Low dose selegiline (L‐Deprenyl) in social phobia

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Simpson et al.

DEPRESSION AND ANXIETY 7:126–129 (1998)

LOW DOSE SELEGILINE (L-DEPRENYL) IN SOCIAL PHOBIA H. Blair Simpson, M.D., Ph.D.,1,2* Franklin R. Schneier, M.D.,1,2 Randall D. Marshall, M.D.,1,2 Raphael B. Campeas, M.D.,1,2 Donna Vermes, R.N.,1 Joao Silvestre, C.S.W.,1 Sharon Davies, R.N.,1 and Michael R. Liebowitz, M.D.1,2

INTRODUCTION

Social phobia is a prevalent, chronic, and debilitating

disorder (Kessler et al., 1994; Schneier et al, 1992, 1994). Effective medications for social phobia include the monoamine oxidase inhibitor (MAOI) phenelzine (Liebowitz et al., 1992), the selective serotonin reuptake inhibitors (e.g., fluvoxamine, paroxetine, sertraline; reviewed by Marshall and Schneier 1996), and the benzodiazepine clonazepam (Munjack et al., 1990; Ontiveros and Fontaine, 1990; Reiter et al., 1990; Gelernter et al., 1991; Davidson et al., 1993). However, not all patients respond to these medications nor can all tolerate them. Selegiline (L-Deprenyl) is of clinical interest as a possible alternative treatment of social phobia because it is a MAOI with fewer side effects than phenelzine. In particular, at doses of 10 mg/day or less, selegiline acts as a specific MAO-B inhibitor, and thus is thought primarily to affect dopamine metabolism; in contrasts, nonselective MAOIs (such a phenelzine) affect dopamine, serotonergic, and noradrenergic metabolism (Gerlach et al., 1996; Krishnan, 1995). Because of its MAO-B selectivity, low dose selegiline has minimal risk of causing hypertensive crises when foods containing vasoactive amines (e.g., tyramine) are ingested (cf. Lefebure et al., 1995; Somerset Pharmaceuticals package insert for selegiline). Selegiline is also of interest given recent theories that social phobia is associated with dopaminergic dysfunction in the central nervous system (Potts and Davidson, 1992). Using single photon emission computed tomography (SPECT), one group recently reported lower dopamine reuptake site densities in the striatum in social phobias compared to matched normal control subjects; as a result, this group suggested that there may be a smaller number of dopaminergic synapses and neurons in the basal ganglia of patients with social phobia (Tiihonen et al., 1997). If decreased dopaminergic function underlies the symptoms of social phobia, then a medication that selectively enhances dopaminergic function, such as low dose selegiline, may be an especially effective treatment. We report the results of a 6 week open trial of selegiline in 16 patients with social phobia.

© 1998 WILEY-LISS, INC.

MATERIALS AND METHODS This study was conducted at an outpatient clinic that specializes in the treatment of anxiety disorders. Subjects were recruited by advertisements and referrals from other clinicians. To be eligible, subjects had to meet DSM-III-R criteria for social phobia as their primary diagnosis. Their diagnosis was determined by a psychiatrist during a comprehensive psychiatric assessment, and confirmed using the Structured Clinical Interview for DSM-III-R-Patient Version (SCID-P; Spitzer et al., 1989). In addition, subjects had to be between 18 and 65 years of age and free of major medical illnesses. Women could not be pregnant or lactating. Patients with current DSM-III-R major depressive disorder, drug or alcohol abuse, organic mental disorder or with any history of psychosis or mania were excluded. Subjects were on no psychiatric medication for at least 2 weeks prior to starting the study (and for at least 5 weeks for fluoxetine). Neither cognitive-behavioral therapy nor psychoactive medication other than selegiline were permitted during the study. Written informed consent was obtained after full explanation of the study procedures. The study consisted of a 6 week trial of selegiline. Patients were seen weekly by a psychiatrist for monitoring of clinical state and assessment of side effects. The dose was fixed at 5 mg B.I.D. At this dose, selegiline is not thought to put patients at risk for hypertensive crises (cf. Lefebure et al., 1995); however, all subjects were instructed to follow a standard MAOI diet for added safety. Patients were encouraged by their study psychiatrist to expose themselves to phobic situations in order to overcome phobia avoidance; they were told that the role of selegiline was to make

1

New York State Psychiatric Institute, New York, New York Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York

2

*Correspondence to: H. Blair Simpson, MD, Ph.D. Anxiety Disorders Clinic, New York State Psychiatric Institute, 722 West 168th Street, New York, NY 10032. Received for publication 30 December 1997; Accepted 23 April 1998

Brief Report: Low Dose Selegiline in Social Phobia

such exposure easier. However, no systematic exposure instructions or programmed practice was offered. Patients were seen at week 0, week 3, and week 6 by an independent evaluator (IE). The IE evaluated the patients using the Clinical Global Impression scale (Guy, 1976), the Liebowitz Social Anxiety Scale (LSAS; Liebowitz, 1987), the Liebowitz Social Phobic Disorders Scale-Overall severity (LSPD; Liebowitz et al., 1992), and the Hamilton Depression Rating Scale (HAM-D, 17 item; Hamilton, 1960). Responders were defined by a score of 1 or 2 (much improved or very much improved) on the Clinical Global Impression scale (CGI) at the last observation. A primary analysis was done on the intent-to-treat sample, which included all of the subjects who started selegiline and returned for at least one follow-up visit. A secondary analysis was done on the completer sample. For the analysis, the paired t-test was used to compare baseline and last observation scores on the LSAS, the LSPD, and the HAM-D, with last observations carried forward for patients who dropped out of the study. In addition, those who completed the trial were compared to those who did not on demographic variables and baseline clinical ratings. Finally, those who both completed the trial and responded to the medication were compared to those who completed the trial but did not respond on baseline demographic variables and clinical ratings. For these comparisons, the Fisher’s exact test was used for categorical variables. The independent samples t-test was used for continuous variables; Levene’s test for equality of variances was used to determine whether the t-tests were based on pooled or separate variance estimates. For all tests, significance was defined as a P value < .05 (two-tailed).

RESULTS Sixteen subjects with social phobia entered the study. Nine were males, and seven were females. The mean age was 36.1 years (SD ± 8.3). Twelve met DSM-III-R criteria for generalized subtype; three did not; and one was not subtyped because of missing

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data. Of the 15 subjects on whom prior treatment history was available, 10 had never been on any psychiatric medication. The remainder had had trials of amitriptyline (n=1), atenolol (n=1), fluoxetine (n=1), sertraline and clonazepam (n=1), and diazepam (n=1). Nine subjects completed the trial; seven did not. The reason for dropout was known in three cases. Two patients developed adverse effects: hives (n=1) and gastrointestinal distress (n=1). A third patient stopped selegiline after he developed sinusitis for which he wanted to take medication prohibited by the MAOI diet. Those who completed the study did not differ from those who did not on demographic features of age (t=1.06; df=14, P=.31) or sex (Fisher’s Exact Test, P=.615). Nor did they differ on baseline clinical features as determined by scores on the Liebowitz Social Anxiety Scale (LSAS; t=–.85, df=14, P=.41), the Liebowitz Social Phobic Disorders Scale (LSPD; t=–.69; df=14, P=.50), or the Hamilton Depression Rating Scale (HAM-D; t=.98, df=.54, P=.37). The mean scores before and after treatment of the LSAS, LSPD, HAM-D for the intent-to-treat and completer groups are shown in Table 1. After treatment, there was a small but significant decrease (17%) in the LSAS mean score in the intent-to-treat sample. There was a larger and significant decrease (32%) in the LSAS mean score in the completer sample. There was no significant change in the LSPD or HAM-D mean scores for the intent-to-treat sample or the completer sample. Of the sixteen subjects who entered the study, three (19%) were rated as much or very much improved and thus were “responders.” The response rate for those who completed the study was 33% (3/9). One of the responders was rated as “very much improved” with a dramatic change in her scores on the LSAS (112 to 12) and LSPD (5 to 2). The other two responders were rated as “much improved.” Of the remaining six completers, three were rated as having improved minimally; three were judged to have not changed. Those who completed the study and responded (n=3) did not differ from those who completed the study and did not respond (n=6) on baseline demo-

TABLE 1. Baseline and endpoint ratings Baseline mean (SD)

Endpoint mean (SD)

Intent-to-treat sample (n = 16) Liebowitz Social Anxiety Scale Liebowitz Social Phobic Disorders Scale Hamilton Depression Rating Scale Clinical Global Improvement—1 or 2

88.5 (24.1) 5.1 (.8) 5.2 (2.8)

Completer sample (n = 9) Liebowitz Social Anxiety Scale Liebowitz Social Phobic Disorders Scale Hamilton Depression Rating Scale Clinical Global Improvement—1 or 2

85.9 (25.4) 5.0 (.9) 5.9 (1.1)

t

df

p

73.5 (31.3) 4.8 (1.1) 5.4 (3.0) 3/16 = 19%

2.24 1.58 –.30

14 15 14

.042 .14 .77

58.0 (25.4) 4.4 (1.2) 5.8 (2.5) 3/9 = 33%

2.59 1.64 .11

7 8 8

.036 .14 .92

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graphic features of age (t=–2.24, df=7, P=.06) or sex (Fisher’s Exact Test, P=.226). Nor did they differ on baseline clinical features as determined by scores on the LSAS (t=0, df=7, P=1.0), the HAM-D (t=1.76, df=7, P=.12), or the LSPD (t=–.80, df=7, P=.45). Finally, they did not differ on whether they had previously received psychoactive medication for social phobia (Fisher’s Exact Test, P=1.0) or on whether they had generalized or nongeneralized social phobia (Fisher’s Exact Test, P=1.0). Of the three responders, two had the generalized subtype of social phobia, and one did not. Six of the seven patients who dropped out of the study did so before the third week. Thus, these six subjects had only one set of ratings by the independent evaluator (IE), the baseline ratings, because the second assessment by the IE occurred at the third week. For these six subjects, their baseline ratings were also used as their end point ratings in the intentto-treat analysis, since they were both the last observations and the only observations. A post-hoc analysis, which included only those subjects who had at least two IE ratings (n=10), showed the following: a significant decrease in mean score on the LSAS (28%; 87.8 + –24.5 to 62.9 (SD ± 31.2); t=2.5, df=8, P=.037); a response rate of 30% (three of 10). In general, side effects were not a major problem. While two subjects dropped out because of adverse effects (as described above), most patients either had no side effects or had mild side effects which did not interfere with their daily activities. Four subjects (all completers) reported moderate side effects that interfered with their daily activities at some point during the study. However, these side effects never lasted more than 1 week and did not interfere with their completing the study.

DISCUSSION The results of this 6-week open trial suggest that low dose selegiline may have modest efficacy as a treatment for social phobia. Those who completed the trial experienced a 32% reduction in symptoms (as measured by the Liebowitz Social Anxiety Scale [LSAS]); 33% of completers responded (as measured by a rating of much or very much improved). However, other mediations appear more effective for social phobia. For example, in intent-to-treat analyses of double-blind placebo controlled trials, the percentage decrease in the LSAS ranged from 32% (sertraline; Katselnick et al., 1995) to 45% (phenelzine; Liebowitz et al., 1992) to 51% (clonazepam; Davidson et al., 1993); the corresponding placebo rates were 10%, 12%, and 20%. The response rates were 50% (sertraline), 64% (phenelzine), and 78% (clonazepam); the corresponding placebo rates were 9%, 23%, and 20%. Thus, the improvement on low dose selegiline in those who completed this trial was generally less than for these medications but better

than for placebo. In sum, while selegiline requires further evaluation in controlled studies, it may have a role when other more established treatments for social phobia have failed. The outcome for the intent-to-treat group was much worse than for those who completed the trial: a mere 17% reduction in symptoms; a response rate of only 19%. However, this large discrepancy was due to the timing of when subjects dropped out of the study, as described above. Why three subjects responded to low dose selegiline, but the others did not is not clear. Possible explanations include: (1) the patients who responded did so by chance (Type I error); (2) a subset of patients with social phobia can be successfully treated with a selective MAO-B inhibitor like low dose selegiline; and (3) there were metabolic differences between subjects, such that in those subjects that responded, selegiline was no longer selective for MAO-B but also inhibited MAO-A. Selegiline at higher doses inhibits both MAO-A and MAO-B (Gerlach et al., 1996; Sunderland et al., 1994); thus, at higher doses, its action is presumably equivalent to phenelzine, one of the most effective medications for social phobia. Perhaps metabolic differences in the three subjects who responded caused selegiline to lose its selectivity even at 10 mg (Barrett et al., 1996). A trial of selegiline that started with a fixed dose of 10 mg and then raised the dose in those who remained symptomatic could help resolve these issues. If low dose selegiline were effective in social phobia, it has two advantages over phenelzine: (1) side effects are minimal; and (2) hypertensive reactions are thought to be rare so that dietary restrictions are not mandated (Somerset Pharmaceuticals, package insert for selegiline). At higher oral doses of selegiline, selegiline may still be better tolerated than phenelzine (Sunderland et al., 1994), but MAOI dietary restrictions are required (Sunderland et al., 1985). Selegiline that is administered transdermally may eliminate the need for dietary restrictions even at higher blood levels (Barrett et al., 1997): this route of administration bypasses the gastrointestinal tract, and the putative step permitting dietary amines to cause a hypertensive reaction is inhibition of MAO-A in the gastrointestinal tract. Transdermal administration of selegiline is currently being tested in other clinical disorders; if this route of administration proves to be a safe way to achieve higher selegiline blood levels without requiring MAOI dietary restrictions, it would be worth testing in social phobia as well. This study had limitations. Besides the problems of an open trial, the trial was brief, the sample size was small, and compliance was measured only by pill count. Moreover, outcome ratings were done infrequently, and six of seven patients who did not complete the study dropped out early so that the intent-to-treat analysis was biased towards finding no effect.

Brief Report: Low Dose Selegiline in Social Phobia

CONCLUSIONS We conclude that low dose selegiline may have efficacy in the treatment of social phobia; however, the magnitude of its clinical effect may be small. Further study using higher doses is warranted. The finding that there may be some benefit from selegiline at doses that selectively inhibit MAO-B activity is consistent with the notion that dopamine is involved in the treatment of social phobia. However, if confirmed that the benefit from low dose selegiline is less than that seen from phenelzine (a combined MAO-A and MOA-B inhibitor), clonazepam, and/or the selective serotonin reuptake inhibitors, this finding suggests that the effective treatment of social phobia requires more than the enhancement of dopaminergic function that can be achieved from MAO-B inhibition alone. Acknowledgments. We would like to thank Donald F. Klein, MD, and Deborah Goetz, MPH, for their comments on an earlier version of this manuscript.

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