European Neuropsy~hopharmacology, 2 (1992) 21--29 ;() 1992 Elsevier Science Publishers B.V. All rights reserved 0924-977X/92/$05.00
21
ENP 00042
Psychopharmacological treatment of social phobia: clinical and biochemical effects of brofaromine, a selective MAO-A inhibitor I r e n e M. v a n Vliet, J o h a n A. d e n Boer a n d H e r m a n G . M . W e s t e n b e r g Department ~/~Biological Psyehiatry, Academic Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands (Received 5 July, 1991) (Revised, received 21 October, 1991) (Accepted 23 October, 1991)
Key words." Social phobia; Brofaromine treatment; MAO-A inhibitors Summary There is circumstantial evidence that antidepressants, particularly monoamine oxidase inhibitors (MAOIs) and f-blockers, may have some beneficial effects in social phobia. In this study 30 patients with social phobia (DSM-IIIR) were treated with the selective and reversible MAO-A inhibitor brofaromine, using a 12-week double-blind placebo controlled design. A clinical relevant improvement was seen in 80% of the patients treated with brofaromine (150 mg daily). A significant improvement was found on measures of social anxiety, phobic avoidance, general (or anticipatory) anxiety and interpersonal sensitivity in patients on brofaromine, but not on placebo. Biochemical measurements revealed a decrease in turnover of noradrenaline, serotonin and dopamine as assessed by the plasma metabolite levels, and an increase in nocturnal release of melatonin. Most prominent side-effect was middle sleep disturbance. No changes in blood pressure were observed. During a follow-up period of 12 weeks a further improvement was found in patients treated with brofaromine.
Introduction Social phobia was already delineated as a separate diagnostic category before the introduction of DSM-III (Marks 1970). In DSM-III-R patients are considered to suffer from social phobia (SP) when they are afraid of, and avoid situations in which the individual is exposed to the scrutiny of other people due to fear of acting in an embarrassing way (American Psychiatric Association, 1987). In these situations they experience both subjective and somatic Correspondence to." Dr. H.G.M. Westenberg, Department of Biological Psychiatry, Academic Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Tel.: (30) 507472; Fax: (30) 541844.
symptoms of anxiety, like trembling, blushing and sweating. Epidemiological studies have suggested that, in contrast to panic disorder, the male/female ratio in SP is approximately 1:1 (Marks et al., 1966; Solyom et al., 1986; Amies et al., 1983). The age of onset is usually in late adolescence (Marks et al., 1966, 1970; Amies et al., 1983; Solyom et al., 1986). Traditionally the treatment of social phobia has been psychoanalytic psychotherapy or behavior therapy (Emmelkamp, 1982; Leary 1983; Nichols 1974). Pharmacological treatment of social phobia has not been extensively studied. There is circumstantial evidence that/~-blockers might relieve some of the somatic symptoms of social phobia, e.g. trembling and palpitations (Falloon et al., 1980; Gorman and Liebowitz, 1985, 1990). In several
22 studies a beneficial effect of monoamine-oxidase inhibitors (MAOIs) was found. In most studies a reduction in social anxiety is seen after treatment with phenelzine (Kelly et al., 1970; Solyom et al., 1981; Tyrer et al., 1973; Tyrer and Steinberg, 1975: Mountjoy et al., 1977; Liebowitz et al., 1985). Tranylcypromine was found to improve symptomatology in about 60% of social phobia patients (Versiani et al., 1988). A major disadvantage of these nonselective MAOIs is the occurrence of hypertensive crises following ingestion of tyramine containing food (the so-called 'cheese effect' of MAOls). Since most MAOls used so far are irreversible, this effect may last several weeks. In this study we used the recently developed selective and reversible MAO-A inhibitor, brofaromine, which is devoid of tyramine potentiating properties. The putative monoamine neurotransmitters, such as serotonin (5-hydroxytryptamine; 5HT) and noradrenaline (NA), are preferentially deaminated by MAO-A, whereas other amine, such as phenylethylamine (PEA), are endogenous substrates for MAO-B (Robinson and Kurz, 1987). Tyramine, which was held responsible for the serious side effects of MAOIs without dietary restrictions, is a mixed substrate for both types of enzymes. Thus, selective MAOIs, leaving one metabolic pathway of metabolism open, are less likely to cause tyramine related side effects, and do not require dietary restrictions. The aim of the present study was to evaluate the efficacy of brofaromine in the treatment of SP.
Material and methods Patients
Patients were recruited from the outpatient clinic of the department of Biological Psychiatry of the University Hospital in Utrecht. Informed consent was obtained from all patients. The study was approved by the ethics committee of the academic hospital. Included in the study were patients suffering from social phobia according to DSM-III-R criteria. Excluded were patients with another anxiety disorder, major affective disorder or psychotic disorder, alcohol abuse and those patients suffering from medical problems on the basis of a complete medical evaluation. During treatment, the use of other psychotropic drugs was not allowed except oxazepam, which was permitted if required to a maximum of 30 mg daily. There
were 21 females and 9 males. Mean age ( ± SEM) was 32.8 ± 2.0 years and the mean duration of illness was 12.4 _+ 2.5 years. Thirty patients were enrolled and treated 1"or 12 weeks using a doubleblind placebo controlled design. Patients were randomly allocated to one of the two treatment groups. The dose of brofaromine was gradually increased from 50 to 150 mg daily (75 nag b.i.d.) in 3 weeks. If patients judged themselves to be improved they could continue their medication under doubleblind conditions in a tk)llow-up period which lasted another 12 weeks. S.FDI])Iotl? assgsstllt, llls
At the outset and the end of the study period, patients completed the 90-items Symptom Checklist (SCL-90; Derogatis et al., 1973). The Hamilton Depression Scale (HDS: Hamilton, 1959) was completed on baseline and at the end of treatment. Efficacy of the treatment was assessed using the Social Phobia Scale (SPS; Liebowitz, 1987), the Spielberger State Anxiety Inventory (STAI; Van der Ploeg et al., 1981) and the Hamilton Anxiety Scale (Hamilton, 1959). Adverse events were assessed by open questioning at week 1, 2, 4, 8 and 12. Laboratory measurements
Blood pressure, pulse rate and body weight were assessed on baseline, and at the end of week 1,2, 4, 8 and 12. Blood samples were taken between 8.30 and 9.(10 a.m. by venepuncture. Plasma levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured on admission and at week 12. Blood was collected into plastic tubes containing 1 ml sodium citrate (3.8%) as anticoagulant. Platelet-rich plasma (PRP) was obtained by centrifugation at 200 × g for 10 min. Concentrations of 5-HT, 5-HIAA and HVA in PRP were determined by HPLC as described by Westenberg et al. (1982). Plasma 3-methoxy-4-hydroxyphenylglycol (M HPG) levels were assayed on admission and at the end of week 4, 8, and 12. Blood was collected in siliconized glass tubes containing EDTA. Plasma was transferred after centrifugation into polypropylene tubes using polypropylene pipettes. After extraction with ethyl acetate, using iso-MHPG as internal standard, and evaporation of the organic layer the compounds were separated by liquid
23 chromatography and quantitated by means of amperometric detection. The sensitivity of the method is about 0.2 ng/ml. The interassay variability was 8% at 7 ng/ml. Plasma M H P G was measured by H P L C with electrochemical detection as will be described elsewhere. Early morning plasma melatonin concentrations were determined on admission and at the end of the trial. Blood was collected in polypropylene tubes containing EDTA. Determination of plasma melatonin levels was carried out using a commercially available RIA kit (Euro Diagnostics, Apeldoorn, The Netherlands) with t251-melatonin as tracer. All plasma samples were extracted with diethyl ether. The cross-over reactivity of the method was less than 1% for related substances. The interassay variability was 9.5% at a concentration of 35 pg/ml. Plasma cortisol levels were measured on admission and at the end of treatment. Blood (1 ml) was collected in silicon-coated ice chilled glass tubes, serum was separated by centrifuging and cortisol was assayed by RIA as described by Thijssen et al. (1980). Cross-reactivity with 21-deoxycortisol was 62%; that with corticosterone 11%. Sensitivity of the assay was 0.01 ffmol/1. Plasma brofaromine levels were measured weekly by gas chromatography as described by Schneider et al. (1991).
Data analysis The treatment effects as assessed with the psychometric scales were analyzed by one-way analysis of variance with repeated measures on the factor time. The contrasts at the different time points are reported significant when the probability value was less than 5 %. The drop-out was excluded in these analyses. Bartlett's test for homogeneity of group variances indicated significant differences for the biochemical data, therefore these results were evaluated by means of the Kruskal-Wallis one-way analysis of variance on the independent groups (group effects) and the Friedman one-way analysis of variance with repeated measures for related samples (treatment effects). Follow up data in the brofaromine group were tested by means of the Student t-test for related data (paired tests). The Systat statistical package was used for all analyses.
Results
Clinical variables Of the 30 subjects who entered the study, one subject from the placebo group decided to withdraw from the study after 8 weeks of treatment because of lack of effect. The two treatment groups did not differ in mean age, mean age of onset and sex. At the outset of the study 10 patients (4 in the placebo group and 6 in the brofaromine group) took occasionally oxazepare; 2 patients used 5 rag, 4 patients used 10 rag, and 3 patients used 20 mg of oxazepam per day if required. At the end of the study, 2 patients (1 in the placebo and 1 in the brofaromine group) were still taking oxazepam occasionally. Both patients considered themselves as nonresponders to treatment. Of the subjects who completed the study 12 (80%) in the brofaromine group and 2 (14%) in the placebo group considered themselves as responders to treatment. Taking a HAS score of equal to or less than 10 at endpoint as criterion, 11 (73%) of the brofaromine patients and none of the placebo patients were classified as responders to treatment. The efficacy of the treatment as assessed with the SP scale is depicted in Figs. 1 and 2. The anxiety subscore and phobic avoidance subscore were analyzed separately. At the outset of the study, the SP anxiety ratings (Fig.l) were 40.9 _+ 2.5 (mean _+ SEM) and 36.7 _+ 2.5 in the brofaromine and placebo group, respectively. During treatment this rating gradually fell to 21.7 SOCIAL. PHOBIA SCALE SUBSCALE ANXIETY 45 T 40
T. . . . .
35
t ...........
~
30 25 20
J.
15 10 5 0
I
I
I
I
I
I
I
0
2
4
6
8
10
12
Weeks of O,,
Brofarornine
treatment --O--
Placebo
Fig. 1. Mean (_+ SEM) score on the anxiety subscale of the social phobia scale in patients with social phobia treated with brofaromine ( n = 1 5 ) or placebo ( n - 1 4 ) . Brofaromine was superior to placebo from week 8 (P
21
ENP 00042
Psychopharmacological treatment of social phobia: clinical and biochemical effects of brofaromine, a selective MAO-A inhibitor I r e n e M. v a n Vliet, J o h a n A. d e n Boer a n d H e r m a n G . M . W e s t e n b e r g Department ~/~Biological Psyehiatry, Academic Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands (Received 5 July, 1991) (Revised, received 21 October, 1991) (Accepted 23 October, 1991)
Key words." Social phobia; Brofaromine treatment; MAO-A inhibitors Summary There is circumstantial evidence that antidepressants, particularly monoamine oxidase inhibitors (MAOIs) and f-blockers, may have some beneficial effects in social phobia. In this study 30 patients with social phobia (DSM-IIIR) were treated with the selective and reversible MAO-A inhibitor brofaromine, using a 12-week double-blind placebo controlled design. A clinical relevant improvement was seen in 80% of the patients treated with brofaromine (150 mg daily). A significant improvement was found on measures of social anxiety, phobic avoidance, general (or anticipatory) anxiety and interpersonal sensitivity in patients on brofaromine, but not on placebo. Biochemical measurements revealed a decrease in turnover of noradrenaline, serotonin and dopamine as assessed by the plasma metabolite levels, and an increase in nocturnal release of melatonin. Most prominent side-effect was middle sleep disturbance. No changes in blood pressure were observed. During a follow-up period of 12 weeks a further improvement was found in patients treated with brofaromine.
Introduction Social phobia was already delineated as a separate diagnostic category before the introduction of DSM-III (Marks 1970). In DSM-III-R patients are considered to suffer from social phobia (SP) when they are afraid of, and avoid situations in which the individual is exposed to the scrutiny of other people due to fear of acting in an embarrassing way (American Psychiatric Association, 1987). In these situations they experience both subjective and somatic Correspondence to." Dr. H.G.M. Westenberg, Department of Biological Psychiatry, Academic Hospital Utrecht, P.O. Box 85500, 3508 GA Utrecht, The Netherlands. Tel.: (30) 507472; Fax: (30) 541844.
symptoms of anxiety, like trembling, blushing and sweating. Epidemiological studies have suggested that, in contrast to panic disorder, the male/female ratio in SP is approximately 1:1 (Marks et al., 1966; Solyom et al., 1986; Amies et al., 1983). The age of onset is usually in late adolescence (Marks et al., 1966, 1970; Amies et al., 1983; Solyom et al., 1986). Traditionally the treatment of social phobia has been psychoanalytic psychotherapy or behavior therapy (Emmelkamp, 1982; Leary 1983; Nichols 1974). Pharmacological treatment of social phobia has not been extensively studied. There is circumstantial evidence that/~-blockers might relieve some of the somatic symptoms of social phobia, e.g. trembling and palpitations (Falloon et al., 1980; Gorman and Liebowitz, 1985, 1990). In several
22 studies a beneficial effect of monoamine-oxidase inhibitors (MAOIs) was found. In most studies a reduction in social anxiety is seen after treatment with phenelzine (Kelly et al., 1970; Solyom et al., 1981; Tyrer et al., 1973; Tyrer and Steinberg, 1975: Mountjoy et al., 1977; Liebowitz et al., 1985). Tranylcypromine was found to improve symptomatology in about 60% of social phobia patients (Versiani et al., 1988). A major disadvantage of these nonselective MAOIs is the occurrence of hypertensive crises following ingestion of tyramine containing food (the so-called 'cheese effect' of MAOls). Since most MAOls used so far are irreversible, this effect may last several weeks. In this study we used the recently developed selective and reversible MAO-A inhibitor, brofaromine, which is devoid of tyramine potentiating properties. The putative monoamine neurotransmitters, such as serotonin (5-hydroxytryptamine; 5HT) and noradrenaline (NA), are preferentially deaminated by MAO-A, whereas other amine, such as phenylethylamine (PEA), are endogenous substrates for MAO-B (Robinson and Kurz, 1987). Tyramine, which was held responsible for the serious side effects of MAOIs without dietary restrictions, is a mixed substrate for both types of enzymes. Thus, selective MAOIs, leaving one metabolic pathway of metabolism open, are less likely to cause tyramine related side effects, and do not require dietary restrictions. The aim of the present study was to evaluate the efficacy of brofaromine in the treatment of SP.
Material and methods Patients
Patients were recruited from the outpatient clinic of the department of Biological Psychiatry of the University Hospital in Utrecht. Informed consent was obtained from all patients. The study was approved by the ethics committee of the academic hospital. Included in the study were patients suffering from social phobia according to DSM-III-R criteria. Excluded were patients with another anxiety disorder, major affective disorder or psychotic disorder, alcohol abuse and those patients suffering from medical problems on the basis of a complete medical evaluation. During treatment, the use of other psychotropic drugs was not allowed except oxazepam, which was permitted if required to a maximum of 30 mg daily. There
were 21 females and 9 males. Mean age ( ± SEM) was 32.8 ± 2.0 years and the mean duration of illness was 12.4 _+ 2.5 years. Thirty patients were enrolled and treated 1"or 12 weeks using a doubleblind placebo controlled design. Patients were randomly allocated to one of the two treatment groups. The dose of brofaromine was gradually increased from 50 to 150 mg daily (75 nag b.i.d.) in 3 weeks. If patients judged themselves to be improved they could continue their medication under doubleblind conditions in a tk)llow-up period which lasted another 12 weeks. S.FDI])Iotl? assgsstllt, llls
At the outset and the end of the study period, patients completed the 90-items Symptom Checklist (SCL-90; Derogatis et al., 1973). The Hamilton Depression Scale (HDS: Hamilton, 1959) was completed on baseline and at the end of treatment. Efficacy of the treatment was assessed using the Social Phobia Scale (SPS; Liebowitz, 1987), the Spielberger State Anxiety Inventory (STAI; Van der Ploeg et al., 1981) and the Hamilton Anxiety Scale (Hamilton, 1959). Adverse events were assessed by open questioning at week 1, 2, 4, 8 and 12. Laboratory measurements
Blood pressure, pulse rate and body weight were assessed on baseline, and at the end of week 1,2, 4, 8 and 12. Blood samples were taken between 8.30 and 9.(10 a.m. by venepuncture. Plasma levels of 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured on admission and at week 12. Blood was collected into plastic tubes containing 1 ml sodium citrate (3.8%) as anticoagulant. Platelet-rich plasma (PRP) was obtained by centrifugation at 200 × g for 10 min. Concentrations of 5-HT, 5-HIAA and HVA in PRP were determined by HPLC as described by Westenberg et al. (1982). Plasma 3-methoxy-4-hydroxyphenylglycol (M HPG) levels were assayed on admission and at the end of week 4, 8, and 12. Blood was collected in siliconized glass tubes containing EDTA. Plasma was transferred after centrifugation into polypropylene tubes using polypropylene pipettes. After extraction with ethyl acetate, using iso-MHPG as internal standard, and evaporation of the organic layer the compounds were separated by liquid
23 chromatography and quantitated by means of amperometric detection. The sensitivity of the method is about 0.2 ng/ml. The interassay variability was 8% at 7 ng/ml. Plasma M H P G was measured by H P L C with electrochemical detection as will be described elsewhere. Early morning plasma melatonin concentrations were determined on admission and at the end of the trial. Blood was collected in polypropylene tubes containing EDTA. Determination of plasma melatonin levels was carried out using a commercially available RIA kit (Euro Diagnostics, Apeldoorn, The Netherlands) with t251-melatonin as tracer. All plasma samples were extracted with diethyl ether. The cross-over reactivity of the method was less than 1% for related substances. The interassay variability was 9.5% at a concentration of 35 pg/ml. Plasma cortisol levels were measured on admission and at the end of treatment. Blood (1 ml) was collected in silicon-coated ice chilled glass tubes, serum was separated by centrifuging and cortisol was assayed by RIA as described by Thijssen et al. (1980). Cross-reactivity with 21-deoxycortisol was 62%; that with corticosterone 11%. Sensitivity of the assay was 0.01 ffmol/1. Plasma brofaromine levels were measured weekly by gas chromatography as described by Schneider et al. (1991).
Data analysis The treatment effects as assessed with the psychometric scales were analyzed by one-way analysis of variance with repeated measures on the factor time. The contrasts at the different time points are reported significant when the probability value was less than 5 %. The drop-out was excluded in these analyses. Bartlett's test for homogeneity of group variances indicated significant differences for the biochemical data, therefore these results were evaluated by means of the Kruskal-Wallis one-way analysis of variance on the independent groups (group effects) and the Friedman one-way analysis of variance with repeated measures for related samples (treatment effects). Follow up data in the brofaromine group were tested by means of the Student t-test for related data (paired tests). The Systat statistical package was used for all analyses.
Results
Clinical variables Of the 30 subjects who entered the study, one subject from the placebo group decided to withdraw from the study after 8 weeks of treatment because of lack of effect. The two treatment groups did not differ in mean age, mean age of onset and sex. At the outset of the study 10 patients (4 in the placebo group and 6 in the brofaromine group) took occasionally oxazepare; 2 patients used 5 rag, 4 patients used 10 rag, and 3 patients used 20 mg of oxazepam per day if required. At the end of the study, 2 patients (1 in the placebo and 1 in the brofaromine group) were still taking oxazepam occasionally. Both patients considered themselves as nonresponders to treatment. Of the subjects who completed the study 12 (80%) in the brofaromine group and 2 (14%) in the placebo group considered themselves as responders to treatment. Taking a HAS score of equal to or less than 10 at endpoint as criterion, 11 (73%) of the brofaromine patients and none of the placebo patients were classified as responders to treatment. The efficacy of the treatment as assessed with the SP scale is depicted in Figs. 1 and 2. The anxiety subscore and phobic avoidance subscore were analyzed separately. At the outset of the study, the SP anxiety ratings (Fig.l) were 40.9 _+ 2.5 (mean _+ SEM) and 36.7 _+ 2.5 in the brofaromine and placebo group, respectively. During treatment this rating gradually fell to 21.7 SOCIAL. PHOBIA SCALE SUBSCALE ANXIETY 45 T 40
T. . . . .
35
t ...........
~
30 25 20
J.
15 10 5 0
I
I
I
I
I
I
I
0
2
4
6
8
10
12
Weeks of O,,
Brofarornine
treatment --O--
Placebo
Fig. 1. Mean (_+ SEM) score on the anxiety subscale of the social phobia scale in patients with social phobia treated with brofaromine ( n = 1 5 ) or placebo ( n - 1 4 ) . Brofaromine was superior to placebo from week 8 (P
