As noted above, efforts to achieve full remission and return of function have encompassed the evaluation of combination therapy in comparison with either pharmacotherapy or psychotherapy monotherapy as well as treatment sequences. The literature on the benefit of combining pharmacotherapy with psychotherapy from the outset of the treatment is relatively small in terms of randomized controlled trials. We know much less than we should about this approach to treatment on an empirical basis.
Hollon et al (
52) suggest that combined treatments may confer additive benefits because the strengths of each modality are promoted while the weaknesses of each modality are minimized. Thus, response and remission rates for combined treatment should be superior to those of either treatment modality as a monotherapy. They argue that combined treatment increases the magnitude, probability, and breadth of clinical response. Adding drug therapy to psychotherapy may bring about a more rapid relief of symptoms than psychotherapy alone, permitting the patient to participate more productively in psychotherapy (Thase ME, personal communication). Conversely, adding psychotherapy to drug therapy may increase medication adherence, decrease the presence and risk of residual symptoms following drug discontinuation, and facilitate the patient’s development of healthy coping skills (
53).
Thase has argued that combination treatment as a general approach for the treatment of unipolar depression has yet to receive adequate empirical support. While the Agency for Health Care Policy and Research guideline supports the use of combined treatments for depressive disorders (
54). Thase and Howland believe it is best indicated for patients with severe, refractory, or incapacitating mood and anxiety disorders (
55). Below, we review the relatively small number of randomized controlled trials in the English language literature that test the relative efficacy of monotherapies and poly-therapies for depression.
Comparing monotherapy and polytherapy
The study by Klerman et al in 1974 examined the effects of 8 months of psychotherapy in comparison with continued pharmacotherapy in 150 depressed women who had been receiving amitriptyline therapy for 4 to 6 weeks (
26). Patients then received weekly IPT, medication, combination IPT and medication, or placebo and no therapy. Relapse rates were highest for patients receiving placebo alone (36%). Relapse rates in the other three active treatment groups were 12% on medication alone, 16.7% on IPT alone, and 12.5% on combined IPT and medication. This was one of the first controlled trials reported in the literature examining the protective capacity of psychotherapy.
The first combined treatment trial of cognitive therapy was conducted by Blackburn and colleagues in Scotland in 1981 (
56). They compared CT, tricyclic antidepressant (TCA) therapy, and CT combined with TCA (CT+TCA) among 64 hospital outpatients or general practice patients diagnosed with recurrent depression (≥ 1 previous episode). After 12 to 20 weeks of acute treatment, among the hospital outpatients, response rates (50% reduction in the Hamilton Rating Scale for Depression [HRSD]) suggested that CT was minimally more effective than TCA, and CT+TCA was more effective than monotherapy. For general practice patients, response rates were equivalent for the CT and CT+TCA groups, but significantly less for the TCA group. In a follow-up report, Blackburn et al (
57) reported that TCA was less effective than CT or CT+TCA for sustaining remission in both the hospital outpatient and general practice groups. They note that TCA alone may have been less effective than the two other conditions because of poor medication adherence; plasma levels were not monitored during the trial. Two years of naturalistic follow-up revealed that no patients receiving CT+TCA relapsed during the first 6 months of follow-up, compared with 30% in the TCA group and 6% in the CT group. Despite a small sample size, Blackburn et al’s results suggested to many that combination treatment may bring about the greatest change and improvement among depressed individuals (
58).
Our group has examined the efficacy of maintenance medication and IPT in preventing recurrences (
29). The Pittsburgh Study of Maintenance Therapies in Recurrent Depression contrasted IPT-M with maintenance pharmacotherapy (imipramine [IMP]), combination pharmacotherapy–psychotherapy, and a control condition (placebo and no therapy) over a period of 3 years in depressed patients who had clear histories of recurrent depression (at least three episodes; sample mean was seven episodes) and had been treated acutely with a combination of IPT and IMP. Active medication provided the best prophylaxis, with or without IPT-M. No advantage was observed for the combination; however, survival time without a new episode of major depression following discontinuation of medication was significantly and positively related to monthly IPT-M alone or with a placebo tablet.
We conducted a similar placebo-controlled study of maintenance pharmacotherapy and psychotherapy (IPT) in 180 geriatric patients with nonpsychotic unipolar major depression (
59). Patients were treated acutely with nortriptyline (NTP) and IPT. After 16 weeks of stabilized depression scores, patients were randomly assigned to one of four maintenance therapy conditions: (i) medication clinic plus NTP; (ii) medication clinic plus placebo; (iii) IPT-M plus NTP; or (iv) IPT-M plus placebo. Survival analyses suggest that maintenance NTP and IPT, together and singly, is superior to medication clinic visits and no pharmacotherapy in preventing or delaying a depressive recurrence. Patients assigned to the combined treatment condition had the best outcome, with 80% remaining depression-free during the 3-year maintenance period.
A 1997 analysis involving patients from several studies conducted at Western Psychiatric Institute and Clinic (
60) revealed that, among 595 patients experiencing a unipolar major depressive episode, for the more severely depressed patients, remission rates (HRSD <7 for 4 weeks) were higher for those receiving concurrent IPT and antidepressant pharmacotherapy with IMP than were remission rates for CT or IPT alone (43% versus 25%, P = 0.001). For the less severely ill, combination treatment had no additive effect.
Keller et al (
5) demonstrated the superiority of combination treatment among 681 patients with chronic depression (episode exceeds 2 years). In this trial, 85% of patients treated with combined CBASP and nefazadone (CBASP+NFZ) experienced a response during acutephase treatment compared with 55% of patients treated only with NFZ and 52% of patients treated only with CBASP (
P = 0.001). Despite impressive response rates after 12 weeks, many patients experienced residual symptoms (
5).
Results from one study are less than definitive concerning the efficacy of combination treatment. Hollon et al (
52) compared CT and IMP as mono-therapies with combined CT and IMP among 107 patients (only 64 completed the study) with major depression. They found no significant differences in acute-phase response rates and no significant differences in full remission rates, although there was a trend among individuals (who completed the study) receiving combined treatment (75%) to reach and sustain remission more frequently than individuals receiving monotherapy (50% CT, 56% IMP). For the 64 patients who completed the study, Evans et al (
61) report no significant differences at 2-year follow-up.