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Cognitive Behavioral Therapy, Imipramine, or Their Combination for Panic Disorder 

Cognitive Behavioral Therapy, Imipramine, or Their Combination for Panic Disorder
Cognitive Behavioral Therapy, Imipramine, or Their Combination for Panic Disorder

Amanda Sun

, and Tobias Wasser

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Subscriber: null; date: 23 October 2019

Combining imipramine and CBT appeared to confer limited advantage acutely but more substantial advantage by the end of maintenance. Each treatment worked well immediately following treatment and during maintenance; CBT appeared durable in follow-up.

Barlow et al.1

Research Question:

When treating adults with panic disorder, is imipramine in combination with cognitive behavioral therapy (CBT) more effective than monotherapy with either treatment alone?


National Institute of Mental Health

Year Study Began:


Year Study Published:


Study Location:

Four anxiety research clinics

Who Was Studied:

Adults with panic disorder with or without mild agoraphobia

Who Was Excluded:

Patients with psychotic or bipolar disorders, suicidal ideation, significant substance abuse, and significant medical illnesses. In addition, patients with contraindications to CBT or imipramine, with history of poor response to similar treatments, receiving competing treatment, and those with pending disability claims.

How Many Participants:


Study Overview:

See Figure 1.1 for a summary of the study design.

Figure 1.1 Summary of Study Design

Figure 1.1 Summary of Study Design

note: CBT = cognitive behavioral therapy.

Study Intervention:

During the three-month acute treatment phase, those receiving CBT participated in 11 sessions lasting approximately 50 minutes each over 12 weeks. Those in combined treatment saw two therapists for a total of 75 minutes weekly. Maintenance phase treatment involved six monthly appointments involving treatment similar to the acute phase. Those who were responders were randomized to either treatment discontinuation or an extended maintenance pilot project and were reassessed after an additional six months of follow-up.

Participants randomized to imipramine or placebo received their interventions in a double-blind, fixed flexible-dose design, in which patients started imipramine (or placebo equivalent) at 10 mg/day, increased every other day by 10 mg until they were given 50 mg/day. Then, the dose was increased to 100 mg/day by week 4, and to 200 mg/day by week 5 unless the patient experienced intolerable side effects. The dose was further increased up to 300 mg/day by week 5 if the patient was still experiencing significant symptoms.


Acute (three months after treatment initiation), maintenance (nine months after initiation), and follow-up (six months after treatment discontinuation).


Panic Disorder Severity Scale (PDSS) response rate, defined as a 40% reduction from baseline scores. Clinical Global Impressions (CGI) response rate, defined as the percent of subjects who scored a 2 (much improved) or better while also having less than 3 (mild) on the CGI severity.


  • CBT alone and imipramine alone versus placebo:

    • Both imipramine and CBT were significantly superior to placebo in both acute and maintenance phases of treatment based on PDSS.

    • Post-acute CGI scores were not significantly different between imipramine or CBT and placebo, but after six months of maintenance, imipramine and CBT were both significantly superior to placebo for both the PDSS and CGI.

  • There was no significant difference in acute or maintenance analyses for CBT alone versus imipramine alone, but follow-up analyses favored CBT over imipramine.

  • In the acute phase, combined therapy (CBT and imipramine) did not produce higher efficacy compared to CBT and placebo or to imipramine alone but did demonstrate superiority in maintenance analysis.

  • Among treatment responders, imipramine produced a higher quality response than CBT; however, among those randomized to the no-treatment follow-up period, those who received CBT alone or CBT and placebo fared significantly better than responders to imipramine (Table 1.1).

Table 1.1 Summary of Study Findings


CBT (%)

P valuea

Imipramine (%)

P valueb

CBT + Imipramine (%)

P valuec

Placebo (%)

Acute PDSS response








PDSS response at six months








PDSS response six months after treatment ended








a P value of CBT compared to placebo.

b P value of imipramine compared to placebo.

c P value of CBT+impiramine compared to imipramine alone.

note: PDSS = Panic Disorder Severity Scale.

Criticisms and Limitations:

This study began when selective serotonin reuptake inhibitors (SSRIs) were not yet considered first line for panic disorder because of their favorable side-effect profile compared to tricyclic antidepressants. Thus, there was no comparator arm of patients receiving SSRIs.

Other limitations of this study include its generalizability to patients with higher levels of phobic avoidance, as the study only included patients with none or mild agoraphobia.

Other Relevant Studies and Information:

  • See the Cochrane Database articles on psychological therapies in the treatment for panic disorder1 and on combined psychotherapy plus antidepressants in panic disorder2 to obtain more information on these topics.

  • There have been other trials that studied psychotherapy,3,4 pharmacotherapy5,6,7 and both.8 These studies have demonstrated conflicting evidence regarding the superiority of a combination of medication and psychotherapy.

  • Based on this evidence, the American Psychiatric Association (APA) guidelines recommend psychotherapy such as CBT and antidepressants such as SSRIs in the treatment of panic disorder9 in most circumstances.

Summary and Implications:

This study found that imipramine, CBT, as well as a combination of the two treatments are superior to placebo in the treatment of panic disorder. Combination treatment was superior to each treatment alone, though it took time for this advantage to emerge. The study also showed that while imipramine produced a higher quality of response, CBT appears to exhibit more durability and is better tolerated. Notably, this study also indicates that initiating antidepressants might diminish the long-term durability of CBT after treatment withdrawal, though this finding requires replication. Based on this study and subsequent trials, the APA supports the use of antidepressants such as SSRIs and/or psychotherapy in the treatment of panic disorder.

Clinical Case: Treatment of Panic Disorder

Case History

A 21-year-old woman with a history of unspecified anxiety disorder presents to an outpatient psychiatrist after being referred by her primary care physician with complaints of increasing frequency of panic attacks. She describes frequent, almost daily, episodes of severe anxiety, palpitations, shortness of breath and gastrointestinal distress lasting about 15 minutes each. She was diagnosed with panic disorder without agoraphobia. Her primary care physician had prescribed her clonazepam for the treatment of her panic disorder, but the patient experienced only partial response and was also concerned about benzodiazepines’ addictive potential. She asked about whether she could transition to an alternative treatment.

Based on this study, what therapeutic approaches should the outpatient psychiatrist take?

Suggested Answer

This study found that in the long run, CBT in combination with an antidepressant (such as imipramine) is indicated in the treatment of panic disorder.

The patient described in the vignette fits the criteria for inclusion in this study, and considering the severity of her illness, an antidepressant along with referral for CBT should be started. Of course, side effects and efficacy should be monitored closely in the acute period.


1. Barlow, D. H., Gorman, J. M., Shear, M. K., & Woods, S. W. (2000). Cognitive-behavioral therapy, imipramine, or their combination for panic disorder. Journal of the American Medical Association, 283(19), 2529–2536.Find this resource:

2. Pompoli, A., Furukawa, T. A., Imai, H., Tajika, A., Efthimiou, O., & Salanti, G. (2016). Psychological therapies for panic disorder with or without agoraphobia in adults: A network meta-analysis. Cochrane Database Systematic Reviews, 4, CD011004.Find this resource:

    3. Furukawa, T. A., Watanabe, N., & Churchill, R. (2007). Combined psychotherapy plus antidepressants for panic disorder with or without agoraphobia. Cochrane Database Systematic Reviews, 1, CD004364.Find this resource:

    4. Clark, D. M., Salkovskis, P. M., Hackmann, A., Middleton, H., Anastasiades, P., & Gelder, M. (1994). A comparison of cognitive therapy, applied relaxation and imipramine in the treatment of panic disorder. British Journal of Psychiatry, 164(6), 759–769.Find this resource:

    5. Ballenger, J. C., Burrows, G. D., DuPont, R. L., Lesser, I. M., Noyes, R., Pecknold, J. C., . . . & Swinson, R. P. (1988). Alprazolam in panic disorder and agoraphobia: Results from a multicenter trial: I. Efficacy in short-term treatment. Archives of General Psychiatry, 45(5), 413–422.Find this resource:

    6. Woodman, C. L., & Noyes, R. (1994). Panic disorder: Treatment with valproate. Journal of Clinical Psychiatry, 55(4), 134–136.Find this resource:

    7. Pande, A. C., Pollack, M. H., Crockatt, J., Greiner, M., Chouinard, G., Lydiard, R. B., . . . & Shiovitz, T. (2000). Placebo-controlled study of gabapentin treatment of panic disorder. Journal of Clinical Psychopharmacology, 20(4), 467–471.Find this resource:

    8. Gould, R. A., Ott, M. W., & Pollack, M H. (1995). A meta-analysis of treatment outcome for panic disorder. Clinical Psychology Review, 15(8), 819–844.Find this resource:

    9. American Psychiatric Association. (2009). Practice guideline for the treatment of patients with panic disorder. Washington, DC: Author, p. 11.Find this resource: