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Biomedical subjects

D S Charney

Publications and source records attributed to D S Charney.

At least 19 recordsLinked to original sources
PubMed2001

Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder.

BACKGROUND: Limited studies of hypothalamic-pituitary-adrenal axis regulation in posttraumatic stress disorder have been performed in premenopausal women. We therefore undertook a study of hypothalamic-pituitary-adrenal axis regulation in this population. METHODS: Outpatient posttraumatic stress disorder subjects were compared with healthy, age- and weight-matched nontraumatized subjects. Subjects were free from psychotropic medications, alcohol and other illicit substances for at least 4 weeks before study. Menstrual cycle phase was determined by monitoring the LH surge and plasma progesterone levels. Corticotropin releasing factor and adrenocorticotropin stimulation tests, as well as 24-hour urinary-free cortisol measurements were performed. RESULTS: Corticotropin releasing factor test: Baseline adrenocorticotropic hormone and cortisol levels did not differ between the 12 PTSD and 11 comparison subjects, but the posttraumatic stress disorder group had greater adrenocorticotropic hormone and cortisol responses to corticotropin releasing factor, as well as a later cortisol peak. Adrenocorticotropic hormone test: Baseline cortisol levels did not differ between the 10 posttraumatic stress disorder subjects and seven controls, but the posttraumatic stress disorder group showed greater cortisol responses to adrenocorticotropic hormone. Peak cortisol responses to corticotropin releasing factor and adrenocorticotropic hormone were correlated with each other and with 24-hour urinary-free cortisol excretion. CONCLUSIONS: Pituitary and adrenal hyperreactivity to exogenous corticotropin releasing factor and adrenocorticotropic hormone is demonstrated in premenopausal women with chronic posttraumatic stress disorder. Cortisol hyperreactivity thus may play a role in the pathophysiology of posttraumatic stress disorder in women.

Adrenocorticotropic Hormone↗
PubMed2001

Stimulation of reactive oxygen species production by an antidepressant visible light source.

BACKGROUND: The mechanism by which visible light stimulates chronobiological phase-shifting or antidepressant effects in humans is unknown. METHODS: Normal human NIH/3T3 nonpigmented fibroblasts were irradiated with a visible light source (SunRay) used in the treatment of winter seasonal depression. Electron spin resonance was assessed before and after 10 min of illumination at 2 mW/cm(2) (illuminance of 3700 lux), with and without the presence of 5 microL of 0.0214 mg/mL vitamin C. RESULTS: The fibroblasts showed evidence of production of reactive oxygen species after 10 min of irradiation. CONCLUSIONS: These in vitro data establish that an antidepressant source of visible light is capable of inducing the production of reactive oxygen species in skin. Such species may participate in signal transduction pathways leading to mood changes.

Cell Line↗
PubMed2001

Consistency of atypical antipsychotic superiority to placebo in recent clinical trials.

BACKGROUND: The use of control placebos in clinical trials of new antipsychotic medications is increasingly under examination. The active controlled equivalence study could offer a potential alternative design. First, however, it must be clear that any proposed standard control agent has been consistently superior to placebo in previous studies. METHODS: Through a Freedom of Information Act request, we identified nine placebo-controlled trials of risperidone, olanzapine, or quetiapine. RESULTS: Meta-analysis indicated that the pooled estimate of the true population effect size +/- SE was 0.46 +/- 0.06 for categorical response rates and >0.53 +/- 0.07 for the continuous Brief Psychiatric Rating Scale change score outcome measure. If the desired detectable effect size is set very conservatively at a 95% confidence lower bound for the estimate of true effect size, statistical power for random samples of 80 per group drawn from a population of subjects similar to that of the nine meta-analyzed studies is.67 for categorical response rates and >.82 for the continuous measure, based on one-sided alpha =.05. CONCLUSIONS: These data suggest substantial confidence that a therapeutic dose of an atypical antipsychotic will be statistically superior to placebo in an adequately sized randomized trial, when reporting a continuous measure as the principal outcome.

Antipsychotic Agents↗
PubMed2001

Reductions in occipital cortex GABA levels in panic disorder detected with 1h-magnetic resonance spectroscopy.

BACKGROUND: There is preclinical evidence and indirect clinical evidence implicating gamma-aminobutyric acid (GABA) in the pathophysiology and treatment of human panic disorder. Specifically, deficits in GABA neuronal function have been associated with anxiogenesis, whereas enhancement of GABA function tends to be anxiolytic. Although reported peripheral GABA levels (eg, in cerebrospinal fluid and plasma) have been within reference limits in panic disorder, thus far there has been no direct assessment of brain GABA levels in this disorder. The purpose of the present work was to determine whether cortical GABA levels are abnormally low in patients with panic disorder. METHODS: Total occipital cortical GABA levels (GABA plus homocarnosine) were assessed in 14 unmedicated patients with panic disorder who did not have major depression and 14 retrospectively age- and sex-matched control subjects using spatially localized (1)H-magnetic resonance spectroscopy. All patients met DSM-IV criteria for a principal current diagnosis of panic disorder with or without agoraphobia. RESULTS: Patients with panic disorder had a 22% reduction in total occipital cortex GABA concentration (GABA plus homocarnosine) compared with controls. This finding was present in 12 of 14 patient-control pairs and was not solely accounted for by medication history. There were no significant correlations between occipital cortex GABA levels and measures of illness or state anxiety. CONCLUSIONS: Panic disorder is associated with reductions in total occipital cortex GABA levels. This abnormality might contribute to the pathophysiology of panic disorder.

Adult↗
PubMed2001

Methadone patients exhibit increased startle and cortisol response after intravenous yohimbine.

Brain noradrenergic systems have been shown to be altered in opioid dependence and to mediate aspects of opioid withdrawal. Pre-clinical and clinical studies by others have shown that yohimbine, which increases noradrenergic activity, also increases both baseline and fear enhancement of the magnitude of the acoustic startle response (ASR). In a separate report from this experiment, it was shown that yohimbine produced opioid withdrawal-like symptoms, including anxiety, in clinically stable methadone-maintained patients and also produced elevations in the norepinepherine (NE) metabolite, 3-methoxy-4 hydroxyphenethyleneglycol (MHPG), and cortisol serum levels. The current study reports the effects of intravenous yohimbine hydrochloride, 0.4 mg/kg versus saline (double-blind), on ASR magnitude, plasma MHPG, and cortisol levels in eight methadone-maintained patients and 13 healthy subjects in a double-blind fashion. Yohimbine increased startle magnitude in both groups. There was no basal (placebo day) difference between the startle response of the two groups, but methadone patients had a larger startle magnitude increase in response to yohimbine than healthy controls. Methadone-maintained patients had lower baseline plasma levels of MHPG and similar baseline plasma cortisol levels compared with normal subjects. Yohimbine caused significant elevation in cortisol and MHPG in both groups. Methadone-maintained subjects had higher elevations in cortisol levels and MHPG (methadone main effect) levels in response to yohimbine. However, when MHPG levels were corrected for baseline differences by analysis of covariance (ANCOVA), the yohimbine effect, but not the methadone effect remained statistically significant. These results are consistent with the previous report and support the hypothesis that abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and of noradrenergic mechanisms of stress response persist in opioid-agonist maintenance. The ASR effect extends the previous report and provides an additional objective measure for perturbation of noradrenergic and stress responses in these patients.

Acoustic Stimulation↗
PubMed2001

Neurobiology of generalized anxiety disorder.

On reviewing the literature on GAD and trying to summarize the various developments in the field of neurobiology of GAD, we see that a range of hypotheses try to explore and integrate the observations found into potentially meaningful theories. Abnormal serotonergic and GABAergic function occur in many patients with GAD. Functional imaging data have shown increased cortical activity and decreased basal ganglia activity in patients with GAD, which reverses with treatment, but it is apparent that no one theory is sufficiently comprehensive to propose a unitary hypothesis for the development of GAD and other anxiety disorders. GAD is a relatively new diagnosable condition, first introduced into the classification system of psychiatric disorders in 1980, and since then has undergone a series of changes in its conceptualization, with some investigators questioning the existence of the condition as a distinct entity. Any inferences that may be drawn from various studies must be guarded, and it is appropriate to compare studies using the same diagnostic criteria. Significant research has been done and may lead to exciting new discoveries in the treatment of anxiety disorders in general and GAD in particular. Gray's model of behavioral inhibition, in which the septohippocampal system acts by assessing stimuli for the presence of danger and, when that is detected, activates the behavioral-inhibition circuit, provides a neuroanatomic conceptualization that has been expanded by preclinical research. Some exciting work has been done on CRF and the concept of development, vulnerability, and kindling and some investigators have contributed to this area of interest. This concept supports the hypothesis that a genetic predisposition, coupled with early stress, in the crucial phases of development may result in a phenotype that is neurobiologically vulnerable to stress and may lower an individual's threshold for developing anxiety or depression on additional stress exposure. The pharmaceutical industry is exploring treatment options using CRF antagonists, and research on other neuropeptides, especially NPY, will be of interest. Research on neurosteroids also may bring the opportunity for pharmacologic treatment approaches. Future research on the startle reflex and on the NMDA and the metabotropic glutamate receptors is important. Future studies of a more homogenous patient population and using more sophisticated techniques, such as molecular genetic strategies and better imaging techniques, may answer some of the outstanding questions.

Anxiety Disorders↗
PubMed2001

The cellular neurobiology of depression.

Major depressive disorders, long considered to be of neurochemical origin, have recently been associated with impairments in signaling pathways that regulate neuroplasticity and cell survival. Agents designed to directly target molecules in these pathways may hold promise as new therapeutics for depression.

Antidepressive Agents↗
PubMed2000

Imaging serotonergic neurotransmission in depression: hippocampal pathophysiology may mirror global brain alterations.

The recent development of [carbonyl-(11)C]WAY-100635 for serotonin (5-HT)(1A) and [(18)F]setoperone and [(18)F]altanserin for 5-HT(2A) positron emission tomography receptor imaging has allowed studies of 5-HT neurotransmission in depressive disorders. The hippocampus is likely to be an important brain structure in the pathophysiology of depression because it may mediate both cognitive deficits and hypercortisolemia found in this disorder. Decreased 5-HT(1A) binding was reported in the medial temporal cortex, which receives dense 5-HT innervation, and also throughout neocortical regions. Because the 5-HT(1A) antagonist pindolol may hasten antidepressant effects of selective serotonin reuptake inhibitor medications, its receptor occupancy has been measured in both presynaptic and postsynaptic sites. The results are controversial but suggest that pindolol has preferential occupancy of somatodendritic autoreceptors in the raphe. The results of 5-HT(2A) receptors are mixed, with one showing a significant decrease in the right orbitoinsular cortex and three not detecting a significant change. The disparate findings in patients with depression almost certainly reflect the heterogeneity of the disorder, and we highlight the utility of the hippocampus as a useful target region not only to compare depressed subjects with healthy subjects but also to correlate findings with cognitive function and activity of the limbic-hypothalamic-pituitary axis system.

Atrophy↗
PubMed2000

Effects of early adverse experiences on brain structure and function: clinical implications.

Child abuse is associated with markedly elevated rates of major depression and other psychiatric disorders in adulthood. This article reviews preclinical studies examining the effects of early stress, factors that modify the impact of these experiences, and neurobiological changes associated with major depression. Preclinical studies demonstrate that early stress can alter the development of the hypothalamic-pituitary-adrenal axis, hypothalamic and extrahypothalamic corticotropin releasing hormone, monoaminergic, and gamma-aminobutyric acid/benzodiazepine systems. Stress has also been shown to promote structural and functional alterations in brain regions similar to those seen in adults with depression. Emerging data suggest, however, that the long-term effects of early stress can be moderated by genetic factors and the quality of the subsequent caregiving environment. These effects also can be prevented or reversed with various pharmacologic interventions. Preclinical studies of early stress can provide valuable insights in understanding the pathophysiology and treatment of major depression. They also can provide an important tool to use to investigate interactions between genes and environments in determining an individual's sensitivity to stress. More research is needed to understand how inherent factors interact with experiences of abuse and other psychosocial factors to confer vulnerability to develop depression.

Age Factors↗
PubMed2000

Temporal lobe volume in panic disorder--a quantitative magnetic resonance imaging study.

Although previous studies have used magnetic resonance imaging (MRI) to demonstrate qualitative abnormalities of the temporal lobes in patients with panic disorder, no study to date has applied quantitative volumetric methods to evaluate brain changes in panic disorder. The purpose of this study was to measure the volume of the temporal lobe and the hippocampus in patients with panic disorder and healthy control subjects using quantitative MRI measures. The volume of the temporal lobe, hippocampus and whole brain was measured in 13 patients with panic disorder and 14 healthy subjects. The mean volume of the left and right temporal lobes was significantly smaller in panic disorder compared to healthy subjects (16770+/-909 mm(3) vs. 18343+/-1740 mm(3)). This result was significant after controlling for differences in whole brain volume. There was no significant difference in volume of the hippocampus between patients and control subjects. These findings are consistent with smaller temporal lobe volume in panic disorder despite normal hippocampal volume.

Adult↗
PubMed2000

Genetic polymorphism at the CLOCK gene locus and major depression.

Genetic analysis in both mouse and Drosophila has indicated that the product of the CLOCK gene is an essential component of a circadian rhythm timing system. A single nucleotide polymorphism (SNP), T3111C, in the 3' flanking region of the human CLOCK gene has been identified. Homozygotes or heterozygotes for the 3111C allele have been reported to have higher mean scores on a measure of evening preference for activity (vs. morning preference) than subjects homozygous for the 3111T allele. Since major depression is hypothesized to be closely linked to circadian rhythms, we explored whether this polymorphism might be related to susceptibility to major depression. We also ascertained allele frequency in an African-American control population, to begin to evaluate population variation at this locus. CLOCK T3111C allele frequencies were determined in 280 European American (EA) subjects, 143 with a history of major depression and 137 screened controls, and in 58 African American (AA) screened control subjects, using a polymerase chain reaction (PCR) - restriction fragment length polymorphism (RFLP) method. There was no significant difference between EA depressed and control subjects in allele frequency. There was a significant difference in allele frequency between EA and AA subjects, demonstrating a potential for population stratification. In none of these groups were significant deviations from Hardy-Weinberg equilibrium found. The present data do not support an association between CLOCK gene alleles at the T3111C locus and major depression.

Alleles↗
PubMed2000

Plasma neuropeptide-Y concentrations in humans exposed to military survival training.

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.

Adult↗
PubMed2000

Hormone profiles in humans experiencing military survival training.

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.

Adult↗