Evidence-based psychotherapy for treatment-resistant depression

Introduction

There is strong evidence from a large number of studies that several psychotherapies are as effective for depression as pharmacotherapy ( ). Moreover, a combined approach employing both psychotherapy and pharmacotherapy typically provides better outcomes than either treatment alone ( ). Yet there has been limited research on psychotherapies for treatment-resistant depression (TRD), and categorization systems for TRD rarely have included psychotherapy, despite its potential value in reducing symptoms and in directly addressing many of the common problems in TRD. As this chapter illustrates, psychotherapies can treat inherent TRD difficulties such as demoralization, hopelessness, complicated grief, interpersonal conflicts and deficits, behavioral deactivation and inertia, and entrenched low self-esteem. The lack of attention to psychotherapy for TRD may be due, in part, to the concept of treatment resistance having developed within psychopharmacology, which narrowly defined it as failure to respond to antidepressant medications.

We begin this chapter with a brief review of treatment guidelines and metaanalyses that support use of psychotherapy for depression in general before turning to evidence for the effectiveness of psychotherapy in TRD. After capsule summaries of several commonly used psychotherapies and their application for depression that has not responded to previous treatments, we propose possible criteria for the adequacy of a psychotherapy trial for TRD.

Effectiveness of psychotherapy for depression

Treatment guidelines of the and the recommend several evidence-based psychotherapies for depression ( Table 25.1 ).

Effectiveness of psychotherapy for TRD

The overall findings of randomized, controlled trials of psychotherapy for TRD have been examined in systematic reviews and metaanalyses ( ; ; ). Drawing from these analyses and from our literature search, we summarize the current evidence base for psychotherapy for TRD in Table 25.2 .

In a metaanalysis of multiple psychotherapies for TRD, examined seven different approaches in 21 trials. Because they included 10 studies of chronic depression which may have included patients who did not meet stated criteria for TRD, the results are not specific to depression refractory to antidepressant medication. Also, definitions of TRD, and of comparators such as treatment as usual (TAU), varied from trial to trial. Nevertheless, this metaanalysis reported a moderate overall effect size of 0.42 for addition of psychotherapy to treatment as usual (TAU) compared to TAU alone. The most frequently studied psychotherapy in this metaanalysis was CBT ( N = 7). All studies of CBT were performed with patients who met criteria for TRD. The relative effects of the different therapies were not reported.

A separate metaanalysis of CBT for TRD included 6 randomized controlled trials with a total of 847 participants ( ). Four of the studies used standard CBT or a variant tailored to treatment-resistant depression, while two investigations utilized mindfulness-based CBT (MCBT). The blending of approaches makes this analysis difficult to interpret. However, the results favored CBT compared to a control group (most commonly TAU). The pooled standard mean difference was − 0.42, indicating that CBT was superior in reducing depression symptoms immediately after intervention. Where remission data were reported, CBT had a significantly higher remission rate (25.8%) than the control condition (14.2%).

Among studies of standard CBT or CBT tailored for TRD ( ; ; ; ; ; ; ), the largest investigation was the CoBalT trial ( ) ( N = 469)—a comparison of CBT plus TAU versus TAU alone in primary care that found a robust advantage for CBT. CBT response rates more than doubled (46.1%) those of TAU (21.6%). A smaller trial of rumination-focused CBT ( ) also found significantly better outcome in CBT than TAU. One study of different treatment formats found that individual CBT, but not group CBT, led to significantly better improvement in TRD than TAU ( ). Taken together, studies of CBT for TRD indicate that this widely used psychotherapy is an effective intervention for depression resistant to antidepressant medication.

Although interpersonal psychotherapy (IPT) has been studied extensively for MDD ( ), only one RCT has tested IPT specifically for TRD. recruited 40 adults with TRD in a tertiary care setting in Brazil and randomly assigned them to adjunctive IPT ( n = 17) in addition to pharmacotherapy (TAU), or to TAU alone ( n = 23). The definition of TRD was modest: “failure to respond to one antidepressant medication in adequate dose [equivalent of amitriptyline ≥ 75 mg] and duration [≥ 4 weeks].” In a study the authors acknowledge was underpowered, both groups significantly improved over time (IPT + TAU, d = 0.93; TAU, d = 0.73), without significant between-group differences in ratings on the Hamilton Rating Scale for Depression. Response (IPT + TAU = 35.5%; TAU = 22.2%) and remission (IPT + TAU = 28.6%; TAU = 16.7%) rates also did not significantly differ.

Another approach to assessing the value of IPT for TRD is to consider the related entity of persistent depressive disorder. Patients with this condition report deeply engrained symptoms and outlook ( ), and many, if not most, prove hard to treat and thus may qualify for TRD ( ). Because IPT was originally designed to address a current life crisis in acute major depression, Markowitz and associates developed an adaptation (IPT-D) to treat what DSM-IV then termed dysthymic disorder ( ). IPT-D lowered symptoms in a randomized trial of patients with “pure” DSM-IV dysthymic disorder (i.e., with chronic mild but not “double” depression) ( ), but fared less well than sertraline or combined IPT + sertraline, and roughly as well as an active brief supportive therapy comparator. This outcome supports a conclusion that many TRD patients are most likely to benefit from the combination of a vigorous pharmacotherapy trial in conjunction with an evidence-based psychotherapy ( ).

Brief psychodynamic psychotherapy has been studied in one trial for TRD. compared the effectiveness of Intensive Short-Term Dynamic Psychotherapy (ISTDP) ( ) with TAU in 60 patients whose depression did not remit after at least one antidepressant course. Among the participants who enrolled in the study, at least 34% had failed two or more pharmacotherapy trials from two distinct antidepressant medication classes for the current depressive episode. After a maximum 20-session course of treatment, analyses showed that change in depressive symptoms over time was significantly greater in the ISTDP group than in TAU. Relative to TAU, patients who received ISTDP were significantly more likely at the 6-month follow-up to have remitted (36.0% vs 3.7%) or partially remitted (48.0% vs 18.5%).

Long-term psychoanalytic treatment also has been investigated for TRD. randomly assigned 129 primary care patients either to long-term psychoanalytic psychotherapy plus TAU or to TAU alone. Treatment lasted up to 18 months. Treatment resistance was defined as having two failed treatment attempts, one of which must have been an antidepressant medication and the other was either an antidepressant medication or a psychological intervention. Remission rates were low in both conditions at the end of treatment (9.4% for those receiving psychodynamic treatment vs 6.5% for those in TAU only), as well as at a 42-month follow-up (14.9% vs 4.4%). Partial remission rates did not significantly differ at the end of treatment (32.1% vs 23.9%) but did favor psychoanalytic treatment at 24-month (38.8% vs 19.2%) and 42-month (30.0% vs 4.4%) follow-up assessments. These authors suggest that long-term psychoanalytic psychotherapy may be useful in improving the long-term outcome of treatment-resistant depression and that end-of-treatment evaluations or short follow-ups may miss the emergence of delayed therapeutic benefit. One additional study has been conducted on long-term psychoanalytic therapy for long-standing depression ( ), but did not specifically define TRD or require it for inclusion.

We found no randomized, controlled trials of problem-solving therapy (PST) or supportive therapy (SP) for TRD. Although SP was included in the only metaanalysis ( ) on psychotherapy effectiveness for TRD, the results should be interpreted with caution because study inclusion criteria required chronic depression, not TRD. In the REVAMP trial ( ), patients with chronic depression (defined as having MDD plus persistent depressive symptoms for more than 2 years) were randomized to either receive 12 weeks of continued pharmacotherapy plus CBASP, continued pharmacotherapy plus SP, or continued pharmacotherapy alone. Outcomes did not differ between the two psychotherapy options or medication management alone. Another RCT ( ) compared CBASP and SP in patients with early-onset (before age 21) chronic depression who were not taking antidepressant medication. Of note, most participants expressed a strong preference for psychotherapy over medication. Patients receiving CBASP reported significantly less depressive symptoms than those in SP at the end of the acute phase; however, the actual differences were quite small and barely reached statistical significance. Both CBASP and SP led to significant improvements in depressive symptoms and quality of life.

There have been three RCTs of mindfulness-based cognitive therapy (MBCT) for TRD ( ; ; ). A study of 43 patients nonresponsive to antidepressant medication found that depressive improvement was significantly greater for MBCT than a psychoeducational control group ( ). In a much larger study ( N = 173), reported that MBCT yielded better outcomes than a health enhancement program (physical fitness, music therapy, and nutritional counseling) in reducing depressive symptoms and improving treatment response rates, but not remission. In contrast, another trial ( ) found that MBCT plus TAU did not outperform TAU on the primary outcome measure, depressive symptoms; yet produced significantly higher remission rates than TAU alone. MBCT also performed better on measures of quality of life, mindfulness skills, self-compassion, and rumination. The overall results of these three RCTS of MBCT indicate a positive benefit for this form of psychotherapy for TRD.