Neurosurgery for obsessive-compulsive disorder: problems with comorbidity.
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Adult↗
Biomedical subjects
G C Curtis
Publications and source records attributed to G C Curtis.
Effect of alcohol on social phobic anxiety.
OBJECTIVE: Previous research has demonstrated a greater-than-expected association between social phobia and alcohol use disorders. The purpose of this study was to test the hypothesis that drinking alcohol reduces social phobic anxiety. METHOD: Treatment-seeking individuals with social phobia (N = 40) were asked to give two impromptu speeches. Twenty subjects received a placebo alcoholic drink before both speeches, and 20 subjects received a placebo before the first speech, followed by a moderate dose of alcohol before the second speech. Subjective anxiety ratings, heart rate, and cognitions related to social anxiety were used as measures of anxiety. RESULTS: Repeated measures analyses of variance yielded no significant differences in anxiety (subjective, physiological, cognitive) between the alcohol and placebo groups. Current and past drinking habits did not significantly alter the effect of alcohol on anxiety. The belief that one received alcohol was significantly related to levels of subjective anxiety and negative cognitions. CONCLUSIONS: Alcohol does not directly reduce social phobic anxiety. The belief that one received alcohol may reduce social anxiety.
Adult↗
Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder.
The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (l) and short (s) variants of the HTT promoter have different transcriptional efficiencies. HTT promoter genotype and blood 5-HT concentration were examined in 70 subjects from 20 families ascertained through children and adolescents with a DSM-III-R diagnosis of OCD. The HTT promoter variant had a significant effect on blood 5-HT content. Subjects with the l/l and l/s genotypes had significantly higher blood 5-HT levels than did those with the s/s genotype. There was a significant interaction between HTT promoter genotype and seasonal variation in blood 5-HT content, with significant seasonal differences in 5-HT occurring only in the subjects with the l/l genotype. Further studies of the regulation of HTT gene expression are indicated.
Adolescent↗
Specific fears and phobias. Epidemiology and classification.
BACKGROUND: Data on eight specific fears representing DSM-III-R simple phobia were analysed to evaluate: (a) their prevalence and (b) the validity of subtypes of specific phobia defined by DSM-IV. METHOD: A modified version of the Composite International Diagnostic Interview was administered to a probability sample of 8098 community respondents. Correlates of responses to questions concerning these fears were analysed. RESULTS: The most prevalent specific fears were of animals among women, and of heights among men. Slight evidence was found for specific phobia subtypes. Number of fears, independent of type, powerfully predicted impairment, comorbidity, illness course, demographic features, and family psychopathology. CONCLUSION: Number of specific fears may mark a general predisposition to psychopathology. More detailed information is needed to resolve the question of specific phobia subtypes.
Adolescent↗
Adrenocorticotropic hormone and cortisol responses to corticotropin-releasing hormone: changes in panic disorder and effects of alprazolam treatment.
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.
Adrenocorticotropic Hormone↗
Childhood adversity and vulnerability to mood and anxiety disorders.
Based upon epidemiological surveys, adverse childhood events are proposed to be risk factors for adult depressive and anxiety disorders. However, the extent to which these events are seen in clinical patient populations is less clear. We examined the prevalence of a number of proposed risk factors for depression in 650 patients with mood and anxiety disorders at the time of presentation for treatment in an outpatient subspecialty clinic. Emotional abuse, physical abuse, or sexual abuse (childhood adversity) was found in approximately 35% of patients with major depression and panic disorder, was more common in women than men, and was associated with an earlier onset of symptoms. Childhood adversity was also strongly associated with marital discord/divorce, and psychopathology in a parent, suggesting family discord predisposes to childhood abuse. Furthermore, the association of childhood abuse with parental mental illness suggests that genetic and environmental factors are difficult to separate as etiological factors in vulnerability.
Adult↗
Hypothalamic-pituitary-adrenal axis activity in panic disorder. 24-hour secretion of corticotropin and cortisol.
BACKGROUND: Oversecretion of corticotropin-releasing hormone and/or dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to pathophysiologic processes in panic disorder, but documentation of HPA axis disturbance in panic has been inconsistent. In the current study we examined HPA axis activity in panic disorder over a full circadian cycle, using frequent blood sampling to provide detailed assessment of corticotropin and cortisol secretion. METHODS: Twenty patients with panic disorder and 12 normal control subjects were studied. Blood samples were drawn every 15 minutes for 24 hours and assayed for corticotropin and cortisol levels. RESULTS: Patients with panic disorder had elevated overnight cortisol secretion and greater amplitude of ultradian secretory episodes. Patients who entered the study through clinical referral channels had greater cortisol secretion than those recruited by advertisements. Patients with panic disorder who had a low frequency of panic attacks had elevated daytime corticotropin levels and elevated corticotropin ultradian amplitude. Patients with a high frequency of attacks had shifted corticotropin circadian cycles. CONCLUSIONS: Patients with panic disorder demonstrate subtle alterations in HPA axis activity, characterized by overnight hypercortisolemia and increased activity in ultradian secretory episodes, but HPA axis alterations in panic are modulated by illness severity and treatment seeking. It remains unclear whether HPA axis dysregulation in panic represents a pathogenic defect within the axis itself. Inconsistencies in prior work may reflect the subtlety of the abnormalities seen, differences in clinical characteristics of patients studied, and the use of different probes and measurement contexts.
Activity Cycles↗
Neuroendocrine responses to laboratory panic: cognitive intervention in the doxapram model.
Doxapram is a respiratory stimulant that appears to be a potent and specific panicogenic agent. It also elicits an abnormal ventilatory response in patients with panic. A replication study confirmed these findings and demonstrated that behavioral and ventilatory responses to doxapram were significantly modified by a psychological intervention designed to cognitively block panic. The replication study provided an opportunity to simultaneously investigate the neuroendocrine effects of the illness, the drug, the drug-induced panic attacks, and the cognitive intervention. Epinephrine (EPI), norepinephrine (NE), growth hormone (GH), adrenocorticotropin (ACTH), and cortisol were studied in patients with panic and control subjects given placebo and doxapram injections after receiving either standard instructions or a brief cognitive intervention. Patients with panic had elevated levels of EPI, ACTH, and cortisol throughout the study. Doxapram had little or no detectable effects on plasma NE, GH, ACTH, and cortisol. Doxapram-induced panic attacks were not associated with elevations in NE, GH, ACTH, or cortisol. Doxapram led to a rapid and very brief rise in plasma EPI, which was small in subjects who did not panic and pronounced in patients who did panic. The cognitive intervention attenuated the EPI response to doxapram, perhaps through its effect on panic, and modified the temporal pattern of ACTH and cortisol secretion. These results suggest that: (1) further study of catecholamine responses within the first few minutes after panic induction is needed; (2) intense panic can occur without significant activation of the hypothalamic-pituitary-adrenal axis; and (3) cognitive factors can modulate neuroendocrine activity in laboratory studies of patients with panic.
Acoustic Stimulation↗
Hypothalamic-pituitary-adrenal axis activity in panic disorder: prediction of long-term outcome by pretreatment cortisol levels.
OBJECTIVE: The authors sought to determine whether hypothalamic-pituitary-adrenal (HPA) axis activity in patients before their treatment for panic disorder can predict follow-up functional status. Although baseline HPA axis disturbances in patients with panic disorder appear to attenuate with treatment, there is evidence that they may be linked to poorer long-term outcomes. METHOD: Follow-up clinical data were obtained for 18 of 20 patients with panic disorder who participated in a detailed study of HPA axis activity in panic, both before and during their treatment with alprazolam. HPA axis assessment included monitoring of adrenocorticotropin and cortisol over a full circadian cycle. The relationships between disability and clinical status at 2-year follow-up and HPA axis overactivity at entry were examined. RESULTS: Mean 24-hour cortisol levels before treatment provided a strong, positive predictor of disability scores at follow-up. Those patients who achieved the treatment goal of medication-free remissions had less evidence of HPA axis overactivity at entry than those who were not in remission. CONCLUSIONS: HPA axis activity before treatment did predict outcome 2 years later. This relationship appears robust and reproducible. Further work is needed to define the neuroendocrine mechanisms underlying the HPA axis markers that are linked to long-term functioning and to determine the biological, psychological, and social processes that link HPA axis disturbance to poorer outcomes.
Adolescent↗
Absorption, pharmacokinetics and metabolism of 14C-sumatriptan following intranasal administration to the rat.
1. Studies have been carried out to investigate the absorption of sumatriptan after intranasal administration to rats. The pharmacokinetics, metabolism and excretion of 14C-sumatriptan were compared following intranasal and intravenous dosing to male and female albino rats using an aqueous buffered formulation at pH 5.5. 2. Following intravenous administration sumatriptan was eliminated from plasma with a half-life of about 1.1 h. After intranasal administration there was rapid absorption of part of the dose and two peak plasma concentrations were observed, initially at 0.5 and then at 1.5-2 h. The elimination half-life after the second peak was estimated as being about 4 h. 3. Radioactivity was largely excreted in urine (up to 89% of dose in 168 h) after both intravenous and intranasal administration, with a faster rate of excretion after intravenous dosage (73% males, 64% females within 6 h) than after intranasal dosage (37% males, 40% females within 6 h). 4. 14C-sumatriptan was the major component in urine and in extracts of faeces after both intravenous and intranasal administration. The major metabolite excreted in urine and faeces was GR49336, the indole acetic acid analogue. 5. The results of this in vivo rat study suggest that absorption of the dose via the nasal mucosa is incomplete after intranasal administration and that there is a secondary absorption phase probably reflecting oral absorption of part of the dose. The bioavailability is estimated as about 30%, for the period 0-6 h.
Absorption↗
The effects of central cholecystokinin receptor blockade on hypothalamic-pituitary-adrenal and symptomatic responses to overnight withdrawal from alprazolam.
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Adult↗
NMR study of whole rat bile: the biliary excretion of cefoperazone and benzyl chloride by an isolated perfused rat liver.
1H NMR spectroscopy at 400 MHz has been applied to the analysis of whole bile samples produced by the isolated perfused rat liver. Using relatively simple NMR experiments biliary excretory products of cefoperazone and benzyl chloride were identified as cefoperazone itself and a benzyl-glutathione conjugate, respectively. Our use of 13C isotopic labelling demonstrates how 1H/13C heteronuclear NMR techniques can be used to produce uncrowded and informative spectra from whole bile. From the use of a HMQC-COSY experiment the structure of a benzyl-glutathione conjugate contained in whole bile was confirmed.
Animals↗
NMR study of whole rat bile: the biliary excretion of 4-cyano-N,N-dimethyl aniline by an isolated perfused rat liver and a liver in situ.
The structure of two biliary metabolites of 4-cyano-N,N-dimethyl aniline (CDA) contained in whole rat bile have been studied in detail by NMR at 400 MHz. A 4-cyano-N-methyl glutathione-N-aniline conjugate was identified as a biliary metabolite of CDA using relatively simple 1H NMR techniques. Isotopically 13C labelled CDA was used to generate 13C labelled xenobiotic conjugates. Our use of 1H/13C heteronuclear NMR techniques, in particular a 13C-selective HMQC-TOCSY experiment, allowed a N-beta-glucuronide conjugate, a previously unknown biliary metabolite of CDA, to be identified. Bile samples obtained from both the isolated perfused rat liver and the rat liver in situ were analysed.
Aniline Compounds↗
Kinetics and disposition of picumeterol in animals.
1. The pharmacokinetics and disposition of picumeterol, a novel beta 2 receptor agonist agent, have been studied in the rat and dog following administration by inhalation, intravenous and oral routes at various dose levels. 2. Picumeterol was found to be transferred across the lung of the rat and dog following inhalation dosage. After i.v. dosage picumeterol was eliminated from plasma with a half-life of about 1 h in the rat and about 2 h in the dog. Plasma clearance in the rat was about twice liver blood flow and the plasma levels of picumeterol were low after oral administration. 3. Following instillation of 14C-picumeterol to the trachea of isolated respiring rat lung preparations radioactivity was transferred from the airways to perfusion media as unchanged drug within 2 min. After 2 h perfusion, no metabolites were detected in the recirculation perfusate or lung. 4. Picumeterol was extensively metabolized in vivo in the rat (about 95%) and dog (about 90%) and in vitro in microsomal preparations of rat, dog and human liver. O-dealkylation and beta-oxidation are important as routes of metabolism. 5. Radioactivity was largely excreted in the urine of the rat and dog (> 50% of dose), as metabolites, following i.v. administration. There was some excretion of radioactivity in dog bile. Extensive first-pass metabolism was found after oral administration in the rat.
Administration, Inhalation↗
Late local and remote structural changes after capsulotomy for obsessive compulsive disorder.
Stereotactic subcaudate capsulotomy (SC) is used to treat medically intractable obsessive compulsive disorders (OCD). Although clinical improvement has been observed, post-SC structural correlates are lacking in this biological disorder. Our study provides imaging evidence for local and distant alterations in structures which may have an important role in the manifestations of OCD. Five OCD patients treated with SC received MR imaging for pre-SC planning, early (1-7 days) post-SC assessment, and late (5-12 months) follow-up. The volumes of the anterior limb of the internal capsules, caudate heads, third ventricle, mamillary bodies, thalami, and hippocampal formations were digitally computed. Volumes from each of the serial imaging studies were compared. At 5-12 months post-SC, all patients showed reduction in volume of the anterior limbs of the internal capsules, caudate heads, thalami, and increased volume of the third ventricle (reflecting thalamic/caudate atrophy). 2-5 patients showed reduction in hippocampal formation volume. The post-SC reduction in volume of these structures, some far distant to the stereotactic lesion, suggests that the interrelationships of the anterior limb of the internal capsule, the caudate/thalamic nuclei, and possibly the pallidal and limbic systems are necessary for the manifestations of OCD and their variants.
Brain↗
Panic attacks induced by doxapram.
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Adult↗
Maintenance drug therapy of panic disorder.
The efficacy of tricyclics and benzodiazepines in the short term (approximately 2-4 months) treatment of panic disorder is well demonstrated, but efficacy over the longer term is not considered established. The present study provided systematic data from a double blind comparison of maintenance therapy (up to 8 months) of panic disorder with or without agoraphobia with alprazolam, imipramine, or placebo in 181 patients who had responded to the same regimen in a randomized 8-week treatment trial. All three groups had improved during the first 2 months (active treatments more than placebo and about equal to each other), and all maintained or extended their improvement over the next 6 months without any significant change in dose. More than twice as many alprazolam and imipramine than placebo patients (15%) remained in treatment for the full 8 months and did slightly better on symptom measures than the remaining placebo patients. Both medications were well tolerated during the maintenance period. The data suggest sustained efficacy and safety of imipramine and alprazolam over an extended period. More specifically, they suggest that tolerance does not develop to the therapeutic effects of either drug.
Agoraphobia↗
Endocrine, cardiovascular, and behavioral responses to clonidine in patients with panic disorder.
We examined adrenergic regulation in patients with panic disorder by challenging 10 patients and 14 age-matched and sex-matched controls with intravenous infusions of clonidine hydrochloride (2 micrograms/kg), an alpha 2-adrenoreceptor agonist. Growth hormone, 3-methoxy-4-hydroxyphenylglycol (MHPG), blood pressure, heart rate, and behavioral (anxiety, sedation) responses were monitored. The data replicated the previously reported finding of blunted growth hormone (GH) responses to clonidine in patients with panic disorder. Reported abnormalities in MHPG, cardiovascular, and behavioral responses of panic patients to clonidine infusion were not replicated. The robustly blunted GH response to clonidine in panic patients supports the adrenergic dysregulation hypothesis of panic disorder, but alternative interpretations of this finding are available and further study is needed.
Adrenergic Fibers↗