Pii: s0006-3223(02)01552-4

Context in the Clinic: How Well Do Cognitive-BehavioralTherapies and Medications Work in Combination? Edna B. Foa, Martin E. Franklin, and Jason Moser Cognitive-behavioral therapy (CBT) and pharmacother- ety disorders. Because other articles in this special issue apy demonstrate efficacy across the anxiety disorders, but address neural pathways and pharmacotherapy, we focus recognition of their limitations has sparked interest in primarily on examining how CBT fares when delivered combining modalities to maximize benefit. This article with and without medication and how information-pro- reviews the empirical literature to examine whether com- cessing theory of pathologic anxiety can account for the bining treatments influences efficacy of either mono- empirical picture. We first discuss the theory and practice of CBT for anxiety disorders and the mechanisms thought We conducted a comprehensive literature search of pub- to underlie its efficacy. We then review some theoretical lished randomized trials that compared combined treat- considerations for and against adding medication to CBT, ment with pharmacologic or CBT monotherapies. Ten and we summarize empirical studies that compare the studies that met our inclusion criteria were reviewed indetail, and within-subjects effect sizes were calculated to benefit of combined treatment over monotherapies. Fi- compare treatment conditions within and across studies. nally, we consider the empirical findings within an infor-mation-processing perspective and outline questions for At posttreatment and follow-up, effect size and percentageresponder data failed to clearly demonstrate an advantage or disadvantage of combined treatment over CBT alone Early behavioral models for the treatment of anxiety for obsessive-compulsive disorder, social phobia, and have been based on two suppositions: First, fears and generalized anxiety disorder. Some advantage of com- phobias are acquired through classical conditioning, that bined treatment over pharmacotherapy alone emerged is, through the formation of association between a neutral from the few studies that allowed for such a direct stimulus and an aversive stimulus such the former acquires comparison. In contrast, combined treatment for panic the aversive properties of the latter. The neutral stimulus is disorder seems to provide an advantage over CBT alone at then designated as a conditioned stimulus (CS), and the posttreatment, but is associated with greater relapse after original aversive stimulus is called an unconditioned stimulus (UCS). Second, the acquired fears can be un- The advantage of combined treatment may vary across the learned through extinction, that is, through presentation of anxiety disorders. The potential differences in usefulness the CS in the absence of the UCS. This conceptualization of combined treatment are discussed, directions for future gave rise to exposure therapy (EX), in which patients research are suggested, and implications for clinical systematically confront their feared situations, objects, 987–997 2002 Society of Biological Psychiatry responses (e.g., tachycardia), or memories, under safecircumstances with the goal of extinguishing their phobic Key Words: Anxiety disorders, CBT, pharmacotherapy,
fear. Although there have been debates about the mecha- combined treatment, emotional processing, randomized nisms through which exposure therapy reduces anxiety symptoms, the benefit of this therapy has been demon-strated by a large body of research (cf. Discontent with nonmediational (automatic) accounts Introduction
for acquisition and extinction of pathologic anxiety led tothe development of theories that posited a pivotal role for The purpose of this article is to review the advantages cognitive factors in anxiety (e.g., The and disadvantages of adding medication to cognitive– assumption here is that it is not the events themselves but behavioral therapy (CBT) and pharmacotherapy for anxi- rather their threat meaning that is responsible for theevocation of anxiety. Meaning in these theories is oftenassumed to be represented in language. Accordingly, From the University of Pennsylvania School of Medicine, Philadelphia, Pennsyl- cognitive therapy (CT) for anxiety disorders uses verbal Address reprint requests to Edna B. Foa, Department of Psychiatry, University of discourse to challenge the patient’s threat interpretations of Pennsylvania School of Medicine, 3535 Market Street, Philadelphia PA 19104.
Received March 18, 2002; revised July 12, 2002; accepted July 16, 2002.
events and to help replace them with more realistic ones.
The focus on the meaning of events as accounting for core pathology of OCD lies in the erroneous meaning of pathologic anxiety paralleled the reconceptualization of external events. The supposition that inaccurate negative conditioning in learning theories. For example, Rescorla cognitions underlie the anxiety disorders has also been at the noted that “conditioning depends not on the contiguity heart of theories posed by cognitive therapists (e.g., between the CS and US but rather in the information that If fear and avoidance reflect the activation of an and that the “organism is better seen as an information underlying cognitive fear structure, then changes in the seeker using logical and perceptual relations among events fear structure should result in corresponding changes in along with its own preconception to form a sophisticated representation of its world” p. 154). In the proposed that psychologic interventions known to reduce same vein, when discussing the phenomenon of extinction, fear, such as EX, achieve their effects through modifying the fear structure. According to emotional processing tioning situation, the signal winds up with two available theory, two conditions are necessary for therapeutic fear- ‘meanings’ ” p. 58). Obviously, for rats the reduction to occur: first, the fear structure must be acti- meaning of events cannot be represented in verbal lan- vated; second, information that is incompatible with the guage; rather, it is represented as associations between pathologic aspects of the fear structure must be available and incorporated into the existing structure. Thus, within Advances in information-processing theories of condi- this framework, exposure therapy is thought to correct the tioning and of pathologic anxiety (e.g., influ- erroneous cognitions that underlie the specific disorder enced conceptualizations of treatment for the anxietydisorders. One such conceptualization, emotional process- (e.g., tachycardia ϭ heart attack). This is also the explicit mechanism by which CT is thought to reduce fear. In this theory, fear is viewed as a cognitive structure in memory way the mechanisms that are thought to operate during that serves as a blueprint for escaping or avoiding danger exposure greatly overlap with those of CT. Moreover, that contains information about the feared stimuli, fear some cognitive therapists (e.g., D.M. Clark, personal responses, and the meaning of these stimuli and responses.
communication 2002) explicitly posit that fear activation When people are faced with a realistically threatening situa- is necessary to refute the patient’s false interpretations, tion (e.g., a car accelerating toward them), the fear structure and CT programs routinely include an exposure compo- supports adaptive behavior (e.g., swerving away); however, a nent in the form of “behavioral experiments.” fear structure becomes pathologic when the associations The essence of both exposure and behavioral experi- among stimulus, response, and meaning representations do ments is to engineer fear-arousing situations in which the not accurately reflect reality in that harmless stimuli or patient is expecting unrealistically that something bad will responses assume threat meaning. In emotional processing happen, but where the bad consequences do not occur.
theory, meaning is thought to be embedded in associations Accordingly, exposure and behavioral experiments do not among stimuli, responses, and consequences (as in substantially differ from one another, but the way they are as well as in language in the form of thoughts, conducted can be somewhat different. It is interesting to note that this view of exposure therapy is consistent with Within emotional processing theory the anxiety disor- contemporary conditioning theories that “emphasize the ders are thought to reflect the operation of specific importance of a discrepancy between the actual state of the world and the organism’s representation of that state. They example, the fear structure of individuals with panic [learning theorists] see learning as a process by which the disorder is characterized by erroneous interpretations of two are brought into line” pp. 153).
physiologic responses associated with their panic symp- The cognitive– behavioral treatments derived from the toms (e.g., tachycardia) as dangerous (e.g., leading to heart theoretical approaches discussed above have generally attack). As a result of this misinterpretation, individuals proven quite efficacious for the anxiety disorders (cf.
with panic disorder avoid locations they anticipate will give rise to panic attacks or similar bodily sensations, such nin reuptake inhibitors, tricyclic antidepressants, mono- as physical exertion. The fear structure of individuals with amine oxidase inhibitors, and benzodiazepines, has also obsessive– compulsive disorder (OCD) most often in- been found efficacious with these disorders (e.g., volves the erroneous interpretation of safe stimuli (e.g., brown spots) as dangerous (e.g., AIDS-contaminated blood).
however, among treatment completers, neither Accordingly, the core pathology in panic disorder lies in the CBT nor pharmacotherapy helps all individuals, and those erroneous meaning of physiologic responses, whereas the who are helped remain, on the whole, somewhat symp- Combined Treatments for Anxiety Disorders tomatic. The limitations of these therapies are com- methodology including a) random assignment, sufficiently large sample sizes for statistical power, use of manualized In the quest to improve on the available interventions, psychotherapies, and adequate treatment quality, dosage, and experts (e.g., have advocated combining CBT duration to allow for symptom reduction; b) blind indepen- with pharmacotherapy. One way by which medication is dent evaluation conducted by a trained assessor; and c) thought to enhance CBT outcome is through the reduction presentation of essential statistics for calculating within- of the patient’s anxiety and thereby promotion of his or her ability to tolerate longer exposures to feared situations.
Twenty-six RCTs evaluating combined treatments were Indeed, long exposure has been found more effective than identified through the literature searches. Nine studies met the inclusion criteria and are discussed here. Of the 17 studies that were excluded, 5 did not allow for a clear test anxiety during exposure is thought to enhance processing of of combined versus monotherapy, 9 failed to use adequate the corrective information embedded in the exposure situa- methodology, 4 failed to include blind independent eval- tion and thereby promote amelioration of pathologic fear.
uation, and 10 failed to present essential statistics for In contrast to these arguments, other theoretical consid- calculating within-group effect sizes. presents the erations suggest that the addition of medication to CBT studies that were excluded from the review and the reasons may impede its outcome. Specifically, the reduction of anxiety by medication may block fear activation that, as Three departures from the criteria should be noted.
noted earlier, is a necessary condition for the cognitive Because of the paucity of treatment outcome studies in changes that mediate treatment success. Blocking of fear social phobia (SP) that compared combined treatment and during CBT may be particularly detrimental for panic disorder, for which the erroneous cognitions involve a study, despite the absence of independent assessment and catastrophic belief about anxiety-related bodily responses essential statistics for calculating within-group effect siz- and treatment aims at disconfirming this belief. For es; we included here percent responders data from that example, a panic patient whose panic attacks stopped or study. Second, to illustrate issues emerging from the were largely attenuated after the administration of alpra- discussion, two studies that did not meet the above criteria zolam is likely to attribute the nonoccurrence of heart attack during exposure therapy to the medication. Under and the Connor et al (2002) posttraumatic stress disorder this circumstance, the perception that panic sensations are (PTSD) study. It should also be noted that for the dangerous cannot be disconfirmed. Because the core erroneous cognition had not been eradicated, after treat- conditions because the study design allowed for the ment discontinuation the panic and associated threat introduction of behavioral experiments (exposure) into the CT and discussion of expectations of disastrous conse- We now turn to review empirical studies that examine quences (cognitive procedures) into the EX after the the relative efficacy of combined treatment versus that of Method for Inclusion/Exclusion of Studies for the Method for Calculating Effect Sizes When available, we present the completer data only In preparing this article, we first located all randomized because we are interested in comparing combined treat- controlled trials (RCTs) involving combined treatments for ment to monotherapies when the treatments are delivered anxiety disorders via PsycINFO and MEDLINE electronic at adequate doses and for sufficient periods of time; use of database searches and via reference lists in the extant anxiety intent-to-treat data would allow for the inclusion of pa- disorder literature. Next, we selected studies for the review tients who did not receive optimized treatment, and thus by using the following four criteria: 1) study patients had an their inclusion here could obscure effects of interest. For established diagnosis; studies using samples with mixed each of the studies presented, we selected the main diagnoses were excluded; 2) the study included at least two independent evaluator measure of the primary symptoms treatment groups, one of which received pharmacotherapy or CBT monotherapy (CBT with or without pill placebo) and [Y-BOCS]for OCD) for calculation of within-subject ef- the other received treatment combining CBT and medication; fect sizes using Cohen’s d. The formula for 3) the study design had to permit unequivocal test of combined versus monotherapy; studies using crossover de-signs were excluded; 4) the study had to employ adequate Table 1. Reasons for Exclusions of Studies PD, panic disorder; GAD, generalized anxiety disorder; SP, social phobia; OCD, obsessive-compulsive disorder were as follows: 69% for EX/RP ϩ FLV, 40% for EX/RP ϩ treatment means for each treatment group on the selected PBO, and 54% for FLV at posttreatment; 64% for EX/RP ϩ FLV, 50% for EX/RP ϩ PBO, and 45% for FLV at When follow-up data were provided, we calculated the follow-up. Chi-square analyses failed to detect group differ- effect sizes by replacing the posttreatment means with ences at either posttreatment or follow-up.
follow-up means and pooling the pretreatment and fol- low-up standard deviations. To ease the reader’s task, all EX/RP ϩ FLV or EX/RP ϩ PBO. In this study, CBT of the within-subjects effect sizes are presented in comprised a 3-week assessment followed by a 4-weektreatment that included six 3-hour involving therapist-aided EX/RP sessions that included cognitive restructuring Combined versus Monotherapy Treatment
and daily homework exposure assignments. Medication began 1 week into the assessment and was gradually increased over 5 weeks. Assessment was conductedweekly, with posttreatment conducted at week 9. The main Four studies met our inclusion criteria. outcome measure was assessor’s ratings on total score of randomized 60 patients to one of three conditions: exposure and ritual prevention (EX/RP) ϩ fluvoxamine were conducted on a subset of patients (n ϭ 49), with nine (FLV), EX/RP ϩ placebo (PBO), and FLV. Treatment outliers dropped to equate the two groups on baseline was discontinued after 24 weeks, with a 4-week medica- Y-BOCS severity. Both groups improved significantly tion taper. The EX/RP treatment was conducted weekly from pre- to posttreatment on Y-BOCS total scores, with and involved eight sessions of imaginal exposure in no significant group differences. Percent responders, de- sessions and in vivo exposure as homework followed by fined as greater than or equal to 35% reduction on the total 16 sessions of therapist-guided in vivo exposure and ritual Y-BOCS, were as follows: 87.5% for EX/RP ϩ FLV and prevention. Follow-up assessment was conducted 6months posttreatment. It is important to note that 55% of 60% for EX/RP ϩ PBO. Chi-square analyses revealed an those who received FLV only were on medication during follow-up in contrast to 21% in the combined group and 25% in the EX/RP ϩ PBO group. Assessment included blind 117 patients into 1) CT; 2) EX/RP; 3) FLV ϩ CT; 4) FLV assessors’ ratings of daily duration of rituals. At posttreat- ϩ EX/RP; and 5) wait-list. In this study, CBT was ment (week 24, n ϭ 44) there was a trend for EX/RP ϩ FLV conducted over 16 45-min sessions (6 in the first 8 weeks, to be superior to EX/RP ϩ PBO on this measure, which 10 during the remaining weeks). In the two combined disappeared at follow-up. Percent responders, defined as treatments, FLV was administered alone for 8 weeks, after reduction in daily rituals of greater than or equal to 30%, which medication was stabilized and a 10-session CBT Combined Treatments for Anxiety Disorders Table 2. Effect Sizes for Included Studies TX, treatment; OCD, obsessive-compulsive disorder; PD, panic disorder; SP, social phobia; GAD, generalized anxiety disorder; Y-BOCS, Yale-Brown Obsessive- Compulsive Scale; WP2, Anxious Inhibition Widlocher-Pull; PDSS, Panic Disorder Severity Scale; CGI, Clinical Global Improvement; HAM-A, Hamilton Anxiety Scale;EX/RP, exposure and response prevention; FLV, fluvoxamine; PBO, placebo; CBT, cognitive-behavioral therapy; CMI, clomipramine; ALP, alprazolam; EX, exposure;RLX, relaxation; BUS, buspirone; IMP, imipramine; SRT, sertraline; DZ, diazepam.
a This study only reported percent responders was added for an additional 8 weeks. The wait-list 122 patients were randomized to four conditions: EX/RP condition was conducted over 8 weeks. Assessment was ϩ clomipramine (CMI), EX/RP alone, CMI alone, and conducted at pre, mid, and posttreatment. The main PBO. EX/RP included a two-session assessment period outcome measure was the independent assessor’s ratings followed by 15 sessions of two hours each, conducted over of the Y-BOCS. Results indicated that at midtreatment (n 3 weeks and 8 weekly maintenance sessions. Medication was ϭ 100), all four active treatments were superior to waitlist, administered for 12 weeks, after which it was tapered over 3 with no significant differences among active treatments.
weeks. Assessment was conducted at pretreatment, posttreat- At posttreatment (n ϭ 86), the four active treatments did ment (12 weeks), and at follow-up 12 weeks later (week 24).
not differ from one another. Because we focus here on the The main outcome measure was assessor’s ratings on the relative efficacy of monotherapies versus CBT ϩ medica- Y-BOCS. At posttreatment (n ϭ 87), all active treatments tion, and because of the considerable procedural overlap were superior to PBO; EX/RP ϩ CMI and EX/RP alone were between cognitive therapy and EX/RP after the 8-week both superior to CMI but did not differ from one another midpoint assessment, we collapsed the pre- and posttreat- ment data for the four active treatments into two groups: 1) groups that received EX/RP were superior to CMI alone CBT ϩ FLV; 2) CBT alone. Percent responders data are but did not differ from one another. Percent responders, defined as a Clinical Global Improvement (CGI) rating of In a recently completed multicenter study conducted at 1 or 2, at posttreatment were as follows: 79% for EX/RP the University of Pennsylvania and Columbia University ϩ CMI, 86% for EX/RP, 48% for CMI, and 10% for PBO.
(E.B. Foa and M.R. Liebowitz, principal investigators), At the week 24 follow-up, percent responders were 80% for EX/RP ϩ CMI, 89% for EX/RP, and 55% for CMI. As related physical sensations. Patients were instructed to with the Y-BOCS data, at posttreatment and at follow-up, conduct self-exposure between sessions. The BUS was the groups that received EX/RP were superior to CMI but administered simultaneously with PCT for 16 weeks and tapered over 1 week following posttreatment assessment.
Taken together, the studies of combined treatment in During the follow-up period, no patients in the CBT ϩ OCD suggest that CBT is not impeded by medication, nor BUS condition and five patients in the CBT ϩ PBO does the addition of medication enhance the efficacy of condition required further CBT treatment for their agora- phobia. Moreover, four patients in the CBT ϩ BUS conditions that involved CBT were superior to SRI mono- condition and one patient in the CBT ϩ PBO condition required the prescription of additional medication during the follow-up period. Measures included assessor’s ratingson the Anxious Inhibition Widlocher–Pull (WP2). In contrast with the modest effect sizes found for the WP2measure (see percent responder rates, defined as Three studies on panic disorder (PD) met our inclusion at least 50% reduction on the first agoraphobic target criteria. In a multicenter study, random- behavior, were quite sizable: 67% for CBT ϩ BUS and ized 154 patients into four conditions: Exposure (EX) ϩ 74% for CBT ϩ PBO at posttreatment; 44% of the CBT ϩ alprazolam (ALP), EX ϩ PBO, relaxation (RLX) ϩ ALP, BUS and 68% of CBT ϩ PBO at follow-up. No treatment and RLX ϩ PBO. The EX and RLX were conducted over differences were detected here as well.
8 weeks; ALP and PBO were administered simultaneously with EX or RLX for 8 weeks and were tapered over the randomly assigned 312 patients to one of five conditions: following 8 weeks. In this study, RLX was conceived of as CBT ϩ imipramine (IMP), CBT ϩ PBO, CBT alone, IMP a psychologic placebo; EX comprised six 2-hour sessions alone, and PBO. In this study, CBT consisted of panic conducted over 8 weeks, which included therapist-aided control treatment (PCT) conducted over 9 months. During exposure during sessions and self-directed homework the first 3 months, patients received 11 50-min sessions of exposure 1 to 2 hours per day. In RLX, patients underwent PCT and or 11 30-min sessions of medication manage- therapist-aided relaxation training during 6 1-hour ses- ment. Medication and CBT were conducted simulta- sions conducted over 8 weeks. Homework consisted of neously. Following the acute phase of treatment, respond- practicing relaxation 1-hour daily with the aid of an audio ers to treatment received monthly sessions of PCT and or tape. Measures included assessor’s ratings on the phobic medication management, for an additional 6 months (maintenance). Postdiscontinuation of treatment assess- ment (n ϭ 129), both EX ϩ ALP and EX ϩ PBO ment was conducted 6 months later. The PCT consisted of produced greater improvement in phobic avoidance than cognitive restructuring, exposure to interceptive cues, and did ALP and PBO. At a medication-free follow-up (n ϭ breathing retraining exercises. Assessment included blind 76) conducted 5 months posttreatment, EX ϩ PBO was evaluations of panic symptoms, using the Panic Disorder superior to all other groups; the combined treatment lost its superiority over ALP. Percent responders, defined as a At both the 3-month (n ϭ 213) and 9-month (n ϭ 170) CGI 1 or 2, at posttreatment were as follows: 71% for EX assessments, CBT ϩ IMP was superior to CBT alone. Six ϩ ALP, 71% for EX ϩ PBO, 51% for RLX ϩ ALP, and months after treatment discontinuation (n ϭ 116) there 25% of RLX ϩ PBO. Percent responders at follow-up was relapse in the combined treatment, so that both groups were as follows: 36% for EX ϩ ALP, 62% for EX ϩ PBO, that received CBT without IMP had a superior outcome to 29% for RLX ϩ ALP, and 18% for RLX ϩ PBO.
the combined treatment. Percent responders, defined as a Chi-square analysis again indicated that, at posttreatment, 40% reduction on the PDSS, at the end of the 3-month the groups that received EX were superior to those who acute phase were as follows: 84% for CBT ϩ IMP, 80% did not. At follow-up, the EX ϩ PBO group was superior for CBT ϩ PBO, 67% for CBT alone, 75% for IMP, and 39% for PBO. At the end of maintenance, percent re- sponders were as follows: 90% for CBT ϩ IMP, 76% for randomized study (n ϭ 77), failed to CBT ϩ PBO, 73% for CBT alone, 80% for IMP, and 38% detect differences between CBT ϩ buspirone (BUS) and for PBO. At 6 months postdiscontinuation, 50% for CBT CBT ϩ PBO. In this study, CBT consisted of 16 1-hour ϩ IMP, 83% for CBT ϩ PBO, 85% for CBT alone, and weekly sessions of panic control treatment (PCT; 60% for IMP. Inconsistent with the picture emerging from the PDSS means, Chi-square analyses failed to detect imaginal and in vivo exposure, and exposure to anxiety- superiority of the combined treatment over CBT at the end Combined Treatments for Anxiety Disorders of acute and maintenance treatment; no differences be- CBT or to pharmacotherapy. The available results suggest tween combined treatment and IMP were detected on neither an advantage nor a disadvantage of combined percent responder data at either test point; however, at postdiscontinuation, the two groups that received CBTwithout IMP were superior to combined treatment.
The overall picture emerging from the three PD studies is Only one study of generalized anxiety disorder (GAD) met more complex than that emerging from the OCD studies: at posttreatment the combined treatment was found advanta- signed 113 patients to one of five treatment conditions: CBT ϩ diazepam (DZ), CBT ϩ PBO, CBT alone, DZ alone, and PBO. In this study, CBT consisted of a maximum of seven sessions over 9 weeks in which without medication were superior to the combined treat- patients received cognitive therapy and progressive mus- ment, suggesting that the addition of pharmacotherapy cle relaxation. Homework included exposure to anxiety may have impeded the long-term benefits of CBT.
eliciting thoughts and situations. Medication managementwas as follows: 1) 1 week of single-blind placebo; 2) 6 weeks of double-blind DZ or PBO; and 3) 3-week drug No studies of social phobia (SP) met our inclusion criteria, taper. Follow-up assessment was conducted at 6 months although data from a collaborative study, conducted at the posttreatment. Assessment included assessor’s ratings us- University of Pennsylvania and at Duke University ing the Hamilton Rating Scale for Anxiety (HAM-A; is currently being analyzed. In that study 309 At posttreatment (week 10; n ϭ 83), patients with primary generalized SP were randomized to combined treatment was superior to DZ alone but not to one of five conditions: CBT ϩ fluoxetine (FLX), CBT ϩ CBT alone. No HAM-A means were reported for the PBO, CBT alone, FLX alone, and PBO. When available, 6-month follow-up assessment. Percent responders, de- results from that trial will allow for a comparison of fined as reduction of Ն2 SD from pretreatment at post- combined treatments to both CBT and pharmacotherapy treatment were as follows: 90.5% for CBT ϩ DZ, 83% for CBT ϩ PBO, 86% for CBT, 68% for DZ, and 37% for In light of the paucity of SP studies, we have included PBO. All active treatments were superior to PBO but did here a recent effectiveness study conducted by primary not differ from one another. Percent responders at 6 months follow-up were as follows: 71% for CBT ϩ DZ, ologic limitations that would have precluded its inclusion 67% for CBT ϩ PBO, 71% for CBT, and 41% for DZ.
(e.g., absence of blind assessors). In this study, 387 Chi-square analysis revealed the superiority of treatments patients with primary diagnosis of SP were randomized to that included CBT treatments over DZ alone.
one of four treatment conditions: EX ϩ sertraline (SRT),EX ϩ PBO, SRT, or PBO. Therapists were 47 physicians who underwent 30 hours of training in assessment and In this article, we present an overview of the advantages treatment delivery. In this study, EX consisted of nine and disadvantages of adding medication to cognitive 20-min sessions conducted over 16 weeks and a final visit behavioral therapy (CBT) and to pharmacotherapy for four at week 24. During these sessions, patients were given anxiety disorders: OCD, PD, SP, and GAD. We now assignments for self-exposure homework and feedback for summarize the findings and discuss them within an infor- their progress. Medication management consisted of 10 mation processing framework of pathologic anxiety, visits, 9 of which were held during the first 16 weeks of treatment and the 10th at week 24. Assessment includedclinicians and self-report ratings on degree of improve-ment on the CGI. At posttreatment (week 24), percent responders were as follows: 45% for EX ϩ SRT, 33% for EX ϩ PBO, 40% for SRT, and 24% for PBO. Both active found an advantage for combined treatment over CBT medication conditions, but not EX ϩ PBO, were superior alone, and only on their categorical analyses of the to PBO; active treatments did not differ from one another, however. Because pre- and posttreatment means and the combined treatment, which disappeared at follow-up.
standard deviations were not reported, effect sizes could No value for combined treatment over CBT was found in Existing data are quite insufficient for arriving at The failure to find a clear advantage for combined treat- conclusions regarding the benefit of adding medication to ment over CBT is consistent with experts’ recommenda- tion that CBT alone should be the first-line treatment for tion discontinues and panic sensations return the unshaken beliefs resume their effects in maintaining symptoms.
combined versus medication treatment, one found benefit Because the OCD core fear structure involves association for combined and one did not. It should be noted that between threat and external stimuli, the reduction of studies reviewed here conducted combined treatment si- anxiety responses by medication does not interfere with multaneously and such programs may not maximize the disconfirmation of such erroneous beliefs.
Consistent with the view that medication that sup- presses panic impedes the necessary cognitive changes for long-term maintenance of gains in PD are findings by examination of the combined treatment versus the two monotherapies, revealed similar effect sizes for the com- receiving open-label benzodiazepine treatment and wished bined and medication alone treatments, whereas the effect to discontinue their medication were randomly assigned to size for EX/RP was much larger in the Foa et al study.
CBT for PD or no additional treatment during a 10-week Because the two studies were similar in two treatments, drug taper period. Among the CBT patients, 76% discon- the inconsistency with regard to CBT alone outcome is not tinued benzodiazepines successfully, compared with only likely to reflect differences in the two samples. A more 25% of patients who did not receive CBT. Presumably, plausible explanation lies in the procedural differences in CBT promoted cognitive change that allowed patients to the two EX/RP programs. Indeed, in a meta-analytic give up their “safety pills.” Furthermore, in a secondary in EX/RP influence outcome. EX/RP in the Cottraux et found that patients who at the end of 8 weeks of treatment al’s study involved fewer sessions and thus less therapist- attributed their gains to medication (either placebo or assisted exposure; treatment was delivered once per week as alprazolam) were more likely to relapse than those patients opposed to daily in the Foa et al’s study. Given that “diluted” who attributed their gains to their own efforts.
treatment is more likely to be the routine in general clinicalpractice, the effect sizes in the Cottraux et al’s study may Social Phobia and Generalized Anxiety Disorder point to the potential benefit for combined treatment in It is difficult to draw conclusions about combined treatments settings where EX/RP is not conducted optimally.
for SP and GAD given the paucity of well-controlled studies.
The two studies discussed above The picture emerging from the three PD studies discussed bined treatment over CBT, but Power et al found com- here is somewhat different from that of OCD. Just as for bined treatment superior to diazepam. The limitations of OCD, the short-term advantage of combined treatment comparing across diagnostic groups should be noted.
over monotherapies is unclear. In only one of threestudies, albeit the largest one, found anadvantage for combined treatment over CBT whereas Conclusions
As we have seen in this review of the empirical literature, only to medication. More interesting findings emerged at the hope that combined treatment will be a panacea for all follow-up, where in two of the three studies combined patients with anxiety disorder has not been fulfilled. On treatment interfered with long-term maintenance of gains the other hand, with the exception of PD, the worry that of CBT. No such interference was evident in the two OCD combined treatment will impede CBT also has not been studies with follow-up data. This discrepancy may be due realized. Before concluding from the studies discussed to differences in the fear structures of the two disorders.
here that combined treatment is irrelevant, several issues Earlier we suggested that the core erroneous belief in PD pertains to threat associated with anxiety-related phys- First, in a review of this kind in which it is necessary to ical responses such as tachycardia and dizziness. For PD, summarize across disorders, different CBT protocols, and CBT is designed to elicit such responses and the absence different medication classifications, certain information is of the anticipated disaster is provides corrective informa- inevitably lost. For example, because only a small number tion about their safety. The diminished anxiety responses of studies met our inclusion criteria, it is possible that via medication may hamper the ability of CBT exercises to certain medications may be more compatible with CBT disconfirm the erroneous beliefs associated with these responses. The absence of disasters attributed to the Second, all controlled studies to date adopted a simul- medication rather than to mistaken beliefs. When medica- taneous treatment design, which may not be optimal for Combined Treatments for Anxiety Disorders detecting the benefit of combining CBT and medication.
completed before the effects of medication could be expected. To realize the benefit of combined treatment, a lier, the various methodologic limitations of these studies sequential design would have been more appropriate. Such preclude strong conclusions, as does the apparent incon- a design was indeed adopted in an ongoing study of PTSD sistency in their outcomes. Second, all the studies we reviewed used multiple measures and raters, the results of open-label SRT, followed by random assignment to either which were sometimes inconsistent. In an attempt to continued SRT alone, or SRT ϩ 10 sessions of CBT present a coherent picture, we focused our review on delivered over 5 weeks. Preliminary results suggest the measures of the primary diagnosis as rated by an indepen- advantage of CBT augmentation. Several augmentation dent assessor. A slightly different picture might have emerged in some instances had we selected self-ratings.
Third, studies in anxiety disorders generally suggested Third, to allow comparison of outcome across studies of significant relapse upon medication discontinuation (e.g., the same disorder and across different disorders, we calculated effect sizes. Because studies vary with respect Would the addition of CBT protect against relapse to placebo response rates, we chose to present within- rather than between-subjects effect sizes, which inevitably inflated our estimates of treatment effects. Fourth, our this appears to be the case. Future studies should examine decision to review in detail only methodologically sound studies that were directly related to the topic at hand Fourth, in all well-controlled studies examining com- limited our discussion to only nine studies, which clearly bined versus monotherapy, samples included all patients underscores the provisional nature of our conclusions.
that met the target diagnosis; however, combined treat- Much more work is needed on this critical topic, and we ment may be more beneficial for certain subsets of patients recommend that the following research areas be consid- than for others. Not targeting specific populations may ered: 1) more randomized controlled trials directly com- have obscured the benefit of combined treatment. This paring combined treatment to CBT and pharmacotherapy alone for social phobia, PTSD, and GAD; 2) more studies PTSD study. Patients who had a modest response to SRT across the anxiety disorders testing combined treatment after 10 weeks and received CBT augmentation continue strategies using designs that better mimic clinical practice, to improve substantially, whereas modest SRT responders such as an adequate pharmacotherapy trial followed by that continued on SRT alone did not show any further CBT; 3) examination of long-term outcomes for patients improvement. The advantage of CBT augmentation over who received combined treatment versus those who re- continuing SRT alone was less evident in patients who ceived monotherapies, with medication status at follow-up as a key dependent variable; 4) more studies examining Another group of patients that may be especially suit- augmentation strategies including CBT for pharmacother- able for combined treatment are those with comorbid apy partial responders; and 5) effectiveness studies that depression. This hypothesis was supported by post hoc examine patient preferences for CBT, medication, or patients who received combined treatment fared better Implications for Clinical Practice
than those receiving EX/RP alone, whereas no benefit ofcombined treatment was observed for nondepressed pa- Information from this review has several implications for tients. The relationship between patient variables and treatment providers who offer CBT, pharmacotherapy, or outcome of treatment programs can greatly enhance our a combination of these therapies in their clinical practice.
ability to optimize success rates and may also shed light on First and foremost, it is important to recognize that the jury is still out with respect to whether combined treatment is Several caveats should be kept in mind regarding superior to monotherapy because there are few adequate conclusions that can be drawn from the studies reviewed studies from which to draw conclusions. Only in OCD are here. First, we have excluded 17 studies, some of which there more than three studies employing adequate meth- yielded disparate findings from the selected studies and odology. Second, with the exception of PD, it appears that inconsistencies with one another. For example, whereas pharmacotherapy and CBT are compatible in that there is four of these more methodologically limited PD studies no evidence for interference effects. This conclusion is suggested an advantage for combined treatment over consistent with results from a recent open study of intensive CBT for OCD in the context of a fee-for-service clinic, in which patients who received intensive CBT with Bouton ME (2000): A learning theory perspective on lapse, or without concomitant serotonin reuptake inhibitor phar- relapse, and the maintenance of behavior change. HealthPsychol 19:57–63.
Bux DA, Franklin ME, Churchill E, Street GP, Segee P, Potts N, Thus, from the literature on combined treatment it does not et al (2000): Efficacy of fluoxetine and comprehensive CBT appear that concomitant pharmacotherapy is generally for generalized social phobia. Convention proceedings for the necessary for patients to profit from CBT. Third, the few 34th annual meeting of the Association for the Advancement studies that directly compared combined treatment to of Behavior Therapy. New York, NY: AABT.
pharmacotherapy alone did show an advantage for the Chaplin EW, Levine BA (1981): The effects of total exposure combined conditions, which may suggest that a course of duration and interrupted versus continued exposure in flood-ing therapy. Behav Ther 12:360 –368.
CBT should be considered for patients receiving pharma-cotherapy alone. As highlighted in the preliminary results Clark DB, Agras WS (1991): The assessment and treatment of performance anxiety in musicians. Am J Psychiatry 148:598 – especially important to consider when the patient has Clark DM (1986): A cognitive approach to panic. Behav Res evidenced only a partial medication response.
Cohen J (1977): Statistical power analysis for the behavioral sciences, rev. ed. New York: Academic Press.
Aspects of this work were presented at the conference, “Learning andUnlearning Fears: Preparedness, Neural Pathways, and Patients,” held Connor KM, Rothbaum BO, Foa EB, Davidson JRT, Cahill SP, March 21, 2002 in Austin, TX. The conference was supported by an Clary CM (2002): A controlled trial of combined sertraline unrestricted educational grant to the Anxiety Disorders Association of and prolonged exposure therapy in posttraumatic stress dis- America (ADAA) from Wyeth Pharmaceuticals, and jointly sponsored order. Euro Neuropsychopharmacol 12(suppl 3):S335.
by the ADAA, the ADAA Scientific Advisory Board, and the National Cottraux J, Mollard E, Bouvard M, Marks I, Sluys M, Nury AM, et al (1990): A controlled study of fluvoxamine and exposurein obsessive-compulsive disorder. Int Clin Psychopharmacol5:17–30.
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