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Behaviour Research and Therapy 44 (2006) 657–665

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One-year follow-up of pharmacotherapy-resistant patientswith panic disorder treated with cognitive-behavior therapy:

Outcome and predictors of remission

Elizeth Heldta, Gisele Gus Manfroa,�, Leticia Kippera, Carolina Blayaa,Luciano Isolana, Michael W. Ottob

aAnxiety Disorders Program, Hospital de Clınicas de Porto Alegre, RS and Post-Graduate Program in Medical Sciences:

Psychiatry, Universidade Federal do Rio Grande do Sul, BrazilbCenter for Anxiety Related Disorders, Boston University, MA, USA

Received 23 December 2004; received in revised form 19 May 2005; accepted 22 May 2005

Abstract

Non-response to pharmacotherapy for panic disorder (PD) is a well-documented problem. However,little information exists to guide next-step strategies for these non-responders. In addition to pharmacologicaugmentation strategies, several studies support the efficacy of cognitive-behavior therapy (CBT) for thesepatients, although data on long-term outcomes has been lacking. In this study, we provide one-yearoutcomes on a sample of 63 patients who completed group CBT for PD after failing to respond adequatelyto previous pharmacotherapy. Sustained significant benefit was found for all dimensional outcome scores,and nearly two-thirds of the sample met remission criteria. This occurred with reductions in medication useover the follow-up period. Negative predictors of remission status included comorbid dysthymia, socialphobia, and generalized anxiety disorder. These results provide additional evidence for the efficacy of CBTfor medication non-responders with PD.r 2005 Elsevier Ltd. All rights reserved.

Keywords: Panic disorder; Cognitive-behavior therapy; Group therapy; Co morbidity; Follow-up

see front matter r 2005 Elsevier Ltd. All rights reserved.

brat.2005.05.003

ding author. Luiz Manoel Gonzaga 630/11, 90470-280. Porto Alegre, RS Brazil.

51 33289234.

ress: gmanfro@portoweb.com.br (G. Gus Manfro).

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Introduction

The last two decades have been marked by dramatic progress in the treatment of panic disorder(PD), with consistent evidence for the efficacy of both pharmacologic and cognitive-behavioraltreatments (for meta-analytic reviews see Gould, Otto, & Pollack, 1995). Despite these successes,however, it is clear that treatment non-response remains an all-to-common phenomenon(Ballenger, 1999; Rosenbaum, 1997). For example, in a review of controlled trials for PD utilizingserotonin selective reuptake inhibitors (SSRI), 45% of patients failed to achieve panic-free statusby the endpoint of acute treatment (Otto, Tuby, Gould, McLean, & Pollack, 2001). Despite thisclinical reality, only limited attention has been devoted to ‘‘next-step’’ strategies for patients whofail to respond adequately to initial treatment. Of augmentation strategies for pharmacotherapy,case reports have provided initial evidence for the efficacy of the combination of tricyclic andfluoxetine treatment (Tiffon, Coplan, Papp, & Gorman, 1994), the addition of anticonvulsants(Pollack, Matthews, & Scott, 1998), and atypical antipsychotic agents (Etxebeste, Aragues, Malo,& Pacheco, 2000; Khaldi, Kornreich, Dan, & Pelc, 2003). In addition, a single randomized,placebo-controlled study provided support for the use of pindolol to augment SSRI treatment(Hirschmann et al., 2000). On the psychosocial side, three separate case series support the efficacyof adding a program of brief (12-session) cognitive-behavior therapy (CBT) to improve outcomeamong patients who failed to respond to an adequate trial of pharmacotherapy (Heldt et al., 2003;Otto, Pollack, Penava, & Zucker, 1999; Pollack, Otto, Kaspi, Hammerness, & Rosenbaum, 1994).However, absent from the treatment literature are follow-up studies to document the longer-termoutcomes for patients who have received these next-step strategies.The present study reports one-year outcome data for a sample of treatment-resistant patients

with PD who subsequently received CBT delivered in a group format. We also examine theclinical characteristics associated with remission at one-year follow-up.

Method

Participants

Patients with a primary diagnosis of PD according to DSM-IV criteria were selected from theAnxiety Disorder Outpatient Unit of Hospital de Clınicas de Porto Alegre (HCPA) to participatein CBT for panic during 1998 and 2002. In order to be part of the study, patients had to haveresidual symptoms of PD such as panic attacks, anticipatory anxiety and phobic avoidancedespite being on a stable dose of medications for at least 4 months. A Clinical Global Impressionsscale (CGI) (see below) severity score of three or greater was required for participation. TheBrazilian version (Amorin, 2000) of the Mini International Neuropsychiatric Interview (MINI)was used to confirm the PD diagnosis, and establish comorbid diagnoses (Sheehan et al., 1998).Patients with psychotic symptoms or significant cognitive impairment were excluded from theprotocol.Seventy-one patients provided consent for participation. Of these patients, 7 (4 women and 3

men) with mean age of 34 years (SD ¼ 12) and mean duration of the PD of 9 years (SD ¼ 8) wereexcluded from analysis: 2 for increased antidepressant doses during the treatment phase, 2 were

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not able to participate due to a job change, 2 for having missed 50% of the sessions, and 1 for amedical illness that required hospitalization. Thirty-two patients had participated in a previousstudy of acute outcome (Heldt et al., 2003). Sixty-four patients completed treatment in the 12-week protocol; this sample (46 women and 18 men) was characterized by a mean age of 39 years(SD ¼ 10) and mean duration of the PD of 9 years (SD ¼ 8.5). All patients had been undergoingpharmacological treatment for PD at the time of treatment, with a mean duration ofpharmacotherapy of 3 years. Of the 64 patients, only one was lost to follow-up across the 1-year evaluation period.

Measures

The Clinical Global Impressions scale (CGI; Guy, 1976), Panic Inventory, and HamiltonRating Scale for Anxiety (HAM-A) (Hamilton, 1959) were used to assess severity at baseline, afterthe 12th weekly session, and one-year post treatment (using a two-month period as the frame ofreference for ratings). The CGI was used to provide a global rating of the severity of illness (1–7)according to the frequency and intensity of panic attacks, anticipatory anxiety, phobic avoidance,and role dysfunction. The Panic Inventory characterizes the frequency (spontaneous orsituational, full or limited) and intensity (rated on a scale from 0 to 10) and duration (minutes)of panic attacks. Agoraphobia and anticipatory anxiety severity were rated on a scale from 0(none) to 10. At study entry, ratings were completed by the clinicians running the group. Outcomeratings at the end of the treatment and follow up were completed by trained clinicians who did notparticipate in the group or know the results of the baseline ratings.A semi-structured clinical interview was used to assess the age of the onset of the PD, family

history of psychiatric disorders, treatment history, and negative life events occurring in the lastyear (e.g., physical illness, separation—interpersonal, death, loss of job—and conflict). Childhoodhistory of anxiety was assessed by structured interviews including the Schedule for AffectiveDisorder, and Schizophrenia for School age Children-Epidemiologic Version (K-SADS-E)(Orvaschel & Puig-Antich, 1987). The Defense Style Questionnaire (DSQ) (Andrews, Singh, &Bond, 1993), a 40-question self-report instrument translated and validated in Portuguese (Blaya etal., 2004), was used to evaluate defense mechanisms, providing scores for 20 individual defenses,organized into three factors: mature, neurotic and immature defenses were used at baseline.Consistent with previous studies (e.g., Keller et al., 1994; Pollack et al., 1994), remission was

defined by no panic attacks and CGIp2 in the last two months of follow up. Improvement wasdefined by a 50% or greater reduction from pretreatment in the HAM-A, agoraphobia, andanticipatory anxiety scales.

Treatment

CBT was an adaptation of the procedures manualized by Otto, Jones, Craske, and Barlow(1996). The patients were treated in one of nine groups (with a mean of seven patients per group)offering 12-sessions of treatment over 4 months provided by 2 therapists: a psychiatrist (GGM),and a nurse specialized in psychiatry (EH), both with an experience of at least five years in CBT.Treatment emphasized information, cognitive-restructuring, exposure to feared sensations ofanxiety and panic (interoceptive exposure), and step-wise exposure to agoraphobic situations.

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Treatment was initiated with the presentation of a cognitive-behavioral model of PD, followed bytraining in diaphragmatic breathing and muscle relaxation skills. By session two, cognitiverestructuring and interoceptive exposure was introduced, and were stressed in each subsequentsession, with the addition of instruction for in vivo exposure. Relapse prevention strategies wereemphasized during the final sessions of treatment.

Statistical analysis

Analysis of variance (ANOVA) was used to assess changes in symptom severity acrosstreatment and follow-up. These tests were complemented by presentation of within-group effectsizes (Cohen’s d ¼M1 �M2=

pSD2

1 þ SD22 � 2� r� SD1 � SD2). For evaluation of variables

associated with remission at follow-up categorical variables were evaluated with 2-tailed Fisher’sexact tests, and duration of disorder with a Mann-Whitney test. Evaluation of changes inmedication use across follow-up utilized the McNemar test. A t-test (2-tailed) for independentsamples was used to evaluate the association between defense mechanisms and response to CBT.Statistical analysis was completed using the SPSS Program version 10.0. Results were consideredsignificant when po:05.

Results

Psychiatric comorbidity was common in the sample: 40(63%) patients met criteria for majordepression, 9(14%) for dysthymia, 21(33%) for generalized anxiety disorder, 11(17%) for socialphobia, 2(3%) for obsessive-compulsive disorder, and 2(3%) for bipolar disorder. Twenty-threepatients (36%) met criteria for more than one comorbid disorders. Thirty-three patients (51%)met criteria for childhood onset of an anxiety disorder, and 54(84%) reported a family history of apsychiatric disorder. Forty-three patients (68%) reported a negative life event occurring duringthe follow-up period, with physical illness (n ¼ 11), conflicts (n ¼ 9) and death (n ¼ 8), being themost common events reported.

Treatment outcome at follow-up

As summarized in Table 1, significant reductions in symptoms were evident for all outcomemeasures (frequency of panic attacks, agoraphobia and anticipatory anxiety) across treatment,with maintenance of these gains at one-year follow-up. At least a 50% reduction in symptoms wasachieved by 78% of the sample (n ¼ 49) for ratings of agoraphobia, 62% (n ¼ 39) for anticipatoryanxiety, and 49% (n ¼ 31) for the HAM-A scale. Fully 81% (n ¼ 51) of the sample achieveda panic-free status, and 64% (n ¼ 40) met our criteria for PD remission (no panic attacks andCGI p2).Comparison of pharmacotherapy at baseline and the follow-up periods indicated a significant

reduction in both antidepressants and benzodiazepine use (po:001) across treatment and follow-up (see Table 2), and 28 (43%) patients were not in psychiatric treatment during the follow-upperiod. In the context of this general reduction in medication use, 15 patients switched orincreased their medication use: 6 (9%) patients switched antidepressants and 2 (3%) increased

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Table 1

Symptom severity outcome measures across the study period

Baseline

mean (+SD)

Four month

mean (+SD)

df Effect

sizeaOne year

mean (+SD)

df pb Effect

sizec

CGI 4.7 (0.8) 2.6 (1.1) 63 2.2 2.2 (1.2) 62 o.001 2.4

Panic attack 10.6 (13.6) 2.9 (7.1) 63 0.6 2.9 (8.4) 62 o.001 0.6

Agoraphobia 7.5 (2.4) 3.4 (3.0) 63 1.3 2.6 (3.2) 62 o.001 1.6

Anticipatory anxiety 8.0 (2.0) 4.4 (2.6) 63 1.1 3.5 (2.9) 62 o.001 1.3

Hamilton anxiety 29.1 (8.8) 17.1 (9.0) 63 1.3 15.5 (10.7) 62 o.001 1.5

aEffect size between baseline and the month four assessment.bAnalysis of variance with repeated measures, multiple comparisons test of least significant difference comparing

baseline vs. 1 year follow-up.cEffect size between baseline and 1 year.

their doses, 4 (6%) switched their benzodiazepine agent, and 3 (5%) increased their doses. These15 patients fared significantly worse than the remainder of the sample at the one-year evaluation,with only 2 (13%) achieving remission (po:001).

Prediction of remission status

We examined the predictive significance of affective comorbidity, childhood anxiety disorders,family history, and duration of the PD on long-term outcome as defined by the achievement ofremission status. As presented in Table 3, major depression exhibited only a trend-levelassociation (p ¼ :065), but the presence of dysthymia at pre-treatment was associated with a lowerlikelihood of remission (p ¼ :001). The presence of both generalized anxiety disorder and socialphobia were also associated with a lower rate of achieving remission (p ¼ :015; p ¼ :006,respectively).No significant associations were found between remission and the presence of childhood history

of anxiety disorder (p ¼ :70), duration of disorder (p ¼ :260), and family history of psychiatricdisorder (p ¼ :999). Likewise, the occurrence of a negative life event during the one-year follow-upperiod was not associated with remission (p ¼ :12).Patients who used more mature defenses (5.8 vs. 5.0; t ¼ �2:65, df ¼ 62, p ¼ :010) and less

immature defenses (3.5 vs. 4.6; t ¼ 4:48, df ¼ 62, po:001) were more likely to achieve remissionstatus at follow-up. A significant association was not found between neurotic defenses andremission (4.6 vs. 5.2, t ¼ 1:66, df ¼ 62, p ¼ :100).

Discussion

Our study provides further evidence for the efficacy of CBT as a next-step strategy for patientswho fail to respond adequately to pharmacotherapy for PD. Moreover, we found strongmaintenance of treatment gains in this treatment-resistant sample, consistent with evidenceindicating that this maintenance is a particular strength of CBT (e.g., Clark et al., 1994; Fava,

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Table 2

Medication use across the study period

Baseline

(n ¼ 64) n(%)

Four month

(n ¼ 64) n(%)

One year

(n ¼ 63) n(%)

pa

Antidepressants 61(95) 53(84) 45(71) o.001

Fluoxetine (10–80mg) 36(56) 31(48) 25(40)

(mean dose) 33.4mg 31.3mg 27.8mg

Paroxetine (10–40mg) 5(8) 5(8) 4(6)

(mean dose) 20mg 20mg 20mg

Sertraline (50–150mg) 5(8) 5(8) 4(6)

(mean dose) 90mg 90mg 62.5mg

Clomipramine (50–150mg) 13(20) 10(16) 8(13)

(mean dose) 90.9mg 82.1mg 66.6mg

Imipramine (75–150mg) 2(3) 2(3) 2(3)

(mean dose) 87.5mg 87.5mg 112.5mg

Amitriptiline (25–225mg) 3(5) 2(3) 2(3)

(mean dose) 125mg 137.5mg 125mg

Nortiptiline (150mg) 1(2) 1(2) 1(2)

(mean dose) 150mg 150mg 150mg

MAO inhibitors (100mg) 1(2) — —

(mean dose) 100mg — —

Buspirone (5mg) 1(2) 1(2) —

(mean dose) 5mg 5mg —

Lithium (300–600mg) 2(3) 2(3) 1(2)

(mean dose) 450mg 450mg 600mg

Venlafaxine (75mg) — — 1(2)

(mean dose) — — 75mg

Benzodiazepines 31(49) 19(30) 14(22) o.001

Clonazepan (0.25–3mg) 16(25) 10(16) 10(16)

(mean dose) 1.1mg 1.3mg 1.5mg

Diazepan (5–10mg) 7(11) 2(3) —

(mean dose) 7mg 10mg —

Alprazolan (0.25–1.5mg) 6(9) 6(9) 3(5)

(mean dose) 0.8mg 0.55mg 1mg

Bromazepan (3–6mg) 2(3) 1(2) 1(2)

(mean dose) 4.5mg 3mg 3mg

Combinations

SSRI and TCAs 4(6) 4(6) 2(3)

Antidepressants and Benzodiazepines 28(45) 18(28) 14(22) o.001

SSRI and lithium 2(3) 2(3) 1(2)

aMcNemar test.

Zielezny, Savron, & Grandi, 1995; Gould et al., 1995). Symptomatic improvement was evidentacross all measures used in the study, and approximately two-thirds of the sample of treatmentcompleters met remission status at the one-year follow-up assessment. The improvement was alsomaintained despite overall reductions in medication use, consistent with other findings indicatingthat CBT can be used as a strategy for medication discontinuation, with longer-term maintenance

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Table 3

Rates of remission at 1 year in patients with and without affective comorbidities (n ¼ 63)

Affective comorbidity Remission Status (CGIp2 and no

panic attack) % Remitted (n)

pa

Mood disorders

With depression (n ¼ 40) 55% (22)

Without depression (n ¼ 23) 78% (18)0.065

With dysthymia (n ¼ 9) 11% (1)

Without dysthymia (n ¼ 54Þ 72% (39).001��

Anxiety disorders

With GAD (n ¼ 21) 42% (9)

Without GAD (n ¼ 42) 74% (31).015��

With social phobia (n ¼ 11) 27% (3)

Without social phobia (n ¼ 52) 71% (37).006��

aFisher’s exact test.��po:05.

of treatment gains (Otto, Hong, & Safren, 2002; Schmidt, Wollaway-Bickel, Trakowski, Santiago,& Vasey, 2002).Our sample was marked by high levels of comorbidity, and even though in many cases patients

with comorbidity achieved remission, rates tended to be less than those without comorbidity. Thenegative effects of major depression were particularly subtle, consistent with other evidence that inmany cases CBT for anxiety will be resilient to the presence of major depression as well as othercomorbidities (Brown, Antony, & Barlow, 1995; Martinsen, Olsen, Tonset, Nyland, & Aarre,1998; Tsao, Mystkowski, Zucker, & Craske, 2002). On the other hand, remission rates wereparticularly low for patients with dysthymia. Dysthymia typically receives less empirical attentionthan major depression; our data suggest this inattention may well be a mistake, at least forunderstanding the influence of comorbidity on panic treatment response. Defensive style was alsoa predictor of longer term outcome, with better outcome for patients with more mature defenses, afinding consistent with results from investigations of acute outcome (Heldt et al., 2003).Although outcomes cannot be attributed unequivocally to CBT, the likelihood that our results

are due to non-specific factors or time are unlikely given the history of inadequate response toopen pharmacotherapy for this sample; our sample had a duration of disorder of 9 years, with amean of 3 years of previous pharmacotherapy without remission.Our results are limited by the challenges to internal validity characteristic of an open clinical

follow up study. On the other hand the use of independent evaluators to access the outcome reducesthe likelihood that the results are driven by clinician expectations. Overall, this study provides aperspective on long-term outcome that can be achieved in clinical practice. Our results are specific toindividuals who completed a course of brief CBT. As compared to pharmacotherapy, treatmentdropout in CBT for PD tends to be low (Gould et al., 1995), including CBT with treatment-refractory samples (Heldt et al., 2003). Accordingly, CBT appears to be both an acceptable andefficacious treatment when offered in a low-cost group setting, and should be considered as aroutine option for patients who are refractory to pharmacotherapy for PD.

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