Strategies for Assessing and Treating Comorbid Panic and Generalized Anxiety Disorder

February 1, 2009

The 2 most common anxiety disorders are generalized anxiety disorder (GAD) and panic disorder. Approximately 5.7% of people in community samples will meet diagnostic criteria for GAD in their lifetime; the rate is about 4.7% for panic disorder (with or without agoraphobia).1 GAD-which is characterized by excessive and uncontrollable worry about a variety of topics (along with associated features such as trouble sleeping and impaired concentration)-is often chronic and is associated with significant costs to the individual and to society.

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The 2 most common anxiety disorders are generalized anxiety disorder (GAD) and panic disorder. Approximately 5.7% of people in community samples will meet diagnostic criteria for GAD in their lifetime; the rate is about 4.7% for panic disorder (with or without agoraphobia).1 GAD-which is characterized by excessive and uncontrollable worry about a variety of topics (along with associated features such as trouble sleeping and impaired concentration)-is often chronic and is associated with significant costs to the individual and to society.2,3

Panic disorder-characterized by recurrent, unexpected panic attacks-can be similarly intractable (particularly when is it accompanied by agoraphobia) and costly.4,5 Panic attacks are discrete periods of intense fear or discomfort that manifest with sweating, trembling, accelerated heart rate, and concern about having another panic attack. Many people experience panic attacks without meeting full diagnostic criteria for panic disorder (about 28.3% lifetime prevalence).6 Furthermore, panic attacks have been identified as a risk factor for various other forms of psychopathology, including GAD.7

Given the widespread occurrence of GAD, panic disorder, and panic attacks, it is not surprising that these conditions are frequently comorbid. An international study of lifetime comorbidities found a high rate (21.8%) of panic disorder and GAD; most people (55.8%) reported that the symptoms of GAD and panic disorder began within 1 year of each other.8 Unfortunately, while effective treatment strategies are available for both panic disorder and GAD, little is known about how to best treat these disorders when they are comorbid.

Diagnostic issues
The first task to effectively address comorbid GAD and panic disorder is to make the appropriate diagnosis. A variety of general medical conditions that mimic features of panic

disorder and/or GAD (eg, hyperthyroidism, pheochromocytoma) need to be considered. In addition, somatic and associated symptoms may be present in both GAD and panic disorder; thus it is important to understand the context of these symptoms.

In GAD, somatic symptoms such as muscle tension or feeling “keyed up” or “on edge” may occur, but they present differently than those that arise during a panic attack. Panic attack–related somatic symptoms tend to develop abruptly, then peak and subside relatively quickly, whereas GAD-related somatic symptoms tend to come on more gradually, and are present at a lower level for longer periods. GAD-related somatic symptoms may be experienced as aversive by the individual but generally are not catastrophically misinterpreted (eg, “I am dying”).

In addition to the symptom overlap between GAD and panic attacks, there is overlap between GAD and panic disorder; worry is a component of both disorders. Panic disorder is associated with recurrent panic attacks and worries about future attacks and their consequences or meaning.

With GAD, worry is much more pervasive and tends to cover a variety of life’s domains (eg, finances, work, family). Thus, if the worry is confined to apprehension about having a panic attack or about the implications or consequences of a panic attack, the diagnosis of GAD is excluded. However, a diagnosis of panic disorder is ruled out if a person has GAD and panic attacks, but does not exhibit a month or more of fear of having another attack, worry about the implications of the attack, or significant behavior change (ie, behavioral avoidance). In this case, only GAD is diagnosed, although the presence of panic attacks should be noted as a clinically significant feature.

It is also important to establish whether GAD or panic disorder is primary, because this will probably affect the treatment plan. This assessment can be difficult given the symptom overlap that exists. However, it is often particularly helpful to consider which disorder is having the greatest functional impact or the most potential to impede treatment compliance and outcome. Many patients with moderate to severe panic disorder report that the symptoms are more interfering than GAD symptoms. These patients tend to be more motivated to seek treatment because of the intense fear produced by attacks. They may also be more likely to be referred to treatment because of frequent emergency department (ED) visits. However, there are persons for whom GAD is far more interfering, so this issue warrants consideration.

Treatment
There is little empirical guidance in the area of treatment planning for comorbid GAD, panic disorder, and panic attacks, but more work is emerging in this area. For example, psychosocial approaches, such as cognitive-behavioral therapy (CBT), are being tailored specifically for treating comorbid GAD and panic disorder.9

CBT is the most researched and effective psychotherapy for both panic disorder and GAD. Findings from CBT trials that target GAD or panic disorder suggest that CBT should be the first-line psychological treatment-regardless of whether panic disorder or GAD is primary.10,11 The elements of empirically supported CBTs for panic disorder and GAD generally include similar techniques, and treatment for the comorbid conditions can include all or some of these elements: psychoeducation, exposure, cognitive restructuring, and relaxation.

Psychoeducation is critically important for individuals with comorbid panic disorder and GAD. The patient’s expectations about treatment are set and treatment goals are developed collaboratively. The next focus of treatment depends on the goals arrived at with the patient. However, keep in mind that research has demonstrated that panic disorder may interfere with GAD treatment more than other comorbid disorders.12 This may be because the intense nature of panic attacks leads to increased functional impairment and obscures the significance of GAD treatment. Frequent and severe panic attacks have the potential to interfere with treatment compliance, particularly if agoraphobia develops. Therefore, it is often prudent to address panic attacks early in treatment.

One way to address panic attacks directly is through interoceptive exposure, which draws on principles of habituation and extinction learning to reduce the occurrence of panic attacks. Generally, during interoceptive exposure, the patient engages in a variety of exercises that induce the feared physical sensations that often precede or accompany a panic attack. Exercises might include spinning in a chair, breathing through a straw, hyperventilating, or walking up stairs. The patient is instructed to continue the exposure until he or she experiences a reduction in anxiety (ie, habituation has occurred).

While interoceptive exposure is intended to reduce panic, it may also help reduce symptoms of GAD. There are models of GAD and a growing research literature, which suggest that worry and GAD are characterized by a tendency to avoid a variety of emotional experiences, including fear, sadness, anger, and positive emotions.13 There is a distinct possibility that exposure to the uncomfortable emotions and sensations of a panic attack will also reduce the emotional avoidance typical of GAD by introducing or reinforcing the notion that fear and fear-related sensations and thoughts are not harmful.

Another CBT element that may be applied to both panic disorder and GAD symptoms is cognitive restructuring. In panic disorder, cognitive restructuring is used to address catastrophic beliefs about one’s physical sensations and/or panic attacks. For example, many people believe they are dying during a panic attack. In cognitive restructuring, this thought is identified and the patient is encouraged to examine the evidence that this thought is true. The process is much the same when doing cognitive restructuring of worry; an anxious thought is identified (eg, “What will happen if I lose my job?”) and the evidence of the likelihood and/or catastrophic outcome of the thought is examined.

Finally, many CBTs for panic disorder and GAD include a relaxation component that may include skills such as diaphragmatic breathing or progressive muscle relaxation. These skills are popular with clinicians and patients because they are easy to learn (and teach), and often have significant short-term impact on panic symptoms, worry, and GAD somatic symptoms.

Both panic disorder and GAD respond to pharmacological management. Some medications have dem­onstrated efficacy for both conditions (although they may be FDA-approved for only 1 condition), including some benzodiazepines, tricyclic antidepressants, SSRIs, and serotonin noradrenaline reuptake inhibitors. Other medications, such as azapir­ones and b-blockers, may alleviate symptoms of GAD but are less effective for panic.14

High-potency benzodiazepines, such as alprazolam, have shown superior efficacy for panic symptoms. However, the disadvantages of benzodiazepines, such as abuse potential and rebound anxiety after discontinuation, detract from their overall value in treating comorbid panic disorder and GAD.15 (A recent effect-size analysis suggests that GAD is generally less responsive than panic disorder to pharmacotherapy; also, residual symptoms of GAD may need to be addressed by CBT.16)

Studies that compared treatment responses to medication or CBT have found that while medication may initially produce greater symptom reduction, CBT may produce a more durable response.17 Many practitio­ners have adopted combination (pharmacotherapy plus CBT) treatment approaches, particularly for those patients with symptoms severe enough to interfere with adherence to psycho­therapy. However, there is reason to use this combination approach judiciously. Research has shown that concurrent use of pharmacotherapy and CBT may not be helpful or may be problematic in many individuals with anxiety symptoms. Randomized controlled trials have generally found that combination treatments have limited value over monotherapies for panic disorder, and studies of naturalistic combination treatments for panic disorder have demonstrated poorer outcomes than CBT alone.17,18

There are theoretical reasons to avoid combination therapy for panic disorder and GAD.15 First, it is possible that the phenomenon of state-dependent learning may be implicated in relapse following combination treatment. The extinction learning that occurs during CBT in combination with a medication may not be retrieved as readily from memory once the medication is discontinued. In addition, medication may reinforce a patient’s belief that his internal ex­periences should be avoided, which may detract from the CBT message that emotions, physical sensations, and thoughts are not harmful and do not need to be avoided. Furthermore, combination therapy may cause patients to attribute symptom reduction to the medication and thereby increase the risk of relapse following medication withdrawal.19

Case Vignette

Julia is a 19-year-old who referred herself for psychiatric treatment following 3 visits to the ED for heart palpitations, shortness of breath, dizziness, and trembling. These attacks began a few months after her father learned he had cancer. All physical causes of the attacks were ruled out. In addition to the panic attacks, Julia reported that she was very worried that she would have another attack in public. She mentioned (when asked) that she worried a lot about many issues in her day-to-day life, including paying her bills, the health of family members, and school. She also reported that for much of her life she had been “an anxious person.” After thorough assessment, panic disorder without agoraphobia and GAD was diagnosed.

Julia was offered pharmacotherapy and CBT but felt that her life circumstances would prevent her from attending therapy appointments regularly. She opted for pharmacotherapy and an SSRI was prescribed for her. At her follow-up appointment she reported that she had decided to stop taking the medication after 2 weeks because it was making her feel jittery. After she switched to a benzodiazepine, the number of panic attacks was significantly reduced, as were the somatic symptoms of GAD. Nevertheless, she continued to worry excessively.

After 1 year of therapy, Julia noted that her life circumstances had become less stressful. The benzodiazepine dosage was slowly tapered, but within 1 week after the medication had been discontinued, Julia had another panic attack. Her psychiatrist decided to try another SSRI but this time at a much lower initial dosage. She was also referred to a CBT therapist for treatment of both panic disorder and GAD.

Julia was quite motivated for CBT treatment and complied with all therapy elements. While she was initially apprehensive about interoceptive exposure exercises, she was willing to try them and did report less fear of her physical sensations after completing these exercises. She also reported that the cognitive restructuring and relaxation skills helped her feel greater mastery over her anxiety and worry. At the conclusion of the 16 sessions of CBT, Julia no longer met diagnostic criteria for panic disorder but still met criteria for GAD (although she reported reduced severity of symptoms). One year after CBT treatment, she was continuing to take the SSRI and was still experiencing some symptoms of GAD but had not had a panic attack since completing CBT.

Conclusions
This hypothetical vignette demonstrates several important and common issues in the treatment of comorbid panic disorder and GAD. Julia experienced a typical course of panic disorder and GAD, including onset in the late teens, with a relapsing/remitting course of panic disorder and chronic GAD (with relatively less GAD response to pharmacotherapy). Her initial treatment with an SSRI was unsuccessful because of non-compliance with the treatment regiment secondary to discomfort with the physical sensations associated with medication initiation, a problem that is common in persons with panic disorder.20

Although the panic attacks remitted with the benzodiazepine, there was little effect on the GAD symptoms, and the panic disorder returned on discontinuation (despite slow taper), possibly due to rebound anxiety. A trial of a slowly titrated SSRI helped reduce both symptoms of panic disorder and GAD. This, combined with a course of CBT that focused on reducing symptoms of both disorders, was most effective.

Although combination treatment is common, this practice raises concerns that patients may experience symptom relapse if the medication is withdrawn at some point in the future. During or immediately after SSRI discontinuation, a short booster course of CBT may be indicated to prevent relapse and reinforce previously learned anxiety management skills.

Drug Mentioned in This Article
Alprazolam (Xanax)

References:

1. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.
2. Noyes R,Woodman C, Garvey MJ, Cook BL. Generalized anxiety disorder vs. panic disorder: distinguishing characteristics and patterns of comorbidity. J Nerv Ment Dis. 1992;180:369-379.
3. Wittchen HU. Generalized anxiety disorder: prevalence, burden, and cost to society. Depress Anxiety. 2002;16:162-171.
4. Yonkers KA, Bruce SE, Dyck IR, Keller MB. Chronicity, relapse, and illness-course of panic disorder, social phobia, and generalized anxiety disorder: findings in men and women from 8 years of follow-up. Depress Anxiety. 2003;17:173-179.
5.Batelaan N, Smit F, de Graaf R, et al. Economic costs of full-blown and subthreshold panic disorder. J Affect Disord. 2007;104:127-136.
6. Kessler RC, Chiu WT, Jin R, et al. The epidemiology of panic attacks, panic disorder, and agoraphobia in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2006;63:415-424.
7. Goodwin RD, Lieb R, Hoefler M, et al. Panic attack as a risk factor for severe psychopathology. Am J Psychiatry. 2004;161:2207-2214.
8. Kessler RC, Andrade LH, Bijl RV, et al. The effects of co-morbidity on the onset and persistence of generalized anxiety disorder in the ICPE surveys: International Consortium in Psychiatric Epidemiology. Psychol Med. 2002;32:1213-1225.
9. Labrecque J, Dugas MJ, Marchand A, Letarte A. Cognitive-behavioral therapy for comorbid generalized anxiety disorder and panic disorder with agoraphobia. Behav Modif. 2006;30:383-410.
10. Roemer L, Orsillo SM, Salters-Pedneault K. Efficacy of an acceptance-based behavior therapy for generalized anxiety disorder: evaluation in a randomized controlled trial. J Consult Clin Psychol. 2008;76: 1083-1089.
11. Tsao JC, Mystkowski JL, Zucker BG, Craske MG. Impact of cognitive-behavioral therapy for panic disorder on comorbidity: a controlled investigation. Behav Res Ther. 2005;43:959-970.
12. Provencher MD, Ladouceur R, Dugas MJ. Comorbidity in generalized anxiety disorder: prevalence and course after cognitive-behavior therapy [in French]. Can J Psychiatry. 2006;51:91-99.
13. Roemer L, Orsillo SM. Mindfulness- and Acceptance- Based Behavioral Therapies in Practice. New York: Guilford Press; 2008.
14. Roy-Byrne P, Wingerson D, Cowley D, Dager S. Psychopharmacologic treatment of panic, generalizedanxiety disorder, and social phobia. Psychiatr Clin North Am. 1993;16:719-735.
15. Westra HA, Stewart SH. Cognitive behavioural therapy and pharmacotherapy: complementary or
contradictory approaches to the treatment of anxiety? Clin Psychol Rev. 1998;18:307-340.
16. Hidalgo RB,Tupler LA, Davidson JR.An effect-size analysis of pharmacologic treatments for generalized anxiety disorder. J Psychopharmacol. 2007;21:864- 872.
17. Barlow DH, Gorman JM, Shear MK, Woods SW. Cognitive-behavioral therapy, imipramine, or their combination for panic disorder: a randomized controlled trial [published corrections appear in JAMA. 2000;284:2450; JAMA. 2001;284:2597]. JAMA. 2000;283:2529-2536.
18. Arch JJ, Craske MG. Implications of naturalistic use of pharmacotherapy in CBT treatment for panic disorder. Behav Res Ther. 2007;45:1435-1447.
19. Basoglu M, Marks IM, Kiliç C, et al.Alprazolam and exposure for panic disorder with agoraphobia: attribution of improvement to medication predicts subsequent relapse. Br J Psychiatry. 1994;164:652-659.
20. Mathew SJ, Coplan JD, Gorman JM. Management of treatment-refractory panic disorder. Psychopharmacol Bull. 2001;35:97-110.

Evidence-Based References
Arch JJ, Craske MG. Implications of naturalistic use of pharmacotherapy in CBT treatment for panic disorder. Behav Res Ther. 2007;45:1435-1447.
Labrecque J, Dugas MJ, Marchand A, Letarte A. Cognitive-behavioral therapy for comorbid generalized anxiety disorder and panic disorder with agoraphobia. Behav Modif. 2006;30:383-410.