Six-Year Outcome for Cognitive Behavioral Treatment of Residual Symptoms in Major Depression

The original protocol from which this study group was drawn was detailed in our previous report (2). Forty consecutive depressed outpatients who met the Research Diagnostic Criteria (RDC) (4) for a primary major depressive disorder were treated for at least 3 months with full doses of antidepressant drugs. They were randomly assigned to cognitive behavioral treatment of residual symptoms (primarily anxiety and irritability) or clinical management. Antidepressant drugs were tapered and discontinued.

A clinical psychologist, who was blind to treatment assignment, reassessed the 40 patients (20 in each group) every 6 months up to 72 months. Further treatment (psychotherapy, antidepressants, or both) was not allowed during follow-up unless a relapse occurred. Follow-up evaluations consisted of a brief update of clinical and medical status, including any treatment contacts or use of medications. Relapse was defined as the occurrence of an RDC-defined episode of major depression. Written informed consent was obtained after the procedures had been explained fully to the patients.

Patients were instructed to call during the follow-up period if any depressive symptoms occurred. Since prodromal symptoms of relapse often mirror those of the initial episode (5), patients were also warned to look specifically for those symptoms. If patients presented in a state of substantial clinical worsening, they were observed and evaluated within a 7-day period by both the independent clinical evaluator (C.R.) and the treating clinician (G.A.F.). Once a relapse was ascertained by the consensus of both, patients were prescribed the same antidepressant drug at the same dose as in the index episode. No patient received further cognitive behavioral treatment. All patients who relapsed were treated for at least 3 months with full doses of antidepressant drugs according to a standardized protocol (6). Antidepressant drugs were again tapered, at the rate of 25 mg of amitriptyline or its equivalent every other week, and then were withdrawn completely. Drug discontinuation was not feasible for one patient in the standard clinical management group. The patients rated as “better” or “much better” according to Kellner’s global rating scale of improvement (7) and those rated as in full remission (8) were defined as responders.

Survival analysis (9) was used for time until relapse into major depression. Six factors were investigated as possible predictors of outcome: assignment to cognitive behavioral treatment or standard clinical management, age, sex, duration of depressive episode, past history of depression, and the number of residual symptoms regardless of treatment assignment after completion of the study. The Kaplan-Meier method was used for estimating survival curves. The log-rank test was employed to compare any two survival distributions for each of the six factors considered (9).

In addition, t test for independent data was used to compare the number of depressive episodes during follow-up in the two treatment groups. For all tests performed, the significance level was set at 0.05, two-tailed.

During the 6-year follow-up, 10 of the patients (50%) in the cognitive behavioral treatment group and 15 (75%) in the standard clinical management group relapsed. None of the risk factors examined attained statistical significance by survival analysis. Only treatment assignment (figure 1) was close to significance (log-rank test, χ²=3.45, df=1, p=0.06).

Of the 25 patients who relapsed, 16 did so more than once during the 6-year follow-up. This included the patient for whom discontinuation of antidepressant drugs was not feasible. This 64-year-old woman, who belonged to the standard clinical management group, relapsed while on a regimen of desipramine, 150 mg/day. Increase of the dose to 250 mg (the highest she could tolerate) was unsuccessful. However, she responded to fluoxetine, 40 mg/day, which she continued throughout the study with no further relapse. Patients in the cognitive behavioral treatment group had a significantly lower number of new depressive episodes (mean=0.80; SD=0.95) than those in the standard clinical management group (mean=1.70, SD=1.30) (t=2.50, df=38, p<0.05); that is, multiple relapses during follow-up were less frequent.

Excluding the patient who received continuation treatment for part of the study period, there were 47 new occurrences of depression. In 45 of the cases, patients responded to the same treatment used in the index episode; in two cases (4%)—both involving desipramine—this did not occur, despite further increases in dose. For these two female patients (ages 48 and 44), response occurred when they were switched to fluoxetine (one patient) or amitriptyline (one patient). The phenomena concerned with resistance that occurred in these two patients did not take place in three other patients who relapsed and were treated again with desipramine or in 12 patients rechallenged with amitriptyline, in four with imipramine, and in three with mianserin.

The 4-year follow-up disclosed that cognitive behavioral treatment of residual symptoms of depression has a substantial effect on relapse rate (3). Such a protective effect for the occurrence of a new depressive episode faded at 6-year follow-up. However, when multiple relapses during the 6-year period were taken into account, patients in the cognitive behavioral treatment group had significantly fewer new episodes of depression than those in the clinical management group. The results thus suggest that treatment of residual symptoms entails a significantly lower risk of relapse within 4 years from the index episode and is associated with an overall more favorable course. The results provide further support to the stage-oriented (10) model of psychotherapy of depression (2). According to this model, the psychotherapeutic intervention, which is considerably different from commonly used approaches (2), is deferred until after pharmacotherapy. The fact that most of the residual symptoms of depression are also prodromal (2) and that prodromal symptoms of relapse tend to mirror those of the initial episode (5) provides an explanation for the protective effect of this targeted treatment. Cognitive behavioral treatment may act on those residual symptoms of major depression that progress to become prodromal symptoms of relapse (11). The methodological limitations of this preliminary investigation, such as the fact that all treatment was carried out by one experienced clinician and our patient group was carefully selected, have been discussed in detail (2, 3).

Two treatment strategies (maintenance drug treatment and intermittent use of medication with frequent follow-ups and attention to prodromal symptoms) have been outlined in recurrent depression (11). A potential negative aspect of the latter strategy is concerned with the issue of resistance: the possibility of the patients’ illness becoming refractory to a previously effective treatment by its intermittent use (12, 13), as reported with lithium prophylaxis (12). Our results indicate that resistance after rechallenge with a drug that was previously successful also occurs with antidepressant drugs, although only in a small percentage of instances (4%). Further, the possibility cannot be excluded that the two patients in whom resistance occurred were initially placebo responders (14) and that after they experienced a relapse, their expectations for a second medication trial might not have been as high as for the initial treatment. Fading or tolerance to ongoing antidepressant treatment, however, may also occur (13) and indeed took place in one patient. The large majority of patients displayed a satisfactory response to drug therapy when a new episode of depression ensued. This confirms the advantages of early treatment of a depressive episode and the value of educating patients to watch for prodromal symptoms of relapse (11).

Received Oct. 17, 1997; revision received April 14, 1998; accepted May 15, 1998. From the Department of Psychiatry, State University of New York at Buffalo; the VA Medical Center, Buffalo, N.Y.; and the Affective Disorders Program and the Laboratory of Experimental Psychotherapy, Department of Psychology, University of Bologna. Address reprint requests to Dr. Fava, Department of Psychology, University of Bologna, Viale Berti Pichat 5, 40127 Bologna, Italy. Supported in part by a grant from the Mental Health Project, Istituto Superiore di Sanità, Rome.Maria Zielezny, Ph.D., performed the statistical analysis.