Respiratory and cognitive mediators of treatment change in panic disorder: evidence for intervention specificity.

The efficacy of psychosocial treatment for panic disorder with or without agoraphobia (PD/A) has been well established (e.g., Barlow, Gorman, Shear, & Woods, 2000; Hofmann & Smits, 2008). However, the question of how and why these treatments work remains largely unanswered. The quest for extracting mediators that are central contributors to treatment success is vital for advancing intervention research. Investigating mediator candidates in PD/A is particularly intriguing given the wealth of interventions available, all with their own proposed mediators (Roth, Wilhelm, & Petitt, 2005). The mechanism of action for cognitive restructuring techniques (CT), for instance, is believed to be alterations in key cognitive processes (e.g., Clark et al., 1999; Gelder, Clark, & Salkovskis, 1993). The cognitive theory postulates that changes in catastrophic thinking are responsible for reductions in panic symptoms by attenuation of fearful interpretation of bodily symptoms (Clark, 1986). Thus, the alteration of symptom appraisal is presumed to be the primary mediator. A crucial first step in examining the validity of a proposed mediator requires the direct manipulation and repeated assessment of such mediators (Kazdin, 2007). Furthermore, to verify that change in symptom appraisal is indeed the proposed mediator, one must manipulate maladaptive cognitions in the absence of additional therapeutic interventions or techniques. However, CT is often combined with behavioral techniques (e.g., exposure), which complicates the direct testing of CT's specific pathways. Current evidence on the role of cognitive mediation on outcomes in PD is mostly limited to multicomponent interventions (e.g., Hoffart, Sexton, Hedley, & Martinsen, 2008; Hofmann et al., 2007; Teachman, Smith-Janik, & Marker, 2008). The one study that targeted changes in symptom appraisal in the absence of additional therapeutic techniques confirmed the validity of the proposed mediator (i.e., changes in daily ratings of beliefs about panic preceded changes in panic apprehension; Bouchard et al., 2007). Another common intervention, based on an influential biological theory of panic, is breathing training. Breathing training is thought, contrary to CT, to derive its therapeutic effect through correction of a biological factor: a deranged respiratory control mechanism (Klein, 1993; Ley, 1985). These theories view hyperventilation or hypocapnia (lower than normal levels of carbon dioxide, or CO2) as the primary (Ley, 1985) or secondary (Klein, 1993) cause of panic symptoms. Hypocapnia can produce unpleasant bodily sensations, the fear of which may contribute to panic (Carr, Lehrer, & Hochron, 1992; Chambless, Caputo, Bright, & Gallagher, 1984), and has been linked to organ injury and a number of organic and mental illnesses (Laffey & Kavanagh, 2002; Meuret, in press). The correction of sustained hypocapnia by therapeutically increasing partial pressure of carbon dioxide (PCO2) should thereby lead to changes in panic symptoms. This theoretical framework was derived from cross-sectional research that identified hypocapnia as a critical biomarker in PD (e.g., Hegel & Ferguson, 1997; Papp, Klein, & Gorman, 1993). As noted earlier, a mandatory element of mechanism research is the successful manipulation of the proposed mediator. Surprisingly, the few studies examining the efficacy of traditional breathing training (Craske, Rowe, Lewin, & Noriega-Dimitri, 1997; Schmidt et al., 2000) have neither targeted nor assessed its proposed mechanism: the correction of hypocapnia. In contrast, the typical respiratory instructions (to breathe slowly and/or deeply; e.g., Craske et al., 1997; Schmidt et al., 2000) are likely to lead to compensatory deeper breathing, which in turn perpetuates hyperventilation and intensifies panic symptoms (Conrad et al., 2007; Meuret, Wilhelm, Ritz, & Roth, 2003). Capnometry-assisted respiratory training, or CART, was developed to systematically change hypocapnia in patients with PD. CART is a brief, tightly controlled 4-week training that uses immediate feedback of end-tidal PCO2 to teach patients how to raise subnormal levels of PCO2, thereby gaining control over dysfunctional gas exchange and associated panic symptoms (e.g., shortness of breath, dizziness). Patients use a portable capnometer to continuously monitor the essential feature of hyperventilation, PCO2. Thus, CART differs substantially from traditional breathing retraining, as it assures the manipulation and assessment of respiratory physiology (Meuret et al., 2003). Due to the novelty of CART, empirical evidence is limited but promising. Preliminary results from a first randomized controlled trial study (CART vs. wait list; Meuret, Wilhelm, Ritz, & Roth, 2008) showed that clinically significant reductions in panic symptom severity were achieved by 68% of patients with PD/A at posttreatment (d = 2.21) and by 79% and 93% of such patients at 2-and 12-month follow-up; reductions were comparable to those achieved with cognitive behavior therapy or cognitive therapy (e.g., Barlow et al., 2000; Clark et al., 1999). These improvements were accompanied by sustained normalized levels of PCO2. Preliminary support for the proposed mediator, PCO2, was established with longitudinal mediation analysis that found PCO2 to mediate and drive changes in symptom appraisal (Meuret, Rosenfield, Suvak, Hofmann, & Roth, 2009). Notwithstanding, secondary effects of PCO2 on symptom appraisal can be theorized, in that the attenuation of distressing respiratory symptoms may lessen threatening appraisals. Additionally, the ability to control respiratory activity may increase perceived control, an important modality-nonspecific mediator, by providing a strategy and a response plan (Craske & Hazlett-Stevens, 2002). It has been proposed that perceived control is an important determinant for the etiology and maintenance for all anxiety disorders (Barlow, 2002). Individuals with PD are believed to experience unexpected bursts of emotions (“true alarm” or “false alarms”). These emotional bursts (alarms) cause the vulnerable individuals to view their own emotions and bodily reactions as being out of their control. Individuals with PD are therefore believed to avoid agoraphobic situations or certain activities in part because they anticipate a lack of internal control over their emotional response on being exposed to perceived threat. These relations with other variables, and the effect of PCO2 on panic symptom severity over and above other potential mediators, remain untested. Likewise, secondary effects of symptom appraisal, the proposed mediator of CT, on a nonspecific mediator such as perceived control are plausible but have not been examined. The aim in this study was to elucidate distinct and common mechanisms of change in two interventions for PD, CT and CART, and to determine their unique contribution to reductions in panic symptoms. Thus, the primary goal was to evaluate processes, rather than to compare outcomes, and to determine whether the coping skills taught in each treatment actually mediated the outcomes from each treatment. We took the following methodological steps to improve and extend prior research: (a) The interventions focused exclusively on the manipulation of the proposed mediator (symptom appraisal for CT and PCO2 for CART). By doing so, we avoided clouding the evaluation of the proposed mechanism of change with other manipulations. (b) We assessed intervention-specific mediators across multiple dimensions (both psychological and biological). If inconsistent results occurred, this would additionally inform us about method variance or the multifaceted nature of the constructs or dimensions. (c) We systematically examined a third, modality-nonspecific mediator, perceived control. As pointed out by Borden, Clum, and Salmon (1991), a general factor such as perceived control, common to many treatment modalities, “may be responsible for observed improvements in PD patients” (p. 259). Examining both modality-specific and modality-nonspecific mediators across different types of interventions offers insight as to whether these mediators emerge only when targeted directly by specific treatments or whether they also mediate relations in other treatment scenarios. The outlined methodological steps were based on the recommended guidelines for advanced meditational design (Kazdin, 2002). Using longitudinal, moderated mediation analyses, we examined the following specific hypotheses: Changes in respiratory regulation and symptom appraisal will be modality-specific mediators of outcome (panic symptom severity) in CT and CART, respectively. Perceived control over emotional reactions and external threats will be a nonspecific mediator of outcomes across treatment modalities. Among the mediators, PCO2 will partially mediate and precede changes in symptom appraisal and perceived control in CART, and symptom appraisal will partially mediate and precede changes in perceived control in CT.