Peptides and anxiety: a dose-response evaluation of pentagastrin in healthy volunteers

A large body of data suggest that brain cholecystokinin (CCK) systems are involved in the regulation of anxiety, and numerous studies have demonstrated that CCK-4, a CCKB agonist, reliably induces panic attacks in patients with panic disorder. Recently, pentagastrin, a commercially available CCKB agonist, has been reported to have similar anxiogenic properties. To further explore the utility of pentagastrin as a challenge agent and to determine whether its effects are dose-related, a dose-response study was conducted in ten healthy volunteers. Pentagastrin (0.2 microgram/kg, 0.6 microgram/kg and 1.0 microgram/kg) and inactive placebo were infused over one minute on four separate challenge days in a double-blind fashion. Subjects received pentagastrin while participating in a structured social interaction task. Repeated measures of anxiety, blood pressure, pulse, ACTH, and cortisol were taken at baseline and postinfusion. Pentagastrin administration led to increases in anxiety, pulse, ACTH, cortisol and physical symptoms of panic, in a dose-related manner. Participation in the social interaction task led to increases in measures of anxiety as well as increases in pulse and blood pressure. Few differences were found between the 0.2 microgram/kg dose of pentagastrin and placebo, or between the 0.6 microgram/kg and the 1.0 microgram/kg doses of pentagastrin. These findings support the notion that CCK systems are involved in the regulation of anxiety, and suggest that the 0.6 microgram/kg dose may be optimal for increasing symptoms of anxiety while minimizing unpleasant side effects. The powerful anxiogenic effects of the social interaction task underscore the importance of contextual variables in challenge studies.     

T cell hyperreactivity to IL-6 in chronic nonviremic HBV carriers despite normal IL-6 receptor or gp130 expression

We studied the effect of the cholecystokinin tetrapeptide (CCK4), a potent CCKB antagonist, in patients with panic disorder. Two different dosages (25 and 50 micrograms) of CCK4 and saline were tested in 12 patients who were randomly allocated to 2 of the 3 possible treatment groups. Patients were tested on 2 separate occasions, 1 week apart, using an unbalanced single-blind incomplete block design. A total of 24 intravenous injections were carried out. The panic rate with 25 micrograms CCK was 44% (4/9) and 71% (5/7) with 50 micrograms. None of the patients panicked with saline (0/8). Patients' symptom responses were very similar to their spontaneous panic attacks. Taking the Panic Symptom Scale (PSS) as outcome variable, we found that CCK4 provoked symptoms of panic in a dose-dependent fashion. The behavioral response to CCK4 was not accompanied by activation of the hypothalamic-pituitary-adrenal (HPA) axis as measured by the prolactin and cortisol responses. Moreover, CCK4-induced panic symptoms were not correlated with plasma increases in the principal noradrenergic metabolite, 3-methoxy-4-hydroxy-phenylglycol (MHPG), suggesting that activation of the locus coeruleus may not be critical for CCK4-induced panic.     

Hemiplegia following general anaesthesia: an unusual presentation of migraine

OBJECTIVE: Flumazenil is a benzodiazepine receptor antagonist that has been reported to provoke panic attacks in patients with panic disorder. This study was undertaken to compare the effects of flumazenil and sodium lactate, the most widely studied panic provocation agent. METHOD: Ten patients with panic disorder were given infusions of saline, sodium lactate, and flumazenil in randomized order. Panic attacks, psychopathological changes, heart rate, and cortisol and ACTH secretion were recorded. RESULTS: Eight of the 10 patients experienced a panic attack after sodium lactate, but none did after flumazenil or saline. Cortisol and ACTH secretion were not enhanced by any of the treatments. Sodium lactate increased heart rate, whereas flumazenil had the opposite effect. CONCLUSIONS: These findings do not lend support to the view that the benzodiazepine receptors of lactate-susceptible patients with panic disorder are hypersensitive and that flumazenil can therefore act as an inverse agonist.     

Co-morbidity and familial aggregation of alcoholism and anxiety disorders

BACKGROUND: This study examined the patterns of familial aggregation and co-morbidity of alcoholism and anxiety disorders in the relatives of 165 probands selected for alcoholism and/or anxiety disorders compared to those of 61 unaffected controls. METHODS: Probands were either selected from treatment settings or at random from the community. DSM-III-R diagnoses were obtained for all probands and their 1053 first-degree relatives, based on direct interview or family history information. RESULTS: The findings indicate that: (1) alcoholism was associated with anxiety disorders in the relatives, particularly among females; (2) both alcoholism and anxiety disorders were highly familial; (3) the familial aggregation of alcoholism was attributable to alcohol dependence rather than to alcohol abuse, particularly among male relatives; and (4) the the pattern of co-aggregation of alcohol dependence and anxiety disorders in families differed according to the subtype of anxiety disorder; there was evidence of a partly shared diathesis underlying panic and alcoholism, whereas social phobia and alcoholism tended to aggregate independently. CONCLUSIONS: The finding that the onset of social phobia tended to precede that of alcoholism, when taken together with the independence of familial aggregation of social phobia and alcoholism support a self-medication hypothesis as the explanation for the co-occurrence of social phobia and alcoholism. In contrast, the lack of a systematic pattern in the order of onset of panic and alcoholism among subjects with both disorders as well as evidence for shared underlying familial risk factors suggests that co-morbidity between panic disorder and alcoholism is not a consequence of self-medication of panic symptoms. The results of this study emphasize the importance of examining co-morbid disorders and subtypes thereof in identifying sources of heterogeneity in the pathogenesis of alcoholism.     

Drugs and the college athlete: an analysis of the attitudes of student athletes at risk

This study examines the degree to which untreated anxiety disorders and major depressive disorder, occurring either singly or in combination, reduce functioning and well-being among primary care patients. Adult patients were screened using the SCL-52 to identify those with clinically significant anxiety symptoms. They also completed the Rand Short-Form (SF-36) to measure self-reported patient functioning and well-being. Patients with untreated disorders were identified using the Q-DIS-III-R to diagnose six DIS-anxiety disorders (generalized anxiety disorder, post-traumatic stress disorder (PTSD), simple phobia, social phobia, panic/agoraphobia, obsessive/compulsive disorder) and major depression. Of 319 patients identified, 137 (43%) had a single disorder and 182 (57%) had multiple disorders. Regression models estimated the relative effects of these disorders on health status (SF-36) by comparing patients with the disorders to patients screened as being not-anxious. Estimates of these effects were consistent with available national norms. The estimated effect of each single disorder on all subscales for physical, social and emotional functioning was negative, often as much as a 20-30 point reduction on this 100-point scale. Major depression had the greatest negative impact, followed by PTSD and panic/ agoraphobia. For patients with multiple disorders, the presence of major depression was associated with the greatest reduction in functioning status. The impact of untreated anxiety disorders and major depressive disorder on functioning was comparable to, or greater than, the effects of medical conditions such as low back pain, arthritis, diabetes and heart disease.     

Medical utilisation and costs in panic disorder: a comparison with social phobia

There is considerable evidence that people with panic disorder utilise the physical health care system more frequently than people in the general community and so incur for themselves, and impose on the public health care system, considerably greater costs. Although this is probably because of specific characteristics to do with panic disorder, it may also be a function of having any anxiety disorder where panic is prominent. This study represents one of the few comparisons of medical utilisation and costs incurred by people with panic disorder to those incurred by people with another anxiety disorder, in this case, social phobia. Before treatment, 41 people with panic disorder, 15 with social phobia and 43 nonanxious controls were interviewed about their use of the medical care system over the previous 12 months. As expected, people with panic disorder had significantly higher utilisation rates than either the nonanxious controls or the socially phobic subjects, and incurred substantially higher costs. Adequate screening for panic disorder at the primary medical care level together with appropriate treatment referral therefore have the potential to substantially reduce the personal and community costs incurred by people with panic disorder.     

Blockade of accumbens 5-HT3 receptor down-regulation by ondansetron administered during continuous cocaine administration

The present experiment examined whether ondansetron, co-administered with continuous cocaine, would block the down regulation of accumbens 5-HT3 receptors. Rats were exposed to a 14-day pretreatment regimen that involved the continuous infusion of 40 mg kg(-1) day(-1) cocaine or 0.9% saline via a subcutaneously implanted osmotic minipump. In addition to the continuous cocaine or saline administration, all subjects received daily subcutaneous (s.c.) injections of either vehicle or 0.1 mg kg(-1) ondansetron for the entire 14-day pretreatment regimen. The rats were then withdrawn from this pretreatment regimen for seven days, and slices from the nucleus accumbens obtained. The slices were perfused with 25 mM K+ in the absence and presence of 0, 12.5, 25, or 50 microM m-Chlorophenyl-biguanide HCl (mCPBG). The efflux samples were assayed for dopamine content by high pressure liquid chromatography (HPLC) with electrochemical detection. Continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+-induce dopamine overflow compared to saline control rats. In addition, the rats that received ondansetron and cocaine during the 14-day pretreatment period, the ability of mCPBG to enhance K+ stimulated dopamine release was not significantly different from the saline control subjects. For all groups except the cocaine alone group, the effects of mCPBG on K+ stimulated dopamine release were Ca2+ dependent, suggesting that these effects are receptor mediated. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and that this down-regulation can be blocked by chronic ondansetron administration. Hence, a functional down regulation of accumbens 5-HT3 receptors represents a significant contribution to the tolerance induced by continuous cocaine administration.     

Validation of the Social Interaction Anxiety Scale and the Social Phobia Scale across the anxiety disorders.

The psychometric adequacy of the Social Interaction Anxiety Scale (SIAS; R. P. Mattick & J. C. Clark, 1989), a measure of social interaction anxiety, and the Social Phobia Scale (SPS; R. P. Mattick & J. C. Clark, 1989), a measure of anxiety while being observed by others, was evaluated in anxious patients and normal controls. Social phobia patients scored higher on both scales and were more likely to be identified as having social phobia than other anxious patients (except for agoraphobic patients on the SPS) or controls. Clinician-rated severity of social phobia was moderately related to SIAS and SPS scores. Additional diagnoses of mood or panic disorder did not affect SIAS or SPS scores among social phobia patients, but an additional diagnosis of generalized anxiety disorder was associated with SIAS scores. Number of reported feared social interaction situations was more highly correlated with scores on the SIAS, whereas number of reported feared performance situations was more highly correlated with scores on the SPS. These scales appear to be useful in screening, designing individualized treatments, and evaluating the outcomes of treatments for social phobia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mediation of changes in anxiety and depression during treatment of social phobia.

To investigate the interactive process of changes in social anxiety and depression during treatment, the authors assessed weekly symptoms in 66 adult outpatients with social phobia (social anxiety disorder) who participated in cognitive- behavioral group therapy. Multilevel mediational analyses revealed that improvements in social anxiety mediated 91% of the improvements in depression over time. Conversely, decreases in depression only accounted for 6% of the decreases in social anxiety over time. Changes in social anxiety fully mediated changes in depression during the course of treatment. The theoretical and clinical implications of these findings for the relationship between anxiety and depression are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Panic and Comorbid Anxiety Symptoms in a National Anxiety Screening Sample: Implications for Clinical Interventions.

Questionnaire data from 2,033 participants in the National Anxiety Disorders Screening Day sample were used to assess the presence of panic and comorbid anxiety problems. These participants were selected from more than 15,000 attendees on the basis of never having received treatment for a psychiatric disorder and meeting screening criteria for panic disorder. With each comorbid anxiety problem (generalized anxiety disorder, posttraumatic stress disorder, social phobia, and obsessive-compulsive disorder), participants had a corresponding increase in interference in daily living as well as readiness to seek treatment. The addition of generalized anxiety or depression with panic symptoms resulted in marked increases in interference scores. Clinical treatment implications for panic disorder are discussed in terms of the effects of comorbid anxiety problems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cognitive therapy of anxiety disorders.

A review of studies of cognitive-behavioral therapy (CBT) for generalized anxiety disorder, panic disorder with and without agoraphobia, and social phobia indicates that CBT is consistently more effective than waiting-list and placebo control groups. In general, CBT has proved more beneficial than supportive therapy as well. Comparisons with active behavioral treatments provide more variable results. Converging evidence suggests that cognitive change may be a strong predictor of treatment outcome, but that such change may be produced by a number of therapeutic approaches. Pretest–posttest change with CBT is depicted in meta-analytic summary form for each disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The 5-HT3 antagonist, BRL 46470 does not attenuate m-chlorophenylpiperazine (mCPP)-induced changes in human volunteers

Results from animal studies have suggested that serotonin (5-HT) antagonists acting on the 5-HT3 receptor may have anxiolytic properties. We have assessed whether pretreatment with the 5-HT3 receptor antagonist BRL 46470 (1 mg orally) attenuates the increase in anxiety induced in healthy volunteers by intravenous infusion of m-chlorophenylpiperazine (mCPP: 0.08 mg/kg over 2 min). In this double-blind placebo-controlled crossover study in 12 healthy men who were volunteers, infusion of mCPP caused significant increases in self-ratings for the psychological and physical symptoms of anxiety, for the symptoms of panic attack, and in the plasma levels of cortisol and prolactin, with four subjects (33%) experiencing an mCPP-induced "panic attack." Pretreatment with BRL 46470 did not attenuate any of these mCPP-induced changes. These results do not support suggestions from animal studies that 5-HT3 receptor antagonists can attenuate mCPP-induced anxiety, although it is conceivable that a different dose of BRL 46470 may have been effective.     

Comorbid anxiety disorders and treatment of depression in people with multiple sclerosis.

Objective: Anxiety is highly comorbid with depression, but little is known about the impact of anxiety disorders on the effectiveness of empirically supported psychotherapies for depression. We examined such outcomes for people with Multiple Sclerosis (MS) and depression, with versus without comorbid anxiety disorders. Design: Participants with MS (N = 102) received 16 weeks of telephone-administered psychotherapy for depression and were followed for one year post-treatment. Results: Participants with comorbid anxiety disorders improved to a similar degree during treatment as those without anxiety disorders. Outcomes during follow-up were mixed, and thus we divided the anxiety diagnoses into distress and fear disorders. The distress disorder (GAD) was associated with elevated anxiety symptoms during and after treatment. In contrast, fear disorders (i.e., panic disorder, agoraphobia, social phobia, specific phobia) were linked to depression, specifically during follow-up, across 3 different measures. Conclusions: People with GAD receiving treatment for depression may benefit from additional services targeting anxiety more specifically, while those with comorbid fear disorders may benefit from services targeting maintenance of gains after treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of bulimics, obese binge eaters, social phobics, and individuals with panic disorder on comorbidity across DSM-III—R anxiety disorders.

82 women, presenting as normal-weight bulimics, obese binge eaters, social phobics, and individuals with panic disorder, were compared on anxiety, depression, and substance abuse. All were administered the Anxiety Disorder Interview Schedule—Revised and completed the Michigan Alcohol Screening Test, Drug Abuse Screening Test, and Self-Consciousness Scale. A striking proportion of eating disorder Ss were comorbid for 1 or more anxiety disorders, the most frequent diagnoses being generalized anxiety disorder and social phobia. The results suggest that the place of anxiety in bulimia nervosa goes beyond that discussed within the context of the anxiety reduction model. Conflicting comorbidity findings among this and prior investigations are noted, however, and discussed in terms of the issue of differential diagnosis between eating and anxiety disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Body vigilance in panic disorder: Evaluating attention to bodily perturbations.

Body vigilance, consciously attending to internal cues, is a normal adaptive process. The present report investigated whether body vigilance is exaggerated among those with panic disorder, a condition characterized by intense fear and worry regarding bodily sensations. The Body Vigilance Scale is validated in nonclinical and anxiety disorder patients. Study 1 suggests that body vigilance is normally distributed in a nonclinical sample (n?=?472) but vigilance is related to a history of spontaneous panic attacks, anxiety symptomatology, and anxiety sensitivity. Study 2 suggests that body vigilance is elevated in panic disorder patients (n?=?48) relative to social phobia patients (n?=?18) and nonclinical controls (n?=?71). During cognitive-behavioral treatment, panic disorder patients show substantial reductions in body vigilance associated with reductions in anxiety symptomatology. Anxiety sensitivity was found to be related to body vigilance and to predict changes in body vigilance during treatment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Rethinking the mood and anxiety disorders: A quantitative hierarchical model for DSM-V.

The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994) groups disorders into diagnostic classes on the basis of the subjective criterion of "shared phenomenological features." There are now sufficient data to eliminate this rational system and replace it with an empirically based structure that reflects the actual similarities among disorders. The existing structural evidence establishes that the mood and anxiety disorders should be collapsed together into an overarching class of emotional disorders, which can be decomposed into 3 subclasses: the bipolar disorders (bipolar I, bipolar II, cyclothymia), the distress disorders (major depression, dysthymic disorder, generalized anxiety disorder, posttraumatic stress disorder), and the fear disorders (panic disorder, agoraphobia, social phobia, specific phobia). The optimal placement of other syndromes (e.g., obsessive-compulsive disorder) needs to be clarified in future research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

5-HT3 receptor modulation of behavior during withdrawal from continuous or intermittent cocaine

The present experiments examined alterations in 5-HT3 receptors during withdrawal from continuous or intermittent cocaine. Rats were pretreated with 40 mg/kg/day cocaine for 14 days by either SC injections or osmotic minipumps. The rats were then withdrawn from the pretreatment regimen for 7 days. In Experiment 1, rats received 0-16 mg/kg IP injections of ondansetron, a selective 5-HT3 receptor antagonist. In Experiment 2, the rats received 0-16 mg/kg IP ondansetron in combination with a 15 mg/kg IP injection of cocaine. In Experiment 3, the subjects received 0-16 mg/kg IP injections of ondansetron in combination with a 7.5 mg/kg IP injection of cocaine. Following these injections, the subjects' behavior was rated using the Ellinwood and Balster (18) rating scale. The results of Experiment 1 indicated that ondansetron had no effect on the behavior of the subjects, nor was there a differential effect of pretreatment regimen the effects of ondansetron. The results of Experiment 2 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats, but did have a slight, statistically significant, suppressive effect in the injection rats. In contrast, ondansetron had a robust facilitative effect on cocaine-induced locomotion in the continuous infusion rats. The results of Experiment 3 indicated that ondansetron had no effect on cocaine-induced locomotion in the saline control rats or the cocaine injection pretreatment subjects. In the continuous infusion subjects, ondansetron did have a slight, statistically significant, facilitative effect on cocaine-induced locomotion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Noradrenergic and serotonergic function in posttraumatic stress disorder

BACKGROUND: Yohimbine hydrochloride produces marked behavioral and cardiovascular effects in combat veterans with posttraumatic stress disorder (PTSD). In the present study, yohimbine was used as a probe of noradrenergic activity, and meta-chlorophenylpiperazine (m-CPP) as a probe of serotonergic activity. To our knowledge, this is the first study to describe the behavioral and cardiovascular effects of meta-CPP in patients with PTSD, and to compare these effects with those of yohimbine. METHOD: Twenty-six patients with PTSD and 14 healthy subjects each received an intravenous infusion of yohimbine hydrochloride (0.4 mg/kg), m-CPP (1.0 mg/kg), or saline solution on 3 separate test days in a randomized balanced order and in double-blind fashion. Behavioral and cardiovascular measurements were determined at multiple times. RESULTS: Eleven (42%) of the patients with PTSD experienced yohimbine-induced panic attacks and had significantly greater increases compared with controls in anxiety, panic, and PTSD symptoms, but not in cardiovascular measurements. Eight patients (31%) with PTSD experienced m-CPP-induced panic attacks and had significantly greater increases compared with controls in anxiety, panic, and PTSD symptoms, and in standing diastolic blood pressure. Yohimbine-induced panic attacks tended to occur in different patients from m-CPP-induced panic attacks. CONCLUSION: These data suggest the presence of 2 neurobiological subgroups of patients with PTSD, one with a sensitized noradrenergic system, and the other with a sensitized serotonergic system.     

Modulation of pentagastrin-induced histamine release by histamine H3 receptors in the dog

BACKGROUND: The histamine H3 receptor has been shown to inhibit pentagastrin-induced gastric acid secretion in dogs. Since pentagastrin releases histamine in dogs, we have now assessed whether the effects of H3-receptor ligands may be indirectly mediated by changes in gastric histamine release. METHODS: Pentagastrin infusions (1 or 6 micrograms/kg/h), alone or together with the H3-receptor agonist (R) alpha-methylhistamine (1.2 mumol/kg/h) or the antagonist thioperamide (0.1 mumol/kg/h), were performed in dogs. One group (anaesthetized) was used for enzyme immunoassays of plasma histamine and, when required. (R) alpha-methylhistamine in the gastrosplenic vein, and another group (non-anaesthetized) for measurement of gastric acid secretion. RESULTS: Histamine levels were increased five- and eight-fold after 1 and 6 micrograms/kg/h pentagastrin, respectively, whereas acid output was nearly maximal at the lower dosage. (R) alpha-methylhistamine, at a plasma concentration of 0.15 microM, inhibited histamine release by 78% (P < 0.007) and 37% (not significant) and the total acid output by 44% (P < 0.05) and 19% (not significant) after infusion of 1 and 6 micrograms/kg/h pentagastrin, respectively. Thioperamide, together with pentagastrin in low dose, significantly increased histamine release by 212% (P < 0.05), whereas acid output increased by 34% (not significant). CONCLUSIONS: The histamine H3 receptor mediates a negative feedback control of pentagastrin-induced release of gastric histamine. It is tonically activated by endogenous histamine after pentagastrin in low dosage. The control of acid secretion by the H3 receptor seems to involve modulation of endogenous histamine release, possibly by means of enterochromaffin-like cells.     

Confirmatory factor analysis of the Fear Questionnaire in panic disorder with agoraphobia.

The Fear Questionnaire responses of 390 patients with panic disorder with agoraphobia were used in a confirmatory factor analysis. The results provide strong support for the 3-factor model of this scale (agoraphobia, social phobia, blood/injury phobia) and the multidimensional model of fears proposed by W. A. Arrindell (1980). The presence of fear clusters other than agoraphobia existing in panic disorder is also discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)