Cognitive-Behavioral Therapy, Imipramine, or Their Combination for Panic Disorder: Title and subTitle BreakA Randomized Controlled Trial FREE

Panic disorder (PD) is a chronic condition associated with substantial reduction in quality of life,¹ and lifetime prevalence rates are approximately 3%.^{2 - 3} Role functioning is substantially lower in patients with PD than in patients with diabetes, heart disease, or arthritis.⁴ Individuals with PD frequently use both emergency department and general medical services,⁵ presenting with high rates of unexplained cardiac symptoms,^{6 - 7} dizziness, and bowel distress.^{6 ,8} These patterns continue indefinitely.^{9 - 10} The social and economic costs of PD are considerable.^{11 - 13} Successfully treating PD can produce medical cost offsets as high as 94%.¹² Thus, efforts to ascertain effective treatments or a combination of treatments for PD are important.

Earlier psychosocial treatments were directed specifically at unexpected panic attacks and associated anxiety.^{14 - 15} A growing number of studies support the effectiveness of these psychosocial approaches for PD compared with no treatment or credible psychosocial placebos.¹⁶ By the 1980s, the efficacy of pharmacological treatment with imipramine in patients with PD had been well established.^{17 - 21} Imipramine was regarded as the pharmacological criterion standard for the treatment of PD for more than 20 years,^{22 - 24} until the emergence of the selective serotonin reuptake inhibitors (SSRIs).

Despite the proven efficacy of both drug and psychosocial treatments for PD and some emerging evidence on the possible synergistic effects of these approaches, particularly on phobic behavior,²⁵ studies of medication and psychosocial approaches have, until recently, run on parallel and sometimes hostile tracks.^{15 ,26 - 29} We assembled a team of 4 investigators, 2 committed to each approach, to undertake a comparative study that would determine optimal treatment for PD.

We conducted a randomized controlled trial comparing cognitive-behavioral therapy (CBT), imipramine plus medical management, the combination of CBT and imipramine (CBT+imipramine), pill placebo plus medical management, and CBT+placebo for PD (Figure 1). Randomization was stratified by site and presence of Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition–defined current major depression and was blocked within stratum. To improve trial efficiency,³⁰ unequal numbers of patients were randomized to the treatments (6 CBT, 6 imipramine, 5 CBT+imipramine, 25 CBT+placebo, and 2 placebo per block of 24) based on expected pairwise comparison effect sizes. The acute treatment phase consisted of 11 sessions during 12 weeks. Each CBT session lasted approximately 50 minutes and each drug treatment session approximately 30 minutes. Patients in combined treatment saw 2 therapists for a total of about 75 minutes per week. Responders to acute treatment entered a 6-month maintenance phase without breaking the study blind. Maintenance-phase treatment consisted of 6 monthly appointments in which treatment similar to the acute treatment was continued. After 9 months of treatment (3 months acute and 6 months maintenance), patients were assessed again. Responders to maintenance treatment were then assigned to discontinuation of treatment, except for 17 patients who were randomized to an extended maintenance pilot project. Remaining patients were assessed again after 6 months of follow-up (15 months after treatment was initiated). The trial was conducted between May 1991 and April 1998 and was approved by institutional review boards at each site.

All patients passing diagnostic screening for a principal diagnosis of PD with or without mild agoraphobia (N=497) were entered in the pretreatment phase after signing written, informed consent. Pretreatment included drug washout for patients taking anxiolytic or antidepressant medication. Patients were permitted up to 10 doses of benzodiazepine (0.5 mg of alprazolam-equivalent) in the 2 weeks before the first treatment visit and up to 20 doses during baseline and acute treatment combined. During the 2 weeks prior to the first treatment visit, patients underwent physical and laboratory examinations, and diagnosis was confirmed using the Anxiety Disorders Interview Schedule-Revised (ADIS-R).^{31 - 32} Mild agoraphobia was operationally defined as a score less than or equal to 18 on the ADIS-R avoidance scale. In addition, inclusion required at least 1 full or limited panic attack in the 2 weeks before the first treatment visit.

Exclusion criteria were psychotic, bipolar, or significant medical illnesses, suicidality, significant substance abuse, contraindications to either treatment, prior nonresponse to similar treatments, and concurrent competing treatment or pending disability claims. More details are available on request from the authors. Patients with comorbid unipolar depression were not excluded unless suicidal. A detailed analysis of reasons for pretreatment attrition is provided elsewhere.³³

Therapists providing CBT were doctoral-level clinicians who underwent extensive training and certification supervised by the Boston site prior to treating study patients. Clinicians were not required to have prior training in cognitive-behavioral procedures. Pharmacotherapists were experienced psychiatrists who underwent additional training and certification in the study protocol under the direction of the Columbia/Hillside site. All CBT therapists and pharmacotherapists received ongoing supervision of their cases from the responsible site during biweekly telephone calls, and adherence and competence ratings were routinely collected after listening to a sample of audiotaped sessions.

Cognitive-behavioral therapy for PD, developed at the Boston site, combines interoceptive exposure, cognitive restructuring, and breathing retraining. This treatment was described in a manual containing detailed instructions for the conduct of each session.³⁴

The imipramine and placebo interventions were administered in a double-blind, fixed flexible-dose design, according to a manual developed for this study. Both the imipramine and placebo arms included a medical management component, specified in the manual. The purpose of medical management was to monitor adverse effects, clinical state, and the patient's physical/mental condition; maximize compliance with the pharmacological treatment protocol; and proscribe specific interventions included in CBT (eg, cognitive restructuring of anxiety and panic symptoms). Patients who experienced clinical deterioration were removed from the study and offered alternative treatment for 3 months free of charge.

Starting dosages of imipramine were 10 mg/d (or pill placebo equivalent), increased every other day by 10 mg until 50 mg/d was reached. The dosage was then increased more rapidly, with an effort made to reach 100 mg/d by the end of week 3 and 200 mg/d by week 5, even if the patient became symptom-free earlier, unless adverse effects became intolerable. If the patient was not symptom-free, the dosage could be increased up to 300 mg/d by week 5. Blood levels of imipramine were assessed at 6 and 12 weeks and benzodiazepine screening of urine samples performed by local commercial laboratories.

The combined treatment conditions were administered according to a manual essentially consisting of the CBT and the imipramine manuals.

Prior to beginning the study, independent evaluators participated in training and certification on the rating instruments, supervised by the Pittsburgh site. Bimonthly conference calls were held for evaluators to discuss any questions and/or discrepancies among sites, and regular, random interviews were monitored for continued reliability of diagnosis and ratings. Reliability on main measures remained above 90%. Evaluator assessments occurred at baseline and after acute, maintenance, and follow-up phases, and evaluators were blind to treatment assignment.

The primary continuous outcome measure was the average item score for the Panic Disorder Severity Scale (PDSS), a clinician-rated scale of PD severity.³⁵ We also present results for a 40% reduction from baseline on PDSS. The primary categorical outcome measure involved determination of a responder based on the Clinical Global Impression Scale (CGI),³⁶ consisting of 7-point scales rating overall improvement and severity. We added specific PD-based anchor points for rating the CGI in this study. To be a responder, a patient needed to achieve a score of 2 (much improved) or better while being rated as 3 (mild) or less on CGI severity. Receipt of nonstudy treatment was evaluated at each assessment point. Patients who received nonstudy treatment for anxiety or panic were determined to be nonresponders, both for PDSS and CGI responder definitions.

The study was designed to address if both CBT alone and imipramine alone performed better than placebo; if either CBT or imipramine performed better relative to each other; and if there was an advantage to combining CBT and imipramine as evidenced by superiority of CBT+imipramine to CBT+placebo, imipramine alone, and CBT alone. These questions were addressed at each of 3 assessment points: postacute, postmaintenance, and follow-up. At each point, we performed an intent-to-treat (ITT) analysis, using an early-termination assessment. The baseline was carried forward as an assumption of nonresponse or return to baseline if the early-termination assessment was missing or contaminated by nonstudy treatment. Similarly, the baseline was also carried forward in follow-up analyses for the same reasons. Intent-to-treat analyses included all randomized patients except those discovered to be ineligible after randomization (Figure 1). At postmaintenance and follow-up assessments, we also conducted intent-to-continue (ITC) analyses, restricted to patients completing the preceding phase as responders. At postacute assessment, we present results for completers only.

Data were subjected first to omnibus testing of all 5 treatments and then to pairwise post hoc testing when the omnibus test indicated statistical significance. The Freeman-Halton and Fisher exact tests were used for categorical measure analyses, analysis of variance for PDSS baseline analysis, and analysis of covariance for subsequent analyses using baseline as the covariate. When analyses indicated a significant baseline-by-treatment interaction on the dependent measure, analysis of covariance was replaced by repeated-measures analysis of variance, with treatment assignment as the independent (between groups) variable and time as the dependent (within groups) variable. Significance was defined as P≤.05 with a 2-tailed test.

Of the 326 patients randomized, 312 are included in the analysis. Thirteen were excluded following uniform screening for loss of eligibility, and 1 was removed because of inadvertent unblinding. Proportions of excluded patients were not significantly different among treatment assignments.

There were no significant differences on demographic measures or on baseline PDSS score among the 5 randomized groups (Table 1). The mean PDSS scores indicate a moderate-to-average severity. No significant site effect, depression stratum effect, site-by-treatment interaction, or stratum-by-treatment interaction was observed in the acute ITT analyses for any of the 3 measures; thus, all data were aggregated across sites and across strata. Similarly, there were no significant interactions between treatment and other baseline variables (Table 1) in multivariate acute ITT analyses for any of the 3 measures. No important differences at baseline were observed between treatment groups entering vs not entering maintenance or follow-up. It has been suggested that when P<.10 level heterogeneity of the slope is present across treatments, treatment effects that apply to an important portion of the baseline severity spectrum may be obscured in analyses of covariance.³⁷ For slope heterogeneity, P>.25 for 8 of 9 omnibus PDSS analyses of covariance, suggesting little heterogeneity.

Acute completion rates did not differ significantly across treatment groups. Among the 8 noncompliant patients was 1 patient receiving imipramine alone who violated protocol by using benzodiazepines at rates exceeding those allowed, and 1 patient receiving CBT who began nonprotocol antidepressant treatment during acute treatment. Figure 1 also shows that 82% to 90% of maintenance-eligible patients completed maintenance across active treatments, compared with 33% of placebo patients. The omnibus test for this analysis was significant. Pairwise comparisons were significant for all active treatments vs placebo, including CBT alone (P=.006), imipramine alone (P=.007), CBT+imipramine (P=.001), and CBT+placebo (P=.004).

Patients receiving medication reported taking doses of 175 to 180 mg/d across treatments by week 6 and 214 to 239 mg/d by week 12. Mean (SD) imipramine+desipramine plasma levels at week 6 were 219 (186) ng/dL and 223 (127) ng/dL for CBT+imipramine and imipramine alone, respectively, and 225 (148) ng/dL and 263 (156) ng/dL at week 12.

Rates of urine samples that tested positive for benzodiazepines were low. At week 6, 3 (1.5%) of 197 samples tested positive (1 CBT+imipramine, 1 CBT, 1 imipramine), and at week 12, 3 (1.8%) of 164 (1 CBT+imipramine, 1 CBT, 1 imipramine) tested positive. Rates of missing urine samples were not significantly different across treatments.

CBT Alone and Imipramine Alone vs Placebo. In the acute ITT analysis, both CBT alone and imipramine alone were superior to placebo for the PDSS continuous measure (Table 2). Both treatments had significantly fewer dropouts for lack of efficacy than did placebo (4/18 for CBT and 10/30 for imipramine vs 8/10 for placebo [Figure 1]), and the imipramine group had significantly more dropouts for adverse effects than did the placebo group. Maintenance ITT analysis (Table 2) confirms the superiority of both CBT alone and imipramine alone to placebo.

CBT vs Imipramine. We found no significant difference between CBT alone and imipramine alone in the acute ITT or completer analyses or in the maintenance ITT or ITC analyses (Table 2). As expected, significantly more patients in the imipramine group than in the CBT group dropped out because of adverse effects (Figure 1). The follow-up analyses (Table 2) show trends favoring CBT over imipramine.

Combined CBT+Imipramine vs Single Treatment. We hypothesized that CBT+imipramine would be better than all 3 of the relevant comparison groups. Table 2 shows that CBT+imipramine was superior to CBT alone on 1 of 3 ITT analyses and 1 of 3 completer analyses but was not superior to CBT+placebo. In the maintenance ITT analysis (Table 2), combined treatment was better in the PDSS average analysis than in all 3 comparison treatments (thereby meeting our criteria for superiority) and better than CBT and CBT+placebo on ITC analyses.

Intent-to-continue analyses showed that responders to imipramine, with or without CBT, fared significantly worse in the no-treatment follow-up period than those who received either CBT alone or CBT+placebo (Table 2). After treatment discontinuation in the follow-up ITT analyses, the treatments that continued to show evidence of superiority to placebo were CBT alone (Table 2) and CBT+placebo (statistically significant for all 3 measures).

In a secondary analysis restricted to responders based on the CGI definition (Table 3), acute imipramine responders had significantly lower PDSS average scores than acute CBT responders, indicating a higher quality of response. Maintenance responders showed the same pattern at the trend level. Responders to combined CBT+imipramine had higher-quality responses than CBT responders at acute and maintenance points, as well as a higher quality of response than patients taking CBT+placebo at maintenance.

Timing of loss of response could be determined in 4 of 5 imipramine follow-up completers, losing response during months 3, 4, 5, and 6 (1 case each) and in 1 of 2 CBT follow-up completers, losing response during month 3. Among 9 CBT+imipramine follow-up completers losing response, relapse occurred during months 2, 4, and 5 (2 cases each), months 1, 3, and 6 (1 case each), and in the CBT+placebo relapser during month 1.

Our results demonstrate that both imipramine and CBT are better than pill placebo for treatment of PD. Imipramine produced a superior quality of response, but CBT had more durability and was somewhat better tolerated.

In our study, ITT placebo response did not differ from active treatment on acute-phase assessment when CGI was used to determine responder status. By contrast, the 7-item PDSS successfully discriminated between conditions. Moreover, the placebo response in the ITT analysis of 37.5% based on CGI criteria after 3 months drops to 13% after 9 months of treatment. Several studies have made similar observations in the treatment of depression and PD.^{38 - 41} While attrition in the placebo group may have compromised comparisons at the end of maintenance, placebo response is weak in magnitude and transient in duration.^{1 ,24}

There are several differences between active treatments. Although no differences emerged on a priori planned completer or ITT analyses, patients treated with imipramine and designated responders based on CGI criteria following the acute phase showed significantly more improvement on the PDSS than patients who responded to CBT. A trend level of significance remained at the end of maintenance. Thus, among those who did well with either treatment, patients receiving imipramine responded more completely. However, at follow-up, patients who had received CBT alone maintained their improvement significantly better (4% relapse) than those treated with imipramine (25% relapse) based on PDSS responder criteria. We discontinued imipramine by tapering during a 1- to 2-week period, following standard practice at the time. Relapses in medication-treated patients appeared to be evenly distributed across follow-up, suggesting that withdrawal played little role in the results. We did not aim to determine optimal tapering strategy or to ascertain the duration of medication maintenance that produces the best long-term outcome. Our results indicate the need for such work.

Findings of high acceptability and durability of CBT are consistent with previous reports,¹⁶ although attrition in the CBT-alone group was higher than reported previously.^{6 ,14 - 15 ,42} Adverse effects with imipramine and relapse following discontinuation are also consistent with previous reports.^{38 - 40} However, our results that show a superior quality of response with imipramine among responders to both treatments in the acute phase underscore the need to reduce attrition and develop optimal maintenance and discontinuation procedures for those receiving medication.

Acute coadministration of imipramine and CBT resulted in limited benefit over monotherapy. Adding medication to CBT achieved significantly better results than CBT alone at postacute assessment on some measures, but this combination was never better than CBT+placebo. By the end of maintenance, CBT+imipramine was superior to both CBT alone and CBT+placebo (as well as imipramine alone) on the PDSS average measure. However, this robust combination treatment produced the highest relapse rate at follow-up assessment. Surprisingly, the addition of CBT to imipramine did not mitigate relapse following medication discontinuation; addition of imipramine appeared to reduce the long-term durability of CBT. More work is needed to elucidate this result. A selection effect may account for the relatively poor outcome of combined treatment after discontinuation. Combined treatment could conceivably select patients who had been in particular need of long-term treatment from the beginning. We have not been able to detect important differences at baseline on variables in Table 1 between patients who did and did not enter the follow-up phase, but these analyses do not exclude the possibility of selection on an unmeasured prognostic factor.

There are several limitations of this study. First, to avoid the complications and possible confounding factors of adding exposure-based interventions to each condition, we enrolled patients with only limited degrees of phobic avoidance, and results are generalizable only to this group. Second, it could be argued that we underestimate the benefits of medication by using a tricyclic antidepressant instead of an SSRI. Current recommendations⁴³ (not yet in place when this study began) consider SSRIs to be the first-line medication. While there is little question that SSRIs are more convenient and have a more limited adverse-effect profile, studies examining differences from tricyclic antidepressants do not consistently find higher efficacy for SSRIs. In fact, of 4 randomized studies, none found significant differences in the end-of-study acute ITT analyses.^{44 - 47} One study found evidence for a more rapid response for the SSRI,⁴⁴ and another found that the tricyclic antidepressant but not the SSRI was more effective than placebo.⁴⁶ Moreover, there have also been refinements in CBT since we began our study. Thus, we believe it likely that results of a similar comparative study using an SSRI would not differ substantially from ours. Third, at the time we designed this study, a consensus existed that an adequate dose of imipramine should be at least 200 mg/d. A recent study, however, suggests that imipramine/desipramine plasma levels of about 150 mg/mL may be optimal in treating PD.⁴⁸ Hence, it is conceivable that we underestimate the therapeutic potential of imipramine in this study. Finally, the use of nonstudy medication is a possible confounding factor to any anxiety study. We made the decision to permit limited use of benzodiazepines, because we sought to simulate clinical practice. Rates of urine samples that tested positive for benzodiazepine use among the 5 treatments were equivalent and low. Only 1 subject's data were censored because of excessive benzodiazepine use. Thus, we believe benzodiazepine use did not play a significant role in our results.

This study represents, to our knowledge, the first multicenter trial comparing medication and psychosocial therapies and their combination for PD. Prior studies contrasting the 2 approaches have been criticized because of possible investigator-allegiance bias in study design, implementation, and/or analysis. Our study sites included 2 with psychotherapy and 2 with pharmacotherapy expertise. In this context, the absence of site differences in ITT outcome supports the important implication that both types of treatment should be transportable to most clinical settings and confirms the generalizability of the results.