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Flesinoxan in generalised anxiety disorder: A meta-analysis of two double-blind, placebo-controlled comparisons with alprazolam
P.5 Anxietydisorders andanxiolytics a specific phenomenon or largely depends on changes in stimulus control, or impulsivity? Does serotonin affect the functioning of GABAergic receptor complex, as evaluated by modification of the effects of allosteric modulators of this receptor complex in monoamine depleted animals? The aim of our research was to answer some questions related to this matter. To that end we have analyzed the effects of selective depletion of brain serotonin with neurotoxin (5,7-dihydroxytryptamine. 5,7-DHT) or synthesis inhibitor (p-chlorophenylalanine, p-CPA) at different time points after neurotoxin application, in two animal models of anxiety; the open field model of a neophobic reaction in naive male Wistar rats, and the Vogel conflict test of punished drinking. GABA chloride channel blocker picrotoxin and allosteric full agonist midazolam were also given intra-hippocampally, in p-CPA pretreated animals. Both, neurotoxin and synthesis inhibitor produced very strong and comparable decreases in brain serotonin concentrations. It was also found that p-CPA and 5,7-DHT significantly and selectively disinhibited rats behavior in the Vogel but not in the open field test. More powerful and longer lasting effect was present after 5,7-DHT administration and it was inversely correlated with the extent of monoamine depletion. The disinhibitory influence of p-CPA in the Vogel test was antagonized by local pretreatment of animals with intra-hippocampally injected picrotoxin (0.1 f.Lg). On the other hand, intra- hippocampal administration of midazolam maleate caused potent anticonflict effect in the same test. It can be concluded from these data that both neurotransmitter systems cooperate antagonistically in processing of emotional input. The decrease in serotonergic activity probably leads to activation of limbic GABAeric innervation, thus producing anti-anxiety like effects. Moreover, it seems that hippocampus as a target structure for both GABA and 5-HT innervation is important for interaction between these neuronal systems to occur. It also appears that serotonergic innervation of the brain is not essential for expression of rat neophobic reaction.
I P.5.00S!
Fleslnoxan In generalised anxiety disorder: A meta-analysis of twodouble-blind, placebocontrolled comparisons with alprazolam
J.M. de Voogd, SJ. van den Berg. Solvay DupharB.
v.. C. J. van
Houtenlaan 36. 1381 CP Weesp, TheNetherlands Benzodiazepine treatment for generalised anxiety disorder (GAD) may be associated with abuse liability and impaired psychomotor skills. Flesinoxan is a potent and selective 5-HT 1A receptor agonist. It has a higher receptor affinity than the partial 5-HT lA agonists (Schipper et al., 1991) and has shown anxiolytic activity in animal models. The results from two identical placebo-controlled, multicentre, randomised studies conducted to assess the efficacy and safety of fixed-dose flesinoxan in patients with GAD have been combined in this metaanalysis. Alprazolam was used as the active reference drug in both studies. Following a single-blind, one-week, placebo run-in period, patients with DSM-ill-R GAD (minimal duration of symptoms y 2 months) received double-blind treatment with oral flesinoxan (0.4, 1.2 or 4.0 mglday), alprazolam (1.5 mglday) or placebo for 4 weeks. Thereafter, alprazolam was tapered off over one week, whilst f1esinoxan was replaced with placebo. The primary efficacy variables consisted of the total score on the Hamilton Rating Scale for Anxiety (HAM-A), adjusted for baseline, and the improvement score on the Clinical Global Impression (COl) scale. One hundred and fifty-five patients received 0.4 mglday f1esinoxan, 155 received 1.2 mglday f1esinoxan, 156 received 4.0 mglday f1esinoxan, 154 received alprazolam and 160 received placebo. After 4 weeks of treatment, both f1esinoxan 0.4 mglday and alprazolam were significantly more effective than placebo. The significantly superior effects of f1esinoxan 0.4 mglday and alprazolam, compared with placebo, were confirmed by the COl severity score and the Clinical Anxiety Scale total score. After stopping treatment, the patients on f1esinoxan remained well, whilst the patients on alprazolam suffered from a rapid return of symptoms. The most common adverse events with f1esinoxan were nausea, dizziness and headache. The 0.4 mglday dose was especially well tolerated, with an incidence of adverse events similar to placebo. Flesinoxan had no effect on vital signs or laboratory parameters.
S4-l4l
In conclusion. f1esinoxan at a dose of 0.4 mglday is effective and safe in the treatment of patients with GAD.
Reference Schipper. r, Tulp,M. Th.M.,Berkelmans, B., Mos. J., van der Heijden, lA.M. and Olivier, B. (1991). Preclinical pharmacology of ftesinoxan: a potential anxiolytic and antidepressant drug. HumanPsychopharmacology 6, S53-S61.
IP.5.007!
Long-term effects of alprazolam on memory: A 3 1/2 year follow upof agoraphobic patients
C. Kili.. I, V.C. Curran 2, H. Noshirvani 3, M. Basoglu 3, I.M. Marks 3. 1 Hacettepe University Medical School, Department ofPsychiatry, Ankara06100, Turkey; 2 Clinical Health Psychology, University College London, Gowerstreet, London WClE 6BT; 3 Institute of Psychiatry, 99 Denmark Hill, SE5 8AF, London
Clinical concern about the use of benzodiazepine (BZ) anxiolytics and hypnotics has mainly focussed on issues of dependency on these drugs and the associated withdrawal syndrome often observed when people stop taking BZs. Concern regarding the consequences of BZ use on memory and cognitive function has received rather less prominence, despite the large body of research showing that single doses of BZs can produce anterograd amnesia. It is therefore important to delineate the cognitive effects of BZs while drug is being taken over a period of weeks, or even years. Further. given the evidence of cognitive impairment whilst these drugs are being taken, it is also important to monitor whether cognitive function recovers over time after people stop taking BZs. In a previous study (Curran et al 1994), we assessed 38 patients with a diagnosis of agoraphobia with panic disorder. These patients were a sub-set of the 82 who were the London patients in the London-Toronto treatment study (Marks et al 1993). The patients had been randomly allocated to one of four parallel treatment groups which resulted from combining two drug conditions (alprazolam or matching placebo) with two psychological treatment conditions (exposure or relaxation). Patients were given a battery of memory tests assessing immediate and delayed recall, attention, motor speed and subjective memory. We found that alprazolam produced pronounced impairments on a word recall task at the end of 8 weeks treatment. At the end of 24-week medication-free followup, alprazolam patients were still impaired on the task compared with placebo subjects. One implication of this latter finding could be that alprazolam-induced memory impairments persist at least several weeks beyond drug cessation. The present study aimed to assess whether there are any residual impairments in this patient population approximately 3 112 years after they had taken alprazolam in the clinical trial. We therefore followed up the London patients from the study of Marks et al (1993) many of whom had also been tested for the study of Curran et al (1994). No memory decrements were found, with patients who had originally been treated with alprazolam performing at the same levels as those originally treated with placebo. The implications of these findings are drawn out and we suggest that memory impairments observed in our previous study several weeks after withdrawal of alprazolam are due to the drug's interference with practice and test-exposure effects.
References Curran HV, Bond A, O'Sullivan G. Bruce M, Marks I, Lelliot P, Shine P, Lader M (1994) Memory functions, alprazoJam and exposure therapy: a controlled longitudinal studyof agoraphobia with panicdisorder. Psychological Medicine, 24: 969-976. Marks 1M, Swinson RP, Ba§o~lu M, Kuch K, Noshirvani H.O'SullivanG, Lelliotp. Kirby G, McNamee G. SengunS. Wickwire K (1993)Alprazolam and exposure alone and combined in panic disorderwith agoraphobia: a controlled study in London and Toronto. Br J Psychiatry, 162:776--787.
I P.5.00S!
Fleslnoxan In generalised anxiety disorder: A meta-analysis of twodouble-blind, placebocontrolled comparisons with alprazolam
J.M. de Voogd, SJ. van den Berg. Solvay DupharB.
v.. C. J. van
Houtenlaan 36. 1381 CP Weesp, TheNetherlands Benzodiazepine treatment for generalised anxiety disorder (GAD) may be associated with abuse liability and impaired psychomotor skills. Flesinoxan is a potent and selective 5-HT 1A receptor agonist. It has a higher receptor affinity than the partial 5-HT lA agonists (Schipper et al., 1991) and has shown anxiolytic activity in animal models. The results from two identical placebo-controlled, multicentre, randomised studies conducted to assess the efficacy and safety of fixed-dose flesinoxan in patients with GAD have been combined in this metaanalysis. Alprazolam was used as the active reference drug in both studies. Following a single-blind, one-week, placebo run-in period, patients with DSM-ill-R GAD (minimal duration of symptoms y 2 months) received double-blind treatment with oral flesinoxan (0.4, 1.2 or 4.0 mglday), alprazolam (1.5 mglday) or placebo for 4 weeks. Thereafter, alprazolam was tapered off over one week, whilst f1esinoxan was replaced with placebo. The primary efficacy variables consisted of the total score on the Hamilton Rating Scale for Anxiety (HAM-A), adjusted for baseline, and the improvement score on the Clinical Global Impression (COl) scale. One hundred and fifty-five patients received 0.4 mglday f1esinoxan, 155 received 1.2 mglday f1esinoxan, 156 received 4.0 mglday f1esinoxan, 154 received alprazolam and 160 received placebo. After 4 weeks of treatment, both f1esinoxan 0.4 mglday and alprazolam were significantly more effective than placebo. The significantly superior effects of f1esinoxan 0.4 mglday and alprazolam, compared with placebo, were confirmed by the COl severity score and the Clinical Anxiety Scale total score. After stopping treatment, the patients on f1esinoxan remained well, whilst the patients on alprazolam suffered from a rapid return of symptoms. The most common adverse events with f1esinoxan were nausea, dizziness and headache. The 0.4 mglday dose was especially well tolerated, with an incidence of adverse events similar to placebo. Flesinoxan had no effect on vital signs or laboratory parameters.
S4-l4l
In conclusion. f1esinoxan at a dose of 0.4 mglday is effective and safe in the treatment of patients with GAD.
Reference Schipper. r, Tulp,M. Th.M.,Berkelmans, B., Mos. J., van der Heijden, lA.M. and Olivier, B. (1991). Preclinical pharmacology of ftesinoxan: a potential anxiolytic and antidepressant drug. HumanPsychopharmacology 6, S53-S61.
IP.5.007!
Long-term effects of alprazolam on memory: A 3 1/2 year follow upof agoraphobic patients
C. Kili.. I, V.C. Curran 2, H. Noshirvani 3, M. Basoglu 3, I.M. Marks 3. 1 Hacettepe University Medical School, Department ofPsychiatry, Ankara06100, Turkey; 2 Clinical Health Psychology, University College London, Gowerstreet, London WClE 6BT; 3 Institute of Psychiatry, 99 Denmark Hill, SE5 8AF, London
Clinical concern about the use of benzodiazepine (BZ) anxiolytics and hypnotics has mainly focussed on issues of dependency on these drugs and the associated withdrawal syndrome often observed when people stop taking BZs. Concern regarding the consequences of BZ use on memory and cognitive function has received rather less prominence, despite the large body of research showing that single doses of BZs can produce anterograd amnesia. It is therefore important to delineate the cognitive effects of BZs while drug is being taken over a period of weeks, or even years. Further. given the evidence of cognitive impairment whilst these drugs are being taken, it is also important to monitor whether cognitive function recovers over time after people stop taking BZs. In a previous study (Curran et al 1994), we assessed 38 patients with a diagnosis of agoraphobia with panic disorder. These patients were a sub-set of the 82 who were the London patients in the London-Toronto treatment study (Marks et al 1993). The patients had been randomly allocated to one of four parallel treatment groups which resulted from combining two drug conditions (alprazolam or matching placebo) with two psychological treatment conditions (exposure or relaxation). Patients were given a battery of memory tests assessing immediate and delayed recall, attention, motor speed and subjective memory. We found that alprazolam produced pronounced impairments on a word recall task at the end of 8 weeks treatment. At the end of 24-week medication-free followup, alprazolam patients were still impaired on the task compared with placebo subjects. One implication of this latter finding could be that alprazolam-induced memory impairments persist at least several weeks beyond drug cessation. The present study aimed to assess whether there are any residual impairments in this patient population approximately 3 112 years after they had taken alprazolam in the clinical trial. We therefore followed up the London patients from the study of Marks et al (1993) many of whom had also been tested for the study of Curran et al (1994). No memory decrements were found, with patients who had originally been treated with alprazolam performing at the same levels as those originally treated with placebo. The implications of these findings are drawn out and we suggest that memory impairments observed in our previous study several weeks after withdrawal of alprazolam are due to the drug's interference with practice and test-exposure effects.
References Curran HV, Bond A, O'Sullivan G. Bruce M, Marks I, Lelliot P, Shine P, Lader M (1994) Memory functions, alprazoJam and exposure therapy: a controlled longitudinal studyof agoraphobia with panicdisorder. Psychological Medicine, 24: 969-976. Marks 1M, Swinson RP, Ba§o~lu M, Kuch K, Noshirvani H.O'SullivanG, Lelliotp. Kirby G, McNamee G. SengunS. Wickwire K (1993)Alprazolam and exposure alone and combined in panic disorderwith agoraphobia: a controlled study in London and Toronto. Br J Psychiatry, 162:776--787.