation for medical education, and for promoting an environment for innovation in general.

Aging is not equal across memory systems.

The present experiments compared the effects of aging on learning several hippocampus- and striatum-sensitive tasks in young (3-4 month) and old (24-28 month) male Fischer-344 rats. Across three sets of tasks, aging was accompanied not only by deficits on hippocampal tasks but also by maintained or even enhanced abilities on striatal tasks. On two novel object recognition tasks, rats showed impaired performance on a hippocampal object location task but enhanced performance on a striatal object replacement task. On a dual solution task, young rats predominately used hippocampal solutions and old rats used striatal solutions. In addition, on two maze tasks optimally solved using either hippocampus-sensitive place or striatum-sensitive response strategies, relative to young rats, old rats had impaired learning on the place version but equivalent learning on the response version. Because glucose treatments can reverse deficits in learning and memory across many tasks and contexts, levels of available glucose in the brain may have particular importance in cognitive aging observed across tasks and memory systems. During place learning, training-related rises in extracellular glucose levels were attenuated in the hippocampus of old rats compared to young rats. In contrast, glucose levels in the striatum increased comparably in young and old rats trained on either the place or response task. These extracellular brain glucose responses to training paralleled the impairment in hippocampus-sensitive learning and the sparing of striatum-sensitive learning seen as rats age, suggesting a link between age-related changes in learning and metabolic substrate availability in these brain regions.

Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder.

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.

The role of adipokines in the rapid antidepressant effects of ketamine.

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.

Klotho: a humeral mediator in CSF and plasma that influences longevity and susceptibility to multiple complex disorders, including depression.

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.

Attenuation in rats of impairments of memory by scopolamine, a muscarinic receptor antagonist, by mecamylamine, a nicotinic receptor antagonist.

RATIONALE: Scopolamine, a muscarinic antagonist, impairs learning and memory for many tasks, supporting an important role for the cholinergic system in these cognitive functions. The findings are most often interpreted to indicate that a decrease in postsynaptic muscarinic receptor activation mediates the memory impairments. However, scopolamine also results in increased release of acetylcholine in the brain as a result of blocking presynaptic muscarinic receptors. OBJECTIVES: The present experiments assess whether scopolamine-induced increases in acetylcholine release may impair memory by overstimulating postsynaptic cholinergic nicotinic receptors, i.e., by reaching the high end of a nicotinic receptor activation inverted-U dose-response function. RESULTS: Rats tested in a spontaneous alternation task showed dose-dependent working memory deficits with systemic injections of mecamylamine and scopolamine. When an amnestic dose of scopolamine (0.15 mg/kg) was co-administered with a subamnestic dose of mecamylamine (0.25 mg/kg), this dose of mecamylamine significantly attenuated the scopolamine-induced memory impairments. We next assessed the levels of acetylcholine release in the hippocampus in the presence of scopolamine and mecamylamine. Mecamylamine injections resulted in decreased release of acetylcholine, while scopolamine administration caused a large increase in acetylcholine release. CONCLUSIONS: These findings indicate that a nicotinic antagonist can attenuate impairments in memory produced by a muscarinic antagonist. The nicotinic antagonist may block excessive activation of nicotinic receptors postsynaptically or attenuate increases in acetylcholine release presynaptically. Either effect of a nicotinic antagonist-to decrease scopolamine-induced increases in acetylcholine output or to decrease postsynaptic acetylcholine receptor activation-may mediate the negative effects on memory of muscarinic antagonists.

Chronic administration of anticonvulsants but not antidepressants impairs bone strength: clinical implications.

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.

Phase II study of selumetinib (AZD6244, ARRY-142886) plus irinotecan as second-line therapy in patients with K-RAS mutated colorectal cancer.

BACKGROUND: More than half of colorectal tumors harbor activating mutations in RAS/RAF proteins. Selumetinib (AZD6244, ARRY-142886) is a small molecule kinase inhibitor targeting MEK kinase, downstream of RAS. We examined the efficacy and safety of selumetinib with irinotecan in second-line therapy. METHODS: Patients with K-RAS mutated colorectal cancer, progressing on first-line oxaliplatin-based chemotherapy with bevacizumab, were eligible for this multicenter open-label phase I/II trial. In part A, a dose was determined using a standard "3 + 3" design; in part B, efficacy was determined. The primary endpoint was RECIST response rate. Historical data for irinotecan were used as reference. Secondary endpoints included progression-free survival and overall survival. RESULTS: Thirty-two patients entered the study, and 31 were treated. All had K-RAS exon 2 mutated tumors. In phase I, the recommended oral dose of selumetinib was 75 mg twice per day with intravenous (IV) irinotecan, 180 mg/m² every 2 weeks. Three patients (9.7 %) had partial response . Sixteen patients (51.6 %) had stable disease for ≥4 weeks, including three >1 year. The most common grade 3 adverse events included diarrhea, neutropenia, fatigue, anemia, nausea, and dehydration. The study was terminated before a pre-planned accrual of 45 subjects. CONCLUSIONS: Despite termination before full accrual, the point estimates of RR and median PFS show promising results, suggesting that further investigations of MEK inhibition in the treatment of metastatic colorectal cancer are warranted. Studies combining MEK inhibitors with cytotoxics or other targeted agents may lead to improved clinical activity based on the emerging preclinical data.

The organization of the stress system and its dysregulation in depressive illness.

Stressors are imminent or perceived challenges to homeostasis. The stress response is an innate, stereotypic, adaptive response to stressors that has evolved in the service of restoring the nonstressed homeostatic set point. It is encoded in specific neuroanatomical sites that activate a specific repertoire of cognitive, behavioral and physiologic phenomena. Adaptive responses, though essential for survival, can become dysregulated and result in disease. A clear example is autoimmune disease. I postulate that depression, like autoimmunity, represents a dysregulated adaptive response: a stress response that has gone awry. The cardinal manifestation of the normal stress response is anxiety. Cognitive programs shift from complex associative operations to rapid retrieval of unconscious emotional memories acquired during prior threatening situations. These emerge automatically to promote survival. To prevent distraction during stressful situations, the capacity to seek and experience pleasure is reduced, food intake is diminished and sexual activity and sleep are held in abeyance. Monoamines, cytokines, glutamate, GABA and other central mediators have key roles in the normal stress response. Many central loci are involved. The subgenual prefrontal cortex restrains the amygdala, the corticotropin-releasing hormone/hypothalamic-pituitary-adrenal (CRH/HPA) axis and the sympathomedullary system. The function of the subgenual prefrontal cortex is moderately diminished during normal stress to disinhibit these loci. This disinhibition promotes anxiety and physiological hyperarousal, while diminishing appetite and sleep. The dorsolateral prefrontal cortex is downregulated, diminishing cognitive regulation of anxiety. The nucleus accumbens is also downregulated, to reduce the propensity for distraction by pleasurable stimuli or the capacity to experience pleasure. Insulin resistance, inflammation and a prothrombotic state acutely emerge. These provide increased glucose for the brain and establish premonitory, proinflammatory and prothrombotic states in anticipation of either injury or hemorrhage during a threatening situation. Essential adaptive intracellular changes include increased neurogenesis, enhancement of neuroplasticity and deployment of a successful endoplasmic reticulum stress response. In melancholic depression, the activities of the central glutamate, norepinephrine and central cytokine systems are significantly and persistently increased. The subgenual prefrontal cortex is functionally impaired, and its size is reduced by as much as 40%. This leads to sustained anxiety and activations of the amygdala, CRH/HPA axis, the sympathomedullary system and their sequella, including early morning awakening and loss of appetite. The sustained activation of the amygdala, in turn, further activates stress system neuroendocrine and autonomic functions. The activity of the nucleus accumbens is further decreased and anhedonia emerges. Concomitantly, neurogenesis and neuroplasticity fall significantly. Antidepressants ameliorate many of these processes. The processes that lead to the behavioral and physiological manifestations of depressive illness produce a significant decrease in lifespan, and a doubling of the incidence of premature coronary artery disease. The incidences of premature diabetes and osteoporosis are also substantially increased. Six physiological processes that occur during stress and that are markedly increased in melancholia set into motion six different mechanisms to produce inflammation, as well as sustained insulin resistance and a prothrombotic state. Clinically, melancholic and atypical depression seem to be antithesis of one another. In melancholia, depressive systems are at their worst in the morning when arousal systems, such as the CRH/HPA axis and the noradrenergic systems, are at their maxima. In atypical depression, depressive symptoms are at their worst in the evening, when these arousal systems are at their minima. Melancholic patients experience anorexia and insomnia, whereas atypical patients experience hyperphagia and hypersomnia. Melancholia seems like an activation and persistence of the normal stress response, whereas atypical depression resembles a stress response that has been excessively inhibited. It is important that we stratify clinical studies of depressed patients to compare melancholic and atypical subtypes and establish their differential pathophysiology. Overall, it is important to note that many of the major mediators of the stress response and melancholic depression, such as the subgenual prefrontal cortex, the amygdala, the noradrenergic system and the CRH/HPA axis participate in multiple reinforcing positive feedback loops. This organization permits the establishment of the markedly exaggerated, persistent elevation of the stress response seen in melancholia. Given their pronounced interrelatedness, it may not matter where in this cascade the first abnormality arises. It will spread to the other loci and initiate each of their activations in a pernicious vicious cycle.

Higher capecitabine AUC in elderly patients with advanced colorectal cancer (SWOGS0030).

BACKGROUND: The aging process is accompanied by physiological changes including reduced glomerular filtration and hepatic function, as well as changes in gastric secretions. To investigate what effect would aging have on the disposition of capecitabine and its metabolites, the pharmacokinetics between patients ≥70 years and <60 years were compared in SWOG0030. METHODS: Twenty-nine unresectable colorectal cancer patients were stratified to either ≥70 or <60 years of age, where the disposition of capecitabine and its metabolites were compared. RESULTS: Notable increase in capecitabine area under the curve (AUC) was accompanied by reduction in capecitabine clearance in ≥70 years patients (P<0.05). No difference in 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (DFUR), and 5-fluorouracil (5FU) AUCs between the two age groups, suggesting that carboxylesterase and cytidine deaminase (CDA) activity was similar between the two age groups. These results suggest that metabolic enzymes involved in converting capecitabine metabolites are not altered by age. An elevation in capecitabine Cmax and reduction in clearance was seen in females, where capecitabine AUC was 40.3% higher in women. Elevation of DFUR Cmax (45%) and AUC (46%) (P<0.05) was also noted, suggesting that CDA activity may be higher in females. CONCLUSION: Increases in capecitabine Cmax and AUC was observed in patients ≥70 years when compared with younger patients who were >60 years.

Pathological parainflammation and endoplasmic reticulum stress in depression: potential translational targets through the CNS insulin, klotho and PPAR-γ systems.

Major depression and bipolar disorder are heterogeneous conditions in which there can be dysregulation of (1) the stress system response, (2) its capacity for counterregulation after danger has passed and (3) the phase in which damaging molecules generated by the stress response are effectively neutralized. The response to stress and depressed mood share common circuitries and mediators, and each sets into motion not only similar affective and cognitive changes, but also similar systemic manifestations. We focus here on two highly interrelated processes, parainflammation and endoplasmic reticulum (ER) stress, each of which can potentially interfere with all phases of a normal stress response in affective illness, including adaptive neuroplastic changes and the ability to generate neural stem cells. Parainflammation is an adaptive response of the innate immune system that occurs in the context of stressors to which we were not exposed during our early evolution, including overfeeding, underactivity, aging, artificial lighting and novel foodstuffs and drugs. We postulate that humans were not exposed through evolution to the current level of acute or chronic social stressors, and hence, that major depressive illness is associated with a parainflammatory state. ER stress refers to a complex program set into motion when the ER is challenged by the production or persistence of more proteins than it can effectively fold. If the ER response is overwhelmed, substantial amounts of calcium are released into the cytoplasm, leading to apoptosis. Parainflammation and ER stress generally occur simultaneously. We discuss three highly interrelated mediators that can effectively decrease parainflammation and ER stress, namely the central insulin, klotho and peroxisome proliferator-activated receptor-γ (PPAR-γ) systems and propose that these systems may represent conceptually novel therapeutic targets for the amelioration of the affective, cognitive and systemic manifestations of major depressive disorder.

Evaluation of gut bacterial populations using an electronic e-nose and field asymmetric ion mobility spectrometry: further insights into 'fermentonomics'.

The fermentation of undigested foods in the large bowel, by its resident bacteria, results in the production of several chemicals including volatile gases. Perturbance in gut bacteria is known to influence colonic and metabolic health, but to determine this requires prolonged culture (often unsuccessful) or expensive genomic sequencing. Clearly this is not practical for daily clinical practice. Previously, we have reported our insights into fermentonomics through the detection of volatile organic compounds (VOCs) in patients with gastrointestinal and metabolic diseases, using the electronic nose. In this paper we report on the changes in the fermentone produced by patients undergoing complete versus partial bowel cleansing. Using urine samples, preliminary results from 23 individuals receiving bowel cleansing indicate the ability of the electronic nose to distinguish between the partial and complete procedures. Moreover in a subset of individuals, we have been able to track evolving bacterial recolonization over time using the e-nose and field asymmetric ion mobility spectrometry (FAIMS). Such an approach has practical application in tracking bacterial dysbiosis following perturbation.

Acetylcholine release in the hippocampus and prelimbic cortex during acquisition of a socially transmitted food preference.

Interference with cholinergic functions in hippocampus and prefrontal cortex impairs learning and memory for social transmission of food preference, suggesting that acetylcholine (ACh) release in the two brain regions may be important for acquiring the food preference. This experiment examined release of ACh in the hippocampus and prefrontal cortex of rats during training for social transmission of food preference. After demonstrator rats ate a food with novel flavor and odor, a social transmission of food preference group of rats was allowed to interact with the demonstrators for 30 min, while in vivo microdialysis collected samples for later measurement of ACh release with HPLC methods. A social control group observed a demonstrator that had eaten food without novel flavor and odor. An odor control group was allowed to smell but not ingest food with novel odor. Rats in the social transmission but not control groups preferred the novel food on a trial 48 h later. ACh release in prefrontal cortex, with probes that primarily sampled prelimbic cortex, did not increase during acquisition of the social transmission of food preference, suggesting that training-initiated release of ACh in prelimbic cortex is not necessary for acquisition of the food preference. In contrast, ACh release in the hippocampus increased substantially (200%) upon exposure to a rat that had eaten the novel food. Release in the hippocampus increased significantly less (25%) upon exposure to a rat that had eaten normal food and did not increase significantly in the rats exposed to the novel odor; ACh release in the social transmission group was significantly greater than that of the either of the control groups. Thus, ACh release in the hippocampus but not prelimbic cortex distinguished well the social transmission vs. control conditions, suggesting that cholinergic mechanisms in the hippocampus but not prelimbic cortex are important for acquiring a socially transmitted food preference.

Acute liver failure because of chronic lymphocytic leukemia: case report and review of the literature.

Infiltration of the liver by hematologic malignancies is an uncommon cause of liver failure. B-Cell chronic lymphocytic leukemia (cll) is a usually indolent disease that may infiltrate the liver, but based on a review of the literature, has never been reported to induce acute liver failure. Here, we describe the case of a 78-year-old woman with acute liver failure secondary to infiltration with cll being unresponsive to chemotherapy and causing death. This case is notable because of its atypical presentation and ultimate poor prognosis.

Low early morning plasma cortisol in posttraumatic stress disorder is associated with co-morbid depression but not with enhanced glucocorticoid feedback inhibition.

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 (7p.m. to 7a.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.

Glucocorticoid receptor gene polymorphisms in premenopausal women with major depression.

Glucocorticoid receptor gene polymorphisms are associated with glucocorticoid hypersensitivity and visceral obesity. Perturbations in HPA axis sensitivity to glucocorticoids implicated in the pathogenesis of major depression may result from functional alterations in the glucocorticoid receptor gene. We 1) examined the prevalence of genotype distribution of specific polymorphisms of the glucocorticoid receptor gene (Bcl1, N363S, rs33388, rs33389) in a subset of women from the P.O.W.E.R. Study (which enrolled 21- to 45-year-old premenopausal women with major depression and healthy controls) and 2) explored whether such polymorphisms were associated with visceral obesity and insulin resistance. Women with major depression had a higher body mass index, a higher waist:hip ratio, and more body fat than did controls. No differences were observed in plasma and urinary cortisol or in insulin sensitivity. The G/G genotype of the Bcl1 polymorphism was significantly more common (p<0.03) in women with major depression (n=52) than in controls (n=29). In addition, GG homozygotes (depressed n=10; controls n=2) had higher waist:hip ratios than did non-GG carriers (p<0.02). N363S, rs33388, and rs33389 polymorphisms were not different between groups. In conclusion, premenopausal women with both major depression and the GG genotype of the Bcl1 polymorphism had greater abdominal obesity compared with non-GG carriers.