RESEARCH ARTICLE

Predictors of outcome of pharmacological andpsychological treatment of late‐life panic disorderwith agoraphobia

Gert‐Jan Hendriks1,2,4, Ger P. J. Keijsers2, Mirjam Kampman1, Cees A. L. Hoogduin2

and Richard C. Oude Voshaar3

1Centre for Anxiety Disorders “Overwaal”, Lent, the Netherlands2Behavioral Science Institute, Radboud University Nijmegen, Nijmegen, the Netherlands3University Centre of Psychiatry, University Medical Centre Groningen, Groningen, the Netherlands4Department of Psychiatry (966), Radboud University Nijmegen Medical Centre, Nijmegen, the NetherlandsCorrespondence to: G.‐J. Hendriks, PhD, MD, E‐mail: ghendriks@overwaal.nl

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Objective: This study aims to evaluate the differential predictive values of age, age of onset and duration ofillness on paroxetine and cognitive‐behavioural therapy (CBT) outcome in late‐life panic disorder withagoraphobia.

Method: Patients 60 years and older with a confirmed diagnosis of panic disorder with agoraphobia(n= 49) were randomly assigned to paroxetine (40 mg/day) treatment, individual CBT or a waiting‐listcontrol condition. Multiple regression analyses were conducted per treatment arm with post‐treatmentavoidance behaviour and agoraphobic cognitions as the dependent variables.

Results: Higher age at onset and shorter duration of illness were predictors of superior outcomesfollowing CBT, although these variables did not influence the treatment effects of paroxetine.

Conclusions: In late‐life agoraphobic panic disorder, chronological age has no impact on treatmentmodality outcome. In older patients with a late disease onset or shorter duration of illness, CBT is to bepreferred over paroxetine, whereas paroxetine might be the treatment of choice for older people withan early onset and short duration of illness. Copyright © 2011 John Wiley & Sons, Ltd.

Key words: panic disorder; older; predictors of outcome; aged; 80 years and older; randomised controlled trial; serotoninreuptake inhibitors; psychotherapy

History: Received 9 September 2010; Accepted 18 January 2011; Published online 30 March 2011 in Wiley Online Library(wileyonlinelibrary.com).DOI: 10.1002/gps.2700

Introduction

Old age and long illness duration are often seen asnegative predictors of treatment outcome in panicdisorder with or without agoraphobia [PD(A)], justas it is in late‐life anxiety and depression (Basogluet al., 1994; Seivewright et al., 1998; Slaap and denBoer, 2001; Ramnero and Ost, 2004; Tyrer et al., 2004;Mitchell and Subramaniam, 2005; Dow et al., 2007a;Dow et al., 2007b). Empirical studies, however, onlypoint to the severity of the initial symptoms as aconsistent predictor of outcome in PD(A) (Kampmanet al., 2008). As these findings are based on youngerand middle‐aged populations, generalisation to later

ight © 2011 John Wiley & Sons, Ltd.

life is limited. Studies in outcome prediction in olderpatients with anxiety disorders are scarce. In fact, onlyWetherell et al. (2005) studied the predictors ofoutcome in late‐life anxiety. They found in an olderpopulation with generalised anxiety disorder, as wasshown in young and middle‐aged adults with PD(A)also (Kampman et al., 2008), that the initial severity ofsymptoms was related to outcome.

Furthermore, it is suggested that pharmacologicaltreatment should be given more attention in olderpeople having anxiety disorders and that drug treat-ment might be preferable over cognitive‐behaviouraltherapy (CBT) (Schuurmans et al., 2006; Pinquart andDuberstein, 2007). However, the empirical ground for

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147Predictors of outcome in late‐life PD

the preference of drug treatment over psychologicaltreatment for older patients with PD(A) is small. Thusfar, only four studies suggested efficacy for both CBTand drug treatment of late‐life PD(A) (Swales et al.,1996; Sheikh and Swales, 1999; Sheikh et al., 2004;Hendriks et al., 2010). The small number of partici-pants and the lack of a randomised controlled designwith direct comparison of CBT and drug treatment inthree of these studies limit robust conclusions. Onlyour study (Hendriks et al., 2010) used a randomisedcontrolled design and found no differences in outcomebetween CBT and drug treatment in late‐life PD(A).

Interpretation of the results of late(r) life studiescan be complicated because of the sample heteroge-neity caused by both differences in the age of onsetand duration of illness (DOI). Epidemiologicalsurveys show that with a median age of onset of25 years, most patients with late‐life PD(A) have beenexperiencing the effects of their condition for quitesome time (Segui et al., 2000; Kessler et al., 2005).Nevertheless, a substantial number of older patients isreferred on account of a (very) late‐onset type of PD(A) in daily practice, having had their first symptomsas late as in their sixties (Segui et al., 2000). One mayhypothesise that especially this late‐onset type is moresusceptible to CBT than the early‐onset type with itsconsequential lengthy DOI.

The current study evaluated whether chronologicalage, age of onset andDOI have any differential effects onthe outcome of pharmacological and psychologicaltreatment for late‐life PD(A).

Methods

Study design

The present study is a secondary analysis of a randomisedcontrolled trial that has been published elsewhere(Hendriks et al., 2010) and can be summarised asfollows. A total of 49 patients 60 years and olderdiagnosed with PDA, as confirmed by the Dutchversion (C de Ruiter et al., unpublished data) of theAnxiety Disorders Interview Schedule for Diagnosticand Statistical Manual of Mental Disorders, FourthEdition (DiNardo et al., 1994), were randomly allocatedto three study conditions: paroxetine 40 mg/day(n= 17), CBT (n= 20) or a standard waiting‐listcontrol condition (n= 12). Individual CBT consistedof 14 weekly sessions of 50 min each consistent withthat of Craske and Barlow (Craske et al., 1994)delivered by a well‐trained and supervised psychologistat the Master of Science level and with extensive

Copyright © 2011 John Wiley & Sons, Ltd.

experience in cognitive‐behavioural techniques. Allpatients received an assessment at baseline and after14 weeks (end of treatment) including, among others,the Agoraphobic Cognitions Questionnaire (ACQ)(Chambless et al., 1984) and the Mobility InventoryAvoidance scale (MI‐A) (Chambless et al., 1985) asprimary outcome measures. The ACQ consists of 14items that have to be rated on a five‐point rating scaleand aims to assess the severity of catastrophicagoraphobic cognitions. The MI‐A gauges the severityof phobic avoidance of 27 situations using twosubscales: avoidance when alone and avoidance whenaccompanied. Both questionnaires are frequently usedin PD(A) treatment outcome studies and, for bothDutch versions, are available with proven goodpsychometric properties (De Beurs, 1993).

Analyses

Multiple linear regression analyses were conducted topredict post‐treatment effects on agoraphobic avoidanceand agoraphobic cognitions in the paroxetine and theCBT condition separately in terms of the total scores ontheMI‐A (Chambless et al., 1985) and the total scores onthe ACQ (Chambless et al., 1984), respectively.

Participants’ age, age at PDA onset, defined as theparticipant’s age at the time of the first panic attack asreported during the Anxiety Disorders InterviewSchedule for Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition, interview, and DOI,defined as the actual age minus the age at onset, wereregressed on the MI‐A and ACQ sum scores,respectively. Both treatment conditions were examinedin one combined regression analyses after controllingfor baseline symptom severity and treatment condition.In case significant interaction terms were foundwith treatment condition, predictors were examinedin regression analyses per treatment condition. Thesignificance level was set at p< 0.05. Nonetheless, weaccepted p‐levels <0.10 as potentially clinically relevantfor interaction terms to prevent missing a real effectbecause of our small sample size.

Results

Outcome data were available for 14/17 (82%) patientsassigned to the paroxetine condition and for 18/20(90%) patients assigned to the CBT condition. Thepatients’ baseline characteristics did not differ acrossconditions: they were on average 69.2 (SD= 4.7) yearsold, and 57% were women; the mean baseline MI‐Ascore was 2.4 (SD= 0.9), and the mean baseline ACQ

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148 G.‐J. Hendriks et al.

score was 1.7 (SD= 0.5). Post‐treatment mean MI‐Aand ACQ scores were, respectively, 1.8 (SD= 0.9) and1.4 (SD= 0.4) (Hendriks et al., 2010).

With respect to agoraphobic cognitions, only the late‐onset PDA (late‐onset type by condition: R2= 0.50,β=−1.80 and p=0.009) yielded a significant interactiontermwith treatment condition in favour of CBT, whereasinteraction of DOI with treatment condition approachedsignificance (DOI by condition: R2 = 0.49, β=0.81 andp=0.10) and chronological age with treatment conditiondid not reach significance at all (age by condition:R2= 0.39, β=−1.32 and p=0.57).

With respect to avoidance behaviour, neitherchronological age nor DOI yielded a significantinteraction term with treatment condition (age by

a

b

Figure 1 (a) Effect of paroxetine and cognitive‐behavioural therapy (CBT) oncognitions. MI‐A, Mobility Inventory Avoidance; ACQ, Agoraphobic Cognit

Copyright © 2011 John Wiley & Sons, Ltd.

condition: R2 = 0.49, β=−192 and p=0.38; DOI bycondition: R2 = 0.55, β=0.56 and p=0.22), whereasthe interaction of late‐onset type with treatmentcondition approached significance (late‐onset type bycondition: R2 = 0.62, β=−1.04, p=0.07). See Figure 1for the interpretation of the results with respect to theage of onset.

The results of the multiple regression analyses arereported in Table 1. Separate results are presented bytreatment condition for those characteristics thatsignificantly interacted with treatment condition (i.e.p< 0.10). Late‐onset type and shorter DOI predictedsignificantly better outcome with respect to bothagoraphobic cognitions and avoidance behaviour inthe CBT condition.

avoidance behaviour, (b) effect of paroxetine and CBT on agoraphobicions Questionnaire.

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Table 1 Results of the multiple regression analysesa testing the predictive values of three variables of interest on treatment outcome after controllingfor baseline symptom severity

Whole sample (n=37) Paroxetine condition (n=17) CBT condition (n=20)

R2 β p R2 β p R2 β p

Agoraphobic Cognitions Questionnaire (ACQ)• Age 0.38 0.19 0.21 — — — — — —• Late‐onset PDA (yes/no) — — — 0.26 −0.48 0.11 0.61 0.40 0.03• Duration of illnessb — — — 0.14 0.08 0.78 0.68 0.48 0.01

Mobility Inventory Avoidance (MI‐A) scale• Age 0.48 −0.14 0.32 — — — — — —• Late‐onset PDA (yes/no) — — — 0.68 −0.11 0.54 0.60 −0.51 0.01• Duration of illnessb 0.52 0.26 0.05 — — — — — —

CBT, cognitive‐behavioural therapy; PDA, panic disorder with agoraphobia.aRegression analyses, by treatment condition in case of (near) significant interaction terms (p < 0.10), with post‐treatment MI‐A and ACQ total scoresas the dependent variables corrected for baseline MI‐A and ACQ scores, respectively.bBecause of a skewed distribution, the analyses are based on the log‐transformed values.

Key points

• Higher age at onset and shorter illness durationwere predictors of superior outcomes followingCBT, whereas the variables did not influencethe treatment effects of paroxetine.

• Age has no impact on treatment outcome inlate‐life panic disorder with agoraphobia.

• In older patients with a disease onset beyond60 years, CBT may be preferred.

• Because of small sample size, findings arepreliminary.

149Predictors of outcome in late‐life PD

Discussion

Although preliminary because of the small sample size,this first randomised controlled treatment study ofagoraphobic panic disorder in later life revealed someinteresting findings. In contrast to what is generallyassumed in clinical practice, with our study, we showedthat age is not related to treatment outcome. Futurestudies should explore whether these results could alsobe generalised to young and middle‐aged adults.Interestingly, we did find differential effects forparoxetine and CBT for the other predictors tested:those patients with late‐onset PDA and shorter illnessduration had a more favourable outcome followingCBT. No such effects were observed in the paroxetinecondition. As illustrated in Figure 1, in case of late‐onset panic disorder, CBT may be preferred overparoxetine in order to gain better results with respectto avoidance behaviour, whereas in case of early‐onsetpanic disorder, pharmacological treatment may bepreferred over CBT in order to gain better results withrespect to agoraphobic cognitions.

These findings refine upon previous studiessuggesting that pharmacological treatment might bepreferable over CBT in the treatment of late‐lifeanxiety disorders (Pinquart and Duberstein, 2007;Schuurmans et al., 2006). In line with the preferencesof older adults for psychological treatment (Wetherellet al., 2004) and their resistance in using antidepres-sants (Givens et al., 2006), our results suggest thatCBT may be the treatment of choice for the late‐onsettype of PDA. For older patients with the early‐onsettype (with an onset before the age of 60 years) andprolonged illness duration, pharmacological strategiesmay be the preferred modality. Again, our findings haveto be considered with caution because of the small

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number of participants and because not all of our overallanalyses that compared the effects of the two treatmentconditions together yielded significant results.

Acknowledgement

G.‐J. Hendriks received an unconditional researchgrant of €55 000 from GlaxoSmithKline.

Conflict of interest

None declared.

References

Basoglu M, Marks IM, Swinson RP, et al. 1994. Pre‐treatment predictors of treatmentoutcome in panic disorder and agoraphobia treated with alprazolam and exposure.J Affect Disord 30: 123–132.

.

150 G.‐J. Hendriks et al.

Chambless DL, Caputo GC, Bright P, Gallagher R. 1984. Assessment of fear offear in agoraphobics: the body sensations questionnaire and the agoraphobiccognitions questionnaire. J Consult Clin Psychol 52: 1090–1097.

Chambless DL, Caputo GC, Jasin SE, Gracely EJ, Williams C. 1985. The mobilityinventory for agoraphobia. Behav Res Ther 23: 35–44.

Craske MG, Meadows E, Barlow DH. 1994. Therapist Guide for the Mastery ofYour Anxiety and Panic II and Agoraphobia Supplement. Graywind Publications:Albany, NY.

De Beurs E. 1993. The Assessment and Treatment of Panic Disorder and Agoraphobia.Thesis Publishers: Amsterdam.

DiNardo PA, Brown TA, Barlow DH. 1994. Anxiety Disorders Interview Schedule forDSM‐IV: Lifetime Version. Graywind Publications: Albany, NY.

Dow MG, Kenardy JA, Johnston DW, et al. 2007a. Prognostic indices with brief andstandard CBT for panic disorder: II. Moderators of outcome. Psychol Med 37:1503–1509. DOI:10.1017/S0033291707000682

Dow MG, Kenardy JA, Johnston DW, et al. 2007b. Prognostic indices with briefand standard CBT for panic disorder: I. Predictors of outcome. Psychol Med 37:1493–1502. DOI:10.1017/S0033291707000670

Givens JL, Datto CJ, Ruckdeschel K, et al. 2006. Older patients’ aversion toantidepressants. A qualitative study. J Gen Intern Med 21: 146–151. DOI:10.1111/j.1525‐1497.2005.00296.x

Hendriks GJ, Keijsers GP, Kampman M, et al. 2010. A randomized controlled study ofparoxetine and cognitive‐behavioural therapy for late‐life panic disorder. ActaPsychiatr Scand 122: 11–19. DOI:10.1111/j.1600‐0447.2009.01517.x

Kampman M, Keijsers GPJ, Hoogduin CAL, Hendriks GJ. 2008. Outcomeprediction of cognitive behaviour therapy for panic disorder: initial symptomseverity is predictive for treatment outcome, comorbid anxiety or depressivedisorder, cluster C personality disorders and initial motivation are not. BehavCogn Psychother 36: 99–112.

Kessler RC, Berglund P, Demler O, et al. 2005. Lifetime prevalence and age‐of‐onsetdistributions of DSM‐IV disorders in the National Comorbidity SurveyReplication. Arch Gen Psychiatry 62: 593–602. DOI:10.1001/archpsyc.62.6.593

Copyright © 2011 John Wiley & Sons, Ltd.

Mitchell AJ, Subramaniam H. 2005. Prognosis of depression in old age compared tomiddle age: a systematic review of comparative studies. Am J Psychiatry 162:1588–1601. DOI:10.1176/appi.ajp.162.9.1588

Pinquart M, Duberstein PR. 2007. Treatment of anxiety disorders in older adults: ameta‐analytic comparison of behavioral and pharmacological interventions. Am JGeriatr Psychiatry 15: 639–651. DOI:10.1097/JGP.0b013e31806841c8

Ramnero J, Ost LG. 2004. Prediction of outcome in the behavioural treatment of panicdisorder with agoraphobia. Cogn Behav Ther 33: 176–180.

Schuurmans J, Comijs H, Emmelkamp PM, et al. 2006. A randomized, controlled trial ofthe effectiveness of cognitive‐behavioral therapy and sertraline versus a waitlist controlgroup for anxiety disorders in older adults. Am J Geriatr Psychiatry 14: 255–263.DOI:10.1097/01.JGP.0000196629.19634.00

Segui J, Salvador‐Carulla L, Marquez M, et al. 2000. Differential clinical features oflate‐onset panic disorder. J Affect Disord 57: 115–124.

Seivewright H, Tyrer P, Johnson T. 1998. Prediction of outcome in neurotic disorder:a 5‐year prospective study. Psychol Med 28: 1149–1157.

Sheikh JI, Swales PJ. 1999. Treatment of panic disorder in older adults: a pilot studycomparison of alprazolam, imipramine, and placebo. Int J PsychiatryMed 29: 107–117.

Sheikh JI, Lauderdale SA, Cassidy EL. 2004. Efficacy of sertraline for panic disorder inolder adults: a preliminary open‐label trial. Am J Geriatr Psychiatry 12: 230.

Slaap BR, den Boer JA. 2001. The prediction of nonresponse to pharmacotherapy in panicdisorder: a review. Depress Anxiety 14: 112–122.

Swales PJ, Solfvin JF, Sheikh JI. 1996. Cognitive‐behavioral therapy in older panicdisorder patients. Am J Geriatr Psychiatry 1: 46–60.

Tyrer P, Seivewright H, Johnson T. 2004. The Nottingham study of neuroticdisorder: predictors of 12‐year outcome of dysthymic, panic and generalizedanxiety disorder. Psychol Med 34: 1385–1394.

Wetherell JL, Kaplan RM, Kallenberg G, et al. 2004. Mental health treatmentpreferences of older and younger primary care patients. Int J Psychiatry Med 34:219–233.

Wetherell JL, Hopko DR, Diefenbach GJ, et al. 2005. Cognitive‐behavioral therapyfor late‐life generalized anxiety disorder: who gets better? Behav Ther 36: 147–156.

Int J Geriatr Psychiatry 2012; 27: 146–150.