A number of studies have supported the effectiveness of cognitive behavioral therapy (CBT) for panic disorder 123. Several studies also suggested that CBT is effective treatment for panic patients who have failed to respond to adequate pharmacotherapy 4567.

Cognitive model of panic disorder8 have proposed that panic attacks result from the catastrophic misinterpretation of certain bodily sensations. Patients have the tendency to perceive essentially benign and normal sensations as evidence of imminent danger. For example, palpitations are misinterpreted as a signal of a heart attack, dizziness as evidence impeding loss of control, etc. Goldstein and Chambless 9 labelled this fear of experiencing anxiety or panic attacks as "fear of fear". This leads to hypervigilance about bodily sensations, increased arousal of the sympathetic nervous system, more physical sensations, and heightened anxiety, which spiral into a panic attack.

CBT for panic disorder aims to change these catastrophic cognitions10. Taylor 11 reported that modifying patients' catastrophic misinterpretations of bodily sensations results in significant reductions in panic. Although it is unclear whether change in cognition instigates symptomatic change or not, many studies suggest that successful treatment was associated with a reduction in catastrophic cognitions 10121314. These studies reported that CBT intervention successfully caused reduction of catastrophic cognitions and symptomatic improvement in the majority of cases. However there are some patients who fail to modify their catastrophic cognitions or rather experience increase in them during CBT treatment. In a biological challenge study for panic disorder patients, Beck and Shipherd15 found that there were two distinct response patterns to repeated presentation of physical sensations: habituation of fear and fear sensitization. It is clinically and theoretically important to understand about cognitive sensitization of panic disorder during CBT sessions. However the baseline characteristics of the patient who would sensitize their catastrophic cognition during CBT, and the course of panic disorder for them are not well known.

The purpose of present study is 1) to clarify the baseline characteristics of panic patient who would experience sensitization of their catastrophic cognitions through the CBT treatment, and 2) to examine the course of symptomatic changes for them.

Of ninety-five patients who started the CBT program, sixteen patients withdrew from the program before its completion, because of symptom improvement, lack of improvement, inconvenience of attending the program, concurrent physical illness or worsening of depression. The seventy-nine completers (26 men and 53 women) with a mean age of 36.1(SD = 11.3) were classified as CS(N = 11) or CR(N = 52) or no-responder(N = 16) according to the difference of ACQ score across the treatment. Table 1 presents baseline sample demographic and personality characteristics. At the start of the CBT program, there were no significant differences between the four groups.

Table 2 shows the clinical characteristics for CS and CR patients at baseline. CS patients scored significantly lower on the ACQ than CR patients. The mean score of PDSS (11.1 for CS, 13.2 for CR) indicated a high-to-moderate level of panic disorder severity for both groups and the total scores were not significantly different at baseline between the two groups. On the item level, frequency of panic attack, distress of attack, agoraphobic fear/avoidance, and impairment of work or social functioning did not differ significantly. However, CS patients presented a significantly lower score than CR patients on anticipatory anxiety and non-significant trend to a lower score on interoceptive fear/avoidance. The scores of FQ-ag, MI-alone and WHLS did not differ between the groups.

By definition, as can be seen in Table 3, ACQ scores increased significantly across treatment among CS patients. The mean score of ACQ moved from 22.9(SD = 4.7, range: 18 to 33) at baseline to 27.7(SD = 5.0, range: 21 to 36) at endpoint. For CR patients, ACQ score decreased significantly. Their group mean score moved from 30.8(SD = 8.8, range: 18 to 56) at baseline to 20.7(SD = 6.1, range: 14 to 42) at endpoint.

For both groups, PDSS total scores improved significantly; CS patients' mean score moved from 11.1(SD = 4.1) at baseline to 9.1(SD = 4.4) at endpoint. CR patients' mean score moved from 13.2(SD = 4.7) at baseline to 5.9(SD = 4.3) at endpoint. Repeated measures ANOVA for PDSS total score showed a significant main effect of time (F(1,60) = 32.239, p < 0.001), and Group × Time interaction (F(1,60) = 10.80, p = 0.002). The degree of improvement differed between two groups.

With regard to symptomatic and functional changes across treatment, CR patients showed significant improvement for all variables. In contrast, CS patients significantly improved in impairment of social functioning and WHLS, and showed non-significant trend to improve in MI-alone.

Results of repeated measures ANOVA which examined the courses of symptomatic changes from baseline to three month follow-up for the two groups are presented in Table 4. For all variables, we found a significant main effect of time and no significant Group × Time interaction.

As can be seen in Table 5, post hoc Dunnett tests revealed that post-treatment scores of CR patients were significantly reduced compared to baseline scores for all measures. And 3-month follow-up scores of CR patients were also significantly reduced compared to baseline scores. In contrast, at the end of the program CS patients showed non-significant trend to reduce their post-treatment scores in MI-alone and WHLS, and did not show significant reduction in FQ-ag. Whereas compared to baseline scores, 3-month follow-up scores of CS patients were significantly reduced for FQ-ag and MI-alone, and showed non-significant trend to be reduced for WHLS.

With regard to the first objective of the present study, we were able to delineate the baseline characteristics of panic patient who would experience sensitization of their catastrophic cognitions through the CBT treatment as follows. Despite the same degree of panic disorder severity, CS patients showed relatively low level of catastrophic cognitions than CR patients preceding CBT treatment. Furthermore, CS patients reported lower level of anticipatory anxiety and interoceptive fear/avoidance before treatment. These findings are generally consistent with prior research conducted by Beck & Shipherd15 who found that panic disorder patients who showed fear sensitization during repeated CO2 inhalation sessions had shown a relatively low level of anticipatory anxiety preceding CO2 inhalation.

The second purpose of this study was to examine the course of symptomatic change of CS patients. We found that at the end of treatment CS patients showed significant improvement in severity of panic disorder, although the degree of improvement was smaller than that for CR patients. The improvement for CS patients at the end of treatment was mainly due to restoration of social functioning. This improvement for CS patients appears to continue at least for three months following the end of treatment. Consistent with previous findings 3111430, CR patients were significantly and clinically improved at the end of CBT program and they would continue to improve up to three month follow-up. In contrast, CS patients showed lower improvement compared to CR patients at the end of program, but then they would progressively reduce their agoraphobic fear and avoidance, and would improve their functional impairment up to three month of follow-up.

It is interesting to note that panic patients who would experience sensitization of their catastrophic cognitions through the CBT treatment could nonetheless gradually improve. It has already been pointed out that exposure to feared situations or bodily sensations can initially increase anxiety. Otto et al. emphasized that these experience help patients to learn that they can be "OK" despite the presence of anxiety 3. We may then be able to postulate that CS patients had been taking the strategy of cognitive avoidance of the threat cues before attending CBT treatment. Koster et al. reported the paradoxical effects of suppressing anxious thoughts 31. They found that during thought suppression, self-reported anxiety and frequency of anxious thoughts did not increase, and duration of anxious thoughts decreased. After thought suppression, participants experienced an increase in self-reported anxiety and the frequency of anxious thoughts. Thus for anxious patients the strategy of cognitive avoidance might play a role in maintaining anxiety disorder. When cognitive avoidance is present, then sensitization of catastrophic cognitions might be clinically meaningful in CBT for panic disorder.

Several limitations of current study should be mentioned. First, the procedure of categorization that classified patients into "cognitively sensitized" or "cognitive responding" may appear rather arbitrary. A different categorization strategy may have been possible but in the absence of agreed-upon procedure, we set the S_EM as the cut-off point. Second, the sample size was rather small to generalize our results and some of our negative findings might be due to lack of power. However, we can be sure of what positive findings we were able to identify. Third, the study did not include a control group and one cannot be sure if the significant reduction in panic symptomatology observed in the present cohort might be due to passage of time rather than to CBT treatment per se. Fourth, we did not confirm the change of symptomatorogy for depression with objective measure during the treatment and follow-up phase. Therefore we could not perfectly exclude the possibility that the results of this study affected any symptom of depression. Fifth, we did not confirm whether the patient underwent other treatments in the post treatment follow-up phase. Therefore strictly we couldn't rule out the possibility the improvement of patients due to some other treatment.

Casey et al.12 concluded in their study that it is necessary to include measures of positive cognitions (e.g. self efficacy in dealing with anxiety thought) in assessing the impact of catastrophic cognitions. We didn't address the positive cognitions in this study. Further research will be needed to investigate how self efficacy changes, especially in CS patient.

In conclusion, we found that CS patients had a lower level of catastrophic cognition and anticipatory anxiety than CR patients at baseline before starting the CBT program.

Through and at three months after the CBT program, CR patients demonstrated robust and continued improvement in symptomatology and functioning, while CS patients lagged behind CR patients, because they scored worse at the end of acute phase treatment than CR patients but tended to catch up with them at three-month follow-up. When clinically paraphrased we might conclude that temporary sensitization of catastrophic cognition may be necessary before improvement especially among those with initially low catastrophic body sensation fears and that we need not be concerned too much with temporary increase in catastrophic cognition in the process of CBT for panic disorder.

TAF has received research funds and speaking fees from Asahi Kasei, Astellas, Dai-Nippon, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Kyowa Hakko, Meiji, Organon, Pfizer, Tsumura, Yoshitomi, and Zelia. All the other authors declare that they have no competing interests to declare.

YNoda was the primary investigator; YNakano, KL, SO, YK, TF, NW, JC, YNoguchi, MK, MS and TAF performed the clinical investigation (diagnosis, treatment, assessment and follow-up phases); TAF participated on the design of the study and supervised the overall conduct of the study. All authors approved the final manuscript.