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Influence of the serotonin antagonist, metergoline, on anxiogenic and neuroendocrine effects of carbon dioxide in healthy volunteers
S302
I?3 Anxiety disorders and aruiolytics
Methods: We present an observational prospective naturalistic study of all the pathological anxiety cases that followed treatment with Alprazolam XR in two psychiatry outpatient centres. Sixty-eight (68) patients were included in the study. The treatment period was 21 weeks. In each of the 4 control visits, efficacy (HAMA, GCI, GCI improvement) and tolerability (adverse events) were assessed, as well as the dose, dosage pattern and need of change of the medication. Results: Global anxiety (HAMA, GCI and CGI improvement) showed a significant reduction throughout the study. There was a reduction in the number of panic attacks and in the severity of agoraphobia. Global clinical impression (efficacy and tolerability) was good or very good in 75% of the patients, both assessed by the investigator and by the patient. Fifty percent (50%) of the patients had an adverse event (mainly sedation), most cases being mild and transient. Fifty-eight percent (58%) of the patients needed a change in the dosage regimen (dose, number of daily doses), mostly due to clinical dose adjustment. Some patients needed a change in the dosage due to adverse events. Sixteen patients that had been treated with the conventional formulation of alprazolam and started treatment with Alprazolam XR needed a slightly higher dose of the extended release formulation. In these cases the change of medication was easy. Conclusion: The clinical use of Alprazolam XR in the treatment of pathological anxiety was useful in most of the patients (75%). The dose regime was usually 2-3 mg in two daily doses, with a trend to lower the dose (l-2 mg in a single dose) in the third or fourth control. The change from the conventional formulation to the extended release was not difficult in most of the patients.
(p.3.01oj Administration of high dose ketoconazole prevents anxietv-related behavior in an animal model of post-traumatic stress disorder H. Cohen, J. Benjamin, Z. Kaplan, M. Kotler. Mental Health Center: Anxiety & Stress Research Unit, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheua. Israel Posttraumatic stress disorder (PTSD) may affect individuals following exposure to extreme stress such as combat, physical assault, or natural disaster. Abnormal activity of the autonomic nervous system and of the hypothalamic-pituitary-adrenal (HPA) axis have been suggested as the basis of some of the characteristic features of this disorder. Ketoconazole (KTCZ) an imidazole derivative, is an antimycotic agent and a potent inhibitor of gonadal and adrenal steroidogenesis. The aim of this study was to explore the effects of KTCZ blockade of adrenal steroidogenesis on a model of chronic post-traumatic anxiety in rats. Amelioration of anxious behaviors after reduction of corticosterone by KTCZ would suggest that corticosterone (and by implication cortisol in humans) is an important of anxiety related disorder; exacerbation of such behavior would suggest that corticosterone elevations are secondary to the symptoms, and possibly implicate CRH and/or ACTH. In order to examine whether anxiety following a single exposure of a rat to the smell of a predator, i.e. a cat (a prima facie valid model for post traumatic stress disorder) might be blocked by KTCZ, we exposed rats for 10 minutes to cat smell, with and without KTCZ. Treatment with high dose KTCZ for 14 days totally abolished the behavioral effects of exposure to a cat scent. Lower levels of anxious behavior in KTCZ-treated and exposed rats were accompanied by lower plasma corticosterone, plasma ACTH concentration and PRL levels compared to untreated exposed rats. In conclusion, the present results implicate corticosterone, but not ACTH in the pathogenesis of anxiety in this model of PTSD.
Ip.3.0111 Sensitivity to alprazolam effect in the staircase test in five inbred mouse strains C.G. Pick’, L. Paz’, M.M. Backer’, Z. Amiri*, I. Modai*, R. Weizman4. Dep. of Anatomy and Anthropology, Tel Aviv University; 2ShaarMenashe Mental Health Center; ‘Tel Aviv Community Mental Health Center; Israel
The behavioral responses of five inbred mouse strains (HS, C57, Swiss, ICR and BALB/c) to alprazolam was examined in the staircase test, an animal model sensitive to benzodiazepines. Alprazolam administration resulted in a dose-dependent suppression of rearing behavior, but to a different extent among the strains. By contrast, the number of stairs ascended was not suppressed by alprazolam at doses of 0.25 mg/kg and 0.5 mg/kg, except in the C57 mice. The addition of flumazenil antagonized the alprazolam effect on rearing and climbing in all strains. There was a consistency within strains in sensitivity to alprazolam, with some strains being highly sensitive (C57 and HS) or less sensitive (Swiss, ICR and BALBlc) with regard to both rearing and climbing behaviors. Serum alprazolam levels did not differ significantly among the strains. This strain-dependent pattern ofresponse to alprazolam seems to indicate a genetic component in the behavior sensitivity to the benzodiazepine, with a spectrum of degree of responsivity among strains.
IP.3.0121 Influence of the serotonin antagonist, metergoline, on anxiogenic and neuroendocrine effects of carbon dioxide in healthy volunteers G. Meiri, I.Z. Ben-Zion*, B.D. Greenberg, D.L. Murphy, J. Benjamin. Department of Psychiatry, Soroka Medical Center of the &pat Holim Sick Fund, Faculty of Health Sciences, Ben Gurion University of the Negeu, Beer-sheba, Israel
The mechanism of action of carbon dioxide (CO2) angiogenesis in panic disorder patients and in healthy volunteers is unknown; stimulation of noradrenergic (NA) pathways by CO2 has been suggested in preclinical studies, but peripheral measures of NA in human subjects receiving CO2 have been equivocal. Despite evidence that central nervous system serotonin (5-HT) is involved in anxiety, to our knowledge only two studies have investigated possible 5-HT mediation of CO2 anxiogenesis. We therefore performed a placebo-controlled study of the acute influences of the 5-HT antagonist, metergoline on the effects of inhalations of air and of CO2 in healthy volunteers. In addition, we repeated the administration of air and of CO2 one and two days after ingestion of metergoline and of placebo, for two reasons. Firstly, we have previously observed delayed effects of metergoline in human subjects. Secondly, we have previously reported tolerance to daily administrations of the 5-HT agonist m-CPP in human subjects. Continued effects of metergoline on responses to CO2 would support earlier findings in another paradigm; continued effects of CO2 after placebo would suggest that tolerance to m-CPP in a previous study did not reflect non-specific learning effects common to all challenges. Fourteen healthy volunteers received two vital capacity inhalations each of 35% CO2 and of air, after a single capsule of placebo and after a single capsule containing 4 mg metergoline in a double-blind randomized crossover design. Subjects completed three measures of anxiety, and NA, prolactin and cortisol levels were assessed before and after inhalations. Challenges were separated by one week. The inhalations and behavioral assessments were repeated one and two days after the oral medications. Anxiety increased after CO2, and there was a tendency for NA to increase after CO2. CO2 anxiogenesis was significantly enhanced by metergoline. Plasma prolactin levels were lower after metergoline. One and two days after placebo, there were no meaningful changes in anxiety increases that followed CO2; one and two days after metergoline, anxiety responses declined to levels similar to those after placebo. We hypothesize that 5-HT may function as an inhibitor of CO2 anxiogenesis, and that this is opposed by metergoline. Absence of tolerance after repeated CO2 argues against psychological explanations of tolerance after other panicogens.
I?3 Anxiety disorders and aruiolytics
Methods: We present an observational prospective naturalistic study of all the pathological anxiety cases that followed treatment with Alprazolam XR in two psychiatry outpatient centres. Sixty-eight (68) patients were included in the study. The treatment period was 21 weeks. In each of the 4 control visits, efficacy (HAMA, GCI, GCI improvement) and tolerability (adverse events) were assessed, as well as the dose, dosage pattern and need of change of the medication. Results: Global anxiety (HAMA, GCI and CGI improvement) showed a significant reduction throughout the study. There was a reduction in the number of panic attacks and in the severity of agoraphobia. Global clinical impression (efficacy and tolerability) was good or very good in 75% of the patients, both assessed by the investigator and by the patient. Fifty percent (50%) of the patients had an adverse event (mainly sedation), most cases being mild and transient. Fifty-eight percent (58%) of the patients needed a change in the dosage regimen (dose, number of daily doses), mostly due to clinical dose adjustment. Some patients needed a change in the dosage due to adverse events. Sixteen patients that had been treated with the conventional formulation of alprazolam and started treatment with Alprazolam XR needed a slightly higher dose of the extended release formulation. In these cases the change of medication was easy. Conclusion: The clinical use of Alprazolam XR in the treatment of pathological anxiety was useful in most of the patients (75%). The dose regime was usually 2-3 mg in two daily doses, with a trend to lower the dose (l-2 mg in a single dose) in the third or fourth control. The change from the conventional formulation to the extended release was not difficult in most of the patients.
(p.3.01oj Administration of high dose ketoconazole prevents anxietv-related behavior in an animal model of post-traumatic stress disorder H. Cohen, J. Benjamin, Z. Kaplan, M. Kotler. Mental Health Center: Anxiety & Stress Research Unit, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheua. Israel Posttraumatic stress disorder (PTSD) may affect individuals following exposure to extreme stress such as combat, physical assault, or natural disaster. Abnormal activity of the autonomic nervous system and of the hypothalamic-pituitary-adrenal (HPA) axis have been suggested as the basis of some of the characteristic features of this disorder. Ketoconazole (KTCZ) an imidazole derivative, is an antimycotic agent and a potent inhibitor of gonadal and adrenal steroidogenesis. The aim of this study was to explore the effects of KTCZ blockade of adrenal steroidogenesis on a model of chronic post-traumatic anxiety in rats. Amelioration of anxious behaviors after reduction of corticosterone by KTCZ would suggest that corticosterone (and by implication cortisol in humans) is an important of anxiety related disorder; exacerbation of such behavior would suggest that corticosterone elevations are secondary to the symptoms, and possibly implicate CRH and/or ACTH. In order to examine whether anxiety following a single exposure of a rat to the smell of a predator, i.e. a cat (a prima facie valid model for post traumatic stress disorder) might be blocked by KTCZ, we exposed rats for 10 minutes to cat smell, with and without KTCZ. Treatment with high dose KTCZ for 14 days totally abolished the behavioral effects of exposure to a cat scent. Lower levels of anxious behavior in KTCZ-treated and exposed rats were accompanied by lower plasma corticosterone, plasma ACTH concentration and PRL levels compared to untreated exposed rats. In conclusion, the present results implicate corticosterone, but not ACTH in the pathogenesis of anxiety in this model of PTSD.
Ip.3.0111 Sensitivity to alprazolam effect in the staircase test in five inbred mouse strains C.G. Pick’, L. Paz’, M.M. Backer’, Z. Amiri*, I. Modai*, R. Weizman4. Dep. of Anatomy and Anthropology, Tel Aviv University; 2ShaarMenashe Mental Health Center; ‘Tel Aviv Community Mental Health Center; Israel
The behavioral responses of five inbred mouse strains (HS, C57, Swiss, ICR and BALB/c) to alprazolam was examined in the staircase test, an animal model sensitive to benzodiazepines. Alprazolam administration resulted in a dose-dependent suppression of rearing behavior, but to a different extent among the strains. By contrast, the number of stairs ascended was not suppressed by alprazolam at doses of 0.25 mg/kg and 0.5 mg/kg, except in the C57 mice. The addition of flumazenil antagonized the alprazolam effect on rearing and climbing in all strains. There was a consistency within strains in sensitivity to alprazolam, with some strains being highly sensitive (C57 and HS) or less sensitive (Swiss, ICR and BALBlc) with regard to both rearing and climbing behaviors. Serum alprazolam levels did not differ significantly among the strains. This strain-dependent pattern ofresponse to alprazolam seems to indicate a genetic component in the behavior sensitivity to the benzodiazepine, with a spectrum of degree of responsivity among strains.
IP.3.0121 Influence of the serotonin antagonist, metergoline, on anxiogenic and neuroendocrine effects of carbon dioxide in healthy volunteers G. Meiri, I.Z. Ben-Zion*, B.D. Greenberg, D.L. Murphy, J. Benjamin. Department of Psychiatry, Soroka Medical Center of the &pat Holim Sick Fund, Faculty of Health Sciences, Ben Gurion University of the Negeu, Beer-sheba, Israel
The mechanism of action of carbon dioxide (CO2) angiogenesis in panic disorder patients and in healthy volunteers is unknown; stimulation of noradrenergic (NA) pathways by CO2 has been suggested in preclinical studies, but peripheral measures of NA in human subjects receiving CO2 have been equivocal. Despite evidence that central nervous system serotonin (5-HT) is involved in anxiety, to our knowledge only two studies have investigated possible 5-HT mediation of CO2 anxiogenesis. We therefore performed a placebo-controlled study of the acute influences of the 5-HT antagonist, metergoline on the effects of inhalations of air and of CO2 in healthy volunteers. In addition, we repeated the administration of air and of CO2 one and two days after ingestion of metergoline and of placebo, for two reasons. Firstly, we have previously observed delayed effects of metergoline in human subjects. Secondly, we have previously reported tolerance to daily administrations of the 5-HT agonist m-CPP in human subjects. Continued effects of metergoline on responses to CO2 would support earlier findings in another paradigm; continued effects of CO2 after placebo would suggest that tolerance to m-CPP in a previous study did not reflect non-specific learning effects common to all challenges. Fourteen healthy volunteers received two vital capacity inhalations each of 35% CO2 and of air, after a single capsule of placebo and after a single capsule containing 4 mg metergoline in a double-blind randomized crossover design. Subjects completed three measures of anxiety, and NA, prolactin and cortisol levels were assessed before and after inhalations. Challenges were separated by one week. The inhalations and behavioral assessments were repeated one and two days after the oral medications. Anxiety increased after CO2, and there was a tendency for NA to increase after CO2. CO2 anxiogenesis was significantly enhanced by metergoline. Plasma prolactin levels were lower after metergoline. One and two days after placebo, there were no meaningful changes in anxiety increases that followed CO2; one and two days after metergoline, anxiety responses declined to levels similar to those after placebo. We hypothesize that 5-HT may function as an inhibitor of CO2 anxiogenesis, and that this is opposed by metergoline. Absence of tolerance after repeated CO2 argues against psychological explanations of tolerance after other panicogens.