Theoretical Review

LONG-TERM EFFECTIVENESS OF COGNITIVE THERAPYIN MAJOR DEPRESSIVE DISORDER

Paula L. Hensley, M.D.,* Deepa Nadiga, M.D., and E.H. Uhlenhuth, M.D.

Cognitive therapy of depression, based on the cognitive theory of depression, is anestablished treatment for major depressive disorder. Although few cliniciansexpect acute treatment of depression with antidepressant medication to preventlong-term relapse of the illness, some practitioners of cognitive therapy reportlong-term effectiveness in preventing relapse after short-term treatment. We setout to reanalyze follow-up studies in the literature, using intent-to-treatprinciples to assess the long-term effects of acute treatment with cognitivetherapy. From an initial reference list of 97 citations that met our search criteria(controlled clinical trials of cognitive therapy in depression with follow-up), wefound five trials that met our inclusion criteria. This report reviews andreanalyzes these five trials, published between 1981 and 1992, which comparecognitive therapy and tricyclic antidepressant therapy. Overall, the evidencefavors a longer-term effect for cognitive therapy over tricyclic antidepressantsalone. Depression and Anxiety 20:1–7, 2004. & 2004 Wiley-Liss, Inc.

Key words: adult; antidepressive agents; cognitive therapy; depressive disorder; follow-up studies

INTRODUCTIONThe efficacy of antidepressant medication in thetreatment of major depressive disorder (MDD) hasbeen established by multiple clinical trials. Joining theolder generation of antidepressants (tricyclic antide-pressants, TCAs; monoamine oxidase inhibitors,MAOIs), the selective serotonin reuptake inhibitors(SSRIs) emerged in the late 1980s and 1990s todominate the antidepressant market. Although re-sponse rates are defined differently in different studies,the short-term clinical efficacy of antidepressantsranges around 70% [Rosenbaum and Hylan, 1999].At the same time that novel antidepressants werecoming to market, interest in psychotherapeutictreatments of depression has increased. Long-termpsychoanalytic treatment is rare. Manual-basedpsychotherapeutic approaches such as the cognitive psy-chotherapy of Beck [1967] and the interpersonalpsychotherapy of Klerman et al. [1984] are the currentpsychotherapeutic treatments of choice.

Although the efficacy of antidepressant treatmentfor depression has been demonstrated repeatedly inrandomized double-blind clinical trials [Mulrow et al.,2000], the efficacy of cognitive therapy (CT), particu-larly for more severely depressed patients, is less welldefined [Gloaguen et al., 1998]. Published data on CT

for depression show greater variation than we see in thedata on antidepressants. Although many trials showrates of acute response similar to those seen inantidepressant trials, there remain questions about theefficacy of CT for more severely depressed patients.Many authors claim a durable benefit of CT, aprotective effect against further episodes of depressionafter treatment discontinuation. In other words,proponents of CBT assert that it is effective in relapseprevention.

If CT were protective against depressive relapse, itwould clearly offer advantages over antidepressants,which no one assumes protect against relapse oncestopped. But how was the common belief of a

DEPRESSION AND ANXIETY 20:1–7 (2004)

Department of Psychiatry, School of Medicine, University of

New Mexico Health Sciences Center, Albuquerque, New

Mexico

*Correspondence to: Dr. Paula L. Hensley, University of New

Mexico Department of Psychiatry, 2400 Tucker NE, 4th Floor,

Albuquerque, NM 87131. E-mail: phensley@salud.unm.edu

Received for publication 15 December 2003; Accepted 1 June

2004

DOI: 10.1002/da.20022

Published online 19 August 2004 in Wiley InterScience (www.

interscience.wiley.com).

&& 2004 WILEY-LISS, INC.

protective effect established? Our reading of theliterature showed that the common design to investi-gate the durability of therapeutic response deals onlywith patients who improved substantially during acutetreatment.

Intent-to-treat (ITT) analysis is used in most acutetreatment studies; it includes all patients initiallyrandomly assigned or at least those who embarked ontreatment. It takes account of dropouts, usually bycarrying forward the last available observation (LOCF).Dropouts are considered treatment failures, either dueto non-response or adverse events [Rickels andSchweizer, 1998]. ITT analysis prevents the ‘‘sieveeffect,’’ in which patients who benefit from treatmenttend to continue treatment, with narrowing of thecontrast between active and control conditions.

PATIENTS AND METHODSSELECTION OF STUDIES FOR REVIEW

Our initial search included journal articles indexed inMEDLINE, PSYCHINFO, SCISEARCH, SOCSCI-SEARCH, and the Cochrane Library, between 1966–2003. Review articles and other primary sourcesprovided additional references, which were traced andadded. This search produced 97 citations. The follow-ing criteria were applied to the articles identified:

* The report focuses on follow-ups comparing in-dividual CBT with a control treatment in patientswith major depressive disorder.

* Reports of therapies other than CBTand reports ofCBT focusing on treatment of other conditions,such as panic disorder, were eliminated. Thisrequirement eliminated 21 references.

* Follow-up studies lacking a credible control groupwere excluded. We defined credible control groupsas medication groups (in which patients are expectedto relapse after treatment is withdrawn) and groupsin which patients received a clearly inferior treat-ment, such as placebo. We considered such a groupessential to control for ‘‘spontaneous’’ improvementover longer periods. Although studies with controltreatments other than pharmacotherapy were eligi-ble, no such studies met our other inclusion criteria.This requirement eliminated 33 studies.

* Studies designed to evaluate specific components ofCBT were excluded. Our reasoning was that suchindividual components might not be fully effective.This requirement did not eliminate any referencesas all were eliminated due to lack of a control.Studies of group CBTand bibliotherapy using CBTwere excluded. This requirement eliminated fourstudies.

* Studies witho6 months of follow-up were excludedbecause, in our judgment, a treatment effect lasting

o6 months lacks clinical significance. This require-ment eliminated 11 references.

* Studies examining adolescents and children wereexcluded.

* Studies of CBT in dysthymia and minor depressivedisorders were eligible for inclusion, but none ofthese studies met our other inclusion criteria.

* Studies of special samples, such as patients with noor partial response to initial pharmacotherapy, wereexcluded. This eliminated seven citations.

* Follow-up studies limited to cross-sectional evalua-tions at long intervals without interim history wereexcluded because they cannot assess whetherpatients sustained remission without additionaltreatment throughout the follow-up period.

In addition to the requirements listed above, 10references were eliminated due to miscellaneousreasons, such as being Review papers, Letters to theEditor, or presenting reanalysis of data from includedreferences. Six additional studies were excluded due toinadequate information to allow reanalysis, for exam-ple, presenting only data as mean depression scores. Ofthe 97 citations, five studies met our inclusion criteria.

PROCEDURE FOR RE-ANALYZINGFOLLOW-UP DATA

Viewing follow-up studies as long-term outcomestudies, we re-analyzed each study that met selectioncriteria so far as possible using principles commonlyapplied in the analysis of acute therapeutic studies.From this perspective, we applied intent-to-treat (ITT)analysis accounting for all patients initially randomlyassigned to acute treatment. Dropouts present a majorunsolved problem even in acute treatment studies, themore so in long-term studies. Whenever authorspresented the required data, we used clinical status atthe last available visit as the measure of outcome,whether this occurred during the acute treatment phaseor the follow-up phase of the study. The analogy is tolast-observation-carried-forward (LOCF) or end-pointanalysis in acute therapeutic studies. When relevantdata were not available, we counted dropouts astreatment failures, because patients in acute therapeuticstudies usually drop out due to either treatmentineffectiveness or intolerable adverse events [Rush etal., 1977]. Although the analogy between long-termand acute studies in this respect probably is limited, weconsidered this to be the conservative approach[Rickels et al., 1994].

Another issue in follow-up studies is identifying themost appropriate criterion of clinical status. Fewfollow-up studies evaluate patients using standardrating scales with sufficient frequency to assure thecapture of changes in clinical condition betweenevaluations. Therefore, parametric analyses of long-

Hensley et al.2

term course generally are not useful. A commonsolution for this problem is to collect interim historyusing a structured interview incorporating specificclinical criteria for continuing remission. Therefore,we classified patients in each study according to abinary clinical criterion: (1) achieved and maintainedremission versus (2) failed to achieve or maintainremission. We use remission as a generic term for adefined level of improvement without regard to itsduration and avoid arbitrary specification of remissionversus recovery or relapse versus recurrence. Wheneverauthors specified a binary classification of clinicalcondition, we accepted their definition.

Patients who received unscheduled treatment duringthe follow-up period were classified as not remitted atthe final follow-up in each study, whether or not theauthors of the report did so. Reports that did not offerthe data required for these procedures had to beexcluded.

Some might favor survival analysis of a binaryimprovement criterion. Survival analysis would becomplicated where two events (onset of remission andoffset of remission) occur in some patients. We chosethe simpler LOCF approach in the spirit of the analogywith the acute clinical trial and the probability thatsurvival analysis would not be substantially moreinformative about outcome at the end of follow-up.

RESULTSThe five studies that met our criteria for inclusion

are abstracted below. Some of the articles reportedfollow-ups of patients in acute studies publishedpreviously. We include a table showing the results ofour recalculation of the follow-up data for eachabstract.

The study by Kovacs et al. [1981] is the follow-upreport on the Rush et al. [1977] study of acutetreatment. It describes a 1-year naturalistic follow-upof the acute treatment completers in two groups, a CTgroup and a pharmacotherapy (imipramine) group.Both groups were in acute treatment for a maximum of12 weeks. The CT group had up to 20 sessions; theaverage number was 15.3 sessions over 10.9 weeks.Imipramine was prescribed in flexible doses up to 250mg/day; pharmacotherapy sessions were held once aweek for 20 min. The medication was tapered anddiscontinued over the last 2 weeks of treatment. CTwasadministered by relatively inexperienced therapists

(psychiatry residents, clinical psychologists, and psy-chiatrists) supervised by the first three authors of thereport. Pharmacotherapy was prescribed by the sameresidents and psychiatrists who provided the CT; allwere experienced in the medication treatment ofdepression. Patients were followed with monthly in-person interviews, and interval histories were collected.Remitters at the end of the 15-month follow-up weredefined as patients whose monthly Beck DepressionInventory scores (BDIs) remained below 17 consis-tently and who had no additional mental health careduring the follow-up period. See Table 1 for the datarecalculation of this study. Our LOCF analysis used thedata on ‘‘No Relapse’’ from the report’s Table 3[Kovacs et al., 1981] plus one dropout from acute CTwho maintained remission throughout the follow-upperiod. Based on this procedure, the CT group didsignificantly better than the imipramine group at 1 year(P o .02).

The Blackburn et al. [1986] study presents natur-alistic follow-up data on patients in the Blackburn et al.[1981] study of acute treatment. Depressed patientswere treated for 12–20 weeks with CT, pharmacother-apy, or both. The most common antidepressants usedin the trial were amitriptyline and clomipramine,generally at doses of 150 mg/day. Thirty-nine patientswere treated in an outpatient office setting by generalpractitioners who discussed medication doses withhospital psychiatrists. The other 49 were hospitalizedpatients treated by psychiatrists. The patients assignedto CT generally attended therapy twice a week for thefirst 3 weeks, then weekly for the remainder of theacute study. However, some of the patients attendedonly weekly throughout the acute phase of the study.Two experienced cognitive–behavioral therapists con-ducted the sessions. Acute treatment was followed by a6-month period of maintenance on the same treatmentat reduced levels. The investigators apparently had nodirect contact with the patients over the 18-monthfollow-up period. Failure to maintain remission wasdefined as a doctor’s note in the medical recordindicating need for further treatment. See Table 2 forthe data recalculation. Our LOCF analysis includeddata on ‘‘Well’’ patients from the report’s Table 4[Blackburn et al., 1986] plus five patients whoresponded to acute treatment but were lost to follow-up. At 27 months, the two CT groups were doingsignificantly better than the TCA alone group(P o .005).

TABLE 1. Kovacs et al. [1981] LOCF Analysis

CT Imip

Evaluation Criterion of remission n % n % Exact P

Randomized 19 100.00 25 100.0015 monthsa BDIo17 and no Rx 9 47.4 3 12.0 0.016aIncludes one acute treatment dropout who maintained remission throughout follow-up.CT, cognitive therapy.

Theoretical Review: Long-Term Effectiveness of CT in MDD 3

The Simons et al. [1986] study is the follow-up of theMurphy et al. [1984] acute treatment study. The 12weeks of acute therapy consisted of up to 20 sessions ofCT, CT plus nortriptyline, or CT plus active placebo(designed to have mild sedative and anticholinergiceffects). The authors chose nortriptyline due to itstherapeutic window of plasma level. Dosage ofmedication was adjusted to maintain blood levels inthe range 50–150 ng/ml. In-person follow-up inter-views were scheduled at 1 month, 6 months, and 12months after termination of the acute phase oftreatment, and interval histories were obtained. Failureto maintain remission was defined as a BDI 415 at afollow-up interview or reentry into treatment fordepression during the interval. See Table 3 for thedata recalculation. Unfortunately, although 5 of 26non-responders to acute treatment attained remissionduring the follow-up period, their treatment groupswere not identified. Moreover, although 16 of 17dropouts from acute treatment were followed up, theauthors did not provide information about their statuson the binary remission criterion. Therefore, we couldnot do an LOCF analysis and had to count these 22patients as non-remitted for purposes of ITT analysis.Data on acute responders in remission at 15 monthswere taken from the authors’ Table 2 [Simons et al.,1986]. Using these procedures, there were moreremitted patients in the groups that received CT thanin the group that received only nortriptyline (P o .05).

The Evans et al. [1992] study is the follow-up to theacute study described by Hollon et al. [1992]. Acutetreatment consisted of 12 weeks of CT, imipramine, orCT plus imipramine. The mean number of CTsessionswas 14.9. Flexible daily doses of imipramine wereprescribed with a target daily dose range of 200–300mg/day by Week 3. Blood levels were drawn and levelsbelow 180 ng/ml triggered dosage increases. Half ofthe patients who received imipramine alone continued

maintenance medication for 12 months after the acutephase. Follow-up included monthly mailers containinga BDI and a brief questionnaire about life events andadditional treatment throughout the 2-year follow-up.In addition, patients were scheduled for full re-evaluations every 6 months throughout the follow-upperiod. Failure of remission was defined as twoconsecutive BDIs 415 or treatment for MajorDepressive Disorder (MDD). See Table 4 for the datarecalculation. Our LOCF analysis included data onsurvivors from the author’s table [Evans et al., 1992]and data on responders who refused follow-up ordiscontinued follow-up while remitted from the text.We grouped together patients treated with imipraminefor 3 months or 15 months. At 27 months, the CTgroups were doing significantly better than themedication only condition (P o .05).

The Shea et al. [1992] study reports follow-up datafrom the National Institute of Mental Health Treat-ment of Depression Collaborative Research Programdescribed by Elkin et al. [1989]. Patients in the acutephase received either cognitive behavior therapy(CBT), interpersonal therapy (IPT), imipramine (Imip)plus clinical management (CM), or placebo (Plac) plusclinical management. Acute treatment lasted 16 weeks.The average number of CTsessions was 13.0, includingdropouts. In the medication condition, imipraminedoses averaged 185 mg after the first 2 weeks oftreatment. Blood levels were drawn at Weeks 4 and 8.Follow-up assessments occurred at 6, 12, and 18months after acute treatment, with interval datagathered on the Longitudinal Interval Follow-upEvaluation II (LIFE-II). The criteria for failure tomaintain remission were a diagnosis of MDD ortreatment for MDD during the follow-up period.Unfortunately, non-responders to acute treatment werenot followed and reported. In addition, last availabledata on follow-up were not identified as to treatment

TABLE 2. Blackbum et al. [1986] LOCF Analysis

CT+TCA CT TCA

Evaluation Criterion of remission n % n % n % Exact P

Randomized 30 100.0 30 100.0 28 100.027 Monthsa No Rx for depression 14 46.7 12 40.0 2 7.1 0.001

aIncludes 5 patients who were responders to acute Rx but lost to follow up.CT, cognitive therapy; TCA, tricyclic antidepressants.

TABLE 3. Simons et al. [1986]

CT NT CT+Plac CT+NT

Evaluation Criterion of remission n % n % n % n % Exact P

Randomized 24 100.0 24 100.0 17 100.0 22 100.015 Monthsa BDIo16 and no Rx 8 33.3 3 12.5 9 52.9 8 36.4 0.045aIncludes only 12-week responders.CT, cognitive therapy; BDI, Beck Depression Inventory.

Hensley et al.4

group. Therefore, we could not apply LOCF analysisand had to count missing patients as non-remitters forpurposes of an ITTanalysis. Data on responders comefrom the authors’ Table 1. See Table 5 for the datarecalculation. At 18 months follow-up, there wereno differences in the outcomes of the four groups(P 4 .25; Table 5).

DISCUSSIONIn the three studies where an LOCF/ITT analysis

was possible, the proportion of patients in sustainedremission 12–24 months after acute treatment endedwas higher in groups treated with CT than in groupstreated only with an antidepressant. Results from ITTanalyses of the two studies requiring the assumptionthat all dropouts were nonremitters split evenly: oneshowed a higher sustained remission rate among CT-treated patients 1 year after acute treatment, whereasthe other showed no difference in sustained remissionrates among groups 18 months after acute treatment.On balance, the evidence favors a longer-term effectfor CT over tricyclic antidepressants alone. That ashort course of antidepressants generally does notproduce long-term sustained remission is, of course,well known. Studies using antidepressant-treated con-trol groups were selected for review for that reason.Although all of the studies that met our selectioncriteria included a control group of patients treatedwith tricyclic antidepressants, there is little reason tothink that the results would dif fer with newerantidepressants, i.e., that the newer agents producemore sustained remissions after discontinuation.

We were surprised to find so few acceptable studiesof the long-term effects of CT in depression, atreatment that was introduced more than 30 yearsago [Beck, 1967] and has gained wide acceptance ashighly durable. Criticisms of psychotherapy trials andpsychotherapy versus pharmacotherapy trials haveincluded inadequate prescription of pharmacotherapy,

failure to include a pill placebo arm [Klein, 1996],inadequate power, and the allegiance effect [Gaffan,1995; Luborsky, 1999]. Although trials of CT ofteninclude a manualized approach to therapy, the phar-macotherapy arms are often inadequately standardized.In our series, the Shea et al. [1992] study used a pillplacebo combined with clinical management, whereasthe Simons et al. [1986] study combined CT with anactive placebo. Although some of these criticisms areless relevant to the present review, we also noted othervery basic problems in many articles. Examples of suchproblems included: patients were not all identified bytreatment group, numbers in treatment groups did notsum to the reported total, numbers of completers anddropouts did not sum to the reported total, the basesfor calculated percentages were not specified, numbersin the acute treatment report did not correspond tonumbers in the follow-up report, and improvementcriteria in the acute treatment phase dif fered fromthose in the follow-up phase. Such errors not only taxthe reader, but also reduce confidence in the resultspresented and often preclude re-analysis of the data.

Studies that included a maintenance phase for CTseemed to show strikingly positive effects of CT atreduced levels over time. A careful consideration of theissue of maintenance phase CT is outside the scope ofthis review.

An intriguing finding in the Simons et al. [1986]study was the remarkable performance of CT plusactive placebo. At 15 months of follow-up, 52.9% ofpatients in this group remained well, compared to36.4% of the CT plus nortriptyline group, 33.3% ofthe CT group, and 12.5% of the nortriptyline group.Interestingly, in our companion article examining thelong-term effect of CT in panic disorder [Nadiga et al.,2003], two of the three studies [Sharp et al., 1996;Barlow et al., 2000] showed the best response for theCT plus placebo group. Although CT plus antidepres-sant did not show an additive effect, CT plus placeboseemed to do so.

TABLE 4. Evans et al. [1992] LOCF Analysis

Imipa CT CT+Imip

Evaluation Criterion of remission n % n % n % Exact P

Randomized 55 100.0 22 100.0 25 100.0027 Months BDIo16 and no Rx for depression 11 20.0 9 40.9 11 44.0 0.046aIncludes patients treated for 12 weeks and for 15 months.

TABLE 5. Shea et al. [1992]

CBT IPT Imip+CM Plac+CM

Evaluation Criterion of remission n % n % n % n % Exact P

Randomized 59 100.0 61 100.0 57 100.0 62 100.022 Months No relapsea and no Rx for depression 13 22.0 9 14.8 7 12.3 9 14.5 0.526aAs defined in LIFE-II.

Theoretical Review: Long-Term Effectiveness of CT in MDD 5

The conclusions to be drawn from our ITTanalysesdo not diverge from those drawn by the authors of thefive studies included in this review. The ITT analyseswere hampered by the absence of comprehensive dataon outcomes for all randomly assigned patients,including dropouts and patients considered ineligibleto participate in follow-up. Whether the long-termoutcome as assessed by ITTwould have differed in thepresence of such data, therefore, remains an openquestion. Clearly, assumptions regarding the eventualfate of dropouts and early non-responders cannotsubstitute for actual data. A major effort to collectdata on all randomly assigned patients over the entireperiod of study, therefore, is essential to a properevaluation of long-term outcome.

Additional studies designed as long-term treatmentstudies would be helpful. In the studies we reviewed,follow-up was done only for those patients whoresponded to the acute treatment. The differentcriteria used to define remission in the acute versusfollow-up phases suggest that many studies were notdesigned as true long-term treatment studies.

The trials summarized were short with relativelyshort-term follow-up periods. Had we had longer-termfollow-ups available, we may have been able to reach amore definitive conclusion. Our intention is not tocompare the long-term durability of short-term phar-macotherapy versus short-term CBT. We expected themedication group to relapse over long-term follow-up.Proponents of CBT have made a case for long-termprotectiveness of short-term therapies. It was thissupposition that we hoped to examine.

CONCLUSIONUntil the goal of reporting data on all randomly

assigned patients can be more nearly achieved, therelative advantages of studying only relapse andrecurrence among acute responders and long-termoutcome among all randomly assigned patients willremain a matter of conceptual debate. Blackburn[1986] addresses this issue as follows, ‘‘The inclusionof nonresponders would [be] appropriate only forinvestigating the relationship between the naturalhistory of depression and therapeutic interventioninstead of the more specific issue of the effectivenessof dif ferent treatments and relapse/recurrence.’’

In contrast, we submit that a treatment can claimlong-term effectiveness only to the extent that itimproves upon the natural history of the disorder. Ifpatients who drop out or do not respond after a shortperiod of treatment remit later, i.e., ‘‘catch up’’ withacute responders, then a claim of prophylaxis for thetreatment is not sustainable. A treatment that issuperior only in the short term can claim only that itaccelerates remission, a worthwhile goal in itself.

Given the difficulties encountered in this review, wecan only echo Gloaguen [1998]: ‘‘Studiesydealing

with the prevention of recurrence with CT versusantidepressant drugs are now overdue.’’

CAVEATSOur approach of considering dropouts as failures is

one of several ways to deal with inadequate informa-tion. Because we do not know why these patientsdropped from treatment, we have chosen one way todeal with this missing information.

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