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Combination Psychotherapy and Antidepressant Medication Treatment for Depression: For Whom, When, and How W. Edward Craighead1,2 and Boadie W. Dunlop1 1 Department of Psychiatry and Behavioral Sciences and 2 Department of Psychology, Emory University, Atlanta, Georgia 30322; email: [email protected], [email protected]
Annu. Rev. Psychol. 2014. 65:26.1–26.34
Keywords
The Annual Review of Psychology is online at http://psych.annualreviews.org
major depressive disorder, CBT, antidepressant medications, combination treatment, mechanisms of therapeutic change, neurobiology of depression change
This article’s doi: 10.1146/annurev.psych.121208.131653 c 2014 by Annual Reviews. Copyright All rights reserved
Abstract Major depressive disorder (MDD) is among the most frequent and debilitating psychiatric disorders. Efficacious psychotherapy and antidepressant medications have been developed, and two-thirds of depressed patients respond to single-modality treatment; however, only about one-third of patients remit to single-modality treatments with no differential intervention outcomes. This article describes the major clinical considerations in choosing between single-modality or combination treatments for MDD. A review of the relevant literature and meta-analyses provides suggestions for which treatment to use for which patient and when each treatment or combination should be provided. The review summarizes the moderators of single-modality and combination-treatment outcomes. We describe models of mechanisms of treatment efficacy and discuss recent treatment-specific neurobiological mechanisms of change.
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Contents
Annu. Rev. Psychol. 2014.65. Downloaded from www.annualreviews.org by University of Otago on 10/02/13. For personal use only.
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.2 CURRENT TREATMENTS FOR MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.3 Antidepressant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.3 Psychotherapies for MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.4 TREATMENT OUTCOMES FOR MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.4 Outcome Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.4 Efficacy of Single-Modality Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.5 Concerns with Single-Modality Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.6 COMBINATION TREATMENTS FOR MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.6 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.6 Strategies for Combination Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.7 Rationale for Combination Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.7 Considerations for Interpreting Combination-Treatment Study Outcomes . . . . . . . .26.10 Limitations of Meta-Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.12 EFFICACY OF COMBINATION TREATMENTS: ACUTE EFFECTS . . . . . . . . . .26.13 Medication Alone versus Combined Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.13 Psychotherapy Alone versus Combined Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.14 Summary of Acute-Phase Combination Treatments for MDD . . . . . . . . . . . . . . . . . . . .26.14 EFFICACY OF COMBINATION TREATMENTS: PREVENTION OF RELAPSE/RECURRENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.15 Design Issues During Maintenance-Phase Interventions . . . . . . . . . . . . . . . . . . . . . . . . . .26.15 Design Improvements for Maintenance-Phase Interventions . . . . . . . . . . . . . . . . . . . . . .26.16 Mechanisms of Combination Relapse Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.17 Summary of Maintenance-Phase Combination Treatments for MDD . . . . . . . . . . . . .26.18 IMPROVING APPLICATIONS OF COMBINATION TREATMENT . . . . . . . . . . .26.18 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.18 Moderators of Outcomes with Combination Treatment: Which Patients Need Combination Treatment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.19 FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.23 CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.24
INTRODUCTION Major depressive disorder (MDD) is among the most prevalent and debilitating of psychiatric problems affecting about 1 in 6 women and 1 in 10 men over the life span (Kessler et al. 2005). MDD negatively impacts an individual’s quality of life and produces impairments in role functioning (Wells et al. 1989). MDD is a leading cause of family dysfunction and death from suicide (Arato´ et al. 1988, Rich et al. 1988), and it contributes to increased risk of morbidity and mortality from diabetes, cardiovascular disease, and stroke (Barth et al. 2005, Egede 2006, Loeb et al. 2012). MDD reduces productivity and is a major health expense, thereby becoming a societal and economic problem. It is the fourth leading cause of disability worldwide, and by 2020 it is projected to be second only to ischemic heart disease as a cause of disability (Murray & Lopez 1997). By 2030, MDD is expected to be the largest worldwide contributor to disease burden (World Health Organ. 2004). 26.2
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Although highly variable, the average age of onset for initial depressive episodes is late adolescence or emerging adulthood; the majority of individuals who will experience MDD will have done so by early adulthood (Hankin & Abramson 1999, Kessler et al. 2005). MDD is also a recurrent disorder, and it frequently becomes a chronic problem. For example, Lewinsohn et al. (1999; see also Fergusson & Woodward 2002) found that ∼45% of adolescents who suffer an episode of MDD experience a recurrence by age 24, and Rohde and colleagues (2012) found that cumulatively among the same group ∼50% had a subsequent depressive episode by age 30. Episodes in which full criteria for MDD are present continuously for 2 years or more are considered chronic; about 30% of depressed individuals in the community and 50% of those who are in treatment suffer from chronic depression (Klein & Black 2013, Mueller et al. 1999, Waraich et al. 2004). The duration of MDD episodes is also highly variable; estimates of the average time to spontaneous recovery range from 5 months to 13 months (Angst et al. 2003, Lewinsohn et al. 1999). Risk factors for the development of MDD include positive family history for a mood disorder, early life trauma, prior anxiety disorders, and substance abuse (see Ritschel et al. 2013). MDD as defined by current nosologies [e.g., Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; APA 2013)] is a heterogeneous syndrome, with multiple likely etiologies and pathological forms. As shall become apparent, this heterogeneity contributes strongly to the variable response to treatment observed in clinical trials of treatments for depression.
CURRENT TREATMENTS FOR MDD Antidepressant medications (ADM) and psychotherapies are the two primary outpatient treatments for MDD. Various forms of stimulation treatments (e.g., transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, electroconvulsive therapy) exist for patients who do not respond to ADM or psychotherapy, but stimulation treatments are not well studied as forms of combination treatment and are not discussed further in this review (Kennedy & Giacobbe 2007).
Antidepressant Medications Although the first antidepressants were identified through serendipitous discovery, more recent developments in pharmacology are driven by current understandings of the biological functions of neurotransmitter systems within the central nervous system. There are several ADM classes, which are categorized by their structural or functional relationships. No antidepressant class or individual medication has consistently proven to be superior to others for the treatment of MDD (APA 2010). Thus, recommended first-line ADM treatments for MDD are based primarily on tolerability and safety rather than on efficacy. Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, or mirtazapine are considered first-line antidepressants (APA 2010). Owing to their greater health risks, tricyclic antidepressants and monoamine oxidase inhibitors are generally used only after first-line agents fail. Treatment with ADM should be sustained for at least 4–8 weeks prior to determining efficacy. The goal of treatment is essentially to eliminate depressive symptoms; dosage is increased every 2–4 weeks (unless side effects prevent further increases) until either that goal is achieved or the FDA maximum recommended dose is reached (APA 2010). DSM-5 (APA 2013) identifies several clinical subtypes of MDD, including those characterized by melancholic, atypical, or psychotic features. Standard of care for MDD with psychotic features (i.e., episodes characterized by hallucinations, delusions, or catatonia) includes medication treatment with antipsychotics or electroconvulsive therapy. Beyond depression with psychotic www.annualreviews.org • Combination Treatment of MDD
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features, there currently are no reliable clinical or biological measures to match individual patients to specific treatments to maximize outcomes.
Psychotherapies for MDD
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Psychological treatments for MDD are derived from the theoretical constructs about the nature of the disorder and the psychological factors that permit its persistence. Evidence-based psychotherapies for the acute treatment of MDD include Beck’s eponymous cognitive-behavioral therapy (CBT; Beck et al. 1979), interpersonal therapy (IPT; Klerman et al. 1984), and behavioral activation (BA; Jacobson et al. 2001). Other forms of psychotherapy with some support for efficacy in MDD include behavioral marital therapy (Beach et al. 1990), problem-solving focused therapy (e.g., Nezu et al. 2013), and short-term psychodynamic psychotherapy (Driessen et al. 2010). All these therapies are short term, educational, and fairly directive, and they typically comprise 16–20 sessions over 12–16 weeks. Although CBT has been more extensively evaluated and is discussed more thoroughly in this article, there is minimal empirical evidence to support the choice of one treatment over another; therefore, the decision of which treatment to use is typically based on therapist competence, therapist availability, marital status, and patient preference.
TREATMENT OUTCOMES FOR MDD Outcome Definitions The most widely accepted outcome target in the treatment of MDD is remission, in which a patient has returned to the pre-episode level of functioning and has no or only a few mild and infrequently experienced residual depressive symptoms. In clinical trials, remission is defined most often as a rating scale score below a certain threshold, most commonly a Hamilton Depression Rating Scale (HDRS; Hamilton 1960) 17-item total score of ≤7. Some studies use alternative ˚ rating scales, such as the Montgomery Asberg Depression Rating Scale (MADRS; Montgomery ˚ & Asberg 1979), the Quick Inventory of Depressive Symptoms (QIDS; Rush et al. 2003), or the Beck Depression Inventory-II (BDI-II, or a self-report measure; Beck et al. 1996). One important caveat regarding the clinical trial definitions of remission is that these cutoffs were arrived at by consensus (Frank et al. 1991); likewise, subsequent analyses suggest that these thresholds may not accurately or adequately reflect functional recovery (Dunlop et al. 2012b, Zimmerman et al. 2012). Another commonly used outcome measure is response, typically defined as a 50% or more decrease from the baseline score on a rating scale. Response reflects clear improvement with treatment, but it does not imply that full remission has been achieved. Response short of remission is generally an unsatisfactory outcome because the presence of ongoing significant symptoms at the end of treatment is the strongest predictor of future depressive episodes ( Judd et al. 2000, Paykel et al. 1995). A return to a full depressive episode within two months of the end of an episode is termed a relapse, whereas such an episode occurring more than two months after remission or response is consider a recurrence, denoting a new major depressive episode. Consequently, maintaining remission for at least two months is referred to as recovery (Frank et al. 1991). The validity of these distinctions has been questioned (Rush et al. 2006), but they are noted here because they are important concepts for interpreting treatment and relapse-prevention trials discussed below.
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Efficacy of Single-Modality Treatments Only about one-third of individuals with MDD seek and receive treatment of any type, and members of minority groups are particularly unlikely to seek or receive depression treatment (Gonzalez et al. 2010). Among those who do receive treatment, evidence-based psychotherapies and ADM are equally efficacious, on average (APA 2013, Cuijpers et al. 2008, Gelenberg et al. 2010, Khan et al. 2012, Spielmans et al. 2011). The data for head-to-head trials of psychotherapy alone versus medication alone are not included in this review; they have been extensively reviewed by others (Cuijpers et al. 2008, Spielmans et al. 2011). The outcome data from individual clinical trials of treatments for MDD are highly variable. Nevertheless, reviews and meta-analyses consistently conclude that regardless of the form of treatment about two-thirds of all patients with MDD will show a positive response to an active treatment in a clinical trial, but only 30–40% of treated patients with MDD will achieve remission (e.g., DeRubeis et al. 2005b). The overwhelming majority of clinical trials for MDD involve strict inclusion and exclusion criteria that may reduce generalizability of the results to clinical practice. Four common exclusions used in studies of adults with MDD are (a) presence of psychotic symptoms; (b) presence of clinically significant suicidal ideation; (c) mild severity, typically identified as a screening-visit score below a threshold on a depression rating scale; and (d ) a medical illness that may interfere with treatment or impair response to treatment. Many studies also exclude individuals with psychiatric comorbidities, such as concurrent substance abuse, eating disorders, and certain anxiety disorders (e.g., obsessive compulsive disorder). Community, nonresearch protocol patients seeking treatment often fall into one or more of these exclusion categories, which may limit extension of these research findings to treatment selection in routine clinical care. Many measured and unmeasured factors contribute to variability in results between trials, and these are discussed in greater detail below. Although considered in the most sophisticated meta-analyses, these preceding factors severely limit the conclusions that can be reached and the clinical practice implications derived from those reports. The conclusions that investigators do reach are further limited by the small sample sizes in most of the individual clinical trials and the redundant inclusion of those same small trials in extant meta-analytic studies. More recently, clinical scientists have shown increasing concern about the degree of placebo response in clinical trials, an effect that may lead to an exaggerated expectation of benefit in community clinical settings (Dunlop et al. 2012d). Placebo response identified in clinical trials is a multifaceted phenomenon, capturing elements of expectation, time and attention, spontaneous recovery, and regression to the mean effects (Frank & Frank 1991). Patients in clinical trials, particularly those evaluating ADM versus placebo, are provided substantially more contact with a treatment team than is observed in routine clinical practice, thus patients assigned to placebo in clinical trials may experience substantial benefit. For psychotherapy treatments, competence of treatment delivery may be greater in clinical trials, which employ specifically trained therapists, than the level of clinical competence provided in community settings. Thus, for both ADM and psychotherapeutic treatments there are significant concerns regarding the generalizability of clinical trial results. In summary, the aggregated data reported in the higher-quality meta-analytic studies and qualitative reviews support a consistent conclusion. Namely, single-modality treatments for MDD produce essentially identical outcomes regardless of the treatment given, though some individuals benefit specifically from one form of treatment and not another (McGrath et al. 2013). Although two-thirds of patients show a clinical response, only about one-third of treated MDD patients achieve remission.
www.annualreviews.org • Combination Treatment of MDD
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Concerns with Single-Modality Treatments
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Using ADM and psychotherapy as monotherapies can present significant problems and limitations. For example, each of the ADMs has side effects, and these frequently affect the willingness of patients to complete a course of the medicine. The medications can be expensive, especially when they must be maintained over a long time period, such as in the treatment of chronic depression. Both these factors as well as other variables (e.g., patient’s disorganization) result in lower-thaneffective adherence to prescribed medical regimens. Furthermore, up to 20% of patients taking ADM for two years will experience a depressive recurrence (Hansen et al. 2008, Kocsis et al. 2007), a phenomenon known as depressive recurrence on antidepressant therapy (DRAT) or “poop out” (Dunlop 2013). Finally, even very effective ADM have a high relapse rate, exceeding 50%, even if a medication is taken as a maintenance treatment for 12–15 months (Hollon et al. 2005a). Likewise, there are issues related to delivery of short-term evidence-based psychotherapies. For example, when a psychotherapy does not produce a remission, patients frequently experience a resulting demoralization and may be unlikely to seek further treatment; thus, the MDD continues and likely worsens. In contrast to the fairly common aphorism, “at least psychotherapy doesn’t hurt patients,” the demoralized patient does suffer as a result of ineffective treatment (Craighead et al. 2013a). Even though a clinical trial may show that a specific treatment (e.g., CBT or IPT) is efficacious for MDD, these evidence-based therapies are not very well disseminated, thus limiting the availability of evidence-based treatments in much of the United States. Limited dissemination also leads many therapists to claims that they conduct evidence-based therapy, but in fact, they may have had very minimal, if any, formal training in the therapy that is purportedly being delivered. Consequently, psychotherapy may be incompetently delivered (e.g., CBT; DeRubeis et al. 2005b), resulting in poorer clinical outcomes than reported in clinical trials. In a recent study, 10–15% of community psychotherapy providers produced negative outcomes (actual deterioration) among their patients (Kraus et al. 2011). Evidence-based therapies need to be disseminated and delivered in a manner functionally equivalent to those evaluated in the clinical trials that support their effectiveness. For example, after reviewing the relevant literature, the National Health Service in England adopted CBT as the first-line treatment for MDD. They have invested more than £400 million to train 6,000 therapists who will be competent in CBT (Cent. Ment. Health 2012). The greatest concern with all the monotherapies (both ADM and psychotherapies) was previously summarized; namely, only 30–40% of treated MDD patients remit with a monotherapy when treatment is offered under ideal conditions with competent professionals. Despite these concerns, each approach to treatment has its positive aspects. For example, ADM generally produce faster treatment effects (Keller et al. 2000), and psychotherapy (at least CBT) seems to confer more enduring maintenance of positive outcomes (Craighead et al. 2007, Hollon et al. 2005a). As we discuss below, the positive effects of the two treatments have influenced researchers and practitioners to consider treatment combinations in an effort to enhance their overall clinical effectiveness.
COMBINATION TREATMENTS FOR MDD Overview As noted above, failure to achieve full recovery from MDD is the strongest predictor of a future, recurrent episode, so improvement in short-term treatment outcomes and prevention of depressive relapses and recurrences are greatly needed. Over the past 30 years, many studies have examined the 26.6
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efficacy of combined medication and psychotherapy in the acute treatment of MDD and the effect of combination therapy on maintenance of wellness. Outcomes from combination versus singlemodality treatment trials are mixed, although the overall weight of evidence supports combination as superior (see Table 1). However, a key clinical challenge that remains to be solved is to identify which individuals require combination treatment to achieve and maintain recovery from MDD. The remainder of this article summarizes the state of knowledge about the efficacy of combination treatment for MDD, identifies the limitations of the current knowledge base, and suggests directions for future research. The following questions are addressed: Does combination treatment for MDD produce superior short-term outcomes relative to single treatments? Do combination treatments for MDD produce protection against relapse/recurrence? Should combination treatment be administered concurrently from the beginning of treatment, sequentially if response to the initial treatment is inadequate, or in combination after a trial of monotherapy? Of the large clinical trials evaluating combination treatments for MDD, which important limitations affect the internal validity and generalizability of results to impact clinical care of depressed patients?
Strategies for Combination Treatments Practitioners can utilize three strategies to employ monotherapies in combination to treat MDD. First, the treatments may be employed concurrently from the beginning of treatment. Second, the treatments may be employed sequentially: Either ADM or psychotherapy is offered first, and the other is added to augment the first if the monotherapy fails or is only partially successful. Finally, ADM and therapy may be offered within stepped treatment, which when conceptually driven is referred to as clinical staging (see McGorry et al. 2010). Within the clinical staging model, a combination of decisions regarding the patient’s stage of the disorder is used to guide the treatment process. Clinical staging occurs most frequently when ADM is used initially to treat an individual’s debilitating depressive symptoms; the treatment effects may be fairly rapid, and then a psychosocial intervention is added to address the remaining symptoms and problems in daily life (e.g., marital conflict, cognitive distortions, social interactions). A clear demonstration of this process occurs when deep brain stimulation (Ramirez et al. 2013) alleviates a patient’s most severe depressive symptoms, but some combination of evidence-based therapy (e.g., behavioral activation and dialectical behavior therapy) is needed to teach living skills to the chronically depressed patient. Below, we note that data regarding neural impacts of clinical interventions auger for a clinical staging approach to combination treatments.
Rationale for Combination Treatments There are at least three different conceptualizations of the mechanisms by which combined treatment may produce better outcomes than individual treatment. Additive model. At a study level, some individuals remit only with medication, and others remit only with psychotherapy (in addition to those who will remit to neither and those who will remit to either) (Schatzberg et al. 2005). Thus, by simple addition, the proportion of remitters in a combined-therapy condition will be greater than the proportion of those treated with a monotherapy because some of those who will not have remitted to one of the monotherapies will have remitted to the other monotherapy. This effect produces higher rates of remission in the combined treatment. At an individual level, additive effects may be important, particularly for the goal of achieving remission. One of the monotherapies may produce benefit but leave certain symptoms unaddressed (i.e., a response but not a remission). One example of this additive model www.annualreviews.org • Combination Treatment of MDD
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Design
Randomize from start
Randomize from start
Randomize from start
Randomize from start
Keller et al. (2000)
de Jonghe et al. (2001)
Craighead
de Jonghe et al. (2004)
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Inpatients with MDE as part of MDD or BP II HDRS 17: ≥16
Consecutive outpatients with MDD HDRS 17: 12–24 36
15
18
35
23.5
18.1
20.4
26.9 (24item)
ADM (61) ADM + IPT (63)
SPSP (106) SPSP + ADM (85)
ADM (57) ADM + SPSP (72)
ADM (220) CBASP (216) ADM + CBASP (226)
Arms (N)
5
24
24
12
Duration (weeks)
Sertraline, amitriptyline, or amitriptylineN-oxide
Various
Fluoxetine, amitriptyline, moclobemide, sequentially
Nefazodone
Medication
ADM: 15% ADM + IPT: 16%
SPSP: 29% SPSP + ADM: 23%
ADM: 42% ADM + SPSP: 18%
ADM: 26% CBASP: 24% ADM + CBASP: 21%
Dropouts
ADM: 22.8% ADM + SPSP: 43.1% p = 0.02
SPSP: 32.1% SPSP + ADM: 42.4% p = 0.14
ADM: 34% ADM + IPT: 49% p = 0.105
HDRS
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Combination Psychotherapy and Antidepressant Medication Treatment for Depression: For Whom, When, and How W. Edward Craighead1,2 and Boadie W. Dunlop1 1 Department of Psychiatry and Behavioral Sciences and 2 Department of Psychology, Emory University, Atlanta, Georgia 30322; email: [email protected], [email protected]
Annu. Rev. Psychol. 2014. 65:26.1–26.34
Keywords
The Annual Review of Psychology is online at http://psych.annualreviews.org
major depressive disorder, CBT, antidepressant medications, combination treatment, mechanisms of therapeutic change, neurobiology of depression change
This article’s doi: 10.1146/annurev.psych.121208.131653 c 2014 by Annual Reviews. Copyright All rights reserved
Abstract Major depressive disorder (MDD) is among the most frequent and debilitating psychiatric disorders. Efficacious psychotherapy and antidepressant medications have been developed, and two-thirds of depressed patients respond to single-modality treatment; however, only about one-third of patients remit to single-modality treatments with no differential intervention outcomes. This article describes the major clinical considerations in choosing between single-modality or combination treatments for MDD. A review of the relevant literature and meta-analyses provides suggestions for which treatment to use for which patient and when each treatment or combination should be provided. The review summarizes the moderators of single-modality and combination-treatment outcomes. We describe models of mechanisms of treatment efficacy and discuss recent treatment-specific neurobiological mechanisms of change.
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Contents
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INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.2 CURRENT TREATMENTS FOR MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.3 Antidepressant Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.3 Psychotherapies for MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.4 TREATMENT OUTCOMES FOR MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.4 Outcome Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.4 Efficacy of Single-Modality Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.5 Concerns with Single-Modality Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.6 COMBINATION TREATMENTS FOR MDD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.6 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.6 Strategies for Combination Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.7 Rationale for Combination Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26.7 Considerations for Interpreting Combination-Treatment Study Outcomes . . . . . . . .26.10 Limitations of Meta-Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.12 EFFICACY OF COMBINATION TREATMENTS: ACUTE EFFECTS . . . . . . . . . .26.13 Medication Alone versus Combined Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.13 Psychotherapy Alone versus Combined Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.14 Summary of Acute-Phase Combination Treatments for MDD . . . . . . . . . . . . . . . . . . . .26.14 EFFICACY OF COMBINATION TREATMENTS: PREVENTION OF RELAPSE/RECURRENCE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.15 Design Issues During Maintenance-Phase Interventions . . . . . . . . . . . . . . . . . . . . . . . . . .26.15 Design Improvements for Maintenance-Phase Interventions . . . . . . . . . . . . . . . . . . . . . .26.16 Mechanisms of Combination Relapse Prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.17 Summary of Maintenance-Phase Combination Treatments for MDD . . . . . . . . . . . . .26.18 IMPROVING APPLICATIONS OF COMBINATION TREATMENT . . . . . . . . . . .26.18 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.18 Moderators of Outcomes with Combination Treatment: Which Patients Need Combination Treatment? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.19 FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.23 CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .26.24
INTRODUCTION Major depressive disorder (MDD) is among the most prevalent and debilitating of psychiatric problems affecting about 1 in 6 women and 1 in 10 men over the life span (Kessler et al. 2005). MDD negatively impacts an individual’s quality of life and produces impairments in role functioning (Wells et al. 1989). MDD is a leading cause of family dysfunction and death from suicide (Arato´ et al. 1988, Rich et al. 1988), and it contributes to increased risk of morbidity and mortality from diabetes, cardiovascular disease, and stroke (Barth et al. 2005, Egede 2006, Loeb et al. 2012). MDD reduces productivity and is a major health expense, thereby becoming a societal and economic problem. It is the fourth leading cause of disability worldwide, and by 2020 it is projected to be second only to ischemic heart disease as a cause of disability (Murray & Lopez 1997). By 2030, MDD is expected to be the largest worldwide contributor to disease burden (World Health Organ. 2004). 26.2
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Although highly variable, the average age of onset for initial depressive episodes is late adolescence or emerging adulthood; the majority of individuals who will experience MDD will have done so by early adulthood (Hankin & Abramson 1999, Kessler et al. 2005). MDD is also a recurrent disorder, and it frequently becomes a chronic problem. For example, Lewinsohn et al. (1999; see also Fergusson & Woodward 2002) found that ∼45% of adolescents who suffer an episode of MDD experience a recurrence by age 24, and Rohde and colleagues (2012) found that cumulatively among the same group ∼50% had a subsequent depressive episode by age 30. Episodes in which full criteria for MDD are present continuously for 2 years or more are considered chronic; about 30% of depressed individuals in the community and 50% of those who are in treatment suffer from chronic depression (Klein & Black 2013, Mueller et al. 1999, Waraich et al. 2004). The duration of MDD episodes is also highly variable; estimates of the average time to spontaneous recovery range from 5 months to 13 months (Angst et al. 2003, Lewinsohn et al. 1999). Risk factors for the development of MDD include positive family history for a mood disorder, early life trauma, prior anxiety disorders, and substance abuse (see Ritschel et al. 2013). MDD as defined by current nosologies [e.g., Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; APA 2013)] is a heterogeneous syndrome, with multiple likely etiologies and pathological forms. As shall become apparent, this heterogeneity contributes strongly to the variable response to treatment observed in clinical trials of treatments for depression.
CURRENT TREATMENTS FOR MDD Antidepressant medications (ADM) and psychotherapies are the two primary outpatient treatments for MDD. Various forms of stimulation treatments (e.g., transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, electroconvulsive therapy) exist for patients who do not respond to ADM or psychotherapy, but stimulation treatments are not well studied as forms of combination treatment and are not discussed further in this review (Kennedy & Giacobbe 2007).
Antidepressant Medications Although the first antidepressants were identified through serendipitous discovery, more recent developments in pharmacology are driven by current understandings of the biological functions of neurotransmitter systems within the central nervous system. There are several ADM classes, which are categorized by their structural or functional relationships. No antidepressant class or individual medication has consistently proven to be superior to others for the treatment of MDD (APA 2010). Thus, recommended first-line ADM treatments for MDD are based primarily on tolerability and safety rather than on efficacy. Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion, or mirtazapine are considered first-line antidepressants (APA 2010). Owing to their greater health risks, tricyclic antidepressants and monoamine oxidase inhibitors are generally used only after first-line agents fail. Treatment with ADM should be sustained for at least 4–8 weeks prior to determining efficacy. The goal of treatment is essentially to eliminate depressive symptoms; dosage is increased every 2–4 weeks (unless side effects prevent further increases) until either that goal is achieved or the FDA maximum recommended dose is reached (APA 2010). DSM-5 (APA 2013) identifies several clinical subtypes of MDD, including those characterized by melancholic, atypical, or psychotic features. Standard of care for MDD with psychotic features (i.e., episodes characterized by hallucinations, delusions, or catatonia) includes medication treatment with antipsychotics or electroconvulsive therapy. Beyond depression with psychotic www.annualreviews.org • Combination Treatment of MDD
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features, there currently are no reliable clinical or biological measures to match individual patients to specific treatments to maximize outcomes.
Psychotherapies for MDD
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Psychological treatments for MDD are derived from the theoretical constructs about the nature of the disorder and the psychological factors that permit its persistence. Evidence-based psychotherapies for the acute treatment of MDD include Beck’s eponymous cognitive-behavioral therapy (CBT; Beck et al. 1979), interpersonal therapy (IPT; Klerman et al. 1984), and behavioral activation (BA; Jacobson et al. 2001). Other forms of psychotherapy with some support for efficacy in MDD include behavioral marital therapy (Beach et al. 1990), problem-solving focused therapy (e.g., Nezu et al. 2013), and short-term psychodynamic psychotherapy (Driessen et al. 2010). All these therapies are short term, educational, and fairly directive, and they typically comprise 16–20 sessions over 12–16 weeks. Although CBT has been more extensively evaluated and is discussed more thoroughly in this article, there is minimal empirical evidence to support the choice of one treatment over another; therefore, the decision of which treatment to use is typically based on therapist competence, therapist availability, marital status, and patient preference.
TREATMENT OUTCOMES FOR MDD Outcome Definitions The most widely accepted outcome target in the treatment of MDD is remission, in which a patient has returned to the pre-episode level of functioning and has no or only a few mild and infrequently experienced residual depressive symptoms. In clinical trials, remission is defined most often as a rating scale score below a certain threshold, most commonly a Hamilton Depression Rating Scale (HDRS; Hamilton 1960) 17-item total score of ≤7. Some studies use alternative ˚ rating scales, such as the Montgomery Asberg Depression Rating Scale (MADRS; Montgomery ˚ & Asberg 1979), the Quick Inventory of Depressive Symptoms (QIDS; Rush et al. 2003), or the Beck Depression Inventory-II (BDI-II, or a self-report measure; Beck et al. 1996). One important caveat regarding the clinical trial definitions of remission is that these cutoffs were arrived at by consensus (Frank et al. 1991); likewise, subsequent analyses suggest that these thresholds may not accurately or adequately reflect functional recovery (Dunlop et al. 2012b, Zimmerman et al. 2012). Another commonly used outcome measure is response, typically defined as a 50% or more decrease from the baseline score on a rating scale. Response reflects clear improvement with treatment, but it does not imply that full remission has been achieved. Response short of remission is generally an unsatisfactory outcome because the presence of ongoing significant symptoms at the end of treatment is the strongest predictor of future depressive episodes ( Judd et al. 2000, Paykel et al. 1995). A return to a full depressive episode within two months of the end of an episode is termed a relapse, whereas such an episode occurring more than two months after remission or response is consider a recurrence, denoting a new major depressive episode. Consequently, maintaining remission for at least two months is referred to as recovery (Frank et al. 1991). The validity of these distinctions has been questioned (Rush et al. 2006), but they are noted here because they are important concepts for interpreting treatment and relapse-prevention trials discussed below.
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Efficacy of Single-Modality Treatments Only about one-third of individuals with MDD seek and receive treatment of any type, and members of minority groups are particularly unlikely to seek or receive depression treatment (Gonzalez et al. 2010). Among those who do receive treatment, evidence-based psychotherapies and ADM are equally efficacious, on average (APA 2013, Cuijpers et al. 2008, Gelenberg et al. 2010, Khan et al. 2012, Spielmans et al. 2011). The data for head-to-head trials of psychotherapy alone versus medication alone are not included in this review; they have been extensively reviewed by others (Cuijpers et al. 2008, Spielmans et al. 2011). The outcome data from individual clinical trials of treatments for MDD are highly variable. Nevertheless, reviews and meta-analyses consistently conclude that regardless of the form of treatment about two-thirds of all patients with MDD will show a positive response to an active treatment in a clinical trial, but only 30–40% of treated patients with MDD will achieve remission (e.g., DeRubeis et al. 2005b). The overwhelming majority of clinical trials for MDD involve strict inclusion and exclusion criteria that may reduce generalizability of the results to clinical practice. Four common exclusions used in studies of adults with MDD are (a) presence of psychotic symptoms; (b) presence of clinically significant suicidal ideation; (c) mild severity, typically identified as a screening-visit score below a threshold on a depression rating scale; and (d ) a medical illness that may interfere with treatment or impair response to treatment. Many studies also exclude individuals with psychiatric comorbidities, such as concurrent substance abuse, eating disorders, and certain anxiety disorders (e.g., obsessive compulsive disorder). Community, nonresearch protocol patients seeking treatment often fall into one or more of these exclusion categories, which may limit extension of these research findings to treatment selection in routine clinical care. Many measured and unmeasured factors contribute to variability in results between trials, and these are discussed in greater detail below. Although considered in the most sophisticated meta-analyses, these preceding factors severely limit the conclusions that can be reached and the clinical practice implications derived from those reports. The conclusions that investigators do reach are further limited by the small sample sizes in most of the individual clinical trials and the redundant inclusion of those same small trials in extant meta-analytic studies. More recently, clinical scientists have shown increasing concern about the degree of placebo response in clinical trials, an effect that may lead to an exaggerated expectation of benefit in community clinical settings (Dunlop et al. 2012d). Placebo response identified in clinical trials is a multifaceted phenomenon, capturing elements of expectation, time and attention, spontaneous recovery, and regression to the mean effects (Frank & Frank 1991). Patients in clinical trials, particularly those evaluating ADM versus placebo, are provided substantially more contact with a treatment team than is observed in routine clinical practice, thus patients assigned to placebo in clinical trials may experience substantial benefit. For psychotherapy treatments, competence of treatment delivery may be greater in clinical trials, which employ specifically trained therapists, than the level of clinical competence provided in community settings. Thus, for both ADM and psychotherapeutic treatments there are significant concerns regarding the generalizability of clinical trial results. In summary, the aggregated data reported in the higher-quality meta-analytic studies and qualitative reviews support a consistent conclusion. Namely, single-modality treatments for MDD produce essentially identical outcomes regardless of the treatment given, though some individuals benefit specifically from one form of treatment and not another (McGrath et al. 2013). Although two-thirds of patients show a clinical response, only about one-third of treated MDD patients achieve remission.
www.annualreviews.org • Combination Treatment of MDD
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Concerns with Single-Modality Treatments
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Using ADM and psychotherapy as monotherapies can present significant problems and limitations. For example, each of the ADMs has side effects, and these frequently affect the willingness of patients to complete a course of the medicine. The medications can be expensive, especially when they must be maintained over a long time period, such as in the treatment of chronic depression. Both these factors as well as other variables (e.g., patient’s disorganization) result in lower-thaneffective adherence to prescribed medical regimens. Furthermore, up to 20% of patients taking ADM for two years will experience a depressive recurrence (Hansen et al. 2008, Kocsis et al. 2007), a phenomenon known as depressive recurrence on antidepressant therapy (DRAT) or “poop out” (Dunlop 2013). Finally, even very effective ADM have a high relapse rate, exceeding 50%, even if a medication is taken as a maintenance treatment for 12–15 months (Hollon et al. 2005a). Likewise, there are issues related to delivery of short-term evidence-based psychotherapies. For example, when a psychotherapy does not produce a remission, patients frequently experience a resulting demoralization and may be unlikely to seek further treatment; thus, the MDD continues and likely worsens. In contrast to the fairly common aphorism, “at least psychotherapy doesn’t hurt patients,” the demoralized patient does suffer as a result of ineffective treatment (Craighead et al. 2013a). Even though a clinical trial may show that a specific treatment (e.g., CBT or IPT) is efficacious for MDD, these evidence-based therapies are not very well disseminated, thus limiting the availability of evidence-based treatments in much of the United States. Limited dissemination also leads many therapists to claims that they conduct evidence-based therapy, but in fact, they may have had very minimal, if any, formal training in the therapy that is purportedly being delivered. Consequently, psychotherapy may be incompetently delivered (e.g., CBT; DeRubeis et al. 2005b), resulting in poorer clinical outcomes than reported in clinical trials. In a recent study, 10–15% of community psychotherapy providers produced negative outcomes (actual deterioration) among their patients (Kraus et al. 2011). Evidence-based therapies need to be disseminated and delivered in a manner functionally equivalent to those evaluated in the clinical trials that support their effectiveness. For example, after reviewing the relevant literature, the National Health Service in England adopted CBT as the first-line treatment for MDD. They have invested more than £400 million to train 6,000 therapists who will be competent in CBT (Cent. Ment. Health 2012). The greatest concern with all the monotherapies (both ADM and psychotherapies) was previously summarized; namely, only 30–40% of treated MDD patients remit with a monotherapy when treatment is offered under ideal conditions with competent professionals. Despite these concerns, each approach to treatment has its positive aspects. For example, ADM generally produce faster treatment effects (Keller et al. 2000), and psychotherapy (at least CBT) seems to confer more enduring maintenance of positive outcomes (Craighead et al. 2007, Hollon et al. 2005a). As we discuss below, the positive effects of the two treatments have influenced researchers and practitioners to consider treatment combinations in an effort to enhance their overall clinical effectiveness.
COMBINATION TREATMENTS FOR MDD Overview As noted above, failure to achieve full recovery from MDD is the strongest predictor of a future, recurrent episode, so improvement in short-term treatment outcomes and prevention of depressive relapses and recurrences are greatly needed. Over the past 30 years, many studies have examined the 26.6
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efficacy of combined medication and psychotherapy in the acute treatment of MDD and the effect of combination therapy on maintenance of wellness. Outcomes from combination versus singlemodality treatment trials are mixed, although the overall weight of evidence supports combination as superior (see Table 1). However, a key clinical challenge that remains to be solved is to identify which individuals require combination treatment to achieve and maintain recovery from MDD. The remainder of this article summarizes the state of knowledge about the efficacy of combination treatment for MDD, identifies the limitations of the current knowledge base, and suggests directions for future research. The following questions are addressed: Does combination treatment for MDD produce superior short-term outcomes relative to single treatments? Do combination treatments for MDD produce protection against relapse/recurrence? Should combination treatment be administered concurrently from the beginning of treatment, sequentially if response to the initial treatment is inadequate, or in combination after a trial of monotherapy? Of the large clinical trials evaluating combination treatments for MDD, which important limitations affect the internal validity and generalizability of results to impact clinical care of depressed patients?
Strategies for Combination Treatments Practitioners can utilize three strategies to employ monotherapies in combination to treat MDD. First, the treatments may be employed concurrently from the beginning of treatment. Second, the treatments may be employed sequentially: Either ADM or psychotherapy is offered first, and the other is added to augment the first if the monotherapy fails or is only partially successful. Finally, ADM and therapy may be offered within stepped treatment, which when conceptually driven is referred to as clinical staging (see McGorry et al. 2010). Within the clinical staging model, a combination of decisions regarding the patient’s stage of the disorder is used to guide the treatment process. Clinical staging occurs most frequently when ADM is used initially to treat an individual’s debilitating depressive symptoms; the treatment effects may be fairly rapid, and then a psychosocial intervention is added to address the remaining symptoms and problems in daily life (e.g., marital conflict, cognitive distortions, social interactions). A clear demonstration of this process occurs when deep brain stimulation (Ramirez et al. 2013) alleviates a patient’s most severe depressive symptoms, but some combination of evidence-based therapy (e.g., behavioral activation and dialectical behavior therapy) is needed to teach living skills to the chronically depressed patient. Below, we note that data regarding neural impacts of clinical interventions auger for a clinical staging approach to combination treatments.
Rationale for Combination Treatments There are at least three different conceptualizations of the mechanisms by which combined treatment may produce better outcomes than individual treatment. Additive model. At a study level, some individuals remit only with medication, and others remit only with psychotherapy (in addition to those who will remit to neither and those who will remit to either) (Schatzberg et al. 2005). Thus, by simple addition, the proportion of remitters in a combined-therapy condition will be greater than the proportion of those treated with a monotherapy because some of those who will not have remitted to one of the monotherapies will have remitted to the other monotherapy. This effect produces higher rates of remission in the combined treatment. At an individual level, additive effects may be important, particularly for the goal of achieving remission. One of the monotherapies may produce benefit but leave certain symptoms unaddressed (i.e., a response but not a remission). One example of this additive model www.annualreviews.org • Combination Treatment of MDD
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Design
Randomize from start
Randomize from start
Randomize from start
Randomize from start
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de Jonghe et al. (2001)
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Inpatients with MDE as part of MDD or BP II HDRS 17: ≥16
Consecutive outpatients with MDD HDRS 17: 12–24 36
15
18
35
23.5
18.1
20.4
26.9 (24item)
ADM (61) ADM + IPT (63)
SPSP (106) SPSP + ADM (85)
ADM (57) ADM + SPSP (72)
ADM (220) CBASP (216) ADM + CBASP (226)
Arms (N)
5
24
24
12
Duration (weeks)
Sertraline, amitriptyline, or amitriptylineN-oxide
Various
Fluoxetine, amitriptyline, moclobemide, sequentially
Nefazodone
Medication
ADM: 15% ADM + IPT: 16%
SPSP: 29% SPSP + ADM: 23%
ADM: 42% ADM + SPSP: 18%
ADM: 26% CBASP: 24% ADM + CBASP: 21%
Dropouts
ADM: 22.8% ADM + SPSP: 43.1% p = 0.02
SPSP: 32.1% SPSP + ADM: 42.4% p = 0.14
ADM: 34% ADM + IPT: 49% p = 0.105
HDRS
