Subject Flow and Description
113 individuals were screened and 46 met entry criteria and were enrolled in the study (43 entered at Phase 1, and 3 already on Phase 1 endpoint doses of sertraline or escitalopram entered at Phase 2). Two participants were lost to follow-up prior to the first Phase 1 on medication visit and 2 were removed after discovery of current alcohol abuse, leaving 42 patients available for overall analyses (n=40 sertraline, n=2 escitalopram), with n=39 in Phase 1. Phase 2 analyses included 24 individuals, with 19 continuing on to Phase 3 of the study. See for patient demographics and for flow. Agoraphobia was present in 83%; additional psychiatric comorbidity was high with 64% with a current comorbid anxiety disorder and 36% with current Major Depressive Disorder (see ).
Patient Characteristics (n=42)
Phase 1: 6 weeks of open-label pharmacotherapy with moderately dosed SSRI
In Phase 1, 5/39 patients in the ITT sample discontinued treatment prior to week 6 (1 due to adverse events including nausea, vomiting, and headache, 2 due to time constraints, and 2 lost to follow-up). Baseline scores on symptom ratings were as follows (mean ± SD): PDSS = 16.3 ± 4.5, CGI-S = 4.8 ± 0.8, HAM-A = 23.2 ± 8.4, HAM-D = 11.6 ± 4.5, ASI = 34.3 ± 10.5. There was a significant reduction at Phase 1 endpoint for the primary continuous measure, the PDSS (mean ± SD reduction of 4.3 ± 4.3 points, t(df) = 6.3 (38), p < 0.001), with a mean ± SD endpoint CGI-S score of 3.9 ± 1.2. Remission status at Phase 1 endpoint was achieved by 20.5% (8/39), who were thus not eligible to enter Phase 2 (see ).
We examined potential predictors of Phase 1 outcome, adjusting for PDSS score at baseline. Baseline severity alone was significantly predictive of endpoint PDSS (β (SE) = 1.04(0.15), t = 6.76, p<0.001), as was early reduction (in the first 2 weeks) in PDSS score (β(SE) = 0.65(0.21), t = 3.00, p < 0.005). Age, gender, duration of illness, current agoraphobia, current anxiety or depression comorbidity, and current psychiatric comorbidity were not significantly associated with endpoint PDSS score. Patients with a younger age of panic onset had modestly poorer outcomes at the level of a statistical trend (β(SE) = −0.03(0.15), t = 1.89, p = 0.067).
Phase 2: Increased dose SSRI or continued dose SSRI (placebo augmentation)
See for summary of patient flow. Of the 26 Phase 1 completers eligible for randomization in Phase 2, 1 was lost to follow-up after the week 6 assessments (bringing total to n=6 from Phase 1). Three individuals entered Phase 2 already on an SSRI for a mean ± SD duration of 11.7 ± 7.2 weeks prior to entry (one escitalopram 15mg, two sertraline 100mg). Four individuals included in Phase 1 were excluded from Phase 2 and Phase 3 analyses because of design changes made to Phase 2 (eliminating a third arm with the addition of benzodiazepine at week 6 to enhance sample size in the primary SSRI dose comparison) after their participation. Thus, 24 patients were included in Phase 2 group analyses: 13 randomized to adjunctive placebo and 11 to increased SSRI.
There were no significant differences in Phase 2 baseline severity between groups on the PDSS, CGI-S, HAM-A, HAM-D, ASI, or SDS (all ps = n.s.). Patients on increased SSRI had a mean ± SD endpoint dose of 195.5 ± 15.1 mg sertraline or equivalent. Three patients (27%) receiving increased dose SSRI discontinued (n=1 due to adverse events of jitteriness, tremor, and diarrhea, and n=2 lost to follow-up). No patients receiving placebo augmentation discontinued.
Although there was further significant reduction in the PDSS overall (mean ± SD decrease = 2.33 ± 3.84, paired t = 2.98, p < 0.007), increasing the SSRI dose relative to the addition of placebo did not result in greater improvement according to significance testing or estimation of effect size (Cohen’s d = 0.01: see ). Further, increased dose did not result in significant differences in remission at Phase 2 endpoint (placebo augmentation 15% [n=2], increased dose 9% [n=1]: FET p = n.s.), with the one remitter on increased dose also dropping out prior to week 12. During Phase 2, there was no overall reduction in any of the secondary measures including the HAM-A, HAM-D, ASI, and SDS at endpoint (all ps > 0.25), with no significant differences between the placebo and increased dose groups (See ), and with mean ± SD scores on the PDSS of 10.7 ± 5.8 and the CGIS of 4.0 ± 1.1 at Phase 2 endpoint.
Phase 2 and Phase 3 Change in Symptom Scales by Randomized Treatment Assignment
We performed follow-up longitudinal regression analyses to examine whether there were differences in the slope of symptomatic change over time as measured by PDSS scores at each visit, adjusting for severity (PDSS score) at week 6 randomization. While there was a significant reduction in the PDSS over time overall during Phase 2 (β(SE) = −2.12(0.32), p < 0.001), and panic severity at randomization predicted slope of response (β(SE) = 0.13(0.01), p < 0.001); there was no randomization group by week interaction (β(SE) = 0.14(0.45), p = 0.98), supporting that slope of change in PDSS in Phase 2 did not vary for the placebo augmentation versus increased dose SSRI groups.
Phase 3: Cognitive Behavioral Therapy (CBT) Augmentation versus Medication Optimization (MO) with SSRI and Clonazepam
In Phase 3, 19 patients were randomized and eligible for analysis (CBT: n=10 and MO: n=9). At initial entry into Phase 3, sertraline dosing was 100mg/day for n=6 in CBT and n=5 for MO, and 200mg/day for n=4 in CBT and n= 4 in MO. Pharmacotherapy at endpoint in the MO group consisted of 200mg SSRI equivalent for all and a mean ± SD dose of clonazepam of 2.5 ± 0.8 mg/day (range=1.0–3.5). Only one patient discontinued in Phase 3 from each group (both lost to follow up). Nonetheless, only one additional patient in each group achieved remission status by Phase 3 endpoint (MO = 11%; CBT =10%). Although there was significant overall reduction on the PDSS (mean ± SD decrease = 3.32 ± 3.64, paired t = 3.97, p < 0.000), there was no group difference in PDSS reduction, consistent with evidence of only a small effect size favoring pharmacotherapy (d = 0.24: ). Overall in Phase 3, there was a reduction from a mean ± SD PDSS score of 11.6 ± 5.2 at baseline to 8.3 ± 5.8 at endpoint on the PDSS, and a reduction from 4.2 ± 0.8 at baseline to 3.2 ± 1.2 at endpoint on the CGIS. Confirmatory analyses using the independent evaluator (IE) assessments also demonstrated no significant difference in reduction in PDSS (mean ± SD reduction 3.3 ± 3.3 CBT vs. 1.8 ± 4.3 MO, t(df) = 0.9(17), p > 0.39) or CGI-S (1.1± 0.99 CBT vs. 0.78 ± 0.83 MO, t(df) = 0.76(17), p > 0.45) scores. Further, IE ratings and clinician PDSS ratings were highly correlated (r=0.91 week 12, r=0.96 endpoint).
Consistent with the primary analyses, there were no significant differences between the MO and CBT groups on any secondary measures and effect sizes were all small (). Secondary measures demonstrated overall (n=19) improvement on the SDS (mean ± SD decrease = 4.25 ± 5.32, paired t(df) = 3.19(15), p < 0.01), a statistical trend towards improvement on the HAM-A (mean ± SD decrease = 2.79 ± 6.11, paired t(df) = 1.99(18), p < 0.07) and ASI (mean ± SD decrease = 4.53 ± 9.75, paired t(df) = 1.80(14), p < 0.10), but not the HAM-D (paired t(df) = 3.42(32), p > 0.17).
Although there was no significant difference in baseline severity by treatment group, the mean ± SD PDSS at baseline was somewhat higher (13.67 ± 6.12) in the MO group compared to the CBT group (9.70 ± 3.65: p = 0.101). To examine potential differences in the slope of response over time adjusting for baseline score, we performed mixed effects longitudinal regression analyses including terms for week 12 (baseline) PDSS score and Phase 2 randomization group by week. While there was a significant reduction in the PDSS over time (β(SE) = −0.54(0.89), p < 0.001), and baseline score predicted slope of response (β(SE) = 0.03(0.00), p < 0.001), there was no randomization group by week interaction (β(SE) = 0.10(0.10), p = 0.31), supporting a lack of difference in slope of PDSS change over time for the CBT versus MO groups.
The majority of participants experienced at least one side effect in each phase, with 85% (33/39) in Phase 1, 88% in Phase 2 (21/24), and 79% in Phase 3 (15/19). Side effects were generally tolerable and mild to moderate in severity. Two patients withdrew due to intolerable side effects: one in Phase 1 due to nausea and headache and one on increased SSRI in Phase 2 due to jitteriness.
In Phase 1, the most commonly reported side effects were gastrointestinal distress (48.7%), headache (41.0%), nausea or vomiting (38.5%), jitteriness or restlessness (30.8%), and insomnia (28.2%). In Phase 2, the most common were gastrointestinal distress (36.4% SSRI, 23.1% placebo), headache (36.4% SSRI, 23.1% placebo), sedation (27.3% SSRI, 23.1% placebo), insomnia (27.3% SSRI, 7.7% placebo), and jitteriness or restlessness (27.3% SSRI, 7.7% placebo). In Phase 3, the most common side effects were gastrointestinal distress (44.4% MO, 20.0% CBT), headache (22.2% MO, 40.0% CBT), sedation (33.3% MO, 10.0% CBT), and dizziness (33.3% MO, 0% CBT).
Participants were followed naturalistically and reassessed 3 months after study endpoint. An additional 6/17 (35%) of completers achieved remission at 3 month follow up (3 from MO and 3 from CBT), while the 2 completers who had achieved remission at Phase 3 endpoint maintained remission status 3 months later. All but one of these remitters remained on the same pharmacotherapy treatment that they were on in the study with minor fluctuations in dosage; this individual continued on sertraline but initiated augmentation with amitriptyline and clonazepam.