A Pilot Study of Clonazepam versus Psychodynamic Group Treatment plus Clonazepam in the Treatment of Generalized Social Anxiety Disorder

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A Pilot Study of Clonazepam versus Psychodynamic Group Treatment plus

Clonazepam in the Treatment of Generalized Social Anxiety Disorder

Daniela Z.Knijnik, M.D.; Carlos Blanco, M.D., Ph.D.; Giovanni A. Salum Jr.; Carolina

Moraes, M.D.; Clarissa K.Mombach, M.D.; Ellen A. Almeida, M.D.; Marília P. Pereira,

M.D.; Atahualpa P. Strapasson; Gisele G. Manfro, M.D., Ph.D; and Cláudio L. Eizirik,

M.D., Ph.D.

From the Postgraduate Program in Medical Science, Psychiatry, Federal

University of Rio Grande do Sul (Drs. Knijnik, Manfro and Eizirik); the Anxiety

Disorder Program, Hospital de Clínicas de Porto Alegre (Drs. Knijnik, Salum Jr.,

Moraes, Mombach, Almeida, Pereira, Strapasson, Manfro); the Department of

Psychiatry, Federal University of Rio Grande do Sul (Drs. Manfro and Eizirik), Porto

Alegre, Brazil and Columbia University and New York State Psychiatric Institute, NY

(Dr. Blanco).

This research was partially supported by the Fundação de Incentivo à Pesquisa e

Eventos (FIPE) at the Hospital de Clínicas de Porto Alegre, Brazil, by Roche

Pharmaceuticals, Porto Alegre, Brazil (Dr. Knijnik), and by NIH grants DA00482 and

DA019606 (Dr. Blanco).

The authors report no additional financial affiliations or other relationships

relevant to the subject of this article.

Corresponding author and reprints: Daniela Zippin Knijnik, M.D., Rua Hilário

Ribeiro 202 / 503, Porto Alegre, RS, Brazil 90510-040 (e-mail: [email protected]).

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ABSTRACT

Objective: Psychodynamic Group Therapy (PGT) and clonazepam have proven

efficacious in reducing symptoms of generalized social anxiety disorder (GSAD).

Despite their efficacy, many individuals remain symptomatic after treatment with PGT

or clonazepam as monotherapy. The goal of this study was to compare the efficacy of

PGT plus clonazepam administered concurrently versus clonazepam alone for the

treatment of GSAD. Method: Fifty-eight adult outpatients with a diagnosis of GSAD

according to DSM-IV criteria, participated in a 12-week randomized clinical trial: 29

underwent a combined treatment (PGT plus clonazepam) and 29 took clonazepam

alone. The Clinical Global Impression-Improvement (CGI-I) scale was the primary

efficacy measure. Secondary efficacy measures included the Liebowitz Social Anxiety

Scale (LSAS) total score, the World Health Organization Instrument to Assess Quality

of Life-Bref (Whoqol-bref) scale and the Beck Depression Inventory (BDI). The trial

was conducted between March and November 2005. Results: CGI-I data from 57

patients (intent-to-treat population) showed that the PGT plus clonazepam group

presented significantly greater improvement than clonazepam alone (p=0.043). Using a

CGI-I of 1 or 2 as the criterion for response, the difference in the response rate of PGT

plus clonazepam versus clonazepam alone approached significance (79.3% vs. 53.6%,

respectively; p=0.052). Conclusion: This study is the first to compare combined PGT

and medication versus medication alone in the treatment of GSAD. Our study suggests

that addition of PGT may be a promising augmentation strategy for clonazepam

treatment of GSAD.

KEY WORDS: Social Anxiety Disorder; Social Phobia; Augmentation

Strategies; Psychotherapy; Clonazepam

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INTRODUCTION

Social anxiety disorder (SAD), also known as social phobia, is a chronic

psychiatric disorder of adolescence onset with lifetime consequences and significant

economic costs1-3. It interferes with the normal development of social and interpersonal

relationships, often leading to long-term disability in the social, work, and family

domains, and decreased quality of life4-7. Although spontaneous recovery is possible, it

occurs over many years and only in about half of the cases8. In addition, SAD is a risk

factor for the development of other comorbid anxiety, substance use and mood disorders

(particularly major depressive disorder) suicidal ideation and occasionally, suicide9-12.

Early recognition and treatment of SAD have the potential to reduce the risk of other

psychiatric disorders later in life13.

SAD is estimated to affect 6-15% of individuals in the community at some point

in their lives. The lifetime prevalence is similar in the United States (13%)3;14,Europe

(14%)11 and Brazil (12.8%)15, making it the most common anxiety disorder and one of

the most common psychiatric disorders14;16. About half that prevalence represents

individuals who have the generalized type of the disorder (generalized social anxiety

disorder [GSAD]), characterized by fear and avoidance encompassing several social

situations8.

Treatment strategies for SAD have focused on psychotherapy, primarily

cognitive-behavioral therapy (CBT) and pharmacotherapy17-20. Controlled trials and

meta-analyses suggest similar benefits from both CBT and pharmacotherapy 21-25 in the

short-term treatment of SAD. In controlled clinical trials, monoamine oxidase

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inhibitors10;26, selective serotonin reuptake inhibitors17;27-36, venlafaxine13, gabapentin37

and the high-potency benzodiazepines, clonazepam and bromazepam9;38-40 have

demonstrated efficacy for SAD. Two meta-analyses21;41 have suggested that clonazepam

is the medication with the largest effect size in the treatment of SAD (Cohen’s d=0.72).

The efficacy of psychological treatments for SAD has been addressed in several

reviews42-45. To date, most clinical trials of psychotherapy have used CBT as the

experimental intervention21;29;46-53. Very little empirical work has been conducted using

other psychotherapy approaches54-57. More systematic research using therapy modalities

other than CBT is needed in GSAD because many patients achieve only partial decrease

in symptoms or experience recurrence of symptoms in long-term follow-up55.

Most of what is known about psychoanalytic treatment for SAD comes from

case reports or uncontrolled studies58-60. However, in a recent study our group evaluated

the efficacy of a manualized psychodynamic group therapy (PGT) specifically designed

for GSAD61. Knijnik et al. randomized 30 patients to PGT or to a credible placebo

control group for 12 weeks of treatment. The control group had been used previously by

Heimberg et al.22 to examine the efficacy of CBT. At the end of the study, patients

randomized to PGT were rated as more improved than controls, suggesting that PGT

may be an alternative to CBT for patients with GSAD.

Despite the efficacy of both psychotherapy and medication, only two thirds of

patients who receive these treatments are considered responders, and only half of those

(i.e., one third) are considered remitters13;46;62. Most patients remain symptomatic after

the initial treatment63. However, in contrast with the vast literature in the treatment of

major depressive disorder, to date, only a few studies have focused on how to augment

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treatment response on GSAD. Attempts to boost treatment response with combined

CBT and pharmacotherapy have met with limited success to date64-66, suggesting the

need for additional augmentation strategies.

The present study was designed to compare the efficacy of the concurrent

administration of two treatments of proven efficacy for GSAD, Knijnik´s PGT61 and

clonazepam,9;62 versus clonazepam alone.

METHOD

Study Design

This was a randomized, 12-weekstudy of PGT plus flexible-dose clonazepam

versus flexible-dose clonazepam alone in 58 adult outpatients of the Anxiety Program of

Hospital de Clínicas de Porto Alegre (Brazil), who met the DSM-IV67 criteria for

GSAD. The study was approved by the IRB of Hospital de Clínicas de Porto Alegre. All

subjects provided written informed consent prior to their enrollment in the study.

Patient Population

Inclusion criteria. To be eligible for the study, subjects had to be outpatients 18-

65 years old who met DSM-IV criteria for primary diagnosis of GSAD for at least 2

years, and had a baseline LSAS of at least 55, with fear and/or avoidance in ≥4 social

situations (at least 2 involving interpersonal interactions).

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Exclusion criteria. Individuals with a history of failure to respond to 2 mg of

clonazepam taken for at least 12 weeks, a history of hypersensitivity to clonazepam or

other benzodiazepines or prior or current (individual or group) psychotherapy for SAD

in the past (regardless of response) were excluded from enrollment. Patients with

current comorbid anxiety disorders whose symptoms were more severe than those of

SAD, a depressive episode (according to a BDI score of 30 or above), or suicide risk, as

determined by the Mini International Neuropsychiatric Interview (M.I.N.I.)68, in the

previous 6 month were excluded from study participation, as were individuals who met

DSM-IV criteria for OCD, bipolar disorder, or substance use disorder (except nicotine

dependence). Also excluded were patients with mental retardation or any neurological

disease, individuals taking psychotropic medications (including hypnotics) in the 4

weeks prior to the study, and women breastfeeding, pregnant or unwilling or unable to

take adequate contraceptive precautions.

Prestudy Procedures

The trial was performed in 3 successive periods from March 2005 to November

2005 with 8-10 (mean = 9) patients participating in each treatment group. Participants in

the study were recruited from clinical referrals and local media advertisements. Patients

referred to the study were assessed by two psychiatrists with expertise in GSAD to

determine eligibility and willingness to participate. The assessment included a

psychiatric history and the Mini-International Neuropsychiatric Interview (MINI) –

Portuguese version 5.0.68. Eligible subjects were randomly assigned to receive either

PGT plus clonazepam or clonazepam using a computer-generated list of random

numbers provided by a statistician not involved in the clinical trial. To avoid possible

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confounding effects of differential severity across treatment groups, randomization was

stratified by gender and by symptoms severity using a cut off score of 82 in the

Liebowitz Social Anxiety Scale (LSAS) total score69, as suggested by prior studies70.

After random assignment to treatment conditions, patients were scheduled for the

pretreatment (i.e., baseline) assessment.

Treatment Conditions

Clonazepam treatment. Pharmacologic treatment consisted of individual 20-

minute visits in weeks 1, 2, 4, 6, 8 and 10. Patient adherence to the medication regimen

was measured by pill count. No psychoeducational, cognitive or behavioral

interventions were allowed during the visits. Clonazepam regimen was started at an

initial dose of 0.5 mg taken twice a day in the first week. The dose could be increased to

up 1.0 mg taken twice a day in weeks 2-12 to maximize response. Although clonazepam

was not increased above 2 mg/day, dose reduction was allowed if necessary to improve

tolerability (0.5 mg/day and 1 mg/day were considered minimum doses in week 1 and in

weeks 2-12 respectively). At the end of the treatment period (end of week 12)

clonazepam was gradually discontinued using a fixed-dose taper of 0.25 mg/day every 2

weeks. Therefore, 16 weeks were required to taper off patients receiving the maximum

dose of 2.0 mg/day. Safety assessments were based on reports of adverse events

(possible adverse effects were monitored) and the patient’s response to the question “

How have you been feeling since your last visit?”.

PGT and Clonazepam Treatment. The PGT intervention consisted of 12 weekly

90-minute group sessions using a treatment manual developed for a previous

randomized trial of PTG versus educational control57. The psychotherapeutic technique

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used in PGT was derived from Malan´s (1976) focused, short-term psychoanalytic

psychotherapy, based on the hypothesis that recurrent and unconscious internal conflicts

are connected to the symptoms of GSAD. Patients were treated in groups of size 8-10.

Three groups of mean 9 patients per group were conducted to achieve the sample size

needed for the study. Group sessions were conducted by the first author (D.Z.K.), a

psychiatrist and psychotherapist trained in psychoanalytic psychotherapy, and

supervised by the last author (C.L.E.), a supervising and training psychoanalyst of the

International Psychoanalytic Association. Both authors have over 5 years of experience

providing PGT.

The 12 sessions are divided into three phases. Phase I, comprises sessions 1-3

and addresses group formation and ensuring patients’ agreement to focus exclusively on

the treatment of GSAD rather than trying to address other issues. During Phase II,

which includes sessions 4-10, the possible connection between symptoms and conflicts

is investigated and interpreted as appropriate. Phase III, which includes sessions11-12,

addresses termination issues.

Patients in the combined treatment received PGT and clonazepam

simultaneously, according to the procedures separately described above

Efficacy Measures

The Clinical Global Impression (CGI)71 is a scale commonly used to assess

illness severity and treatment response in patients with mental disorders. The severity of

illness item requires the clinician to rate the severity of the patient's illness at the time of

assessment, relative to the clinician's past experience with patients who have the same

diagnosis. The Global Improvement item requires the clinician to rate how much the

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patient's illness has improved or worsened relative to the baseline assessment.

Compared to condition at baseline, a patient's illness is compared to change over time.

The 7-point Clinical Global Impression Severity Scale (CGI-S) with scores ranging

from 1 ("not ill") to 7 ("among most severely ill") and the Clinical Global Impression-

Improvement (CGI-I) scale, a 7-point rating measured improvement were completed by

the blinded independent evaluator. Before each assessment patients were reminded not

to discuss their treatment in order to maintain the blind condition of the assessment.

The LSAS69 is a 24-item clinician-rated scale designed to assess both social

interaction and performance-related anxiety. It rates 24 potentially anxiety-producing

situations in both severity of fear and anxiety (0 = none to 3 = severe) and frequency of

avoidance (0 = never to 3 = usually). Some recent studies72 have used this scale as a

self-report instrument. The psychometric properties of the self-report version of the

LSAS have been described elsewhere72. In the present study the self-report version of

the LSAS (LSAS-SR) was administered with instructions read to the patients prior to

the administration of the scale72-74.

The World Health Organization Instrument to Assess Quality of Life-Bref

(Whoqol-bref)75;76 is a 26-item instrument that measures quality of life in four domains:

physical, psychological, social relationship and environment. Two additional questions

assess General Quality of Life. The scale provides scores from 1-100 in each domain,

with higher scores associated with improved quality of life.

Efficacy Evaluation

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The primary efficacy measure was mean change from baseline of CGI-I total

score, using an ITT analysis, which was assessed at weeks 2, 4, 6, 8, 10 and 12.

Secondary efficacy measures included the proportion of responders (defined as

CGI-I <=2, “much” or “very much improved”, based only on social anxiety symptoms)

and the percentage of patients in full remission according to two different definitions: a)

LSAS total score <= 30; b) CGI-I score of 1 (Liebowitz et al, 2005). Additionally, mean

change from baseline to endpoint of LSAS-SR total score was assessed at weeks 1, 6

and 12 and Whoqol-bref was assessed at weeks 1 and 12.

Statistical Methods

Kolmogorov-Smirnov test and Levene’s test were used to evaluate normality of

distribution and homogeneity of variances, respectively, prior to any statistical testing.

Independent samples t-tests were used to examine differences in demographic and

baseline characteristics between groups. Mann-Whitney Test was used to examine

asymmetric variables. Categorical data were compared using Chi-square test and

Fisher´s Exact Test. Repeated Measures ANOVA was used to examine changes over

time in the two treatment groups in CGI-I, Whoqol-bref, LSAS-SR, BDI and to evaluate

the role of possible confounding factors.

The sample size was estimated a priori based on CGI mean change between

groups on Otto et al. (2000)62 and on Knijnik et al. (2004)61 studies, assuming α=0.05

and power of 80% with an estimated loss to follow-up of 10%, resulting in 29 subjects

in each group.

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All efficacy and adverse effect analyses were based on the intent-to-treat (ITT)

population. For efficacy analyses last observation carried forward (LOCF) were used,

considering all patients that had at least one post randomization evaluation and took at

least one dose of study medication.

Results are considered significant at the α=0.05 level (two-tailed). All analyses

were conducted using the Statistical Package for the Social Sciences (SPSS) 14.0

version for Windows.

RESULTS

A diagram of the patient flow in the study is presented in Figure 1. Out of the

120 subjects screened for GSAD, 24 (20% of the screened sample) did not meet

inclusion criteria, 26 (20%) met inclusion criteria but were excluded due to BDI ≥30

and/or a suicide risk and an additional 12 (10%) met inclusion criteria but were

excluded because they were already on medication. The remaining 58 (48%) were

randomly assigned to either arm of the study (29 to each treatment group). One subject

in the clonazepam group was lost to follow-up prior to the baseline evaluation and was

not included in the analysis. Therefore, 57 (98%) patients were included in the ITT

efficacy and safety analyses. No statistically significant differences between groups

were detected with regard to demographic characteristics or mean baseline rating scale

scores (Table 1).

There were no significant differences in the proportion of patients who

completed the study in each treatment group: 28 (96.6%) in the PGT and clonazepam

group and 24 (82.1%) in the clonazepam group (Fisher’s Exact p-value=0.102). Three

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patients in the clonazepam group withdrew from the study due to adverse effects

(somnolence) and one patient from the clonazepam group withdrew from the study due

to lack of efficacy. No patients in the PGT plus clonazepam withdrew from the study.

However, one patient from each group failed to complete the endpoint assessments,

despite completing the 12-week treatment period (Figure 1).

In order to avoid possible confounding factors due to randomization, Repeated

Measures ANOVA was performed to evaluate the influence of three co-morbidities

(between subjects’ factors) on the primary outcome measure (CGI-I across study)

because they showed numerically high (although statistically non-significant)

differences at baseline between the groups. Neither major depressive disorder (F=.946,

df=4.04, p-value=.439), panic disorder (F=.962, df=4.07, p-value=.430) nor

agoraphobia (F=1.19, df=4.09, p-value=.316) showed any relation as a predictor with

the mean change in CGI-I across the study period.

Efficacy Outcomes

Consistent with our hypotheses, we found that the PGT plus clonazepam group

showed significantly greater improvement than the clonazepam alone group (F=2.5,

df=4.2, p=0.043) in the CGI-I (Table 2). Also consistent with our hypotheses, there

were no differences in the BDI between the groups. In contrast, we failed to find

significant differences in the LSAS-SR and in the Whoqol-bref (Table 3).

Table 4 presents the response and remission rate along 12 weeks of treatment.

Using a CGI-I of 1 or 2 as the criterion for response, the difference in the response rate

of PGT plus clonazepam versus clonazepam approached significance (79.3% vs. 53.6%,

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respectively; Fisher’s Exact p-value=0.052). However, there were no significant

difference between remission rate in PGT plus clonazepam and clonazepam treatment

groups based on the LSAS total scores (10.3% vs. 3.6%; Fisher’s Exact p-value=.611)

or on the CGI-I score of 1 (31% vs. 25%; p=.770).

Drug Dosage

Mean dosage over the study period was calculated by dividing the total number

of milligrams taken during the study by the number of treatment days. The mean dose

for the PGT plus clonazepam group was 1.29±0.35 mg/d. (t=1.849, df=55, p=0.07). The

mean dose for the clonazepam group was 1.48±0.41 mg/d. The mean dose for the PGT

plus clonazepam group at week-12 was 1.51±0.525 mg/d. The mean dose for the

clonazepam group at week-12 was 1.67±0.53 mg/d (t=1.1, df=55, p=0.3).

Safety

There were no unexpected or serious adverse effects. Adverse events were

reported by a similar proportion of individuals in both treatment groups: 28 (96.6%) in

the PGT plus clonazepam treatment group and 23 (82.1%) in the clonazepam treatment

group (Fisher’s Exact p=.102). Most of the treatment-emergent adverse events reported

during the study were mild in severity. Table 5 lists the treatment-emergent adverse

effects, reported by at least 5% of the treated patients.

DISCUSSION

This study is the first to compare combined medication and PGT versus

medication alone in the treatment of GSAD. We found that PGT plus clonazepam was

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superior to clonazepam alone as measured by the CGI-I in the treatment of GSAD. Our

results suggest that addition of PGT holds promise as an augmentation strategy to

clonazepam treatment for GSAD. Our results are the first to provide preliminary support

for an augmentation strategy to medication treatment for GSAD.

To date, only two other published studies have examined this question.

Blomhoff et al., (2001)77 conducted a randomized trial (N=387) in primary care to

examine the efficacy of sertraline or exposure therapy, administered alone or in

combination in this setting for 24 weeks and found that combined sertraline and

exposure was superior to placebo, suggesting that combined treatment, conducted by the

general practitioner, may enhance treatment efficacy in primary care. By contrast,

Davidson et al. (2004)29 conducted a randomized trial (N=295) to examine

improvement in response rates with the addition of fluoxetine to CBT and found

treatment versus placebo differences ranging from 15% to 24%, similar to those

previously reported for CBT in the literature. However, addition of fluoxetine resulted

in less than 3% incremental improvement of the combined treatment group over the

CBT group, suggesting that combined treatment did not yield any further advantage

over CBT alone. Interestingly, a recent randomized trial investigated the augmenting

effects of medication on psychotherapy. Hofmann et al. (2006)63 found D-cycloserine

superior to pill placebo in augmenting the efficacy of CBT for SAD, providing

preliminary support for the short-term addition of D-cycloserine as an adjunctive

intervention to CBT for SAD. These results suggest that certain combinations of

medication and psychotherapy might increase the efficacy of either approach alone.

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Our study adds to a growing literature of the superiority of combined treatment

over monotherapy in the treatment of anxiety disorders. For example, in a treatment trial

for panic disorder comparing CBT, imipramine and their combination, Barlow et al.

(2000)78 found combined treatment superior to either monotherapy. Similar findings

have been suggested by some authors in the treatment of chronic major depressive

disorder79;80. However, a recent study81 found no benefit of adding clomipramine to

CBT in the treatment of OCD, confirming the findings of Davidson et al., (2004)29, that

combined treatments are not systematically superior to monotherapy.

In addition to improvements in the CGI-I, in our study both groups improved in

specific symptomatic domains as measured by the LSAS, in the psychological domain

and in the general measure of quality of life as measured by the Whoqol-bref. However,

we did not detect statistically significant differences between the treatment groups.

Failure to detect differences in general quality of life appears to be related to limited

power, although no differences were detected between groups in any domain of

Whoqol-bref, even in the social relationship domain. The reasons for the discrepancy

between clinician-rated scales (CGI) and self-rated scales (LSAS-SR) are less clear and

may represent differences in response perception between clinicians and patients, a

finding previously documented in depression82-85. Furthermore, although the LSAS-SR

has good psychometric properties to assess severity of SAD cross-sectionally, it may be

less sensitive to change than other outcome measures73. Future augmentation studies

should compare the sensitivity to change of the clinician-administered LSAS versus the

LSAS-SR.

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The mean maximum dose of clonazepam in our study was 1.35 mg/day in both

groups, lower than the mean maximum dose of clonazepam of 2.4mg/day at endpoint

(range, 0.5 to 3 mg) in the Davidson et al. (1993)9 study, which achieved a response rate

(CGI ≤2) of 78.3% Similarly, in Versiani et al (1997)39, an open trial with clonazepam

in Brazilian patients with SAD, the mean daily dosage was 4.8mg (maximum dosage of

6mg) and the response rate (CGI ≤2) was 89.4%.

Our study has several limitations. First, our study had a relatively small sample

size. Although we conducted a priori power analysis, we may have overestimated the

expected effect sizes, restricting power to detect differences in the secondary outcome

measures. Second, our study lasted only 12 weeks, a relatively short treatment period

for a condition as chronic as GSAD. A recent reanalysis86 found that the proportion of

patients that responded to paroxetine increased monotonically until week 12 (the

endpoint of the reanalysis), suggesting that improvement may continue after that time.

It is possible that longer periods of psychotherapy may be needed to obtain the full

benefit of PGT for GSAD. Also, we are aware that the doses of clonazepam used in

this study are lower than those used in other studies with benzodiazepines for SAD.

This dosage (0.5-2.0mg/day) was chosen to prevent adverse effects (e.g. daytime

sleepiness, cognitive disturbances) that are more common with higher doses and may

interfere with patient functioning9;39. Consistent with this intent, clonazepam was well

tolerated. There were no statistically significant mean differences between groups.

There were no differences in the overall incidence of reported adverse effects between

the groups at week 12, in contrast to previous studies with benzodiazepines that used

higher doses9;39.

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Despite these limitations, our study suggests that the addition of PGT may be a

promising augmentation strategy for clonazepam treatment of GSAD. Future studies

should investigate the effect of longer treatment periods, examine the efficacy of

combining PGT with different medications, and compare PGT versus CBT as an

augmentation strategy for the treatment of GSAD.

Drug Names: clonazepam (Klonopin and others)

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Figure 1. Profile of Patient Flow From Recruitment Through Study Completion

Enr

ollm

ent

Allo

catio

n Fo

llow

-up

Ana

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s

Abbreviations: CNZ = Clonazepam; PGT = Psychodynamic Group Therapy.

Analysed (N=28) Excluded from analysis (N=1)

Lost to follow-up (N=1)

Did not attend assessment measures at week 12 (N=1)

Discontinued intervention (N=5)

Adverse effects: Somnolence (N=3)

Lack of efficacy (N=1)

Dissatisfied with randomization (N=1)

Analysed (N=29) Excluded from analysis (N=0)

Lost to follow-up (N=1)

Did not attend assessment measures at week 12 (N=1)

Discontinued intervention (N=0)

Randomised (N=58)

Assessed for eligibility

(N=120)

Allocated to CNZ + PGT (N=29)

Received allocated intervention (N=29)

Allocated to CNZ (N=29)

Received allocated intervention (N=28)

Did not receive allocated intervention (N=1)

Dissatisfied with randomization (N=1)

Excluded (N=62)

Inclusion/Exclusion criteria (N=24)

Comorbid Bipolar Disorder (N=7), Mental

Retardation (N=3), Schizophrenia (N=2), Severe

OCD (N=6); Age above 65 (N=2); Moving (N=1);

Scheduling (N=2); Pregnant (N=1); BDI > 30

and/or suicide risk (N=26); Already on

Psychotropic Medication (N=12).

Table 1. Demographic and Baseline Characteristics of the Intent-To-Treat Population of Patients

Receiving Clonazepam or Clonazepam plus Psychodynamic Group Therapy in Generalized

Social Anxiety Disorder

CNZ CNZ+PGT Statistic p-value

Characteristic (n=28) (n=29)

Mean age 32.4 ± 9.3 34.3 ± 11.1 tdf=55=-0.676 .502b

Male sex 12 (42.9) 10 (34.5) .592a

Level of education, yr 12.7 ± 4.0 13.1 ± 3.3 tdf=55=-0.401 .690b

Marital status χ2df=2 = 0.265 .876c

Married 10 (35.7) 9 (31)

Single 16 (57.1) 17 (58.6)

Widow/Divorced/Separated 2(7.2) 3 (10.3)

Psychiatric Comorbidity*

Any other psychiatric disorder 23(82.1) 22(75.9) .747a

Major depressive disorder 12 (42.9) 6 (20.7) .092a

Panic disorder 11 (39.3) 5(17.2) .082a

Agoraphobia 18 (64.3) 13 (44.8) .186a

Generalized anxiety disorder 13 (46.4) 14 (48.3) >.999a

Social anxiety disorder Characteristics

Duration of social anxiety disorder, years 16 (9.25 to 24) 18 (13.5 to 31) z = -1.126e .260d

CGI-S 5.86±0.93 5.97±0.9 tdf=55=-0.445 .658b

LSAS-SR 91.1±22.6 92±24.7 tdf=55=-0.142 .888b

BDI 15.4±7.1 13.7±9.1 tdf=55=0751. .456b

Whoqol-Bref Domains

Physical 56.4±14.6 59.8±16.4 tdf=55=-0.83 .410b

Psychological 46.0±13.1 52.7±16.2 tdf=55=-1.73 .090b

Social Relationship 47.0±20.9 47.4±19.6 tdf=55=-0.07 .942b

Environmental 47.6±14.1 54.7±16.3 tdf=55=-1.76 .085b

General Quality of Life 50.9±18.6 55.6±21.8 tdf=55=-0.876 .385b

Note: Values represent count (percent), mean ± SD or median (inter-quartile range). Statistic: aFisher’s Exact Test, b Independent

samples Student t test, cPearson Chi-square test, dMann-Whitney test, estandardized score for the Mann-Whitney test.

Abbreviations: CNZ = Clonazepam, PGT = Psychodynamic Group Therapy, LSAS = Liebowitz Social Anxiety Scale (self-report

version), CGI-S = Clinical Global Impression Scale – Severity of Illness, BDI = Beck Depression Inventory, Whoqol-Bref =

World Health Organization Instrument to Assess Quality of Life (bref version), df = degrees of freedom. * Reported only for

disorders present in at least 10% of each group.

Table 2. Repeated Measures ANOVA of CGI-I comparing Clonazepam versus Clonazepam plus Psychodynamic Group Therapy in

Generalized Social Anxiety Disorder

Assessment Week p-valuea

Interventions Week-2 Week-4 Week-6 Week-8 Week-10 Week-12

Time Treatment Time*Treatment

CNZ 3.2±1.1 2.9±1.1 2.5±1.2 2.4±1.1 2.3±1.1 2.5±1.3 <.001 .389 .043

CNZ+PGT 3.6±1.0 2.8±1.0 2.4±0.9 2.2±0.8 1.9±0.8 1.9±0.7

Note: Values represented mean ± SD. Abbreviations: CNZ = Clonazepam. PGT = Psychodynamic Group Therapy. Statistic: Repeated Measures ANOVA

Table 3. Repeated Measures ANOVA of Clonazepam or Clonazepam plus Psychodynamic Group Therapy in Generalized Social

Anxiety Disorder

Baseline Week 6 Week 12

CNZa CNZ+PGTb CNZ CNZ+PGT CNZ CNZ+PGT p-valuea

(n=29) (n=28) (n=29) (n=28) (n=29) (n=28) Time Treament Time*Treatment

Symptomatic scales

LSASc 91.1±22.6 92±24.7 76.9±24.3 78.1±26.1 74.3±25.9 71.4±27.4 <.001 .907 .689

BDId 15.4±7.1 13.7±9.1 11.2±7.1 10±7.4 12.2±8.6 9.4±8.9 <.001 .298 .681

WHOQOL-Brefe

Quality of life domains

Physical 56.4±14.6 59.8±16.4 60.8±14.9 62.7±16.2 .074 .462 .713

Psychological 46.0±13.1 52.7±16.2 51.0±15.7 57.5±17.2 .010 .081 .931

Social Relationship 47.0±20.9 47.4±19.6 49.1±22.5 52.9±21.5 .097 .687 .454

Environmental 47.6±14.1 54.7±16.3 47.9±13.8 56.3±16.6 .513 .047 .632

General Quality of Life 50.9±18.6 55.6±21.8 57.1±17.1 68.1±16.2 <.001 .083 .148

Note: Values represent mean ± SD. Abbreviations: CNZ = Clonazepam., PGT = Psychodynamic Group Therapy, LSAS = Liebowitz Social Anxiety Scale (self-report version),

BDI = Beck Depression Inventory., WHOQOL-Bref = World Health Organization Instrument to Assess Quality of Life (bref version). Statistics: a Repeated Measures ANOVA

Table 4. Response and Remission Rates of Clonazepam and Clonazepam plus Psychodynamic Group

Therapy for Generalized Social Anxiety Disorder

Week-2 Week-4 Week-6 Week-8 Week-10 Week-12

CNZ 8 (28.6) 11 (39.3) 18 (64.3) 20(71.4) 21 (75) 15 (53.6) Response

(CGI≤2) CNZ+PGT 3 (10.3) 15 (51.7) 17 (58.6) 21 (72.4) 22 (75.9) 23 (79.3)

CNZ 1 (3.6) 1 (3.6) 3 (10.7) 3 (10.7) 5 (17.9) 7 (25) Remission

(CGI=1) CNZ+PGT 0 1 (3.4) 5 (17.2) 4 (13.8) 10 (34.5) 9 (31)

CNZ 1 (3.6) 1 (3.6) 1 (3.6) Remission

(LSAS≤ 30) CNZ+PGT 0 0 3 (10.3)

Note: Values represent counts (percent). Abbreviations: CNZ = Clonazepam, PGT = Psychodynamic Group Therapy, CGI-I = Clinical

Global Impression Scale–Improvement, LSAS = Liebowitz Social Anxiety Scale (self report version).

Table 5. Most Common Treatment-Emergent Adverse Events (at least 5%)

Adverse Event Frequency (%) p-valuec

CNZ CNZ+PGT

Dizziness 7 (25) 11 (37.9) .395

Erectile dysfunctionc 1 (8.3) 0 >.999

Headache 0 3 (10.3) .237

Increased appetite 2(7.1) 0 .237

Irritability 4 (14.3) 5 (17.2) >.999

Decreased libido 8 (28.6) 1 (3.4) .012

Loss of appetite 2 (7.1) 3 (10.3) >.999

Forgetfulness 5 (17.9) 5 (17.2) >.999

Menstrual irregularityb 1 (8.3) 1 (10) >.999

Sadness or depression 5 (17.9) 2 (6.9) .253

Somnolence 21 (75) 21 (72.4) >.999

Note: Values represent count (percent). Abbreviations: CNZ = Clonazepam, PGT = Psychodynamic

Group Therapy. aBased on the number of men. bBased on the number of women. Statistics: cFisher Exact

test was used