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Fluoxetine treatment of children and adolescents with obsessive-compulsive disorders: A open-label trial
P'S Anxietydisorders and anxiolytics
54-142
Ip.5.ooal A new method to quantify effects of
benzodiazepines on normal daily activities: Ambulatory accelerometry in psychopharmacological research
I.H.M. Tulen J, I.B.I. Bussmann2. J Department of Psychiatry, 2 Department of Rehabilitation Medicine. University HospitalRotterdam Dijktlgt, Dr. Molewaterplein 40, 3015 GD Rotterdam. TheNetherlands Ambulatory monitoring devices are increasingly employed to study psychopharmacological processes in real-life situations. In order to evaluate the extend to which the anxiolytic and sedative properties of benzodiazepines affect normal daily functioning, changes in body posture and physical and locomotor activity need to be studied in detail during daytimeambulation. Weevaluated accelerometry, by meansof body mounted piezo-resistive sensors on the sternum and upper legs, as a method to quantify both static (lying, sitting, standing) and dynamic activities (e.g. walking) in an ambulatory study that was designed to assess the effects of alprazolam and lorazepamon normaldaily activities. In a double-blind randomized study, twelvemalevolunteers (mean age: 22 years, range 19-25) received either an oral dose of 2 mg lorazepam, or 0.5 mg alprazolam, or I mg alprazolam, or a placebo, on four different days, which were separated by at least five days. At 8.15 hours, the subjects received the oral dose of alprazolam, lorazepam or placebo. During the morning part of the experiment, the subjects participated in a standardized laboratory protocol. The afternoon part of the study comprised 4 hours of ambulatory measurements of the accelerometer signals by means of a small portabledigitalrecorder(Vitaport System)in a living room in the hospitalwherethe subjects could movearoundfreely, study, relax, or sleep. A separate validation study for our 'ambulatory' environment was performedin whichtheclassification of activities (based on accelerometry) by means of computeranalysisduring6 recording sessions was comparedwith a visual evaluation of simultaneously recorded video tapes. Comparisonof the computerclassification basedon accelerometry with the visual analysis based on videotapes in our validation study revealed an 88% agreement for the static and dynamic activities. Afterplaceboadministration, analysis of spontaneous activities showed that the subjects spent most of their time in the sitting position (76%), with II % of the time lying and 6% of the time standing. Dynamic movements occurred only during 7% of the total recorded time period. After oral benzodiazepine administration, the subjects spent significantly more time in the lying position (p < 0.01; lorazepam highest: 35%; alprazolam 0.5 mg: 26%; alprazolam I mg: 26%), and significantly less time in the sitting position (p < 0.01; lorazepam lowest: 53%; alprazolam 0.5 mg: 62%; alprazolam I mg: 60%). Lorazepam and alprazolam had no effect on the time spent in static standing or general dynamic activities. After benzodiazepine administration, motility (small body movements) during static activities reduced significantly (p < 0.025), with motility after 10razepam administration being lowest We observed no clear dose-related effectsof alprazolam on the activity parameters. The validation study showed that accelerometry forms a reliable method to quantify aspects of normal daily activities. Our psychopharmacological study revealed that quantification of body postures, physical activity and motility by means of ambulatory accelerometry proved to be sufficiently sensitive to differentiate drug from placebo effects, indicating that accelerometry forms a promising tool to evaluate the sedative and anxiolytic properties of benzodiazepines in relation to normal daily functioning.
IP.5.00SI Sympatho-adrenomedullary activity during mental stress and orthostatic challenge: Effects of alprazolam and lorazepam
I.H.M. Tulen J, F. Boomsma2 , L. Pepplinkhuizen J. J Department of Psychiatry, 2 Department of Internal Medicine I. University Hospital Rotterdam Difkzigt, Dr. Molewaterplein 40. 3015 GD Rotterdam, The Netherlands Treatment of anxiety symptoms in patients with cardiovascular dysfunctions often includes benzodiazepines. Becausesuppression of sympathoadrenomedullary activation to stress may be desirable in patients with
stress-related cardiovascular disorders,a benzodiazepine with such properties may be of interest.The present study aimed to investigate whether oral administration of alprazolam suppresses catecholaminergic and cardiovascular activity during mental stress (Color Word Test, CWT) and orthostatic challenge (OCT), differentfrom lorazepam and in comparison with placebo, in 12 healthymale volunteers (mean age 22 ± 2 years). All subjectsreceived, in a randomized double-blind cross-overdesign, either an oral dose of 0.5 mg alprazolam, or I mg alprazolam, or 2 mg lorazeparn, or a placebo, on four different days which were separated by at least five days. On each experimental day, 30 min after dose administration at 8.15 hrs, the subjects were studied during supine rest (three periods of 15 min each), performance of the CWT (10 min) after a stabilization period in the sitting position (10 min), and a 10 min period of active standing (OCT). For determination of plasma catecholamine concentrations, blood samples were collected after each supine or sitting rest period, after 5 min during performance of the CWT and after 10 min of standing. ECG and blood pressure (Finapres device) were recorded continuously. Heart rate and mean blood pressure were quantified per 5 min periods for the rest and ocr situations, and per 2.5 min for'the CWT. Subjective sleepiness was assessed after each rest period by means of the Stanford Sleepiness Scale. Statistical analysis were performed by means of multivariate analyses of variance (MANOVA) for repeated measurements. Versus placebo administration, alprazolam induced a trend towards a reduction of plasma adrenaline concentrations during supine rest and mentalload, and significantly suppressed adrenaline concentrations during orthostatic challenge; the effects during the CWT and the ocr appeared to be dose-dependent In addition, alprazolam significantly suppressed mean blood pressure and plasma noradrenaline concentrations, but only during supinerest. At both dose levels, alprazolam significantly increased subjective sedation. When comparingresponses to alprazolam (l mg) and lorazepam (2 mg), alprazolam showed reduced mean blood pressure levels during supine rest, whereas lorazepam showed a higher heart rate during supine rest, a reduced plasma noradrenaline response to the OCT and a performance deterioration to the CWT. There were no differences between alprazolam (I mg) and lorazepam (2 mg) regarding subjectivesedation. Although the benzodiazepines were similar regarding their increase of sedation, alprazolam and lorazepam induced differential effects on sympatho-adrenomedullary activity during rest and stress, whereby suppression of adrenomedullary activity occurred only after alprazolam administration. In the treatment of anxiety symptoms in patients with stress-related cardiovascular disorders, this characteristic of alprazolam may be an advantage over the use of otherbenzodiazepines.
IP.5.010 I Fluoxetine treatment of children and adolescents with obsessive-compulslve disorders: A open-label trial
Z.B. Baysal, F. Unal. Hacettepe University Department of Child and Adolescent Psychiatry, Ankara, Turkey In recent years, there has been increasing interest in the development of specific serotonin reuptake inhibitors. Some studies have demonstrated that lIuoxetine is effective in relieving OCD symptoms in children and adolescents as well as in adults with OCD (i). Fluoxetine recently has been introduced into general clinical use on the child and adolescents in Turkey. The reported frequency of OCD associated with Gilles de la Tourette syndrome (GTS) has variedfrom 12% to 90%. Most studies have found OCD symptoms in about half of GTS patients (ii). This study was designed to examine the safety and efficacy of fluoxetinein children and adolescents with obsessive-compulsive disorders (OCD) as an open-label trial with fixed-dose (20 mglqd) f1uoxetine for a 20 week period in 25 children and adolescents with OCD, aged 8-16 years. All subjects were evaluated medically and psychiatrically by two different child psychiatrists and all met DSM-IV diagnostic criteria for OCD. In addition, eleven of the subjects received a diagnosis of GTS and two subjects had depression. OCDsymptomsseverity was measured on the Maudsley OCD scale translated and standardized in Turkish and Clinical's Global impression scale.
P.5 Anxietydisorders andanxiolytics
S4-143
Medical assessmentincludingphysicalexamination, weightand blood pressure measurement, clinical laboratory studies including electrocardiogram(ECG),routineclinicalchemistries, blood count,urinalysis were done at the beginningand the end of the study. None of the subjectshad prior history of treatmentwith psychotrophic medications before receiving fluoxetine. Concurrent medications including antipsychotics were used with fluoxetine in eleven subjects (%44), mostlyfor the treatmentof comorbidGTS. The patients with OCD showed a significant decrease in the severity of their OCD symptoms as reflected in the Maudsley OeD scores and Global Assessment Scale. However, one of the 11 OCD patients with comorbid GTS showed worsening of tic severity. Responder rates were similarin the primary OCD (%85.5)and GTS + OCD (%91) (p > 0.05). No relationship was observed between responder status and primary diagnosis, clinical settingor concurrentmedication. Fluoxetine was well toleratedby childrenand adolescents. Side effects reportedby the entire sample includeddyspepsia and nousea (n =3) and skin rash (n = I). They were relatively mild and not severeenoughto discontinuethe drug.There were no ECGchanges,laboratory abnormalities, blood pressureor weightchangesduring the study. In summary, the present open-label trial suggests a new safe and effective drug in the arsenalfor treatingOCD in childrenand adolescents. The major limitations of this study were the fixeddose and open-label design. Further studies of these findings using double-blind, placebo-controlled methodology and larger samplesare warranted. References
[I] Riddle, M.A., Scahill, L.,King, R.A andet aI. (1992) Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with obsessive compulsive disorders, J Am Acad Child Adolesc Psychiatry 31 (6), 1062-1069. [2] Como, P.G., Kurian, R. (1988) Standardized assessment of attention deficit disorder and obsessive compulsive disorders in a Tourette syndrome clinic population (Abstract), J Clin Exper NeuropsychollO, 29.
IP.5.011 I Pharmacotherapy and briefdynamic psychotherapy of panic disorder
A.A. Dahl, 1M. Wiborg. Department Group of Psychiatry, Research Unit, GaustadHospital, University of Oslo, P.O. Box 33, Gaustad, 0320 Oslo, Norway Researchhas shownthat as many as two-thirds of patients with panicdisorder with and withoutagoraphobia (PD)relapseafter end of medication. The primary aim of our study was to test the hypothesis that a treatment which includedmedicationcombinedwith brief dynamicpsychotherapy would result in a lower relapserate after pharmacotherapy. Forty patients with PD (DSM-III-R) were randomly assignedto treatment with, either,clomipramine for 9 months (N = 20), or, clomipramine for 9 months combined with 15 weekly sessions of brief dynamic psychotherapy (N =20). Measuresof anxiety and depressionwere collected at intake and at regular intervals. The patients had blind follow-up interviews at 6, 12, and 18 months after treatmentstart. All patients became free of panic attacks within 26 weeks of start of treatment. On termination of pharmacotherapy, the relapse rate were significantly higher in the clomipramine only group duringthe follow-up period. There were significantly lower scores for most anxiety measures in the clomipranine plus psychotherapy group at 18-month follow-up. The addition of brief dynamic psychotherapy to treatment with clomipramine significantly reduces the relapse rate of panic disorder comparedto clomipramine treatmentalone. References
Klein DF, Gorman JM. (1987) A model of panic disorder and agoraphobia development. Acta Psychiatr Scand Supp!. 335, 87-95. [2] Teich MJ, Lucas RA. (1994) Combined pharmacological and psychological treatment of panic disorder: Current status and future directions. In: Wolfe BE, Maser JD, eds. Treatment ofPanic Disorder. 177-199.
[I]
IP.5.013! Safety profile of fleslnoxan; results form a
meta-analysis of studies In patients with major depressive disorder or generalised anxiety disorder
lM. de Voogd, G. Stevens. Solvay DupharB. v., C.l. van Houtenlaan 36, 1381 CP Weesp, TheNetherlands Flesinoxan is a potentand selective 5-HTIA receptoragonist.Preliminary clinical studies have indicated that flesinoxan is safe and well tolerated at daily doses of up to 8 mg/day. In order to assess the safety profile of flesinoxan further, a meta-analysis of four clinical studies has been conducted. Safety variables were combinedfrom four placebo-controlled, multicentre,randomised, parallel-group studies,two of which were conducted in patients with DSM-III-Rmajor depressive disorderand two in patients with DSM-ill-R generalised anxiety disorder (GAD). Patients received double-blind treatment with oral flesinoxan (0.4, 1.2 or 4.0 mg/day) or placebo; imipramine (150 mg/day) was the activereferencedrug in major depressive disorderand alprazolam (1.5 mg/day)in GAD.Treatmentwas continued for six weeks in patients with major depressive disorder and four weeks in patients with GAD. Two hundred and sixty five patients received 0.4 mg/day flesinoxan, 257 received 1.2mg/day flesinoxan, 261 received4.0 mg/dayflesinoxan, 104 received imipramine, 154 received alprazolam and 374 received placebo.
54-142
Ip.5.ooal A new method to quantify effects of
benzodiazepines on normal daily activities: Ambulatory accelerometry in psychopharmacological research
I.H.M. Tulen J, I.B.I. Bussmann2. J Department of Psychiatry, 2 Department of Rehabilitation Medicine. University HospitalRotterdam Dijktlgt, Dr. Molewaterplein 40, 3015 GD Rotterdam. TheNetherlands Ambulatory monitoring devices are increasingly employed to study psychopharmacological processes in real-life situations. In order to evaluate the extend to which the anxiolytic and sedative properties of benzodiazepines affect normal daily functioning, changes in body posture and physical and locomotor activity need to be studied in detail during daytimeambulation. Weevaluated accelerometry, by meansof body mounted piezo-resistive sensors on the sternum and upper legs, as a method to quantify both static (lying, sitting, standing) and dynamic activities (e.g. walking) in an ambulatory study that was designed to assess the effects of alprazolam and lorazepamon normaldaily activities. In a double-blind randomized study, twelvemalevolunteers (mean age: 22 years, range 19-25) received either an oral dose of 2 mg lorazepam, or 0.5 mg alprazolam, or I mg alprazolam, or a placebo, on four different days, which were separated by at least five days. At 8.15 hours, the subjects received the oral dose of alprazolam, lorazepam or placebo. During the morning part of the experiment, the subjects participated in a standardized laboratory protocol. The afternoon part of the study comprised 4 hours of ambulatory measurements of the accelerometer signals by means of a small portabledigitalrecorder(Vitaport System)in a living room in the hospitalwherethe subjects could movearoundfreely, study, relax, or sleep. A separate validation study for our 'ambulatory' environment was performedin whichtheclassification of activities (based on accelerometry) by means of computeranalysisduring6 recording sessions was comparedwith a visual evaluation of simultaneously recorded video tapes. Comparisonof the computerclassification basedon accelerometry with the visual analysis based on videotapes in our validation study revealed an 88% agreement for the static and dynamic activities. Afterplaceboadministration, analysis of spontaneous activities showed that the subjects spent most of their time in the sitting position (76%), with II % of the time lying and 6% of the time standing. Dynamic movements occurred only during 7% of the total recorded time period. After oral benzodiazepine administration, the subjects spent significantly more time in the lying position (p < 0.01; lorazepam highest: 35%; alprazolam 0.5 mg: 26%; alprazolam I mg: 26%), and significantly less time in the sitting position (p < 0.01; lorazepam lowest: 53%; alprazolam 0.5 mg: 62%; alprazolam I mg: 60%). Lorazepam and alprazolam had no effect on the time spent in static standing or general dynamic activities. After benzodiazepine administration, motility (small body movements) during static activities reduced significantly (p < 0.025), with motility after 10razepam administration being lowest We observed no clear dose-related effectsof alprazolam on the activity parameters. The validation study showed that accelerometry forms a reliable method to quantify aspects of normal daily activities. Our psychopharmacological study revealed that quantification of body postures, physical activity and motility by means of ambulatory accelerometry proved to be sufficiently sensitive to differentiate drug from placebo effects, indicating that accelerometry forms a promising tool to evaluate the sedative and anxiolytic properties of benzodiazepines in relation to normal daily functioning.
IP.5.00SI Sympatho-adrenomedullary activity during mental stress and orthostatic challenge: Effects of alprazolam and lorazepam
I.H.M. Tulen J, F. Boomsma2 , L. Pepplinkhuizen J. J Department of Psychiatry, 2 Department of Internal Medicine I. University Hospital Rotterdam Difkzigt, Dr. Molewaterplein 40. 3015 GD Rotterdam, The Netherlands Treatment of anxiety symptoms in patients with cardiovascular dysfunctions often includes benzodiazepines. Becausesuppression of sympathoadrenomedullary activation to stress may be desirable in patients with
stress-related cardiovascular disorders,a benzodiazepine with such properties may be of interest.The present study aimed to investigate whether oral administration of alprazolam suppresses catecholaminergic and cardiovascular activity during mental stress (Color Word Test, CWT) and orthostatic challenge (OCT), differentfrom lorazepam and in comparison with placebo, in 12 healthymale volunteers (mean age 22 ± 2 years). All subjectsreceived, in a randomized double-blind cross-overdesign, either an oral dose of 0.5 mg alprazolam, or I mg alprazolam, or 2 mg lorazeparn, or a placebo, on four different days which were separated by at least five days. On each experimental day, 30 min after dose administration at 8.15 hrs, the subjects were studied during supine rest (three periods of 15 min each), performance of the CWT (10 min) after a stabilization period in the sitting position (10 min), and a 10 min period of active standing (OCT). For determination of plasma catecholamine concentrations, blood samples were collected after each supine or sitting rest period, after 5 min during performance of the CWT and after 10 min of standing. ECG and blood pressure (Finapres device) were recorded continuously. Heart rate and mean blood pressure were quantified per 5 min periods for the rest and ocr situations, and per 2.5 min for'the CWT. Subjective sleepiness was assessed after each rest period by means of the Stanford Sleepiness Scale. Statistical analysis were performed by means of multivariate analyses of variance (MANOVA) for repeated measurements. Versus placebo administration, alprazolam induced a trend towards a reduction of plasma adrenaline concentrations during supine rest and mentalload, and significantly suppressed adrenaline concentrations during orthostatic challenge; the effects during the CWT and the ocr appeared to be dose-dependent In addition, alprazolam significantly suppressed mean blood pressure and plasma noradrenaline concentrations, but only during supinerest. At both dose levels, alprazolam significantly increased subjective sedation. When comparingresponses to alprazolam (l mg) and lorazepam (2 mg), alprazolam showed reduced mean blood pressure levels during supine rest, whereas lorazepam showed a higher heart rate during supine rest, a reduced plasma noradrenaline response to the OCT and a performance deterioration to the CWT. There were no differences between alprazolam (I mg) and lorazepam (2 mg) regarding subjectivesedation. Although the benzodiazepines were similar regarding their increase of sedation, alprazolam and lorazepam induced differential effects on sympatho-adrenomedullary activity during rest and stress, whereby suppression of adrenomedullary activity occurred only after alprazolam administration. In the treatment of anxiety symptoms in patients with stress-related cardiovascular disorders, this characteristic of alprazolam may be an advantage over the use of otherbenzodiazepines.
IP.5.010 I Fluoxetine treatment of children and adolescents with obsessive-compulslve disorders: A open-label trial
Z.B. Baysal, F. Unal. Hacettepe University Department of Child and Adolescent Psychiatry, Ankara, Turkey In recent years, there has been increasing interest in the development of specific serotonin reuptake inhibitors. Some studies have demonstrated that lIuoxetine is effective in relieving OCD symptoms in children and adolescents as well as in adults with OCD (i). Fluoxetine recently has been introduced into general clinical use on the child and adolescents in Turkey. The reported frequency of OCD associated with Gilles de la Tourette syndrome (GTS) has variedfrom 12% to 90%. Most studies have found OCD symptoms in about half of GTS patients (ii). This study was designed to examine the safety and efficacy of fluoxetinein children and adolescents with obsessive-compulsive disorders (OCD) as an open-label trial with fixed-dose (20 mglqd) f1uoxetine for a 20 week period in 25 children and adolescents with OCD, aged 8-16 years. All subjects were evaluated medically and psychiatrically by two different child psychiatrists and all met DSM-IV diagnostic criteria for OCD. In addition, eleven of the subjects received a diagnosis of GTS and two subjects had depression. OCDsymptomsseverity was measured on the Maudsley OCD scale translated and standardized in Turkish and Clinical's Global impression scale.
P.5 Anxietydisorders andanxiolytics
S4-143
Medical assessmentincludingphysicalexamination, weightand blood pressure measurement, clinical laboratory studies including electrocardiogram(ECG),routineclinicalchemistries, blood count,urinalysis were done at the beginningand the end of the study. None of the subjectshad prior history of treatmentwith psychotrophic medications before receiving fluoxetine. Concurrent medications including antipsychotics were used with fluoxetine in eleven subjects (%44), mostlyfor the treatmentof comorbidGTS. The patients with OCD showed a significant decrease in the severity of their OCD symptoms as reflected in the Maudsley OeD scores and Global Assessment Scale. However, one of the 11 OCD patients with comorbid GTS showed worsening of tic severity. Responder rates were similarin the primary OCD (%85.5)and GTS + OCD (%91) (p > 0.05). No relationship was observed between responder status and primary diagnosis, clinical settingor concurrentmedication. Fluoxetine was well toleratedby childrenand adolescents. Side effects reportedby the entire sample includeddyspepsia and nousea (n =3) and skin rash (n = I). They were relatively mild and not severeenoughto discontinuethe drug.There were no ECGchanges,laboratory abnormalities, blood pressureor weightchangesduring the study. In summary, the present open-label trial suggests a new safe and effective drug in the arsenalfor treatingOCD in childrenand adolescents. The major limitations of this study were the fixeddose and open-label design. Further studies of these findings using double-blind, placebo-controlled methodology and larger samplesare warranted. References
[I] Riddle, M.A., Scahill, L.,King, R.A andet aI. (1992) Double-blind, crossover trial of fluoxetine and placebo in children and adolescents with obsessive compulsive disorders, J Am Acad Child Adolesc Psychiatry 31 (6), 1062-1069. [2] Como, P.G., Kurian, R. (1988) Standardized assessment of attention deficit disorder and obsessive compulsive disorders in a Tourette syndrome clinic population (Abstract), J Clin Exper NeuropsychollO, 29.
IP.5.011 I Pharmacotherapy and briefdynamic psychotherapy of panic disorder
A.A. Dahl, 1M. Wiborg. Department Group of Psychiatry, Research Unit, GaustadHospital, University of Oslo, P.O. Box 33, Gaustad, 0320 Oslo, Norway Researchhas shownthat as many as two-thirds of patients with panicdisorder with and withoutagoraphobia (PD)relapseafter end of medication. The primary aim of our study was to test the hypothesis that a treatment which includedmedicationcombinedwith brief dynamicpsychotherapy would result in a lower relapserate after pharmacotherapy. Forty patients with PD (DSM-III-R) were randomly assignedto treatment with, either,clomipramine for 9 months (N = 20), or, clomipramine for 9 months combined with 15 weekly sessions of brief dynamic psychotherapy (N =20). Measuresof anxiety and depressionwere collected at intake and at regular intervals. The patients had blind follow-up interviews at 6, 12, and 18 months after treatmentstart. All patients became free of panic attacks within 26 weeks of start of treatment. On termination of pharmacotherapy, the relapse rate were significantly higher in the clomipramine only group duringthe follow-up period. There were significantly lower scores for most anxiety measures in the clomipranine plus psychotherapy group at 18-month follow-up. The addition of brief dynamic psychotherapy to treatment with clomipramine significantly reduces the relapse rate of panic disorder comparedto clomipramine treatmentalone. References
Klein DF, Gorman JM. (1987) A model of panic disorder and agoraphobia development. Acta Psychiatr Scand Supp!. 335, 87-95. [2] Teich MJ, Lucas RA. (1994) Combined pharmacological and psychological treatment of panic disorder: Current status and future directions. In: Wolfe BE, Maser JD, eds. Treatment ofPanic Disorder. 177-199.
[I]
IP.5.013! Safety profile of fleslnoxan; results form a
meta-analysis of studies In patients with major depressive disorder or generalised anxiety disorder
lM. de Voogd, G. Stevens. Solvay DupharB. v., C.l. van Houtenlaan 36, 1381 CP Weesp, TheNetherlands Flesinoxan is a potentand selective 5-HTIA receptoragonist.Preliminary clinical studies have indicated that flesinoxan is safe and well tolerated at daily doses of up to 8 mg/day. In order to assess the safety profile of flesinoxan further, a meta-analysis of four clinical studies has been conducted. Safety variables were combinedfrom four placebo-controlled, multicentre,randomised, parallel-group studies,two of which were conducted in patients with DSM-III-Rmajor depressive disorderand two in patients with DSM-ill-R generalised anxiety disorder (GAD). Patients received double-blind treatment with oral flesinoxan (0.4, 1.2 or 4.0 mg/day) or placebo; imipramine (150 mg/day) was the activereferencedrug in major depressive disorderand alprazolam (1.5 mg/day)in GAD.Treatmentwas continued for six weeks in patients with major depressive disorder and four weeks in patients with GAD. Two hundred and sixty five patients received 0.4 mg/day flesinoxan, 257 received 1.2mg/day flesinoxan, 261 received4.0 mg/dayflesinoxan, 104 received imipramine, 154 received alprazolam and 374 received placebo.