Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Gen Psychiatry. Author manuscript; available in PMC 2011 March 1.
Published in final edited form as:
PMCID: PMC2856667

A Placebo-Controlled Trial of Phenelzine, Cognitive Behavioral Group Therapy and their Combination for Social Anxiety Disorder

Carlos Blanco, M.D., Ph.D.,a Richard G. Heimberg, Ph.D.,b Franklin R. Schneier, M.D.,a David M. Fresco, Ph.D.,b Henian Chen, Ph.D.,a Cynthia L. Turk, Ph.D.,b Donna Vermes, N.P.P.,a Brigette A. Erwin, Ph.D.,b Andrew B. Schmidt, L.C.S.W.,a Harlan R. Juster, Ph.D.,b Raphael Campeas, M.D.,a and Michael R. Liebowitz, M.D.a



Medication and cognitive-behavioral treatment are the best established treatments for social anxiety disorder, yet many individuals remain symptomatic after treatment.


To determine whether combined medication and cognitive-behavioral treatment would be superior to either monotherapy alone and to pill placebo.


Randomized, double-blind, placebo-controlled trial.


Research clinics at Columbia University, New York, and Temple University, Philadelphia, Pennsylvania.


Individuals with a primary DSM-IV diagnosis of social anxiety disorder (N=128)


Cognitive-Behavioral Group Therapy (CBGT), phenelzine, pill placebo, and combined CBGT plus phenelzine.

Main Outcome Measures

The Liebowitz Social Anxiety Scale (LSAS) and the Clinical Global Impression Scale (CGI) at weeks 12 and 24.


Linear effects models showed a specific order of effects with steepest reductions in LSAS scores for the combined group, followed by the monotherapies, and the least reduction in the placebo group (Williams test=4.97, p<0.01). CGI response rates in the intention-to-treat sample at week 12 were 9/27 (33.3%) (Placebo), 16/34 (47.1%) (CBGT), 19/35 (54.3%) (Phenelzine), 23/32 (71.9%) (Combined Treatment), yielding a χ2=8.92, df=1, p=0.003. Corresponding remission rates (CGI=1) were 2/27 (7.4%), 3/34 (8.8%), 8/35 (22.9%) and 15/32 (46.9%), yielding a χ2=12.77, p<0.001. At week 24, response rates were 9/27 (33.3%), 18/34 (52.9%), 17/35 (48.6%) and 25/32 (78.1%), resulting in a χ2=12.02, p=0.001. Remission rates were 4/27 (14.8%), 8/34 (23.5%), 9/35 (25.7%) and 17/32 (53.1%), yielding a χ2=10.72, p=0.001.


Combined phenelzine and CBGT treatment was superior to either treatment alone and to placebo on dimensional measures as well as rates of response and remission.

Social anxiety disorder (SAD) is a highly prevalent,13 chronic and disabling anxiety disorder associated with substantial impairment, decreased quality of life,47 and psychiatric comorbidity.8, 9 Although cognitive-behavioral therapy (CBT) and pharmacotherapy are the most efficacious treatments for SAD,1015 only two-thirds of patients who receive these treatments are considered responders, of which only half are considered remitters.16 Most patients remain symptomatic after initial treatment.

Six controlled trials have examined the efficacy of combining medication and psychosocial treatments for SAD. The first compared social skills training plus propranolol to social skills training plus placebo.17 There were no significant differences in efficacy between the groups. The second compared buspirone, placebo, CBT plus buspirone and CBT plus placebo.18 CBT resulted in improvement in SAD symptoms, but buspirone alone was not superior to placebo and did not augment the efficacy of CBT.

In the third study,19 patients were randomized to sertraline or placebo and separately to exposure or general medical care. Sertraline was associated with greater efficacy than placebo, whereas exposure alone was not. The fourth study15 examined the efficacy of fluoxetine, pill placebo, group CBT, CBT plus fluoxetine, and CBT plus pill placebo. All active treatments had greater efficacy than pill placebo, but there were no differences among the active treatments.

Two recent studies have examined the effect of administration of D-cycloserine prior to exposures in the context of CBT, based on clinical and preclinical data on the effects of D-cycloserine on learning.20, 21 Both studies found it superior to placebo as an adjunct to CBT.

In our prior work, we compared the monoamine oxidase inhibitor (MAOI) phenelzine, cognitive-behavioral group therapy (CBGT), pill placebo, and a psychosocial control treatment.10

We found phenelzine and CBGT superior to pill placebo and the psychosocial control on a variety of measures. At the end of the study, many patients in both active treatments were still symptomatic, suggesting the need for more efficacious treatments. The goal of the current study was to examine whether combination of two partially efficacious treatments with different mechanisms of action, pharmacotherapy and CBGT, would be superior to each monotherapy in the treatment of SAD. We selected phenelzine as the medication because it was the best-established medication for the treatment of SAD at the time this study was initiated.



The study was conducted at 2 academic centers with outpatient anxiety disorder programs and complementary expertise, the New York State Psychiatric Institute/Columbia University (pharmacotherapy expertise; hereafter New York) and the Adult Anxiety Clinic of Temple University (expertise in CBT) in Philadelphia (hereafter Philadelphia). Enrollment began in June 1995 and continued through October 2001. Biweekly conference calls were held to ensure homogeneity of procedures. The institutional review board at each site approved the protocol, and all patients provided written informed consent.

The sample consisted of 128 patients referred by local mental health or medical practitioners or responding to advertisements in local media. Eighty-four patients were treated in New York, 44 in Philadelphia. Inclusion criteria were: (1) a primary DSM-IV diagnosis of SAD; and (2) age between 18 and 65 years. To increase the comparability with other treatment studies of SAD and eliminate the possibility that improvements in SAD could be attributed to the antidepressant effects of phenelzine, exclusion criteria were: (1) a comorbid anxiety disorder more clinically salient for the patient (2) lifetime history of schizophrenia, bipolar disorder, or mental disorder due to a general medical condition; (3) major depressive disorder or substance use disorder within the last 6 months; (4) prior failure of treatment with phenelzine or CBT defined as nonresponse to 60 mg or more of phenelzine (or the equivalent dose of another MAOI) for at least 4 weeks or to 6 sessions of CBT for SAD; (5) concurrent psychiatric/psychological treatment; and, (6) pregnancy, lactation, or inability or unwillingness to use contraceptive measures for the duration of the study.

At each site, patients were randomly assigned, in groups of 4–6 to one of four conditions: (a) Phenelzine, (b) CBGT, (c) Combined treatment (CBGT plus phenelzine), or (d) Pill placebo (PBO). Patients were randomized according to a table of pseudorandom numbers by the New York site data manager, who had no patient contact. Patient allocation was concealed from all other research personnel at both sites prior to randomization and from independent evaluators providing the clinician-administered assessments throughout the study.

Medication/PBO was administered and monitored by a psychiatrist. All CBGT sessions were conducted by masters- or doctoral-level therapists. All CBGT sessions were audiotaped and evaluated by R.G.H., who supervised therapists at both sites weekly.

The study had four phases. The first phase (acute treatment) lasted 12 weeks. Medication visits occurred weekly for 4 weeks, then every 2 weeks during this phase. CBGT sessions took place weekly. Patients at least minimally improved on a modified version of the Clinical Global Impression Improvement Scale that included anchors for each level of improvement (CGI-I)22 entered the second phase. In this 12-week intensive continuation phase, patients received the same treatment, with CBGT sessions taking place weekly and the frequency of medication visits reduced to once per month. At the end of this continuation phase, all patients at least much improved on the CGI-I entered the third phase, a 28-week maintenance phase during which they received the same treatment modality, but with monthly visits for both modalities. Patients at least much improved on the CGI-I at the end of the third phase entered a 12-month naturalistic follow-up. In this report, we present the results of acute treatment phase and the main findings of the continuation phase.


CBGT was administered by 2 therapists in 12 2.5-hour sessions to groups of 4–6 participants. In the first 2 sessions, patients were taught to identify negative cognitions (automatic thoughts [ATs]), to observe the covariation between anxiety and ATs, to challenge logical errors in ATs, and to formulate rational alternatives. Thereafter, they confronted increasingly difficult feared situations, first through role-playing in the session and then in real life, while applying cognitive skills. Patients worked on their personal target situations following a standard sequence: 1) identification of ATs; 2) identification of logical errors in ATs; 3) disputation of ATs and formulation of rational responses; and, 4) establishment of observable behavioral goals. Patients practiced cognitive skills while completing behavioral tasks (e.g., conversing with another group member). Goal attainment and use of cognitive skills were reviewed. Patients were given assignments for exposures between sessions and completed self-administered cognitive restructuring exercises before and after these assignments.

Pharmacotherapy patients began with phenelzine 15 mg/day or matching placebo for 3 days, then 30 mg/day for 4 days, 45 mg/day for the second week, and 60 mg/day for weeks 3 and 4. Depending on clinical progress and side effects, dosage could be raised to 75 mg at week 5 and 90 mg at weeks 6–12. Patients were instructed to expose themselves to anxiety-provoking situations and told that the role of medication was to make such exposure easier. However, no systematic exposure instructions or programmed practice was offered. No other psychotropic medication was permitted except chloral hydrate 500–1000 mg or zolpidem 5–10 mg prn for sleep. Patients were instructed about the dietary restrictions appropriate to phenelzine, symptoms that could occur if the restrictions were violated, and procedures to follow in that event.

Patients assigned to combined treatment received both CBGT and phenelzine as described above, beginning in the same week. To remove potential bias in the performance of treatments, neither pharmacotherapists nor CBGT therapists were informed as to whether a specific patient was also receiving the other treatment, and they could not consult each other or attempt to integrate their treatment efforts. Patients were also coached to withhold information that would indicate whether they were receiving combined treatment. Although all combined treatment patients actually received phenelzine, they were told, with the approval of the institutional review board at each site, that they might receive either active medication or placebo.


Assessments were conducted at baseline (week 0), and weeks 6, 12 and 24. Information was collected using both clinician- and self-administered instruments.

Clinician-Administered Measures

Measures administered by independent evaluators (IEs) blinded to treatment condition included: 1) the Liebowitz Social Anxiety Scale (LSAS): a 24-item scale that assesses fear and avoidance of a range of social interaction and performance situations;12,2325 2) the Anxiety Disorders Interview Schedule for DSM-IV Clinician’s Severity Rating (ADIS): a rating from 0 to 8 of the severity of symptoms and impairment associated with SAD;26 3) the modified CGI with anchor points defined specifically in reference to SAD;22 and, 3) the 29-item version of Hamilton Rating Scale for Depression (HAM-D).27

Self-report measures

Patient-rated symptom measures included: 1) the Fear Questionnaire-Social Phobia Subscale (FQ):28 a measure for the assessment of avoidance due to SAD; 2) the Social Interaction Anxiety Scale (SIAS):2932 a measure of anxiety in dyads and groups; 3) the Social Phobia Scale: a measure of anxiety when being observed by others;2928, 30 and, 4) the Sheehan Disability Scale (SDS):33 a 4-item scale to assess impairment in work, social life/leisure activity, family life/home responsibilities, and overall functioning as a result of any psychiatric disorder.


The pharmacotherapist used a checklist (available upon request) to inquire about the presence of 28 potential MAOI side-effects at each visit and rated severity of each on a 0–3 scale (none, mild, moderate, or severe). Emergent adverse effects were identified by an increase of at least two points from baseline to any of the assessment points.15 Side-effects were assessed in patients randomized to the placebo, phenelzine, and combined treatment groups, but not in those randomized to CBGT.


The following hypotheses were tested: 1) Phenelzine, CBGT, and combined treatment would each be superior to pill placebo in ameliorating the symptoms and disability of SAD; and, 2) There would be a gradient of efficacy across the treatments, with combined treatment superior to each monotherapy, which in turn would each be superior to PBO.

To examine hypothesis 1 using continuous measures, outcomes at baseline and weeks 6, 12, and 24 were modeled as a function of time, treatment, and the treatment-by-time interaction using linear mixed-effects models (LMM),34 which take into account baseline differences across groups and the intercorrelations of repeated observations, and SAS Proc MIXED (SAS Institute, Cary, N.C.). Site effects were assessed by including site in the models and by examining the interactions of site with treatment, time, and treatment-by-time. Treatment group differences were assessed by the significance of the interaction term and the comparison of LMM estimates at endpoint (week 12 for the acute treatment phase and week 24 for the maintenance phase). Response and remission rates were compared between groups using χ2-square tests of independence, using the last observation carried forward for those individuals who dropped out prior to endpoint. Odds ratios and their 95% confidence intervals (CIs) were calculated to assess the magnitude of the differences in categorical outcome for each treatment arm compared to placebo. Responder status was defined as a score of much improved or very much improved on the CGI-I at week 12 (i.e., a score of 1 or 2). In accord with previous work, two definitions of remission were used: 1) an LSAS score ≤ 30, previously found to be the optimal value to discriminate between individuals in or outside the clinical range;24 and 2) a score of 1 on the CGI-I.35

To examine hypothesis 2 using categorical measures, we used the linear-by-linear association χ2-test. In contrast to χ2-tests of independence, this test assumes a specific gradation in the magnitude of responses.36 To examine hypothesis 2 using continuous measures, we used Williams’s test.37 Both the linear-by-linear association test and Williams’s test are part of a larger family of tests of constrained statistical inference.38 The use of constrained statistical inference is indicated when the hypothesis to be tested implies an ordering of effects, as in the study of dose-response relationships or augmentation strategies, and has the advantage of providing more powerful tests in those situations.38, 39

For both hypotheses, the primary outcome measures were change over time in the total score of the LSAS and responder classification using the CGI-I. Secondary measures were changes in scores of the ADIS-IV Clinician’s Severity Rating, CGI Severity Scale, Fear Questionnaire-Social Phobia Subscale, Social Interaction Anxiety Scale, Social Phobia Scale, and Sheehan Disability Scale. The HAM-D was included to determine whether effects of treatment were due to reductions in depression, rather than to test differences across treatments in reducing depressive symptoms among individuals with SAD.

We calculated the slope of outcomes on each continuous measure for each participant using linear mixed effects models as implemented by SAS Proc MIXED.40, 41 We entered those individual slopes in the program “ORIOGEN” 42 to calculate the Williams’s statistic and p-value. The critical value and p-value of the Williams’s statistic are determined using nonparametric bootstrapping procedures. For each bootstrap sample, the Williams’s test statistic was computed and compared with the Williams’s test statistic for the actual sample. This process was repeated 100,000 times. Then the bootstrap p-value was defined to be the proportion of times the Williams’s test statistic for the bootstrap sample exceeded the Williams’s test statistic for the actual sample. Note that, unlike the original Williams’s test, which assumes that the data are normally distributed, ORIOGEN is distribution free.42

All tests were considered significant at α=0.05, two-tailed. All analyses were based on the intent-to-treat sample, defined as those who received at least one dose of medication (or placebo) or attended at least one CBGT session. To examine the sensitivity of our results, we repeated the analyses with comorbidity as a predictor. Because comorbidity did not predict outcome, it was excluded from the final models.

Power calculations for linear trends43 and for continuous variables44 under order restrictions indicated that our sample size provided 90% power to detect a linear trend in response rates and a linear trend in the change of LSAS score and 80% power to detect a linear trend in remission rates.



A total of 726 patients were screened and 166 were randomized to one of the four treatment groups (see Figure 1). The most common reasons for screen failure were not meeting diagnostic criteria (n=141) or lack of interest in participating in the research study due to time commitments or unwillingness to be randomized to treatment (n= 242).

Figure 1

Of the 166 subjects randomized, 12 from the placebo group, 10 from the phenelzine group, 6 from the CBGT group, and 10 from the combined group withdrew from the study prior to receiving any treatment (χ2= 3.0, df=3, p=0.4) and were excluded from the analyses. The remaining 128 subjects comprised the intent-to-treat (ITT) sample as follows: phenelzine (n=35), CBGT (n=34), CBGT/phenelzine (n=32), and pill placebo (PBO; n=27). Groups did not differ significantly in demographic characteristics (Table 1). There were some differences between groups, however, in baseline severity of SAD. Individuals randomized to the combined treatment group had significantly lower baseline values on the FQ, SIAS and SPS than those randomized to the other treatment conditions. Differences in baseline scores on the LSAS approached significance (Table 2). Some between-site differences were also observed. There were fewer married and Hispanic patients in Philadelphia than in New York. Mean age was lower in Philadelphia than in New York. Patients in Philadelphia had lower ADIS ratings than those in New York. However, no site-by-treatment condition interactions were observed (data available upon request). Of the 128 subjects 44 (34.4%) had at least one comorbid disorder, generally a comorbid anxiety disorder (26/128 [20.3%]) or dysthymia (19/128 [14.8%]).

Table 1
Demographic Characteristics of Patients with SAD Treated with Placebo, Cognitive-Behavioral Group Therapy (CBGT), Phenelzine, and their Combination
Table 2
Means and SDs for the Outcome Measures in the Treatment of Social Anxiety Disordera

Rates of discontinuation were 37.1% (13/35) in the phenelzine group, 35.3% (12/34) in the CBGT group, 28.1% (9/32) in the combined treatment group and 18.5% (5/27) in the PBO group. Those rates were not significantly different when examining all groups jointly (χ2= 3.0, df=3, p=0.4) or in pairwise treatment comparisons (all ps>.10). There were no differences in demographic or baseline measures between those who dropped out and those who completed the acute treatment phase (data available upon request).


Hypothesis 1

Mean scores and standard deviations for all primary and secondary continuous measures at primary endpoint (week 12) are presented in Table 2. Using LMM analyses, we found significant differences in the outcome of the four treatment groups for most measures, as indicated by the F-tests for the treatment-by-time interaction effects. Pairwise comparisons of each treatment group versus placebo showed that the slope of LSAS change was significantly greater in the combined treatment and phenelzine groups than in the placebo group (t=4.3, p<0.001, and t=3.3, p=0.001, respectively), whereas there was no significant difference between the slopes of CBGT and placebo (t=0.68, p=0.5). The slope of change for the ADIS was significantly larger in combined treatment than in the placebo group (t=3.1, p=0.002), whereas the slope of SPS change was larger in phenelzine than in the placebo group (t=2.1, p=0.04). There were no other significant differences in slopes between any of the treatment groups and placebo (data available on request).

Table 3 presents pairwise comparisons and corresponding effect sizes (Cohen’s d) of all primary and secondary outcome measures at acute phase endpoint for each treatment group versus placebo adjusting for baseline scores. Results were similar to the LMM findings. Phenelzine and combined treatment were superior to placebo on the LSAS, FQ, and SIAS. Combined treatment was also superior to placebo on the ADIS and the SPS. There were no significant differences between CBGT and placebo on any of the outcome measures. Effect sizes were generally small for CBGT, medium for phenelzine, and large for combined treatment.

Table 3
12-Week Mean Pairwise Differences between the Placebo Group and Patients Receiving CBGT, Phenelzine, and Combined Treatment

Categorical measures yielded similar results. Patients randomized to combined treatment were significantly more likely than those randomized to placebo (OR=5.11, 95% CI=1.68–15.52) to be classified as responders. There were no significant differences in the probability of response between patients randomized to phenelzine (OR=2.38, 95% CI=0.84–6.72), CBGT (OR=1.78, 95% CI=0.63–5.06), or placebo. Rates of remission were also significantly higher for patients randomized to combined treatment than for those randomized to placebo (Figure 2). Using a definition of CGI-I=1, 46.9% of patients who received combined treatment were classified as remitters, compared to 7.4 % on PBO (OR=11.03, 95% CI=2.23–54.57). In contrast, the percentage of CGI-I remitters was 22.1% in the phenelzine group (OR=3.70, 95% CI=0.82–19.14) and 8.8% in the CBGT group (1.21, 95% CI=0.19–7.81), neither significantly different than the rate in the PBO group. When remission was defined by an LSAS score ≤ 30, 59.4% of patients in the combined treatment group and 11.1% in the placebo group were classified as remitters (OR=11.69, 95% CI=2.91–47.05). The percentage of remitters was 20.0% in the phenelzine group (OR=2.00, 95% CI=0.47–8.60) and 20.6% in the CBGT group (OR=2.07, 95% CI=0.48–8.93). Here again, the monotherapies did not distinguish themselves from placebo.

Figure 2
Response and Remission Rates by Treatment Group at week 12

Hypothesis 2

Table 4 presents mean slopes of change for all continuous measures and rates of response and remission for all the treatment groups. Across all measures, the results of Williams’s test were highly significant. Examination of categorical measures produced similar results.

Table 4
Statistical Inference under Order Restrictions for Patients with Social Anxiety Disordera

Because in our previous study phenelzine was superior to CBGT on several continuous measures after acute treatment,10 in exploratory analyses of our current study, we reexamined the models hypothesizing the following order: combined treatment, phenelzine, CBGT, and placebo. Our results also support this ordering of treatment effects (Table 4). Additional analyses restricted the sample to responders, in order to examine whether responders to each treatment differed in magnitude of improvement. The mean slope of LSAS change was significantly larger for combined treatment than for the monotherapies considered separately or pooled (Table 5).

Table 5
Overall Liebowitz Social Anxiety Scale Slope for Responders: Williams’s Test


The daily dose of phenelzine at the end of week 12 in the medication (mean: 65.9 mg/day, SD=22.5) and combined group (mean: 62.0, SD=24.6) did not differ significantly (t=0.7, p=.11). However, significant differences in rates of treatment-emergent events were noted for 7 symptoms: insomnia, lightheadedness, dry mouth, weight gain, constipation, anorgasmia, and nervousness (Table 6). For three symptoms, incidence was highest in the combined group; the incidence of three other symptoms was highest in the phenelzine group; and the incidence of one symptom was highest in the placebo group.

Table 6
Significant Differences in Adverse Effects by Treatment Group

Continuation Phase

At week 24, LSAS scores were 59.3 (SD=23.5) for the placebo group, 51.0 (22.9) for the CBGT group, 52.6 (24.0) for the phenelzine group, and 32.0 (19.6) for the combined group, resulting in effect sizes (Cohen’s d) of 0.36, 0.35, and 0.91 respectively. The Williams test was 4.7, p<0.001. The proportion of responders at week 24 were 9/27 (33.3%) in the placebo group, 35/69 (50.7%) among those receiving monotherapy (18/34 [52.9%] for CBGT and 17/35 [48.6%] for phenelzine) and 25/32 (78.1%) among those randomized to combined treatment, yielding a linear-by-linear χ2=12.02, df=1, p=0.001. Rates of remission were 4/33 (14.8%), 17/69 (24.6%; 8/34 [23.5%] and 9/35 [25.7%]) and 17/32 (53.1%), respectively, resulting in a linear-by-linear χ2=10.72, df=1, p=0.001, when remission was defined as LSAS≤30. Rates of remission were 2/27 (7.4%), 14/69 (20.3%; 5/34 [14.7%] and 9/35 [25.7%]) and 15/32 (46.9%), with a linear-by-linear χ2=12.78, df=1, p<0.001, when remission was defined as CGI=1.


This is the first study to show the superiority of a combined treatment over medication, psychotherapy, and placebo in the acute treatment of SAD. In addition, we found that phenelzine, but not CBGT alone, was superior to placebo. These results were consistent across several outcome measures and analytic strategies and maintained over the 12-week continuation phase.

Supporting our main hypothesis, combined treatment was superior to both monotherapies and to placebo. Two mechanisms could explain the higher efficacy of combined treatment: 1) distinct groups of SAD patients could respond only to phenelzine or to CBGT. By receiving both, patients in the combined treatment group would have increased their chances of receiving at least one treatment that was efficacious for them; 2) combined treatment may exert a truly additive or synergistic effect in the treatment of SAD, beyond the effects of either monotherapy delivered alone.

If only the first mechanism was at work, responders in the combined group would not have had larger average improvement than responders in the monotherapy groups. However, individuals receiving combined treatment had larger average improvements than those receiving phenelzine or CBGT alone. This finding suggests an additive or synergistic effect of these treatment modalities, possibly due to their different mechanism of action or by mutually facilitating the other’s effect. For example, phenelzine may reduce anxiety and increase the chances of successful exposures to feared situations, whereas the skills learned through CBGT may help those on phenelzine profit more from their exposures.

Our findings of the superiority of combined treatment are at variance with previous studies of combination treatment of SAD,15, 17, 18 but in accord with some other studies and meta-analyses that have shown the superiority of combined treatment over monotherapies in other mood and anxiety disorders.4548 Discrepancies in the SAD results may be due in some cases to the use of medications with a mixed15 or poor record of efficacy in the treatment of SAD.17, 18

The findings of Blomhoff and colleagues19 are more difficult to interpret. Although the study failed to find an additional benefit of combined treatment over sertraline monotherapy, this result may have been due to the use of pairwise comparisons, rather than tests for ordered responses implied in the design. We reanalyzed the rates of response from that study assuming a gradation of response from placebo to monotherapies to combined treatment using a linear-by-linear test, which yielded a χ2= 8.0, df=1, p=.005. An even more significant result was obtained when the gradation was assumed to be placebo, exposure therapy, sertraline, and combined treatment (χ2= 9.9, df=1, p=0.002). More recent work by the same group, although not formally tested for ordered responses, also suggest a gradient of efficacy in the acute treatment of SAD with placebo having the lowest degree of response, followed by monotherapies (exposure therapy and sertraline) and combined treatment having the highest efficacy at week 24.49 Taken together, the available evidence appears to support the superiority of combined treatment over medication or exposure/CBT alone for the treatment of SAD.

Consistent with prior reports,10, 5052 we found that phenelzine was superior to placebo on most measures, providing additional documentation of its efficacy. Both phenelzine and CBGT, however, were less efficacious than in previous reports,10 and CBGT was generally not superior to placebo in pairwise comparisons, although it was superior to placebo in the analyses using tests of constrained statistical inference, was not different from phenelzine monotherapy in any pairwise comparisons at week 12, and achieved the same efficacy as phenelzine at week 24. The lower efficacy of CBGT in this study is surprising to us and may be due to sample differences (R.G. H. moved from Albany, NY, to Philadelphia, PA, between the time of the previous trial10 and the present one). However, there were no site-by-treatment interactions in either study, making this explanation less likely. Furthermore, in another two-site trial conducted by our group since the time of the study reported here, CBT proved highly efficacious.53 Recent meta-analyses5456 and qualitative reviews57 continue to support the efficacy of CBT for SAD.

Our study has the limitations common to most efficacy trials. First, treatments were provided by experts and may show lower efficacy in less specialized settings. Second, participants had to be willing to be randomized to any of the four treatment cells. Individuals who dropped out of the study postrandomization but prior to receiving any treatment could not be included in the analyses. Our results may not generalize to them. Similarly, because individuals were recruited from advertisements and word of mouth, the results may not be generalizable to all patients with SAD. Third, because the study lacked a CBGT plus pill placebo group, the non-specific effects of phenelzine in the combined treatment cannot be ruled out. Fourth, because self-exposure was neither assessed nor explicitly discouraged in the pill-only groups, it is possible that more spontaneous exposure occurred in the phenelzine group which may have contributed to their improvement. Fifth, our study examined only one medication, one psychotherapy, and their combination, rather than a broader array of treatments. Thus, our findings may not extend to individuals treated with SSRIs or SNRIs. However, both our reanalysis of the Blomhoff et al.19 study and the findings of Haug et al.49 suggest that a gradation of response from placebo to monotherapy to combined treatment may extend to other medications and empirically-supported psychotherapies. Further research is needed to confirm those findings. Sixth, there were some baseline differences across treatment groups and sites. However, the results remained significant after appropriate statistical adjustments, suggesting the robustness of our findings.

In summary, our study is the first one to provide an empirical rationale for the use of combined treatment for SAD. Future studies should prospectively examine whether the combination of an SSRI plus behavior therapy or CBT is superior to either treatment alone, as well as the acceptability, efficacy and cost-effectiveness of combined versus sequentially administered or augmented treatments.


Financial Support

Supported in part by NIH grants DA023200 (Dr. Blanco), MH44119 (Dr. Heimberg) and MH57148 (Dr. Liebowitz), and the New York State Psychiatric Institute (Drs. Blanco, Schneier, Campeas and Liebowitz and Ms. Vermes). This work was also supported in part by GCRC grant RR00349 from the NCRR:NIH to Temple University.


All other authors report no competing interests.


Dr. Blanco reports support from Pfizer and GlaxoSmithKline.

Dr. Heimberg reports support from research funding from GlaxoSmithKline.

Dr. Schneier reports support from research funding from Forest Laboratories and Pfizer; he is also on the Scientific Advisory Board of Jazz Pharmaceuticals.

Dr. Liebowitz reports equity ownership of ChiMatrix LLC, electronic data capture, Liebowitz Social Anxiety Scale, consulting for Avera, Astra Zeneca, Pherin, Tikvah, Wyeth, licensing software of LSAS with GSK, Pfizer, Avera, Tikvah, Lilly, Indevus, Servier Speaking, Wyeth, and has clinical trial contracts with Pfizer, GSK, Forest, Lilly, Pherin, Novartis, Sepracor, Takeda, Horizon, Johnson and Johnson. He is on the speaking bureau of Bristol Myers Squibb.


1. Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51(1):8–19. [PubMed]
2. Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617–627. [PMC free article] [PubMed]
3. Grant BF, Hasin DS, Blanco C, Stinson FS, Chou SP, Goldstein RB, Dawson DA, Smith S, Saha TD, Huang B. The epidemiology of social anxiety disorder in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry. 2005;66(11):1351–1361. [PubMed]
4. Magee WJ, Eaton WW, Wittchen HU, McGonagle KA, Kessler RC. Agoraphobia, simple phobia, and social phobia in the National Comorbidity Survey. Arch Gen Psychiatry. 1996;53(2):159–168. [PubMed]
5. Schneier FR, Johnson J, Hornig CD, Liebowitz MR, Weissman MM. Social phobia. Comorbidity and morbidity in an epidemiologic sample. Arch Gen Psychiatry. 1992;49(4):282–288. [PubMed]
6. Schneier FR, Heckelman LR, Garfinkel R, Campeas R, Fallon BA, Gitow A, Street L, Del Bene D, Liebowitz MR. Functional impairment in social phobia. J Clin Psychiatry. 1994;55(8):322–331. [PubMed]
7. Davidson JR, Hughes DL, George LK, Blazer DG. The epidemiology of social phobia: findings from the Duke Epidemiological Catchment Area Study. Psychol Med. 1993;23(3):709–718. [PubMed]
8. Kessler RC, Stang P, Wittchen HU, Stein M, Walters EE. Lifetime co-morbidities between social phobia and mood disorders in the US National Comorbidity Survey. Psychol Med. 1999;29(3):555–567. [PubMed]
9. Kessler RC, Stein MB, Berglund P. Social phobia subtypes in the National Comorbidity Survey. Am J Psychiatry. 1998;155(5):613–619. [PubMed]
10. Heimberg RG, Liebowitz MR, Hope DA, Schneier FR, Holt CS, Welkowitz LA, Juster HR, Campeas R, Bruch MA, Cloitre M, Fallon B, Klein DF. Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome. Arch Gen Psychiatry. 1998;55(12):1133–1141. [PubMed]
11. Heimberg RG. Current status of psychotherapeutic interventions for social phobia. J Clin Psychiatry. 2001;62(Suppl1):36–42. [PubMed]
12. Blanco C, Schneier FR, Schmidt A, Blanco-Jerez CR, Marshall RD, Sanchez-Lacay A, Liebowitz MR. Pharmacological treatment of social anxiety disorder: a meta-analysis. Depress Anxiety. 2003;18(1):29–40. [PubMed]
13. Gould RA, Johnson MW. Comparative effectiveness of cognitive-behavioral treatment and pharmacotherapy for social phobia: Meta-analytic outcome. In: Hofmann SG, DiBartolo PM, editors. From social anxiety to social phobia: Multiple perspectives. Needham Heights, MA: Allyn & Bacon; 2001. pp. 379–390.
14. Hidalgo RB, Tupler LA, Davidson JR. An effect-size analysis of pharmacologic treatments for generalized social anxiety disorder. J Psychopharmacol. 2007;21(8):864–872. [PubMed]
15. Davidson JR, Foa EB, Huppert JD, Keefe FJ, Franklin ME, Compton JS, Zhao N, Connor KM, Lynch TR, Gadde KM. Fluoxetine, comprehensive cognitive behavioral therapy, and placebo in generalized social phobia. Arch Gen Psychiatry. 2004;61(10):1005–1013. [PubMed]
16. Blanco C, Raza MS, Schneier FR, Liebowitz MR. The evidence-based pharmacological treatment of social anxiety disorder. Int J Neuropsychopharmacol. 2003;6(4):427–442. [PubMed]
17. Falloon IR, Lloyd GG, Harpin RE. The treatment of social phobia. Real-life rehearsal with nonprofessional therapists. J Nerv Ment Dis. 1981;169:180–184. [PubMed]
18. Clark DB, Agras WS. The assessment and treatment of performance anxiety in musicians. Am J Psychiatry. 1991;148:598–605. [PubMed]
19. Blomhoff S, Haug TT, Hellstroem K, Holme I, Humble M, Madsbu HP, Wold JE. Br J Psychiatry. Vol. 179. England: 2001. Jul, Randomised controlled general practice trial of sertraline, exposure therapy and combined treatment in generalised social phobia. 2001. [PubMed]
20. Hofmann SG, Meuret AE, Smits JA, Simon NM, Pollack MH, Eisenmenger K, Shiekh M, Otto MW. Augmentation of exposure therapy with D-cycloserine for social anxiety disorder. Arch Gen Psychiatry. 2006;63(3):298–304. [PubMed]
21. Guastella AJ, Richardson R, Lovibond PF, Rapee RM, Gaston JE, Mitchell P, Dadds MR. A randomized controlled trial of D-cycloserine enhancement of exposure therapy for social anxiety disorder. Biol Psychiatry. 2008;63(6):544–549. [PubMed]
22. Zaider TI, Heimberg RG, Fresco DM, Schneier FR, Liebowitz MR. Evaluation of the clinical global impression scale among individuals with social anxiety disorder. Psychol Med. 2003;33(4):611–622. [PubMed]
23. Safren SA, Heimberg RG, Horner KJ, Juster HR, Schneier FR, Liebowitz MR. Factor structure of social fears: The Liebowitz Social Anxiety Scale. J Anxiety Disord. 1999;13(3):253–270. [PubMed]
24. Mennin DS, Fresco DM, Heimberg RG, Schneier FR, Davies SO, Liebowitz MR. Screening for social anxiety disorder in the clinical setting: using the Liebowitz Social Anxiety Scale. J Anxiety Disord. 2002;16(6):661–673. [PubMed]
25. Heimberg RG, Horner KJ, Juster HR, Safren SA, Brown EJ, Schneier FR, Liebowitz MR. Psychometric properties of the Liebowitz Social Anxiety Scale. Psychol Med. 1999;29(1):199–212. [PubMed]
26. DiNardo P, Brown T, Barlow D. Anxiety Disorders Interview Schedule for DSM-IV: Lifetime Version (ADIS-IV-L) New York: Oxford University Press; 1994.
27. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;32:50–55. [PubMed]
28. Marks I, Mathews A. Brief standard self-rating for phobic patients. Behav Res Ther. 1979;17:263–267. [PubMed]
29. Mattick RP, Clarke JC. Development and validation of measures of social phobia scrutiny fear and social interaction anxiety. Behav Res Ther. 1998;36(4):455–470. [PubMed]
30. Safren SA, Turk CL, Heimberg RG. Factor structure of the Social Interaction Anxiety Scale and the Social Phobia Scale. Behav Res Ther. 1998;36(4):443–453. [PubMed]
31. Rodebaugh TL, Woods CM, Heimberg RG, Liebowitz MR, Schneier FR. The factor structure and screening utility of the Social Interaction Anxiety Scale. Psychol Assess. 2006;18(2):231–237. [PubMed]
32. Heimberg RG, Mueller GP, Holt CS, Hope DA, Liebowitz MR. Assessment of anxiety in social interaction and being observed by others: The Social Interaction Anxiety Scale and the Social Phobia Scale. Behav Ther. 1992;23:53–73.
33. Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol. 1996;11 (Suppl 3):89–95. [PubMed]
34. Diggle P, Liang K, Zeger S. Analysis of Longitudinal Data. Oxford: Oxford University Press; 1994.
35. Liebowitz MR, Mangano RM, Bradwejn J, Asnis G. A randomized controlled trial of venlafaxine extended release in generalized social anxiety disorder. J Clin Psychiatry. 2005;66(2):238–247. [PubMed]
36. Agresti A. Categorical data analysis, 2nd edition. 2. Hoboken, NJ: John Wiley & Sons, Inc; 2002.
37. Peddada S, Lobenhofer E, Li L, Afshari C, Weinberg C, Umbach D. Gene selection and clustering for time-course and dose-response microarray experiments using 0rder-restricted Inference. Bioinformatics. 2003;19(7):834–841. [PubMed]
38. Silvapulle M, Sen P. Constrained Statistical Inference. New York: John Wiley and Sons; 2004.
39. Robertson T, Wright F, Dykstra R. Order Restricted Statistical Inference. New York: John Wiley and Sons; 1988.
40. Hedeker D. An introduction to growth modeling. In: Kaplan D, editor. Quantitative Methodology for the Social Sciences. Thousand Oaks, CA: Sage Publications; 2004. pp. 215–234.
41. Perrin M, Chen H, Sandberg D, Malaspina D, Brown A. Growth trajectory during early life and risk of adult Schizophrenia. Br J Psychiatry. 2007;191:512–520. [PMC free article] [PubMed]
42. Peddada S, Harris S, Zajd J, Harvey E. ORIOGEN: Order restricted inference for ordered gene expression data. Bioinformatics. 2005;21(20):3933–3934. [PubMed]
43. Nam J. A simple approximation for calculating sample size for detecting linear trend in proportions. Biometrics. 1987;43:701–705. [PubMed]
44. Singh B, Halabi S, Schell MJ. Sample size selection in clinical trials when population means are subject to a partial order: one-sided ordered alternatives. J Applied Statistics. 2008;35:583–600.
45. Keller MB, McCullough JP, Klein DN, Arnow B, Dunner DL, Gelenberg AJ, Markowitz JC, Nemeroff CB, Russell JM, Thase ME, Trivedi MH, Zajecka J. A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression. N Engl J Med. 2000;342(20):1462–1470. [PubMed]
46. Thase ME, Greenhouse JB, Frank E, Reynolds CF, 3rd, Pilkonis PA, Hurley K, Grochocinski V, Kupfer DJ. Treatment of major depression with psychotherapy or psychotherapy-pharmacotherapy combinations. Arch Gen Psychiatry. 1997;54(11):1009–1015. [PubMed]
47. Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA, Fagiolini AM, Grochocinski V, Houck P, Scott J, Thompson W, Monk T. Two-year outcomes for interpersonal and social rhythm therapy in individuals with bipolar I disorder. Arch Gen Psychiatry. 2005;62(9):996–1004. [PubMed]
48. Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: A randomized controlled trial. JAMA. 2000;283(19):2529–2536. [PubMed]
49. Haug TT, Blomhoff S, Hellstrom K, Holme I, Humble M, Madsbu HP, Wold JE. Exposure therapy and sertraline in social phobia: 1-year follow-up of a randomised controlled trial. Br J Psychiatry. 2003;182(4):312–318. [PubMed]
50. Gelernter CS, Uhde TW, Cimbolic P, Arnkoff DB, Vittone BJ, Tancer ME, Bartko JJ. Cognitive-behavioral and pharmacological treatments of social phobia. A controlled study. Arch Gen Psychiatry. 1991;48(10):938–945. [PubMed]
51. Liebowitz MR, Schneier F, Campeas R, Hollander E, Hatterer J, Fyer A, Gorman J, Papp L, Davies S, Gully R, et al. Phenelzine vs atenolol in social phobia. A placebo-controlled comparison. Arch Gen Psychiatry. 1992;49(4):290–300. [PubMed]
52. Versiani M, Nardi AE, Mundim FD, Alves AB, Liebowitz MR, Amrein R. Pharmacotherapy of social phobia. A controlled study with moclobemide and phenelzine. Br J Psychiatry. 1992;161:353–360. [PubMed]
53. Ledley DR, Heimberg RG, Hope DA, Hayes SA, Zaider TI, Van Dyke M, Turk CL, Kraus C, Fresco DM. Efficacy of a manualized and workbook-driven individual treatment for social anxiety disorder. Behav Ther. in press. [PubMed]
54. Powers MB, Sigmarsson SR, Emmelkamp PMG. A meta-analytic review of psychological treatments for social anxiety disorder. Int J Cognitive Ther. 2008;1(2):94–113.
55. Acarturk C, Cuijpers P, van Straten A, de Graaf R. Psychological treatment of social anxiety disorder: a meta-analysis. Psychol Med. 2009;39(2):241–254. [PubMed]
56. Hofmann SG, Smits JAJ. Cognitive-behavioral therapy for adult anxiety disorders: a meta-analysis of randomized placebo-controlled trials. J Clin Psychiatry. 2008;69(4):621–632. [PMC free article] [PubMed]
57. Magee L, Erwin BA, Heimberg RG. Psychological treatment of social anxiety disorder and specific phobia. In: Antony MM, Stein MB, editors. Oxford Handbook of Anxiety and Related Disorders. New York: Oxford University Press; 2009. pp. 334–349.