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Background: Elevated levels of proinflammatory cytokines, especially interleukin-6 (IL-6), can mediate the greater risk for cardiovascular disease in individuals with posttraumatic stress disorder (PTSD), particularly in those with comorbid major depressive disorder (MDD). However, IL-6 levels are not consistently elevated in either PTSD or MDD. Although PTSD is associated with supersensitivity to glucocorticoids; prior studies have not evaluated the effect of comorbid MDD., Methods: Serum IL-6 levels were measured hourly between 7:00 pm and 7:00 am in individuals with PTSD with comorbid MDD (PTSD + MDD) (n = 9) and compared with those with PTSD without MDD (PTSD - MDD) (n = 9) and nontraumatized healthy control subjects (n = 14). Group differences in serum IL-6, plasma adrenocorticotropic hormone (ACTH), and plasma cortisol response to 30 mg of intravenous hydrocortisone were evaluated using linear mixed models., Results: Only subjects with PTSD + MDD exhibited higher, overnight serum IL-6 levels compared with individuals with PTSD - MDD (p < .01) and healthy control subjects (p < .001). Peak overnight IL-6 levels positively correlated with severity of PTSD (r = .56, p < .01) and depressive symptoms (r = .54, p < .01). Hydrocortisone administration significantly reduced IL-6 levels in both PTSD groups; however, IL-6 levels in PTSD + MDD were higher than both PTSD - MDD (p < .05) and healthy control subjects (p < .01). Following hydrocortisone administration, there was a greater reduction in levels of ACTH in PTSD - MDD compared with control subjects (p < .01)., Conclusions: Sustained elevations of overnight IL-6 levels and relatively decreased sensitivity to hydrocortisone distinguish PTSD + MDD from PTSD - MDD. Novel strategies that decrease IL-6 levels offer a new direction in the prevention and treatment of PTSD and associated comorbid medical illnesses., (Copyright © 2010. Published by Elsevier Inc.)

Background: In a recent study of several antidepressant drugs in hospitalized, non-Hispanic White patients, Binder et al. reported association of markers located within the FKBP5 gene with treatment response after 2 and 5 weeks. Individuals homozygous for the TT-genotype at one of the markers (rs1360780) reported more depressive episodes and responded better to antidepressant treatment. There was no association between markers in FKBP5 and disease. The present study aimed at studying the associated FKBP5 markers in the ethnically diverse Sequenced Treatment Alternatives to Relieve Depression (STAR*D) sample of non-hospitalized patients treated with citalopram., Methods: We used clinical data and DNA samples from 1809 outpatients with non-psychotic major depressive disorder (DSM-IV criteria), who received up to 14 weeks of citalopram. A subset of 1523 patients of White non-Hispanic or Black race was matched with 739 control subjects for a case-control analysis. The markers rs1360780 and rs4713916 were genotyped on the Illumina platform. TaqMan-assay was used for marker rs3800373., Results: In the case-control analysis, marker rs1360780 was significantly associated with disease status in the White non-Hispanic sample after correction for multiple testing. A significant association was also found between rs4713916 and remission. Markers rs1360780 and rs4713916 were in strong linkage disequilibrium in the White non-Hispanic but not in the Black population. There was no significant difference in the number of previous episodes of depression between genotypes at any of the three markers., Conclusions: These results indicate that FKBP5 is an important target for further studies of depression and treatment response.

Background: Alterations in the gamma-amino-butyric acid (GABA) neurotransmitter system have been identified in some populations with posttraumatic stress disorder (PTSD)., Methods: To further investigate factors of relevance to GABAergic neurotransmission in PTSD, we measured cerebrospinal fluid (CSF) levels of allopregnanolone and pregnanolone combined (ALLO: congeners that potently and positively modulate effects of GABA at the GABA(A) receptor), 5alpha-dihydroprogesterone (5alpha-DHP: the immediate precursor for allopregnanolone), dehydroepiandrosterone (DHEA: a negative modulator of GABA(A) receptor function), and progesterone with gas chromatography, mass spectrometry in premenopausal women with (n = 9) and without (n = 10) PTSD. Subjects were free of psychotropic medications, alcohol, and illicit drugs; all were in the follicular phase of the menstrual cycle except three healthy and four PTSD subjects receiving oral contraceptives., Results: There were no group differences in progesterone, 5alpha-DHP, or DHEA levels. The PTSD group ALLO levels were < 39% of healthy group levels. The ALLO/DHEA ratio correlated negatively with PTSD re-experiencing symptoms (n = -.82, p < 008; trend) and with Profile of Mood State depression/dejection scores (n = -0.70, p < 0008)., Conclusion: Low CSF ALLO levels in premenopausal women with PTSD might contribute to an imbalance in inhibitory versus excitatory neurotransmission, resulting in increased PTSD re-experiencing and depressive symptoms.

Background: Major depression is more prevalent in women than men. The present study evaluated if previous findings that demonstrated decreased 5-hydroxytryptamine (5-HT) transporter availability in depressed patients would be confirmed in a larger sample and also evaluated sex differences., Methods: Depressed (n = 32) and healthy subjects (n = 32), including 16 pairs of women and men, participated in an iodine-123-2 beta-carbomethoxy-3beta-(4-iodophenyltropane) ([(123)I]beta-CIT) single photon emission computed tomography (SPECT) and a magnetic resonance imaging (MRI) scan. Participants were administered [(123)I]beta-CIT (225.7 +/- 3.7 MBq) and imaged 23.0 +/- 1.6 hours later. Statistical analyses included analysis of variance and a regression analysis of the main and interactive effects of age, sex, and depression., Results: Overall, depressed patients demonstrated 12% lower diencephalon and no change in striatal or brainstem [(123)I]beta-CIT uptake. Significant age by sex, sex by depression, and age by sex by depression interactions were noted due to 22% lower diencephalon [(123)I]beta-CIT uptake in depressed women compared with less than a 1% decrease in depressed men., Conclusions: As observed previously, diencephalon 5-HT transporter availability is decreased in depressed patients. However, the decrease appears to be sex-specific and age-dependent. These findings suggest that serotonergic mechanisms mediating depressed mood differ between men and women in an age-dependent manner and may explain why young women respond better to treatment with selective serotonin reuptake inhibitor (SSRI) antidepressants.

Background: Significant controversy has emerged concerning pediatric anxiety disorders. Some researchers question the justification for diagnosing and treating pediatric anxiety disorders, owing to concerns about the inappropriate medicalization of social problems. Others note the importance of diagnosis and treatment, given that pediatric anxiety disorders represent a strong risk factor for serious adult mental disorders. We examine the neural correlates of pediatric anxiety disorders, to consider the validity of the categorization scheme used in recent treatment studies., Methods: Using inclusion criteria derived from recent treatment trials, we compared gray matter volume throughout the brain in children with and without anxiety. Morphometric analyses used optimized voxel-based morphometry, an automated method for examining structural changes throughout the brain., Results: Reductions in left amygdala gray matter volume were noted for patients with anxiety disorders relative to comparison subjects., Conclusions: We discuss implications of these findings for current controversies.

Background: Few studies have investigated the predictive value of central serotonin transporter (SERT) availability for treatment response to serotonin reuptake inhibitors (SSRIs). This study used brain imaging to examine the relationship between pretreatment brain SERT availability and transporter occupancy by SSRIs with treatment response in two independent depressed populations., Methods: Study 1: Twenty-three patients with major depression underwent a single photon emission computed tomography (SPECT) measurement of brain SERT availability using [123I]beta-CIT ([123I]methyl 3beta-(4-iodophenyl) tropane-2beta-carboxylate. The SERT availability was correlated with treatment response to fluoxetine (20 mg/day) assessed with weekly Hamilton Depression Rating Scale (HDRS) for 6 weeks. Study 2: The second group included 10 depressed patients who received 6 weeks of paroxetine treatment (20 mg/day) and serial SPECT scans (baseline, during, and after the treatment)., Results: In Study 1, higher pretreatment diencephalic SERT availability significantly predicted better treatment response 4 weeks later. Similar results were found in Study 2 and supported Study 1 findings. The data showed that greater occupancy of diencephalic transporters by paroxetine correlated with better treatment response., Conclusions: Higher pretreatment availability and greater occupancy of SERT in diencephalon may predict better treatment course in response to SSRIs.

Background: Clinical models of the human response to intense, acute stress have been limited to laboratory settings or cross sectional characterizations. As a result, data about the sensitivity of the human neuroendocrine activation to realistic stressors of varying magnitudes are limited. The U.S. Army survival course offers a unique opportunity to examine, in a controlled manner, the human response to acute, realistic, military stress., Methods: Salivary data were collected in 109 subjects at baseline during four stress exposure time points and at recovery. Serum data was collected at baseline and recovery in 72 subjects and at baseline and during stress exposure in a subgroup of subjects (n = 21)., Results: Cortisol significantly increased during the captivity experience and was greatest after subjects' exposure to interrogations. Cortisol remained significantly elevated at recovery. Testosterone was significantly reduced within 12 hours of captivity. Reductions of both total and free T4 and of total and free T3 were observed, as were increases in thyrotropin., Conclusions: The stress of military survival training produced dramatic alterations in cortisol, percent free cortisol, testosterone, and thyroid indices. Different types of stressors had varying effects on the neuroendocrine indices. The degree of neuroendocrine changes observed may have significant implications for subsequent responses to stress.

Background: Neuropeptide-Y (NPY) is present in extensive neuronal systems of the brain and is present in high concentrations in cell bodies and terminals in the amygdala. Preclinical studies have shown that injections of NPY into the central nucleus of the amygdala function as a central anxiolytic and buffer against the effects of stress. The objective of this study was to assess plasma NPY immunoreactivity in healthy soldiers participating in high intensity military training at the U.S. Army survival school. The Army survival school provides a means of observing individuals under high levels of physical, environmental, and psychological stress, and consequently is considered a reasonable analogue to stress incurred as a result of war or other catastrophic experiences., Methods: Plasma levels of NPY were assessed at baseline (prior to initiation of training), and 24 hours after the conclusion of survival training in 49 subjects, and at baseline and during the Prisoner of War (P.O.W.) experience (immediately after exposure to a military interrogation) in 21 additional subjects., Results: Plasma NPY levels were significantly increased compared to baseline following interrogations and were significantly higher in Special Forces soldiers, compared to non-Special Forces soldiers. NPY elicited by interrogation stress was significantly correlated to the subjects' behavior during interrogations and tended to be negatively correlated to symptoms of reported dissociation. Twenty-four hours after the conclusion of survival training, NPY had returned to baseline in Special Forces soldiers, but remained significantly lower than baseline values in non-Special Forces soldiers. NPY was positively correlated with both cortisol and behavioral performance under stress. NPY was negatively related to psychological symptoms of dissociation., Conclusions: These results provide evidence that uncontrollable stress significantly increases plasma NPY in humans, and when extended, produces a significant depletion of plasma NPY. Stress-induced alterations of plasma NPY were significantly different in Special Forces soldiers compared to non-Special Forces soldiers. These data support the idea that NPY may be involved in the enhanced stress resilience seen in humans.

Background: The amino acid glycine, modulates neurotransmission via actions at GLY-A receptor and GLY-B receptor. The latter are coagonist sites associated with N-Methyl-D-Aspartate (NMDA) glutamate receptors. The central bioavailability of peripherally administered glycine has not been adequately characterized in humans., Methods: Healthy human subjects were administered either oral D-cycloserine (50 mg or placebo) and intravenous glycine (saline, 100 mg/kg or 200 mg/kg) in random order over 4 test days under double-blind conditions. Cerebrospinal fluid was collected by lumbar puncture performed on the first test day was analyzed to determine amino acid levels. The acoustic startle response was measured on the second test day., Results: Intravenous glycine dose-dependently increased both serum and CSF glycine and serine levels. Neither glycine nor DCS produced any significant effects on behavior, cognition or the acoustic startle response. Neither IV glycine nor DCS were associated with any toxicity., Conclusions: Thus, peripheral glycine administration raised CSF glycine levels without producing any clear central nervous system effects. Glycine and D-cycloserine did not worsen cognitive test performance and did not induce behavioral symptoms on their own. The possibility that glycine and D-cycloserine enhanced cognitive test performance cannot be excluded given the psychometric limitations of the test battery.

Background: Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects., Methods: A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96)., Results: A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex., Conclusions: Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.