- Email: [email protected]
Double-blind comparison of sertraline and placebo in patients with panic disorder
P Poster Presentations
112 disorder with agoraphobia was presented in 21.6% and without agoraphobia in 2.4%. GAD was found in 15.9% and OCD in 5.1%. Current major depression in 24.2%. Avoidant personality disorder was found in 57.3%. Some patients (51.6%) were openly treated for 16 weeks with tranylcypromine (n = 16), moclobemide (n = 25). clonazepam (n = 21) and bromazepam (n 19). All drugs were equally efficacious as assessed by several rating instruments. Among this range of efficacious drugs, the risklbenefit ratio of each drug and the presence of cmorbidity must guide all treatments. Comorbidity with mood and other anxiety disorders, drug abuse and personality disorders is frequent. has therapeutic significance and is a major feature associated with non-response.
studies avoid this problem, but so far few have performed and they have usually comprised too few patients. [Il DeVeaugh-Geiss J, et al. Arch Gen Psychiatry 48 (1991) 730--738 [2] Thoren P et al. Arch Gen Psychiatry 37 ( 1980) 1281-1 285 [3J Greist J. et al. Arch Gen Psychiatry 52 1 (995 ) 53-60
=
IP-1 0-1 0 I Sertraline in Obsessive-Compulsive Spectrum Disorders - A Case Study Series J.C. Bisserbe 2 Pfizerlnc.,
I,
R. Lane 2.
I
Hospital La Salpetriere, Paris. France;
New York, USA
Obsessive-compulsive spectrum disorders (OCSDs) have recently emerged as a category of related disorders characterized by intrusive obsessive thoughts andlor repetitive behaviors. The group shares many common features with obsessive-compulsive disorder (OCD), including overlapping symptom profiles. demographics, family history, neurobiology, cornorbidity, clinical course and response to antiobsessional treatment. OCSDs include somatoform disorders. including body dysmorphophobia and hypochondriasis; dissociative disorders; eating disorders ; tic disorders such as Tourette's syndrome; impulse personality control disorders, such as trichtilornania, pathological gambling and sexual compulsions; and impulsive personality disorders. such as borderline and antisocial personality disorders. The selective serotonin re-uptake inhibitors (SSRIs) have been shown to have a role in the treatment of (X'D; preliminary reports in OCSD suggest a preferential response to these agents. This poster will review early case reports of the efficacy of sertraline in Tourette' s syndrome with attention deficit disorder. paraphilia with trichotilomania, impulsive aggression. obsessional jealousy and bulimia nervosa. In addition, small open studies of sertraline in patients with paraphilic and non-paraphilic disorders. and in personality disordered patients with impulsive aggression will be reviewed. The positive response reported in these case studies suggests a role for sertraline in the spectrum of OCD-related disorders and that further controlled trials of SSRl s in these disorders are warranted.
I P-l0-11 I Effect Size, Placebo Response and Tolerability in Clinical Studies in Obsessive-Compulsive Disorder lC. Bisserbe 2
I.
R. Lane 2.
I
Hospital La Salpetriere, Paris. France;
Pfizer Inc.. New York, USA
The original studies of clomipramine in o e D demonstrated a large treatment effect and a minimal response to placebo [1-3]. However, subsequent studies with SSRIs. have demonstrated smaller treatment effects and a greater response to placebo [3]. In the meta-analysis of Greist et al [3) evaluating the results from the multicenter. placebo controlled trials of clomipramine. fluoxetine, fluvoxamine and sertraline, all drugs were found to be superior to placebo. However, a significantly greater percentage of patients receiving clomipramine (60%) were rated as ' much improved ' or ' very much improved ' on the CGI improvement scale compared to those receiving fluoxetine (38%). fluovoxamine (43%) or sertraline (39%). Surprisingly, the total premature treatment discontinuation rate (due to adverse effects, lack of efficacy or other causes) was also significantly lower in the clomipramine trials compared with the other three agents. The differing results in the recent studies may be due to different populations of OCD patients being studied. Later studies. including less severely ill patients with a more relapsing and remitting illness and a previous history of amiobsessional drug therapy manifest smaller treatment effects with increased variance. Important differences between the treatment studies. highlighted by the recent rise in placebo response rates. suggest comparisons across different studies, e.g. using meta-analysis. are likely to be misleading. Head-to-head comparator
IP-1 0-121 The Generalized Anxiety (GA) and Panic AUacks (PA): Pathogenic Targets for Psychopharmacology A. Avedisova, B. Kogan, S. Paniushkina, N. Darovsky. National Cetre for Social & Forensic Psych. The aim of the study was to expose the correlations between clinical picture of anxiety disorders and neurobiological and psychological factors that might establish pathogenic approach in psychopharmacological treatment. Methods: clinical assessment including HAM-A , variety of psychological tests. computerized EEG, neurobiological investigations. The two main pathways of anxiety development were marked out: "adaptational" pathway that was mostly common in GA and "conflict" pathway inherent in PA. The mostly significant features of each pathway were detected. Detached pathways of anxiety disorders may stipulate specific efficacy of psychotropic drugs with divers activities in GA (tranquilizers, Tricyclic antidepressants) or PA (Tricyclic antidepressants, ISSR).
IP-1 0-131Two-Year Follow-Up After Treatment of Panic Disorder with Agoraphobia
AJ .L.M. van Balkom I . E. de Beurs I . R. van Dyck
I,
A. Lange 2 .
Department of Psychiatry. Vrije Universiteit, the Netherlands; 2 Depart1Jlent of Clinical Psychology. University of Amsterdam, the Netherlands I
Patients participating in a randomized controlled twelve week trial comparing various treatment modalities for panic disorder with agoraphobia, were followed-up two years after treatment. Ninety-six patients meeting DSM-III-R criteria of panic disorder with agoraphobia were randomly assigned to four treatment conditions: double-blind, placebo-controlled fluvoxamine followed by exposure in vivo, psychological panic management followed by exposure in vivo and exposure in vivo alone. Outcome was assessed by self-report measures, assessing agoraphobic avoidance and depression, and continuous monitoring of panic attacks. Seventy-six patients completed the twelve-week study. After twelve weeks, all four treatments were effective and resulted in a significant decrease of agoraphobic avoidance and depression. Moreover, on self-rated agoraphobic avoidance the combination of fluvoxamine with exposure in vivo was significantly superior to the other three conditions. Seventy-two of these patients were followed-up two years later with the same measurement instruments as used in the short-term outcome study. During this follow-up period. 75% of the patients got additional treatment. These patients were equally divided over the four conditions. At follow-up, the superiority of fluvoxamine followed by exposure in vivo was no longer present. Patients initially treated with fluvoxamine maintained their treatment gains. while the patients in the other three conditions improved further.
IP-10-14 I Double-Blind Comparison of Sertraline and Placebo in Patients with Panic Disorder
B. Baumel, R. Bielski. J. Carman, W. Goodman. M. Hegel, C. Houck, R. Linden, B. Nakra, K. Ota, R. Rohl, R. Wolkow. Pfizer Inc A multicenter, lO-week, double-blind, flexible dose, outpatient study of patients with a DSM-III-R diagnosis of panic disorder was conducted to evaluate the efficacy and safety of sertraline and placebo. Ten U.S. centers participated and 168 patients 18 years of age and older received double-blind treatment with either sertraline or placebo. After a 2-week single-blind placebo washout period. patients randomized to sertraline received 25 mg/day for one week after which dosage was flexibly tritrated between 50 and 200 mg/day based upon clinical response. The primary efficacy variable was the number of DSM-III-R defined panic attacks per week. At endpoint. sertraline patients exhibited significantly greater reductions than placebo patients in panic attacks and limited symptom attacks, and the MC-PAS. Hamilton Anxiety. and Clinical Global Im-
113
P Poster Presentations pressions scales. Senraline-treated patients experienced a 77% decrease in panic attack frequency in comparison to a 51% decrease among placebo patients. In addition, sen raline patients rated themselve s significantly more improved than placebo patients on Patient Global Evaluation and Quality of Life scales. The most common adverse experiences in senraline-treated patients were headache , nausea, insomnia. and diarrhea. Treatment discontinuation s due to adverse experiences occurred in 9% of senraline-treated patients. There were no significant differences between treatment groups in the incidence of clinically significant laboratory, vital sign, or ECG abnormalities and there were no serious adverse events in any sertraline-treated patient. In this study senraline in doses of 50-200 mg/day was shown to be a safe and effective treatment for patients with panic disorder, as has been previously demonstrated for both depression and obsessive compulsive disorder.
I P-1 0-151 Can Panic Disorder Patients Treated With More Than4 mg/day of Alprazolam Reduce TheirDose? M. Corrigan, J. Jonas, T. Kitt, S. Goldstein, A. Swiontek, S. Stahl. CNS Development, The Upjohn Co., Kalamazoo, MI. USA This multicenter study investigated the ability of panic disorder patients who required > 4 mg/day to reduce their alprazolam dosage following 12 weeks of treatment . Patients who responded to :s 4 mg of ALP during the prerandomization period were excluded from the study. Nonresponders were then treated with doses up to 10 mg/day for 12 weeks. At that time they were divided into a maintained group (66 patients), or had their dose reduced by 50% (63 patients) during an II week maintenance period. Patients overall showed improvement in their condition during the study. Based on Kaplan-Meier estimate s, the initial response rate was 28.6% at 4 mg, 52.5% at 6 mg, and 88.0% at 10 mg of alprazolam. Overall dropouts were similar between groups . No statistically significant differences in response rates (determined by CGI and/or zero panic attacks) were observed between the Maintained Dose (75.6%) and 50% Dose Reduction (68.6%) groups during the study. More patients in the 50% dose reduction group had treatment emergent signs and symptom s, reflecting the symptoms arising during the the time their dosage was decreased . Conversely, more patients in the maintenance group had discontinuation emergent signs and symptoms during taper, perhaps due to their higher dosage. One week following tapering off drug, patients in the maintained group were more likely to be classified as being in remission and less likely to have relapsed. These results suggest that once desired therapeutic effect has been achieved, it may be possible to reduce alprazolam dose. However, there may be long term treatment benefits to maintaining patients at higher doses.
I P-1 0-161 E~icacy and Safety of Paroxetine in Panic
Disorder R. Judge . SmithKline BeechamPharmaceuticals, New Frontiers Science ParkHarlow, Essex. UK
The efficacy and safety of the selective serotonin reuptake inhibitor paroxetine has been evaluated in over 450 patients with panie disorder with or without agoraphobia. In a randomized comparison with placebo plus cognitive therapy in 120 patients with panic disorder, paroxetine plus cognitive therapy significantly reduced the frequency of panic attacks. A short-term comparative study over 12 weeks in 367 patients showed paroxetine to be at least as effective as clomipramine in the treatment of panic disorder. Moreover, paroxetine-treated patients demonstrated significant improvement over clomipramine in the reduction of panic attacks to zero (5 1% panic free vs 37%, p < 0.05). Paroxetine also appeared to have an earlier onset of action. In a long-term extension of this study, 176 patients continued medication under double-blind conditions and demon strated that the efficacy of paroxetine was maintained over time. Additionally, paroxetine was significantly better tolerated than clomipramine. In a dose range finding study, 40 mg was shown to be the minimum effective dose and a long-term extension of this study showed paroxetine to be significantly more effective than placebo in preventing relapse. In all studies, paroxetine was also effective in reducing the associated symptomatology of panic disorder, such as depressive symptoms, generalized anxiety and phobias. In conclusion, paroxetine is an effective and well tolerated treatment for the control of panic disorder.
I
P-10-17 1 Double-Blind Flexible DoseStUdy of Sertraline
and Placebo in Patients with Panic Disorder R. Wolkow, J. Apter, A. Clayton, W. Coryell , L. Cunningham , W. McEntee, D. O'Hair, M. Pollack, 1. Rausch, R. Stewart, R. Weisler. Pfizer, Inc. A multicenter, lOweek, double-blind , flexible dose, outpatient study of patients with a DSM-Ill-R diagnosis of panic disorder was conducted to evaluate the efficacy and safety of sertraline and placebo. Ten U.S. centers participated and 176 patients 18 years of age and older received double-blind treatment with either sertraline or placebo. After a 2-week single-blind placebo washout period, patients randomized to sertraline received 25 mg/day for one week after which dosage was flexibly tritrated between 50 and 200 mg/day based upon clinical response. The primar y efficacy variable was the number of DSM-IlI-R defined panic attack s per week. At endpoint, sertraline patients exhibited significantly greater reductions than placebo patients in panic attacks (P 0.014) and the MCPAS and Clinical Global Impressions scales. Senraline-treated patients experienced a 79% decrease in panic attack frequency in comparison to a 59% decrease among placebo patients. In addition, senraline patients rated themselves significantly more improved than placebo patients on Patient Global Evaluation and Quality of Life scales. Only two adverse experiences - diarrhea and tremor - occurred with a statistically significantly greater incidence in senral ine-treated patients compared with placebo patients. Treatment discontinuation s due to adverse experiences occurred in 8% of sertraline-treated patients and 3% of placebo patients, a non-significant difference. There were no significant differences between treatment groups in the incidence of clinically significant laboratory, vital sign, or ECG abnormalities. In this study sertraline in doses of 50-200 mg/day was shown to be a safe and effective treatment for patients with panic disorder, as has been previously demonstrated for both depression and obsessive compulsive disorder.
=
1P-1 0-181 CCK-4 in cerebrospinal Fluid: A PilotStudy in Healthy MaleVolunteers T. Gunnarsson, T. EkJundh, M. Eriksson, C. Nordin, S. Sjoberg.
Huddinge and Linkiiping University Hospitals. Sweden We have assayed cholecystokinin-tetrapeptide (CCK-4) (a neurotransm itter with panicogenic effect) in cerebrospinal fluid (CSF) obtained from 14 healthy male volunteers punctured in the sitting position after a minimum of eight hours in the fasting state along with strict bedrest. In 12 ml CSF, the mean concentration was 2.24 ± sd 0.60 pM. The length of the spine in the sitting and lying positions made significant contributions to the variance (R =0.75; p < 0.05). There was no difference in CCK-4 levels between the first and the second 6-ml fraction. The concentration per minute of tapping-time (pM/min) correlated with storage-time (2.4 ± sd 1.0 months) (r = -0.57; P < 0.05) and increased with increasing mean daily atmospher ic pressure. In conclusion, the length of the spine has to be accounted for when measuring CCK-4 in CSF after puncture in the sitting position. There is no gradient between the first and the second 6-ml fraction. Tapping-time and storage-time seem to interact which might mirror a proteolytic process. An influence of atmospheric pressure is at least in part in line with previous observations on transmitter metabolites and needs to be funher investigated.
IP-1 0-19\ Effect of a Malor Depressive Episode History on the CCK-4 Response in Women
l .-M. Le Melledo , 1. Bradwejn, D. Koszycki, F. Bellavance, D.G. Bichet.
Psychobiology Unit, Clarke Institute, Toronto. Canada Studies suggest that women with a history of major depress ive episode (MDE) have a biological vulnerability for anxiety disorders and premenstrual dysphoric disorder (PMDD) . To examine this relationship more closely, we compared response to the panicogenic agent, CCK-4, in women with and without a history of MDE (with the last episode ending at least 2 years prior to participating in the study). The subjects were 29 healthy volunteers (8 with and 21 without a past history of MDE) and 18 women with PMDD (6 with and 12 without a past history of MDE).
112 disorder with agoraphobia was presented in 21.6% and without agoraphobia in 2.4%. GAD was found in 15.9% and OCD in 5.1%. Current major depression in 24.2%. Avoidant personality disorder was found in 57.3%. Some patients (51.6%) were openly treated for 16 weeks with tranylcypromine (n = 16), moclobemide (n = 25). clonazepam (n = 21) and bromazepam (n 19). All drugs were equally efficacious as assessed by several rating instruments. Among this range of efficacious drugs, the risklbenefit ratio of each drug and the presence of cmorbidity must guide all treatments. Comorbidity with mood and other anxiety disorders, drug abuse and personality disorders is frequent. has therapeutic significance and is a major feature associated with non-response.
studies avoid this problem, but so far few have performed and they have usually comprised too few patients. [Il DeVeaugh-Geiss J, et al. Arch Gen Psychiatry 48 (1991) 730--738 [2] Thoren P et al. Arch Gen Psychiatry 37 ( 1980) 1281-1 285 [3J Greist J. et al. Arch Gen Psychiatry 52 1 (995 ) 53-60
=
IP-1 0-1 0 I Sertraline in Obsessive-Compulsive Spectrum Disorders - A Case Study Series J.C. Bisserbe 2 Pfizerlnc.,
I,
R. Lane 2.
I
Hospital La Salpetriere, Paris. France;
New York, USA
Obsessive-compulsive spectrum disorders (OCSDs) have recently emerged as a category of related disorders characterized by intrusive obsessive thoughts andlor repetitive behaviors. The group shares many common features with obsessive-compulsive disorder (OCD), including overlapping symptom profiles. demographics, family history, neurobiology, cornorbidity, clinical course and response to antiobsessional treatment. OCSDs include somatoform disorders. including body dysmorphophobia and hypochondriasis; dissociative disorders; eating disorders ; tic disorders such as Tourette's syndrome; impulse personality control disorders, such as trichtilornania, pathological gambling and sexual compulsions; and impulsive personality disorders. such as borderline and antisocial personality disorders. The selective serotonin re-uptake inhibitors (SSRIs) have been shown to have a role in the treatment of (X'D; preliminary reports in OCSD suggest a preferential response to these agents. This poster will review early case reports of the efficacy of sertraline in Tourette' s syndrome with attention deficit disorder. paraphilia with trichotilomania, impulsive aggression. obsessional jealousy and bulimia nervosa. In addition, small open studies of sertraline in patients with paraphilic and non-paraphilic disorders. and in personality disordered patients with impulsive aggression will be reviewed. The positive response reported in these case studies suggests a role for sertraline in the spectrum of OCD-related disorders and that further controlled trials of SSRl s in these disorders are warranted.
I P-l0-11 I Effect Size, Placebo Response and Tolerability in Clinical Studies in Obsessive-Compulsive Disorder lC. Bisserbe 2
I.
R. Lane 2.
I
Hospital La Salpetriere, Paris. France;
Pfizer Inc.. New York, USA
The original studies of clomipramine in o e D demonstrated a large treatment effect and a minimal response to placebo [1-3]. However, subsequent studies with SSRIs. have demonstrated smaller treatment effects and a greater response to placebo [3]. In the meta-analysis of Greist et al [3) evaluating the results from the multicenter. placebo controlled trials of clomipramine. fluoxetine, fluvoxamine and sertraline, all drugs were found to be superior to placebo. However, a significantly greater percentage of patients receiving clomipramine (60%) were rated as ' much improved ' or ' very much improved ' on the CGI improvement scale compared to those receiving fluoxetine (38%). fluovoxamine (43%) or sertraline (39%). Surprisingly, the total premature treatment discontinuation rate (due to adverse effects, lack of efficacy or other causes) was also significantly lower in the clomipramine trials compared with the other three agents. The differing results in the recent studies may be due to different populations of OCD patients being studied. Later studies. including less severely ill patients with a more relapsing and remitting illness and a previous history of amiobsessional drug therapy manifest smaller treatment effects with increased variance. Important differences between the treatment studies. highlighted by the recent rise in placebo response rates. suggest comparisons across different studies, e.g. using meta-analysis. are likely to be misleading. Head-to-head comparator
IP-1 0-121 The Generalized Anxiety (GA) and Panic AUacks (PA): Pathogenic Targets for Psychopharmacology A. Avedisova, B. Kogan, S. Paniushkina, N. Darovsky. National Cetre for Social & Forensic Psych. The aim of the study was to expose the correlations between clinical picture of anxiety disorders and neurobiological and psychological factors that might establish pathogenic approach in psychopharmacological treatment. Methods: clinical assessment including HAM-A , variety of psychological tests. computerized EEG, neurobiological investigations. The two main pathways of anxiety development were marked out: "adaptational" pathway that was mostly common in GA and "conflict" pathway inherent in PA. The mostly significant features of each pathway were detected. Detached pathways of anxiety disorders may stipulate specific efficacy of psychotropic drugs with divers activities in GA (tranquilizers, Tricyclic antidepressants) or PA (Tricyclic antidepressants, ISSR).
IP-1 0-131Two-Year Follow-Up After Treatment of Panic Disorder with Agoraphobia
AJ .L.M. van Balkom I . E. de Beurs I . R. van Dyck
I,
A. Lange 2 .
Department of Psychiatry. Vrije Universiteit, the Netherlands; 2 Depart1Jlent of Clinical Psychology. University of Amsterdam, the Netherlands I
Patients participating in a randomized controlled twelve week trial comparing various treatment modalities for panic disorder with agoraphobia, were followed-up two years after treatment. Ninety-six patients meeting DSM-III-R criteria of panic disorder with agoraphobia were randomly assigned to four treatment conditions: double-blind, placebo-controlled fluvoxamine followed by exposure in vivo, psychological panic management followed by exposure in vivo and exposure in vivo alone. Outcome was assessed by self-report measures, assessing agoraphobic avoidance and depression, and continuous monitoring of panic attacks. Seventy-six patients completed the twelve-week study. After twelve weeks, all four treatments were effective and resulted in a significant decrease of agoraphobic avoidance and depression. Moreover, on self-rated agoraphobic avoidance the combination of fluvoxamine with exposure in vivo was significantly superior to the other three conditions. Seventy-two of these patients were followed-up two years later with the same measurement instruments as used in the short-term outcome study. During this follow-up period. 75% of the patients got additional treatment. These patients were equally divided over the four conditions. At follow-up, the superiority of fluvoxamine followed by exposure in vivo was no longer present. Patients initially treated with fluvoxamine maintained their treatment gains. while the patients in the other three conditions improved further.
IP-10-14 I Double-Blind Comparison of Sertraline and Placebo in Patients with Panic Disorder
B. Baumel, R. Bielski. J. Carman, W. Goodman. M. Hegel, C. Houck, R. Linden, B. Nakra, K. Ota, R. Rohl, R. Wolkow. Pfizer Inc A multicenter, lO-week, double-blind, flexible dose, outpatient study of patients with a DSM-III-R diagnosis of panic disorder was conducted to evaluate the efficacy and safety of sertraline and placebo. Ten U.S. centers participated and 168 patients 18 years of age and older received double-blind treatment with either sertraline or placebo. After a 2-week single-blind placebo washout period. patients randomized to sertraline received 25 mg/day for one week after which dosage was flexibly tritrated between 50 and 200 mg/day based upon clinical response. The primary efficacy variable was the number of DSM-III-R defined panic attacks per week. At endpoint. sertraline patients exhibited significantly greater reductions than placebo patients in panic attacks and limited symptom attacks, and the MC-PAS. Hamilton Anxiety. and Clinical Global Im-
113
P Poster Presentations pressions scales. Senraline-treated patients experienced a 77% decrease in panic attack frequency in comparison to a 51% decrease among placebo patients. In addition, sen raline patients rated themselve s significantly more improved than placebo patients on Patient Global Evaluation and Quality of Life scales. The most common adverse experiences in senraline-treated patients were headache , nausea, insomnia. and diarrhea. Treatment discontinuation s due to adverse experiences occurred in 9% of senraline-treated patients. There were no significant differences between treatment groups in the incidence of clinically significant laboratory, vital sign, or ECG abnormalities and there were no serious adverse events in any sertraline-treated patient. In this study senraline in doses of 50-200 mg/day was shown to be a safe and effective treatment for patients with panic disorder, as has been previously demonstrated for both depression and obsessive compulsive disorder.
I P-1 0-151 Can Panic Disorder Patients Treated With More Than4 mg/day of Alprazolam Reduce TheirDose? M. Corrigan, J. Jonas, T. Kitt, S. Goldstein, A. Swiontek, S. Stahl. CNS Development, The Upjohn Co., Kalamazoo, MI. USA This multicenter study investigated the ability of panic disorder patients who required > 4 mg/day to reduce their alprazolam dosage following 12 weeks of treatment . Patients who responded to :s 4 mg of ALP during the prerandomization period were excluded from the study. Nonresponders were then treated with doses up to 10 mg/day for 12 weeks. At that time they were divided into a maintained group (66 patients), or had their dose reduced by 50% (63 patients) during an II week maintenance period. Patients overall showed improvement in their condition during the study. Based on Kaplan-Meier estimate s, the initial response rate was 28.6% at 4 mg, 52.5% at 6 mg, and 88.0% at 10 mg of alprazolam. Overall dropouts were similar between groups . No statistically significant differences in response rates (determined by CGI and/or zero panic attacks) were observed between the Maintained Dose (75.6%) and 50% Dose Reduction (68.6%) groups during the study. More patients in the 50% dose reduction group had treatment emergent signs and symptom s, reflecting the symptoms arising during the the time their dosage was decreased . Conversely, more patients in the maintenance group had discontinuation emergent signs and symptoms during taper, perhaps due to their higher dosage. One week following tapering off drug, patients in the maintained group were more likely to be classified as being in remission and less likely to have relapsed. These results suggest that once desired therapeutic effect has been achieved, it may be possible to reduce alprazolam dose. However, there may be long term treatment benefits to maintaining patients at higher doses.
I P-1 0-161 E~icacy and Safety of Paroxetine in Panic
Disorder R. Judge . SmithKline BeechamPharmaceuticals, New Frontiers Science ParkHarlow, Essex. UK
The efficacy and safety of the selective serotonin reuptake inhibitor paroxetine has been evaluated in over 450 patients with panie disorder with or without agoraphobia. In a randomized comparison with placebo plus cognitive therapy in 120 patients with panic disorder, paroxetine plus cognitive therapy significantly reduced the frequency of panic attacks. A short-term comparative study over 12 weeks in 367 patients showed paroxetine to be at least as effective as clomipramine in the treatment of panic disorder. Moreover, paroxetine-treated patients demonstrated significant improvement over clomipramine in the reduction of panic attacks to zero (5 1% panic free vs 37%, p < 0.05). Paroxetine also appeared to have an earlier onset of action. In a long-term extension of this study, 176 patients continued medication under double-blind conditions and demon strated that the efficacy of paroxetine was maintained over time. Additionally, paroxetine was significantly better tolerated than clomipramine. In a dose range finding study, 40 mg was shown to be the minimum effective dose and a long-term extension of this study showed paroxetine to be significantly more effective than placebo in preventing relapse. In all studies, paroxetine was also effective in reducing the associated symptomatology of panic disorder, such as depressive symptoms, generalized anxiety and phobias. In conclusion, paroxetine is an effective and well tolerated treatment for the control of panic disorder.
I
P-10-17 1 Double-Blind Flexible DoseStUdy of Sertraline
and Placebo in Patients with Panic Disorder R. Wolkow, J. Apter, A. Clayton, W. Coryell , L. Cunningham , W. McEntee, D. O'Hair, M. Pollack, 1. Rausch, R. Stewart, R. Weisler. Pfizer, Inc. A multicenter, lOweek, double-blind , flexible dose, outpatient study of patients with a DSM-Ill-R diagnosis of panic disorder was conducted to evaluate the efficacy and safety of sertraline and placebo. Ten U.S. centers participated and 176 patients 18 years of age and older received double-blind treatment with either sertraline or placebo. After a 2-week single-blind placebo washout period, patients randomized to sertraline received 25 mg/day for one week after which dosage was flexibly tritrated between 50 and 200 mg/day based upon clinical response. The primar y efficacy variable was the number of DSM-IlI-R defined panic attack s per week. At endpoint, sertraline patients exhibited significantly greater reductions than placebo patients in panic attacks (P 0.014) and the MCPAS and Clinical Global Impressions scales. Senraline-treated patients experienced a 79% decrease in panic attack frequency in comparison to a 59% decrease among placebo patients. In addition, senraline patients rated themselves significantly more improved than placebo patients on Patient Global Evaluation and Quality of Life scales. Only two adverse experiences - diarrhea and tremor - occurred with a statistically significantly greater incidence in senral ine-treated patients compared with placebo patients. Treatment discontinuation s due to adverse experiences occurred in 8% of sertraline-treated patients and 3% of placebo patients, a non-significant difference. There were no significant differences between treatment groups in the incidence of clinically significant laboratory, vital sign, or ECG abnormalities. In this study sertraline in doses of 50-200 mg/day was shown to be a safe and effective treatment for patients with panic disorder, as has been previously demonstrated for both depression and obsessive compulsive disorder.
=
1P-1 0-181 CCK-4 in cerebrospinal Fluid: A PilotStudy in Healthy MaleVolunteers T. Gunnarsson, T. EkJundh, M. Eriksson, C. Nordin, S. Sjoberg.
Huddinge and Linkiiping University Hospitals. Sweden We have assayed cholecystokinin-tetrapeptide (CCK-4) (a neurotransm itter with panicogenic effect) in cerebrospinal fluid (CSF) obtained from 14 healthy male volunteers punctured in the sitting position after a minimum of eight hours in the fasting state along with strict bedrest. In 12 ml CSF, the mean concentration was 2.24 ± sd 0.60 pM. The length of the spine in the sitting and lying positions made significant contributions to the variance (R =0.75; p < 0.05). There was no difference in CCK-4 levels between the first and the second 6-ml fraction. The concentration per minute of tapping-time (pM/min) correlated with storage-time (2.4 ± sd 1.0 months) (r = -0.57; P < 0.05) and increased with increasing mean daily atmospher ic pressure. In conclusion, the length of the spine has to be accounted for when measuring CCK-4 in CSF after puncture in the sitting position. There is no gradient between the first and the second 6-ml fraction. Tapping-time and storage-time seem to interact which might mirror a proteolytic process. An influence of atmospheric pressure is at least in part in line with previous observations on transmitter metabolites and needs to be funher investigated.
IP-1 0-19\ Effect of a Malor Depressive Episode History on the CCK-4 Response in Women
l .-M. Le Melledo , 1. Bradwejn, D. Koszycki, F. Bellavance, D.G. Bichet.
Psychobiology Unit, Clarke Institute, Toronto. Canada Studies suggest that women with a history of major depress ive episode (MDE) have a biological vulnerability for anxiety disorders and premenstrual dysphoric disorder (PMDD) . To examine this relationship more closely, we compared response to the panicogenic agent, CCK-4, in women with and without a history of MDE (with the last episode ending at least 2 years prior to participating in the study). The subjects were 29 healthy volunteers (8 with and 21 without a past history of MDE) and 18 women with PMDD (6 with and 12 without a past history of MDE).