SS Prevention of Relapse Following Cognitive Therapy vs Medications in Moderate to Severe Depression Steven D. Hollon, PhD; Robert J. DeRubeis, PhD; Richard C. Shelton, MD; Jay D. Amsterdam, MD; Ronald M. Salomon, MD; John P. OReardon, MD; Margaret L. Lovett, MEd; Paula R. Young, PRD; Kirsten L, Haman, PhD; rent B. Freeman, BA; Robert Gallop, PhD Background: Antidepressant medication preve return of depressive symptoms, but only as long as tre ment is continued Objectives: To determine whether cognitive therapy (CT) has an enduring effect and to compare this effect against the effect produced by continued antidepressant medication, Design: Patients who responded to CT in a random- ‘zed controlled trial were withdrawn from treatment and compared during a 12-month period with medication re- sponders who had been randomly assigned to either con- \Unuation medication or placebo withdrawal, Patients who survived the continuation phase without relapse were withdrawn from all treatment and observed across a sub- sequent 12-month naturalistic fllow-up. Setting: Outpatient clinics at the University of Penn- sylvania and Vanderbilt Universit Patients: 4 (otal of 104 patients responded to ‘ment (57.8% of those initially assigned) and were en- rolled in the subsequent continuation phase; patients were initially selected to represent those with moderate to se- vere depression. Interves lowed no more than 3 booster sessions during continu ation; patients assigned to continuation medication were kept at full dosage levels. jons: Patients withdrawn from CT were al- Main Outcome Measures: Relapse was defined as a return, forat least 2 weeks, of symptoms sufficient to meet the ctiteria for major depression or Hamilton Depression Rating Scale scores of 14 of higher during the continua- tion phase. Recurrence was defined in a comparable fash- fon during the subsequent naturalistic follow-up. Results: Patients withdrawn from CT were signifi- cantly les likely to relapse during continuation than pa- tients withdrawn from medications (30.8% vs 76.2% .004), and no more likely to relapse than patients who kept taking continuation medication (30.8% vs 47.2%: 10). There were also indications that the effect of CT extends to the prevention of recurrence Conelusions: Cognitive therapy has an enduring elfect that extends beyond the end of treatment, It seems to be as effective as keeping pat is on medication, Arch Gen Psychiatry. 2005;62:417-422 NTIDEPRESSANT MEDICA- (cADM) in preventing subsequent re- Author Affiliations: Departments of Psychology (Dr Hollon) and Psychiatry (Ors Shelton, Salomon, and Haman and Ms Lovet), Vanderbilt University, Nashville Tenn; Departments of Psychology (Dr DeRubes) and Psyehiany (Drs Amsterdam, Reardon, and Young and Mr Freeman), University of Pennsylvania, Philadelphia; and Department of Mathematics and Applied Statistics, West Chester University, West Chester, Pa (Dr Gallop) tion (ADM) is effective in the treatment of moder- ate and severe depres- sion, and it prevents the re- turn of symptoms as long as itis continued. However, evidence is lacking that it does anything to reduce risk once its use isdis- continued. There is some evidence that cognitive therapy (CT) has an enduring effect that reduces risk following success ful treatment? In a series of studies, pa- tients who responded to CT were about hhalf as likely to relapse following treat- ‘ment termination as patients who discon- tinued taking medications after respond ing to ADM.** Prior exposure to CT was. at least as effective as continuation ADM lapse in the one study in which they were compared." To our knowledge, the only study that failed to find an enduring effect for prior CT (pCT) was the National In- stitute of Mental Health Treatment of De- pression Collaborative Research Pro- ‘gram, and in that ial, such differences as ‘were apparent favored CT.” See also page 409 Although these findings have been fairly robust, the studies typically have been small (using cell sizes of $15) and, in most instances, patients have known that medi- cations were being withdrawn, Mor lover, it cannot be asstimed that CT's en- (©2003 American Medical Association. AI rights reserved, jamanetwork.com/ by Jose Luis Bonet on 04/19/2019during effect would be obtained with more severely depressed outpatients. Since the publication of findings from the Treatment of Depression Collaborative Re- search Program, questions have been raised about the ef- fectiveness of CT with more severely depressed pa- dents. To our knowledge, no other published tral has focused specifically on psychosocial treatment in this sub- population, The present study asks whether CT has an enduring effect that extends to the prevention of relapse among more severely depressed outpatients, and it al- lows fora comparison of the magnitude of CT's preven- Udon effect relative to ADM. ss} This study examines the subsequent cours following inital treatment for patents randomised to either CT or ADME A pla ebo-contoed continuation design was used to compare pa tients who responded to 10 wecks of CT with patente who re sponded to 16 weeks of ADM, Subjects were patients with toderate to severe unipolar depresion aged 1810 70 years who svere recruited from outpatient peyehaticlinice at sites, the University of Pennsylvania and Vanderbilt Univers The fall deta ofthe screening process andthe patient characteristics are given elsewhere” Insitutional review boards at the Uni ‘erat of Pennsylvania and Vanderbilt Unverly reviewed and approved the study, including the withdrawal of active medi Cation from patients who responded o weatmentWriten i formed consent was obtained rom al participants otha ll ofthem knew that treatment ight be withdrawn shorty after their ial response ll patients met the criteria for major de- pressive disorder as ascertained by the structured Clinical In Terview fr DSMIV-TR diagnoses” Moreover, they had to have scores of 20 of above for consecutive weeks on the fist 17 items of te Hamilton Depression Rating Scale (HDRS)" Ths twas the criterion used By Elkin and clleagus to define pa tents as severely depresed in the National Insttite of Mental Health Treatment of Depression Collaborative Research Pro- gam. Exclusion eter were kept tom amin, but pa tients were screened oui they had any history of paychoats or bipolar disorder, had anottes xis disorder that was the predominant aspect ofthe clinical presentation or met he ci {cra for borderline, antsocial or schizotypal personality die order, as acertsined by interviews om the sructured Clinical Interview for DSM-II-R Personality Disorders” Patients were also screened out they had clinkally significant medial die order that precluded treatment with an ADM or required hos- pilalization for imminent sulcldal sk “Two hundred fory patients met ail inclusion and excli- sion criteria. They were randomly assigned to 16 weeks of ace treatment with ether CT (n00) of ADM (2120) the r= taining 60 patients received 8 weeks of pil placebo (cF-P) and wll not be considered further in this atc Of the 180 patients who had been signed to one ofthe ac- tiv treatments, 108 (57.8%) met the err for response and svere enrolled into the 12-month continuation phase ofthe st. ‘The definiion of response accounted for he absolute symptom level atthe end of teatment and the stably ofthat evel a tients who completed 16 wecke of treatment met response ci tern they had the following: (1) a Tosweck HDRS seore of 12 or lessand ether a 14-weeke HDRS score of [ot less of 10-and TDeweek HDRS scores of 12 o lessor (@) weeks 13, and 18 HRS scores of 12 or less. These criteria prevented a transient cacerbaton of depresivesympiome atelier week I4or 16 rom precluding recognition of patient a a responder. Beenie all Pallets inthe tal began wth an HDRS sore of 20 or more, (aePmosreD) ARGH GEN NCHIATRVOLES score of 12 reflected a reduction of at least 40%, a substantial reduction in depressive symptoms n the ADM group, 69 (57.5%) 6f 120 patients met the esponse criteria and in the CT group, 35 (58.3%) of 60 patients met these criteria. These 104 patients ‘onsite the focus of this report, STUDY PROCEDURES ‘Thiestudy use placebo- aN ® ee Ap ne)_0 Proves : . ‘ Tl se Tae Tat Tineoloig Share Team mo Pa waht ‘ssa ors Figura. Condave proportion of est apo who sunaed Figue 2. Sustained improve or lps aly aged a ‘hou rape daring conuatonfoln-ap. Cl mesos ogni therapy: cADM, conan icaton paronctn plas posse augmentation) ach nee fo coninaton meteaton (censrng patents who fal ta aha to cantinunton medion) and plsabo ital ont pil pacbo. der (69.2% for another Axis I disorder and 49.0% for an Axis Il disorder), and 33.6% met the criteria for double depression RELAPSE Amun effect of condition was obtained (x!=8.68, P= 00). As shown in Figure ¥, prior exposure lo CT reduced the risk for subsequent relapse relative to cP-P (X!=8 53, 2.004). Relauve to eP-P, ADM reduced relapse atthe level of a nonsignificant end (xi=3.14, P=.08). Prior CT and cADM did not differ significantly (xi=1.62, P=.20). Adjusted relapse rates for each condition were 30.8% for PCT, 47.2% for cADM, and 76.2% for cP-P. Hazard ratios were calculated between cP-P and each of the respective active treatments, Prior exposure to CT was associated with a hazard ratio of 0.30 relative to cP-P, ‘which means that prior exposure to CT reduced risk by TO. Continuation ADM Was associated with a hazard ratio of 0.50 relative to eP-P, which means that keeping palicnts on medications essentially ut risk by hall. This ts comparable to what has been reported elsewhere in the ADM continuation literature.” Four of the patients who relapsed in the cADM con- dition did so when they were not adhering to their medi- cation regimen (defined as taking <75% of the pre- scribed medication fora least | week during the month before relapse). Therefore, a second set of analyses was conducted in which these observations were censored for nonadherence. In these analyses, ADM significantly out- performed eP-P (yi=5.44, P=02). Taking nonadher- tence inlo consideration decreased the relapse rate for ADM to 42% and produced a hazard ratio of 0.37 rela- tive to cP-P. This denotes reduction in risk of 63%, close to that produced by pC SUSTAINED RESPONSE \Wealso examined the proportion of patients in each con- dition who showed sustained response, defined as com- pleting and responding to acute treatment and staying, {ree from relapse across the 12-month continuation phase, adjusted for censored observations. As shown in (werRin TED) RRCH GEN PSYCHIATINVOT tran ADM ndcatsantdapresant medcaton faouate is possible aupmartan} CT, og thay. Figure 2, only 16.4% of the patients intially assigned to ADM and subsequently withdrawn onto eP-P evi- denced a sustained response, compared with 26.0% of the patients originally assigned to ADM who continued to take ADM. Ofthe 60 patients initially assigned to CT 37.3% experienced a sustained response, A main effect of condition was obtained for this variable (x!=7.49, (02). Pairwise Cochran-Mantel-Haenszel tests indi cated a significant difference between only the pCT con- dition and the eP-P condition (x!=7.50, P=.006). NATURALISTIC FOLLOW-UP A total of 40 patients who remained active in ongoing, assessments completed the 12-month continuation phase without relapse. This included 20 patients in the pCT 14 in the cADM, and 6 in the eP-P group. These patients were observed for an additional year in naturalistic fol- low-up; pCT patients were allowed no further booster sessions, and all pills were withdrawn from the patients {in the cADM and cP-P groups in accordance with the same schedule followed at the end of acute treatment. Given that these patients had gone 12 months without relapse following initial remission, they can be considered to have recovered from the index episode. Any subsequent re- turn of symptoms would be considered a recurrence, the onset of a Wholly new episode.” In other respects, re- currence was defined in the same manner as relapse weeks of increased symptoms on the HDRS or Longitu- dinal Interval Follow-up Evaluation). None of these pa- ents were unavailable for follow-up. As shown in Figure 3, survival analyses indicated that CT's endur- ing effect extended to the prevention of recurrence. In the pCT group, 5 of 20 patients had a recurrence during, the naturalistic follow-up, vs 7 of the 14 cADM group patients withdrawn from medication; adjusted recur- rence rates were 17.3% for the pCT vs 53.6% for prior ADM following withdrawal from medication (x!=6.81, (009). The hazard ratio for this comparison was 0.15, ‘meaning that prior expostre to CT reduced risk for re- currence by 85%. Although not depicted in the figure, 2 of 6 patients in whom cP-P was withdrawn also exper enced a recurrence. Although it would be inappropriate toextend analyses across the full 2-year follow-up in the absence of a maintenance medication condition, 15 (©2003 American Medical Association. AI rights reserved, jamanetwork.com/ by Jose Luis Bonet on 04/19/2019(25.0%) ofthe 60 patients initially assigned to CT showed a sustained response [ree of either relapse of recur- rence. Given that only 14 patients assigned to continu- ation medication ended continuation treatment free from relapse (23.3% of total possible 60), cADM could have done no better than pCT even if patients who survived the continuation phase had been kept on maintenance medication, ee} The findings of this study suggest that CT has an endur- ing elfect that reduces risk following successful treat- iment, as indicated by the reduced relapse rates relative to medication withdrawal. Moreover, the magnitude of the CT effect scems to be at least as great as thal achieved by keeping patients on continuation medication, which is widely regarded as the most effective means of pre- venting relapse-* Thus, it seems that there are at least 2 \ways to protect patients against relapse following sue- cessful treatment to either continue ADM or provide CT duringacute treatment, Moreover, there are indications that the enduring effect of CT may extend to the preven- don of recurrence. These findings need to be interpreted cautiously. No one would recommend withdrawing ADM from de- pressed patients treated solely with medication after only 4 months of treatment. In this study, ADM was with- drawn and patients began to take eP-P solely to deter- mine whether CT had an enduring elfect. To the extent that CT has an enduring effec, it might prove less coslly than ADM to provide over ime. Assum- Ing costs of at least $100 per hour for 20 to 25 sessions of CT and $75 per hour for briefer pharmacotherapy ses- sions (and $125 per month for medications), CT costs about twice as much as ADM during a4-month acute phase, but this gap is closed by the eighth month of continua” tion medication treatment, and is reversed beyond that point, such that direct treatment costs for ADM exceed those of CT thereafter. We did not make assessments of other direct or indirect costs that would have allowed us to conduct a sophisticated econometric analysis, but oth- cers who have compared CT with medications on sth in- dexes have found that medications alone may result in a 33% higher expected cost than individual CT. Ic remains unclear just how CT exerts its enduring elfect, Patients are trained from the start to “do the therapy for themselves” rather than to be passive recipients of the therapy. Prom the first session on, patients are encour- aged to test the accuracy oftheir beliefs in homework as- signments, and considerable time is devoted in ater ses- sions to anticipating problems that are likely to arise after \yeatment is completed. Our impression is that patients initially need to apply the skills they learned during treal- ment in a concerted fashion, but that these compensa- tory strategies eventually become second nature, coin- ciding with a parallel change from problematic underlying, beliels to more adaptive ones. Such a change in beliefs would be expected to reduce the likelihood of becom- ing distressed in situations that formerly were problem- atic This process might hold whether the actual mechs- > Pap Pern Gp) ‘Wola ah Na acres vt _" __B os olig hE ot Goniuatin, mo Figur. Cums proportion of recovered patents who sunved without Feence dig naturale oop. Abbrevatons a explain he Tagen agate 2 ‘nism was a change in the content ofthe beliefs ora change fn the way that patients react to their thoughts." The present findings speak primarily to the preven- ton of relapse, the return of the treated episode. Al- though there were indications that CT's enduring elfect may extend to the prevention of recurrence, direct com- parisons to maintenance medication in larger samples would be required to fully assess its relative value. More- over, these findings also do not speak to the conse: quences of combining CT and ADM, although prior stud- tes stiggest that CT's enduring effect is robust even when combined with medications. Both of these questions should be examined further. Submitted for Publication: August 12, 2003; final revi- sion received July 20, 2004; accepted September 9, 2004. Correspondence: Steven D. Hollon, PhD, Department of Psychology, Vanderbilt University, 306 Wilson Hall, Nash- ville, TN 37203 (steven dhollon@vanderbilt edu) Funding/Support: This study was supported by grants ‘MH55875 (R10) and MHO1697 (KO2) (Dr Hollon) and ‘MH50129 (Dr DeRubeis) from the National Institute of Mental Health, Bethesda, Md. Previous Presentation: This study was presented at the 155th Annual Convention of the American Psychiatrie Association; May 23, 2002; Philadelphia, Pa ‘Acknowledgment: We thank GlaxoSmithKline, Brent- ford, Middlesex, United Kingdom, for providing medi- cations and pill placebos for the trial. We also thank the following colleagues for contributing to this research (the specilic contributions of some authors are also noted). Drs Hollon and DeRubeis were the principal investiga- tors and oversaw the implementation of CT at the ¥ spective sites, Drs Shelton and Amsterdam were the coprincipal investigators and supervised the implemen- tation of medication treatment. Edward Schweizer, MD, provided consultation about study design and imple- ‘mentation, especially early in the trial. Ms Lovett and Dr Young served as the study coordinators. Drs Salomon and (O'Reardon and the late Martin Szuba, MD, served as study pharmacotherapists (along with Drs Shelton and Am- sterdam). Cory P. Newman, PhD, Karl N. Jannasch, PRD, Frances Shusman, PhD, and Sandra Seidel, MSN, served as the cognitive therapists (along with Drs Hollon and DeRubeis). Jan Fawcett, MD, provided consultation on (©2003 American Medical Association. AI rights reserved, jamanetwork.com/ by Jose Luis Bonet on 04/19/2019the implementation of clinical management pharmaco- therapy. Aaron T. Beck, MD, Judith Beck, PRD, Chris- tine Johnson, PhD, and Leslie Sokol, PhD, provided con- sultation on the implementation of CT. Madeline M. Gladis, PhD, and Dr Haman oversaw the training of the clinical interviewers, and David Appelbaum, PsyD, Lau- rel L Brown, PhD, Richard C. Carson, PhD, Barrie Prank- lin, PRD, Nana A. Landenberger, PhD, Jessica Londa- Jacobs, PhD, Julie L. Pickholtz, PhD, Pamela Faweett- Pressman, MEd, Sabine Schmid, MA, Ellen D. Stoddard, PhD, Michael Suminski, PhD, and Dorothy Tucker, PhD, served as project interviewers. Dr Gallop and Andrew J Tomarken, PhD, provided statistical consultation. Joyce Bell, BA, Mr Freeman, Cara C. Grugan, BA, Nathaniel R Herr, BA, Mary Hooper, BA, Miriam Hundert, Veni Li- nos, MSc, and Tynya Patton, MA, provided research sup- port. Kelly Bemis Vitousek, PhD, provided helpful com- ‘ments on an earlier draft of the manuscripl Es] 1. Holl 0, Tee ME. Maxton J. Tenant an prevention of presion Pay Sei Pub nest 200238-7 2. Hon SD, Sieton RC eaten gules tr major depres icra. Be ay Te 201 3225-258 4. 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