The majority of persons who have an acute episode of a major depressive disorder will have a response to the first or second treatment tried. (1) In patients with mild or moderately severe episodes, treatment with antidepressant drugs and brief psychotherapies are equally effective; in those with severe episodes, medication is usually recommended. (2) The treatment of chronic depression is more problematic, since in 20 to 30 percent of initial episodes, there is incomplete remission after two years. (3,4) Patients with chronic depression have marked impairments in psychosocial function, poor responses to single therapies, and very high rates of use of health care resources. (3) Furthermore, even if they have a partial remission, they have a risk of relapse of 50 to 80 percent. (4)
The poor response of patients with chronic depression to treatment with antidepressant drugs alone is not fully understood, but it cannot be explained solely on the basis of inadequate dosing or the failure of patients to take their medication. (1) Psychotherapy has been advocated as an alternative. Unfortunately, a review of nine studies of psychotherapy for chronic depression that were published before 1998 revealed that in only two trials were patients appropriately randomized, and the combined sample size was only 126 subjects. (5)
Given the lack of empirical data, establishing the relative efficacy of pharmacotherapy and psychotherapy for this disorder has been difficult. (6) Nonetheless, two trends in research results are apparent. First, there is a relatively low rate of response to placebo (about 15 percent) in trials of psychotherapy or medication. (7) Second, the combination of psychotherapy and medication results in greater improvement than either treatment alone (rate of response, approximately 60 percent vs. 40 percent). (5) However, the evidence to date has not been strong enough to justify unequivocally the use of a combination of the two approaches. (2)
In this issue of the Journal, Keller et al. report the results of a comparison of short-term treatment with an antidepressant (nefazodone), the cognitive behavioral-analysis system of psychotherapy (about 16 sessions), or the two in combination. (8) The study included 681 adults with a chronic nonpsychotic major depressive disorder. After 12 weeks, the group that received the combined treatment had a significantly greater rate of response than the group treated with nefazodone alone or the group treated with psychotherapy alone. The results of Keller et al. confirm previous findings (9) that there is a greater overall reduction in the severity of symptoms (by about 25 percent) among patients who receive combined treatment than among those who receive single therapies. The combined treatment had a less powerful effect when assessed in terms of the gold-standard outcome of complete remission, but the rate of remission was almost twice as high among patients who received both nefazodone and psychotherapy (42 percent) as among patients who received either nefazodone alone (22 percent) or psychotherapy alone (24 percent).
Should physicians now recommend the combination of an antidepressant drug such as nefazodone and the cognitive behavioral-analysis system of psychotherapy as the treatment of choice for patients with chronic depression? The answer is not straightforward. Concentrating on short-term outcomes creates a snapshot of depression and its treatment that is not easy to reconcile with the realities of clinical practice. (10) Additional information is required about whether the reported gains are maintained beyond three months and whether the combined-treatment protocol can be generalized to day-to-day practice.
The findings of Keller et al. support the view that the rate of change -- that is, the trajectory of improvement -- is faster in patients who receive combined treatment than in those who receive a single treatment. (11) However, physicians need to know whether the response rates continue to increase among those treated with antidepressant drugs or psychotherapy alone. If so, the differences among the groups could disappear over time. Most important, longer follow-up would establish how many patients with an early response or remission have sustained clinical improvement. Unfortunately, since Keller et al. used a crossover design in the subsequent long-term phase of the study (treatment was changed at 12 weeks), other studies will be needed to answer these questions.
Two recent randomized, controlled trials evaluated rates of relapse after therapy for chronic depression. (12,13) The studies have important methodologic differences, but both used a brief psychotherapy (10 to 20 sessions), called cognitive therapy, which was adapted to meet the needs of their target population. Fava et al. (12) reported the 6-year outcome in 40 patients, whereas Paykel et al. (13) assessed 158 patients during 20 weeks of treatment and for a year afterward. Both studies demonstrated that the benefits of psychotherapy were sustained after treatment ended; the risk of relapse or persistent symptoms was reduced by 45 to 50 percent. Furthermore, patients who received cognitive therapy plus medication had significantly fewer unscheduled visits with their psychiatrists. (13) Such findings are clearly important in a consideration of the overall benefits and costs of treatment.
The feasibility of combined treatment for chronic depression also depends on the clinical population treated and the ease of delivery. The study subjects recruited by Keller et al., (8) Fava et al., (12) and Paykel et al. (13) exemplify the heterogeneity that is typical of patients with chronic depression. The most clinically significant group of patients excluded from the study by Keller et al. and from other studies was the group with other coexisting conditions, such as substance-abuse or severe personality disorders. Their inclusion would probably have reduced but not eliminated the additional benefit of combined therapy, although patients with complex problems may require a longer course of psychotherapy. (5,6)
Delivery of the combined treatment poses the most challenging problem. There is no evidence that nefazodone has any special benefit as compared with other antidepressant drugs, but following clinical-practice guidelines with regard to the prescribing of these drugs does improve the outcome of case management. (2,8,13) Therapists who can provide brief therapies are scarce, and it is important to know what the interventions entail. The cognitive behavioral-analysis system of psychotherapy helps motivate patients with chronic depression to change by targeting their cognitive and emotional functioning and the consequences of their behavior. The aim of therapy is to help patients develop their social problem-solving and relationship skills. A comparison of this model of psychotherapy with other brief psychotherapies such as cognitive therapy, interpersonal therapy, and behavioral therapy reveals considerable procedural overlap in the areas addressed and the techniques used. (10) The emphasis of each approach varies, but they all assume that cognitive, behavioral, emotional, and interpersonal functions are related, and all attempt to change factors associated with the maintenance of depression.
Although the theoretical mechanisms of action of these approaches are not supported in practice, (10) brief psychotherapies of proven effectiveness in the treatment of depression share a number of clinical characteristics. (14) Each conceptualizes an individual patient's problems and shares the model of this conceptualization with the patient, involves the rational use of techniques in a logical sequence, emphasizes the development of skills that can be transferred to situations outside of the therapy sessions, and attributes changes to the patient's efforts.
If a brief psychotherapy has these characteristics and has demonstrated efficacy in a randomized, controlled trial, the choice of approach will primarily depend on the availability of a competent therapist. Competency is defined by the therapist's ability to use appropriate techniques skillfully and by his or her personal qualities (which affect the therapeutic alliance with the patient). Research has demonstrated a significant correlation between a therapist's competency and the outcome of patients. (6) In the treatment of chronic depression, a therapist's expertise may account for 30 percent of the variance in outcome and for significant differences in the rate of dropping out of therapy. The therapist's adherence to the manual for a given form of psychotherapy is also a critical component of effective treatment. (15)
The results of Keller et al. (8) and Paykel et al. (13) suggest that the combination of optimal doses of antidepressant drugs with 12 to 20 sessions of competently delivered brief psychotherapy may significantly improve the immediate and long-term prognosis of patients with chronic depression. On the basis of current knowledge, the combined treatment may be of particular benefit to patients with chronic severe depression or those who have had only a partial remission when treated with antidepressant drugs alone. In such patients, the balance of evidence suggests that combined therapy has an additive effect. (8,13) Future research needs to clarify which patients at risk for chronic depression will benefit more from combined therapy than from single therapy and to identify the key elements of the psychotherapy. The more intensive combined-treatment approach can then be reserved for those who are most likely to benefit. As the key elements of psychotherapy become better understood, it may be possible to develop a briefer therapeutic approach that will be easier to deliver in general clinical settings.
Jan Scott, M.D.
Gartnavel Royal Hospital
Glasgow G12 0XH, Scotland