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Clinical effects of buspirone in social phobia, a double-blind placebo controlled study
P.5 Anxietydisorders and anxiolytics
S4-150
IP.5.030 IThe effect of the neuroactivesteroid a-THODC, on staircase test behavior In mice
R. Weizman 1, Y. Peter 2, 1. Terkel3, M. Gavish4 , c.o. Pick2. I Tel-Aviv Community MentalHealth Centerand SacklerFaculty of Medicine, Tel-Aviv University, RamatAviv, Haifa, Israel; 2 Department of Anatomy andAnthropology, SacklerFaculty of Medicine. 3 Department of Zoology, Tel-Aviv University, Haifa, Israel; 4 Department of Pharmacology, Faculty of Medicine. Technion-Israel Instituteof Technology, Haifa. Israel This study examined the effect of the neuroactive steroid 3a, 5atetrahydrocorticosterone (a-TIIDOC) as compared to benzodiazepines (diazepam and midazolarn) and the barbiturate phenobarbital (PhB) on rearing (NR) and number of steps ascended(NSA) in the mousestaircase test. According to this paradigmNSA reflects locomotoractivity and NR reflects anxiety. The two benzodiazepines, phenobarbital and a- THDOC reduced NR at doses that did not affect NSA. The NR lowering effect inducedby thebenzodiazepines and a-THOOC, butnotPhB,wasblocked by the benzodiazepine antagonist flumazeniJ. It appears that, although neuroactive steroids, like barbiturates, bind to distinct sites within the chloride ion channel of the gamma-arninobutyric acid type A (GABAA) receptor complex, a-THDOC behavioral activity is modulated by the benzodiazepine recognition site.
IP.5.031 I Pharrnaco-psychological effects of S(+) ON·2327 enantiomerand ON·2327 racemate
B. Dietrich,G. Pabst. LAB. GmbH & Co, Neu-Ulm, Germany DN-2327 is a new non-benzodiazepine compound with anxiolytic properties. Analytical studies showed different characteristics of the two enantiomers. This study was performed to explore the central nervous effects of 0.5, 1, 2 and 4 mg of the S(+) DN·2327 enantiomer in comparison to I, 2, 4 and 8 mg of the DN-2327racemate with the help of psychometric tests. Results from 34 healthy male volunteers could be analyzed. With one week intervals the volunteers received 4 different single doses of the investigational compounds, 2 of the racemate and 2 of the S(+) enantiomer, and additionally placebo. Treatment assignment was randomized approaching a balancedincomplete blockdesignas closelyas possible.Psychometric tests were performed pre-doseand again 2.5 and 5.5 hrs post-dose. The following tests were performed: Critical Flicker Fusion Frequency (CFF), Pegboard Test (PT), Tapping Test (IT), Pauli Calculation Test (PCT), and Computerized Learning and Attention Test CGT-(M). CFF was impaired after intake of 2 and 4 mg of the enantiomer as well as 4 and 8 mg of the racemate. The same result was seen with the pegboard test, while the tapping test was not influenced by any of the two compounds. Performance in the Pauli test decreased already after administrating 1 mg of the enantiomer and 2 mg of the racemate. In the CGT-(M) the number of correct answers was not affected by the two compounds. However, the number of "false alarms" increased already after the lowestdose underboth drug conditions. Since reaction time was only prolonged after intake of 4 mg of the enantiomer and 8 mg of the racemate, this effect was obviously not related to sedative effects. Effects were strongest at 2.5 hrs post-dose. Only after intakeof the higherdoses of 2 and 4 mg of the enantiomer, respectively 4 and 8 mg of the racemate effects persisted at 5.5. hrs post-dose. The relative potency of the enantiomer in comparison to the racemate showed a ratio of 1:2, thus indicating that the S(+) DN-2327 enantiomer is the pharmaco-dynamic activepart of the DN-2327 racemate.
J
P.5.032I Clinical effects of buspirone In social phobia.a double-blind placebo controlled study
I.M. van Vliet, I.A. den Boer, H.G.M. Westenberg, K.L. Ho Pian. Department of Psychiatry. University Hospital Utrecht, P.O. Box 85500. 3508GA Utrecht, The Netherlands Socialphobiais one of the morecommonpsychiatric disorders, occurring in about 2% of the population. Recently, attention is focussed on the pharmacological treatments of social phobia. Selective and nonselective
MAO-inhibitors, as wellas selective serotoninreuptakeinhibitors (SSRIs) appearto be effective treatments. The results of these studies suggestthat serotonergic neuronal systems might be implicated, but which serotonergic subtype(s) are involved is as yet unclear. The results of open pilot studiessuggestthatthe serotonin IA (5-HT1A ) receptoragonistbuspirone might be effective in social phobia In the present study the efficacy of buspirone was investigated in patients withsocialphobiausing a 12 weekdouble-blind placebocontrolled design. Thirty social phobic patients (DSM-IV) were treated with either buspirone 30 mg daily or placebo. Efficacy of treatment was measured using the Social Phobia Scale (subscores anxiety and avoidance) and the Hamilton Anxiety Scale. Results: Taking a reduction of 50% or more on the Social Phobia Scale as a criterion for clinically relevant improvement, only one patient on buspirone and one on placebo were classified as responder to treatment. A subjective and clinically relevant improvement was reported by four patients (27%) on buspirone and two patients (13%) on placebo. There were no statistically significant differences betweenbuspironeand placebo on any of the outcome measures social phobic anxiety, social phobicavoidance and generalanxiety. Generallyspeaking,buspironewas well-tolerated and showed only few side effects. Inconclusion: the resultsof the presentdouble-blind placebocontrolled study do not support the results of open studies, in which a reduction of social anxiety and social avoidance was reported in patients with social phobia treatedwith buspirone.
IP.5.033I EEG abnormalitiesIn anxiety disorders R. Brzezinski, M. Dabkowski, A. Araszkiewicz, 1. Uziallo. Department of Psychiatry, Ludwig RydygierMedical Academyul. Kurpinskiego 19, 85-096 Bydgoszcz; Poland Pathophysiological connections between panic disorders and epilepsy have been repeatedly discussed. Certain phenomenological similarities, some concurrence in treatment paradigms and possible common neuroanatomic localization has to be postulated in limbic system bias towards such hypotheses. (P.V. Nickel and T.W. Uhde, 1994/1995; K. Dantendorfet al. 1995). In our study we assessed the frequency of electroencephalographic (EEG)abnormalities in anxiety patients and in this regards we compared nonanxiety patients. The studyincluded 146patients(52 male, 94 female) without history of any seizures or other neurological diseases, hospitalized in Non-psychotic Wardof Department of Psychiatry. The age ranged from 18 to 57 mean 34 year old. According to DSM-IV we set up three anxiety groups: (l) panic disorders (with/without agorafobia) - 46 persons (15 m, 31 f); (2) general anxiety disorders and posttraumatic stress disorders - 30 persons (II rn, 19 f); (3) fobias (simple,social. agorafobia without panic attacks) -16 persons(8 m, 8 f). As nonanxiety patients' we formed two comparative groups: (4) mood disorders (major depressive disordersinleepisode, recurrent, dysthymia) - 24 persons(9 m, 15 0, and (5) somatoform disorders (somatization disorders. conversion disorders, hypochondriasis) - 30 persons(9 m, 11 f). After 10 days drug free period we made EEG and visually assessed abnormalities revealed general pathology and/or fit's activity in EEG. In group(I) - patients with panicdisorders- we found 14personswith EEG abnormalities (30%); in group (2) - patients with general anxiety disorders - 7 persons(23%)had pathology in EEG;in group(3) - patients with fobias- in 3 persons(19%) EEG was pathological. In group(4)- patients with mooddisorders - we found 19personswith pathology in EEG (21%) and in group (5) - patients with somatoform disorders - we revealed II persons(36%)with EEG abnormalities. Wedid not find any significant differences between data we obtained. We tried to stale the frequency of fit's activity in EEG localized in temporal-limbic structures. The frequencies of such abnormalities were successively as follows (from(1) to (5) group): 13%; 13%;6%; 8%; 13%. The differencies we obtained did not reach to significant level. In our further step we did not find significant differences in frequency of EEG abnormalities either in sex or in age differentiations. Results we obtained are close to those of Jabourian et al. (1992), in respect to relatively high ratio of EEG abnormalities in various types of anxiety disorders (with no special regards to panic disorders) as well as in mood
S4-150
IP.5.030 IThe effect of the neuroactivesteroid a-THODC, on staircase test behavior In mice
R. Weizman 1, Y. Peter 2, 1. Terkel3, M. Gavish4 , c.o. Pick2. I Tel-Aviv Community MentalHealth Centerand SacklerFaculty of Medicine, Tel-Aviv University, RamatAviv, Haifa, Israel; 2 Department of Anatomy andAnthropology, SacklerFaculty of Medicine. 3 Department of Zoology, Tel-Aviv University, Haifa, Israel; 4 Department of Pharmacology, Faculty of Medicine. Technion-Israel Instituteof Technology, Haifa. Israel This study examined the effect of the neuroactive steroid 3a, 5atetrahydrocorticosterone (a-TIIDOC) as compared to benzodiazepines (diazepam and midazolarn) and the barbiturate phenobarbital (PhB) on rearing (NR) and number of steps ascended(NSA) in the mousestaircase test. According to this paradigmNSA reflects locomotoractivity and NR reflects anxiety. The two benzodiazepines, phenobarbital and a- THDOC reduced NR at doses that did not affect NSA. The NR lowering effect inducedby thebenzodiazepines and a-THOOC, butnotPhB,wasblocked by the benzodiazepine antagonist flumazeniJ. It appears that, although neuroactive steroids, like barbiturates, bind to distinct sites within the chloride ion channel of the gamma-arninobutyric acid type A (GABAA) receptor complex, a-THDOC behavioral activity is modulated by the benzodiazepine recognition site.
IP.5.031 I Pharrnaco-psychological effects of S(+) ON·2327 enantiomerand ON·2327 racemate
B. Dietrich,G. Pabst. LAB. GmbH & Co, Neu-Ulm, Germany DN-2327 is a new non-benzodiazepine compound with anxiolytic properties. Analytical studies showed different characteristics of the two enantiomers. This study was performed to explore the central nervous effects of 0.5, 1, 2 and 4 mg of the S(+) DN·2327 enantiomer in comparison to I, 2, 4 and 8 mg of the DN-2327racemate with the help of psychometric tests. Results from 34 healthy male volunteers could be analyzed. With one week intervals the volunteers received 4 different single doses of the investigational compounds, 2 of the racemate and 2 of the S(+) enantiomer, and additionally placebo. Treatment assignment was randomized approaching a balancedincomplete blockdesignas closelyas possible.Psychometric tests were performed pre-doseand again 2.5 and 5.5 hrs post-dose. The following tests were performed: Critical Flicker Fusion Frequency (CFF), Pegboard Test (PT), Tapping Test (IT), Pauli Calculation Test (PCT), and Computerized Learning and Attention Test CGT-(M). CFF was impaired after intake of 2 and 4 mg of the enantiomer as well as 4 and 8 mg of the racemate. The same result was seen with the pegboard test, while the tapping test was not influenced by any of the two compounds. Performance in the Pauli test decreased already after administrating 1 mg of the enantiomer and 2 mg of the racemate. In the CGT-(M) the number of correct answers was not affected by the two compounds. However, the number of "false alarms" increased already after the lowestdose underboth drug conditions. Since reaction time was only prolonged after intake of 4 mg of the enantiomer and 8 mg of the racemate, this effect was obviously not related to sedative effects. Effects were strongest at 2.5 hrs post-dose. Only after intakeof the higherdoses of 2 and 4 mg of the enantiomer, respectively 4 and 8 mg of the racemate effects persisted at 5.5. hrs post-dose. The relative potency of the enantiomer in comparison to the racemate showed a ratio of 1:2, thus indicating that the S(+) DN-2327 enantiomer is the pharmaco-dynamic activepart of the DN-2327 racemate.
J
P.5.032I Clinical effects of buspirone In social phobia.a double-blind placebo controlled study
I.M. van Vliet, I.A. den Boer, H.G.M. Westenberg, K.L. Ho Pian. Department of Psychiatry. University Hospital Utrecht, P.O. Box 85500. 3508GA Utrecht, The Netherlands Socialphobiais one of the morecommonpsychiatric disorders, occurring in about 2% of the population. Recently, attention is focussed on the pharmacological treatments of social phobia. Selective and nonselective
MAO-inhibitors, as wellas selective serotoninreuptakeinhibitors (SSRIs) appearto be effective treatments. The results of these studies suggestthat serotonergic neuronal systems might be implicated, but which serotonergic subtype(s) are involved is as yet unclear. The results of open pilot studiessuggestthatthe serotonin IA (5-HT1A ) receptoragonistbuspirone might be effective in social phobia In the present study the efficacy of buspirone was investigated in patients withsocialphobiausing a 12 weekdouble-blind placebocontrolled design. Thirty social phobic patients (DSM-IV) were treated with either buspirone 30 mg daily or placebo. Efficacy of treatment was measured using the Social Phobia Scale (subscores anxiety and avoidance) and the Hamilton Anxiety Scale. Results: Taking a reduction of 50% or more on the Social Phobia Scale as a criterion for clinically relevant improvement, only one patient on buspirone and one on placebo were classified as responder to treatment. A subjective and clinically relevant improvement was reported by four patients (27%) on buspirone and two patients (13%) on placebo. There were no statistically significant differences betweenbuspironeand placebo on any of the outcome measures social phobic anxiety, social phobicavoidance and generalanxiety. Generallyspeaking,buspironewas well-tolerated and showed only few side effects. Inconclusion: the resultsof the presentdouble-blind placebocontrolled study do not support the results of open studies, in which a reduction of social anxiety and social avoidance was reported in patients with social phobia treatedwith buspirone.
IP.5.033I EEG abnormalitiesIn anxiety disorders R. Brzezinski, M. Dabkowski, A. Araszkiewicz, 1. Uziallo. Department of Psychiatry, Ludwig RydygierMedical Academyul. Kurpinskiego 19, 85-096 Bydgoszcz; Poland Pathophysiological connections between panic disorders and epilepsy have been repeatedly discussed. Certain phenomenological similarities, some concurrence in treatment paradigms and possible common neuroanatomic localization has to be postulated in limbic system bias towards such hypotheses. (P.V. Nickel and T.W. Uhde, 1994/1995; K. Dantendorfet al. 1995). In our study we assessed the frequency of electroencephalographic (EEG)abnormalities in anxiety patients and in this regards we compared nonanxiety patients. The studyincluded 146patients(52 male, 94 female) without history of any seizures or other neurological diseases, hospitalized in Non-psychotic Wardof Department of Psychiatry. The age ranged from 18 to 57 mean 34 year old. According to DSM-IV we set up three anxiety groups: (l) panic disorders (with/without agorafobia) - 46 persons (15 m, 31 f); (2) general anxiety disorders and posttraumatic stress disorders - 30 persons (II rn, 19 f); (3) fobias (simple,social. agorafobia without panic attacks) -16 persons(8 m, 8 f). As nonanxiety patients' we formed two comparative groups: (4) mood disorders (major depressive disordersinleepisode, recurrent, dysthymia) - 24 persons(9 m, 15 0, and (5) somatoform disorders (somatization disorders. conversion disorders, hypochondriasis) - 30 persons(9 m, 11 f). After 10 days drug free period we made EEG and visually assessed abnormalities revealed general pathology and/or fit's activity in EEG. In group(I) - patients with panicdisorders- we found 14personswith EEG abnormalities (30%); in group (2) - patients with general anxiety disorders - 7 persons(23%)had pathology in EEG;in group(3) - patients with fobias- in 3 persons(19%) EEG was pathological. In group(4)- patients with mooddisorders - we found 19personswith pathology in EEG (21%) and in group (5) - patients with somatoform disorders - we revealed II persons(36%)with EEG abnormalities. Wedid not find any significant differences between data we obtained. We tried to stale the frequency of fit's activity in EEG localized in temporal-limbic structures. The frequencies of such abnormalities were successively as follows (from(1) to (5) group): 13%; 13%;6%; 8%; 13%. The differencies we obtained did not reach to significant level. In our further step we did not find significant differences in frequency of EEG abnormalities either in sex or in age differentiations. Results we obtained are close to those of Jabourian et al. (1992), in respect to relatively high ratio of EEG abnormalities in various types of anxiety disorders (with no special regards to panic disorders) as well as in mood