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Biomedical subjects

J M Gorman

Publications and source records attributed to J M Gorman.

At least 37 records · Page 2Linked to original sources
PubMed2001

Glutamate-hypothalamic-pituitary-adrenal axis interactions: implications for mood and anxiety disorders.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.

Journal Article↗
PubMed2001

Effects of LY354740, a novel glutamatergic metabotropic agonist, on nonhuman primate hypothalamic-pituitary-adrenal axis and noradrenergic function.

The search for novel anxiolytics and antidepressants has focused on compounds with the potential to reduce excessive hypothalamic-pituitary-adrenal (HPA) axis activity. L-glutamate, an excitatory neurotransmitter ubiquitously present within the central nervous system, conceivably plays an important role in activating the neural sites involved in stress modulation. Deactivation of the HPA axis by glutamatergic neurotransmission modulation may represent a novel therapeutic approach. Accordingly, the acute intravenous effects of the novel metabotropic (mGlu2/3) agonist LY354740 were tested on bonnet macaques (Macaca radiata) undergoing acute infusions of yohimbine, a noradrenergic stimulant. Dependent measures were the magnitude of the increase of plasma cortisol and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) customarily elicited by yohimbine. Next, the effects of 6 weeks of chronic oral administration of LY354740 on baseline (postcapture) plasma cortisol and MHPG levels in comparison to the identical measure in untreated controls were assessed. Subjects chronically treated with LY354740 received yohimbine infusions which were compared to yohimbine infusions and saline infusions in non-LY354740-treated subjects. Preliminary evidence supports the view that acute LY354740 infusion resulted in a marked diminution of yohimbine-induced stress response, as manifest by a substantial attenuation of cortisol and MHPG response observed in comparison to the saline-treated yohimbine condition. Chronic oral administration of LY354740 led to postcapture baseline cortisol levels which were markedly reduced (approximately 50 percent) in comparison to untreated control subjects; however, there were no significant parallel differences in MHPG levels. Yohimbine infusions elicited an increase in cortisol and MHPG levels in both LY354740-treated and non-LY354740-treated subjects, in comparison to declines in cortisol values observed following vehicle infusions (group X time interaction; P<.0001). Chronic LY354740-treated subjects failed to achieve cortisol levels comparable in range to those of untreated subjects primarily because of their low baseline cortisol levels. In contrast, despite equivalent baselines, yohimbine-induced MHPG values were increased overall in the chronically treated group compared to the saline and yohimbine-alone groups. Thus, LY354740 markedly reduced the acute corticoid and noradrenergic response elicited by yohimbine infusion. Chronic administration of LY354740 appears to present a safe and effective mechanism to markedly down-modulate the HPA axis while retaining noradrenergic responsivity.

Journal Article↗
PubMed2001

Enhanced stress reactivity in paediatric anxiety disorders: implications for future cardiovascular health.

The aim was to clarify the developmental nature of associations between psychiatric illness and risk for cardiovascular disease by investigating differences in cardiac functioning between youth with anxiety disorders and healthy controls. Twenty-two children meeting DSM-IV criteria for either separation anxiety disorder, overanxious disorder, panic disorder/panic attacks, or social phobia and 12 healthy controls underwent continuous electrocardiogram and respiration rate monitoring during a 15 min baseline period and 15 min of exposure to 5% CO(2). Heart rate (HR) and high frequency heart rate variability (HRV), a non-invasive measure of cardiac parasympathetic control, were calculated. Youth with anxiety disorders had higher and less fluctuating HR during baseline. Data also suggested that probands showed diminished overall changes in HRV during baseline and CO(2) inhalation relative to controls. However, as respiration rate affects HRV, these findings were confounded by changes in respiration elicited by CO(2) inhalation. The data suggest that youth with anxiety disorders experience an elevated and less fluctuating HR in the face of a novel situation, possibly due to a failure to appropriately modulate HRV. In adults, sustained elevations in HR in conjunction with deficient vagal modulation predicts risk for future cardiovascular disease. As such, the current data suggest that the presence of an anxiety disorder may identify youth who exhibit autonomic profiles that place them at risk for cardiac disease.

Administration, Inhalation↗
PubMed2001

Therapists, therapist variables, and cognitive-behavioral therapy outcome in a multicenter trial for panic disorder.

The relationship between therapists and treatment outcome was examined in 14 highly trained therapists who participated in the Multicenter Collaborative Study for the Treatment of Panic Disorder. Overall, therapists yielded positive outcomes in their caseloads; yet, therapists significantly differed in the magnitude of change among caseloads. Effect sizes for therapist impact on outcome measures varied from 0% to 18%. Overall experience in conducting psychotherapy was related to outcome on some measures, whereas age, gender, gender match, and experience with cognitive-behavioral therapy (CBT) were not. Therapists with above- and below-average outcomes were rated similarly on measures of adherence and competency. The results suggest that therapists make a contribution to outcome in CBT for panic disorder, even when patients are relatively uniform, treatment is structured, and outcome is positive. Implications for future clinical outcome studies and for training clinicians are discussed.

Adult↗
PubMed2001

Specificity of panic response to CO(2) inhalation in panic disorder: a comparison with major depression and premenstrual dysphoric disorder.

OBJECTIVE: The behavioral response to CO(2) inhalation has been used to differentiate panic disorder patients from normal subjects and other clinical populations. This study extended examination of the diagnostic specificity of CO(2)-induced anxiety by testing panic disorder patients and clinical populations with reported low and high sensitivity to CO(2) inhalation (patients with major depression and patients with premenstrual dysphoric disorder, respectively). METHOD: The behavioral responses to inhalation of 5% and 7% CO(2), administered by means of a respiratory canopy, were studied in 50 patients with panic disorder, 21 with major depression, and 10 with premenstrual dysphoric disorder and in 34 normal comparison subjects. Occurrence of panic attacks was judged with DSM-IV criteria by a blind rater. Subjects were rated on three behavioral scales at baseline and after each CO(2) inhalation. RESULTS: Panic disorder patients had a higher rate of CO(2)-induced panic attacks than depressed patients and normal subjects, whose panic rates were not distinguishable. The panic rate for patients with premenstrual dysphoric disorder was similar to that for panic disorder patients and higher than that for normal subjects. Subjects with CO(2)-induced panic attacks had similarly high ratings on the behavioral scales, regardless of diagnosis, including the small number of panicking normal subjects. Seven percent CO(2) was a more robust panicogen than 5%, and response to 7% CO(2 )better distinguished panic disorder patients from normal subjects than response to 5% CO(2). CONCLUSIONS: Patients with panic disorder and patients with premenstrual dysphoric disorder are highly susceptible to CO(2)-induced panic attacks, and depressed patients appear to be insensitive to CO(2) inhalation. The symptoms of CO(2)-induced panic attacks have a similar intensity regardless of the subject's diagnosis.

Administration, Inhalation↗
PubMed2001

Neurobiological mechanisms of social anxiety disorder.

OBJECTIVE: The authors critically surveyed several preclinical and clinical neurobiological models of social anxiety disorder. METHOD: The authors reviewed the recent literature regarding three animal models of particular relevance to social anxiety. They then examined the recent literature concerning clinical neurobiological aspects of social anxiety disorder, including the developmental neurobiology of anxiety, the genetics of fear and social anxiety, and challenge and imaging studies. RESULTS: The available animal models are useful paradigms for understanding the features of social subordination stress, attachment behavior, and environmental rearing, but they incompletely account for the known neurobiology of human social anxiety disorder. The clinical neurobiology literature surveyed implicates specific neurotransmitter system abnormalities, most notably of the dopamine system, but largely ignores neurodevelopmental processes and the functional interactions between neurotransmitters. Both heritable factors and environmental stress factors appear to be responsible for the onset of social anxiety disorder. CONCLUSIONS: Social anxiety disorder should be conceptualized as a chronic neurodevelopmental illness that might represent a fully compensated state in adulthood. Future investigations from this perspective are discussed.

Adult↗
PubMed2001

Clinical and cognitive factors associated with verbal memory task performance in patients with schizophrenia.

OBJECTIVE: The authors have previously shown the role of depression, slowing of processing speed, and selective attention deficit in verbal memory task performance in schizophrenia. They wished to determine the specific contribution of each of these factors to various types of memory impairment. METHOD: The negative symptom score from the Positive and Negative Syndrome Scale, the Hamilton Depression Rating Scale score, a measure of processing speed, and a measure of selective attention were entered as predictors in regression analyses. Furthermore, analyses of covariance were conducted on the memory measures to test the significance of the differences between schizophrenic patients and healthy comparison subjects after control for processing speed and selective attention. RESULTS: Depression was associated only with deep encoding reflected by semantic clustering. Selective attention was associated only with superficial encoding reflected by serial recall. Slowing of processing speed was associated with both deep and superficial encoding. Negative symptoms were not associated with memory impairment except for the avolition item from the Scale for the Assessment of Negative Symptoms. Processing speed accounted for all the group differences on the memory measures that reflected superficial encoding. In addition, a subgroup of patients with no or minor depression was not significantly impaired on deep encoding relative to the healthy comparison group. CONCLUSIONS: The authors suggest that verbal memory impairment in schizophrenia is a consequence of depression and slowness, rather than a primary feature of the disease.

Adult↗
PubMed2001

Perceptual asymmetries in schizophrenia: subtype differences in left hemisphere dominance for dichotic fused words.

OBJECTIVE: Dichotic listening techniques have been used to study hemispheric dominance for language in schizophrenia. The authors' goal was to compare subjects with paranoid and undifferentiated subtypes of schizophrenia. METHOD: The Fused Rhymed Words Test was used to compare perceptual asymmetries in 16 patients with paranoid schizophrenia, 28 patients with undifferentiated schizophrenia, and 29 healthy comparison subjects. RESULTS: Patients with paranoid schizophrenia had the largest left hemisphere advantage and patients with undifferentiated schizophrenia had the smallest. The asymmetry of healthy subjects was intermediate. Hemisphere advantage varied as a function of gender only in the patients with undifferentiated schizophrenia. CONCLUSIONS: The findings support the hypotheses that undifferentiated schizophrenia is associated with underactivation of left hemisphere resources for verbal processing and that paranoid schizophrenia is characterized by preserved left hemisphere processing.

Adult↗
PubMed2001

Evidence of early onset of antidepressant effect in randomized controlled trials.

Although antidepressant medications are effective in approximately 70% of patients with major depressive disorder, they have a delayed onset of therapeutic effect. This latency is problematic in that it prolongs the impairments associated with depression, leaves patients vulnerable to an increased risk of suicide, increases the likelihood that a patient will prematurely discontinue therapy, and increases medical costs associated with severe depression. No adequately designed prospective trials have been conducted to evaluate comparative time to onset of antidepressant effect. However, evidence suggests that some antidepressant agents may begin to work faster than others. Citalopram, venlafaxine, and mirtazapine each have exhibited statistically significant differences in some measures of antidepressant action within the first 2 weeks of treatment, both in placebo-controlled trials and in head-to-head comparisons with other antidepressants. This article reviews the data that hint at these drug-specific differences in time to onset of action. Given the potential benefits of early-acting antidepressant treatments, the possibility of superior speed of onset of citalopram, venlafaxine, and mirtazapine presented here merits further study in adequately designed, prospective clinical trials.

Antidepressive Agents↗
PubMed2001

An ideal trial to test differential onset of antidepressant effect.

Although various published clinical studies have suggested that some antidepressants may have a more rapid onset of therapeutic effect than others, none of these trials was adequately designed to measure differential time to onset of effect. Thus, existing data do not support claims that one drug reduces the symptoms of depression faster than another. In this article, we propose a study that would be ideal for measuring comparative onset of antidepressant effect. The key features of this ideal trial include (1) a prospective definition of early onset of action, (2) increased frequency of assessment, (3) a data-analytic approach capable of capturing the dynamic nature of symptomatic change, and (4) various strategies to minimize bias and heterogeneity of response.

Antidepressive Agents↗
PubMed2001

Management of treatment-refractory panic disorder.

Treatment resistance remains a relatively common problem in panic disorder (PD) despite the success of the selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) as first-line agents. Factors contributing to medication treatment resistance include inadequacy of trial duration, improper dosage, poor tolerability, noncompliance, and medical and psychiatric comorbidity. Poor tolerability to the SSRIs can frequently be addressed by judicious lowering of the initial dose, with a gradual upward titration. For patients who have not responded to one or more adequate trials of SSRIs, options include combination treatment with a benzodiazepine or tricyclic antidepressant (TCA), augmentation with pindolol, or switching to a different class of medication. The newer antidepressants, particularly venlafaxine XR, seem promising as alternatives, and might be beneficial for the refractory patient with a comorbid mood disorder. Anticonvulsants and olanzapine might be particularly beneficial for the refractory patient with hypomania, irritability, and insomnia, who also has demonstrated acute SSRI hypersensitivity. Experimental therapeutics in refractory panic probably will continue to examine the role of corticotropin releasing factor and glutamate/GABA systems. The role of CBT in the medication refractory patient has been explored, with preliminary suggestions of efficacy.

Antidepressive Agents↗
PubMed2001

Merging the cognitive behavioral and psychopharmacological paradigms in comparative studies: controversies, issues, and some solutions.

In the past, many studies attempting to compare pharmacological and psychosocial treatments for mood and anxiety disorders have been conducted by partisans of either approach. More recently, rigorously conducted, unbiased comparative studies have begun to appear. Here we reviewed our own experience in designing and conducting a multicenter study comparing medication and cognitive behavioral therapy and their combination for the treatment of panic disorder.

Cognitive Behavioral Therapy↗
PubMed2000

Growth hormone response to clonidine in adversely reared young adult primates: relationship to serial cerebrospinal fluid corticotropin-releasing factor concentrations.

A reduction of the growth hormone (GH) response to the alpha(2) adrenergic agonist clonidine is a neuroendocrine abnormality observed with reasonable consistency among human patients with mood and anxiety disorders. In previous primate studies, in comparison to predictably reared controls, monkeys exposed as infants to maternal variable foraging demand (VFD) rearing exhibited persistent elevations of cerebrospinal fluid (CSF) corticotropin-releasing factor (CRF), as well as other biological disturbances. As CRF has been demonstrated to inhibit GH release, the authors hypothesized that within VFD-reared subjects, animals with relatively high CRF concentrations would exhibit relatively diminished GH responses to clonidine. The current study examined the relationship between the GH response to clonidine in VFD-reared adult primates in relation to a range of both juvenile and follow-up CSF CRF concentrations. Nine bonnet macaques (Macaca radiata) were given ascending dosages of clonidine under ketamine anesthesia. Plasma samples for GH-like immunoreactivity were obtained throughout the session. A significant positive correlation was noted between juvenile CSF CRF concentrations and the levels of the neuropeptide observed in young adults. The mean of the serial CSF CRF concentrations exhibited a significant inverse relationship towards the GH response to clonidine in young adulthood, with relatively high CSF CRF associated with relatively attenuated GH responses to clonidine. These data raise the possibility that a reduced GH response to clonidine may inversely reflect trait-like increases of central nervous system (CNS) CRF activity.

Adrenergic alpha-Agonists↗