Treatment-resistant Depression: Definition and Epidemiology

Treatment-resistant depression (TRD) is a prevalent, disabling, and costly condition affecting 1%–4% of the U.S. population. Current approaches to managing TRD include medication augmentation (with lithium, thyroid hormone, buspirone, atypical antipsychotics, or various antidepressant medications), psychotherapy, and ECT. Advances in understanding the neurobiology of mood regulation and depression have led to a number of new potential approaches to managing TRD, including medications with novel mechanisms of action and focal brain stimulation techniques. This review will define and discuss the epidemiology of TRD, review the current approaches to its management, and then provide an overview of several developing interventions. TREATMENT-RESISTANT DEPRESSION: DEFINITION AND EPIDEMIOLOGY Major depressive disorder is a widespread and costly illness, with a 1-year U.S. prevalence of about 7% (1). A variety of antidepressant treatments are available, but many patients fail to achieve sustained symptomatic remission. Continued depressive symptoms are associated with ongoing functional impairment (2), increased usage of health care resources (3), a greater risk of suicide (4 – 6), and overall increased mortality, especially associated with cardiovascular disease (7–10). Despite the growing recognition of the public health importance of treatment-resistant depression (TRD), a consensus definition for this condition does not exist. Various approaches to stages of treatment resistance have been developed, including the Thase-Rush (11), Massachusetts General Hospital (12), and Maudsley systems (13). It has been conservatively estimated that 10% of depressed patients will not respond to multiple, adequate interventions (including medications, psychotherapy, and ECT) (14), and data from a large, community-based sequential treatment study (STAR*D) suggest that up to 33% of patients may fail to achieve full symptomatic remission despite multiple medication attempts (15). Studies of TRD have varied widely in the operational criteria used, but failure of at least two antidepressant treatments (of adequate dose and duration) from two distinct classes is one of the most consistent definitions in the literature (16). This definition also has predictive validity. In STAR*D, remission rates with the first two treatments were quite similar (36.8% in the first level and 30.6% in the second) but decreased significantly after a failure of two treatments (13.7% in the third level and 13.0% in the fourth) (15). Considering these various definitions of TRD, the estimated prevalence ranges from 10% to 60% of all depressed patients (12, 14, 15), resulting in a U.S. prevalence of about 1%– 4%, equal to or greater than the prevalence of schizophrenia, obsessive-compulsive disorder (OCD), or Alzheimer’s dementia. And, for those patients who do eventually respond after multiple treatments, relapse is quite high (up to 80%) (17–19), emphasizing the fact that better strategies are needed to both treat and prevent depressive episodes. CME Disclosure Paul E. Holtzheimer, M.D. Assistant Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA Dr. Holtzheimer has received grant funding from the Dana Foundation, Greenwall Foundation, NARSAD, NIMH (grant K23-MH077869), National Institutes of Health Loan Repayment Program, Northstar, Inc., Stanley Medical Research Institute, and Woodruff Foundation; he has received consulting fees from AvaCat Consulting, St. Jude Medical Neuromodulation, and Oppenheimer & Co. Address correspondence to Paul E. Holtzheimer, M.D., 101 Woodruff Circle, Suite 4000, Atlanta, GA 30322; e-mail: [email protected]. Fall 2010, Vol. VIII, No. 4 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y 488 CURRENT APPROACHES FOR MANAGING TRD ESTABLISHING THE CORRECT DIAGNOSIS When a patient presents with TRD, the first step is to confirm the primary diagnosis, assess for the presence of psychiatric and medical comorbidity, and verify the adequacy of prior treatments through a careful patient interview (with collateral information if available) and review of medical records (20). More than 10% of patients with the initial diagnosis of major depression may ultimately meet the criteria for bipolar disorder (21) and may require a modified treatment approach. Psychiatric comorbidity is common in depression and TRD (primarily anxiety, personality, and substance use disorders) (22, 23), and failure to achieve remission may be associated with inadequate treatment of these other conditions. Similarly, certain comorbid medical illnesses (e.g., sleep apnea, anemia, thyroid disease, hypogonadism, and others), as well as nonpsychiatric medications (e.g., corticosteroids, interferon alfa, and chemotherapy), may be associated with symptoms and side effects that overlap with those of depression. Finally, many patients with depression labeled as “treatment-resistant” may not have actually achieved adequate doses of prior medications for a sufficient duration (12, 14), such that a first step in management often includes increasing and potentially maximizing dose and duration of a current or prior treatment. MEDICATION AUGMENTATION For patients with documented treatment resistance to one or more medications, augmentation is a typical approach. Accepted augmentation agents for TRD include lithium, thyroid hormone, buspirone, and atypical antipsychotics. Combining antidepressant medications is also quite common. Table 1 provides a summary of these approaches, including the highest level of support for each. Lithium. Lithium augmentation (typically at doses 600 mg/day) currently has the most extensive evidence base with reported response rates between 40% and 50% (in depression studies, response is typically defined as a decrease in depression severity of at least 50% compared with baseline) (24). However, it should be noted that the majority of these studies combined lithium with a tricyclic antidepressant (TCA) or monoamine oxidase inhibitor (MAOI). The efficacy of lithium augmentation of newer antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), is less clear (25). It is notable that lithium probably acts in part through modulation of the serotonin neurotransmitter system (26), such that it may be less mechanistically distinct from many newer medications compared with the older agents. In STAR*D, lithium was added after two failed treatment attempts that included bupropion, citalopram plus bupropion, citalopram plus buspirone, sertraline, or venlafaxine (27). Lithium augmentation was compared with triiodothyronine (T3) augmentation (results for T3 are described below). Lithium augmentation was associated with a 16% remission rate and a 16% response rate; 23% of patients dropped out due to side effects. Thyroid hormone. Augmentation with 25–50 g of T3 also has an extensive database in medication-refractory depression (again with most studies adding this agent to a TCA). One meta-analysis found mixed results but generally confirmed a statistically significant advantage for T3 augmentation of TCAs, with an overall response rate of 57% (a 23% improvement over placebo) (28). Another Table 1. Common, Evidence-Based Medication Augmentation Approaches for TRD Approach Highest Level of Support Comments Lithium Several placebo-controlled RCTs Best data are from studies using TCAs or MAOIs; limited data with newer antidepressant medications Thyroid hormone (T3) Several placebo-controlled RCTs Best data are from studies using TCAs; limited data with newer antidepressant medications Buspirone Two placebo-controlled RCTs One RCT was positive for patients with severe depression (but was not positive overall), the other was negative Atypical antipsychotics Several placebo-controlled RCTs for various agents Additional antidepressants Bupropion Open-label studies Most common approach in clinical practice Mirtazapine One placebo-controlled RCT TCA SSRI/SNRI Open-label studies RCT, randomized controlled trial. HOLTZHEIMER focus.psychiatryonline.org FOCUS Fall 2010, Vol. VIII, No. 4 489 C L I N I C A L S Y N T H E S I S meta-analysis identified a statistically significant benefit for T3 in accelerating the response to TCAs (29). In STAR*D, patients were randomly assigned to augmentation with either T3 or lithium after two failed treatments (see above for details). T3 augmentation was associated with a 25% remission rate and a 23% response rate (response was defined using a different scale than that used to define remission; in addition, it is possible that some patients achieved remission without having a 50% decrease in depression severity because of a partial response in the previous STAR*D levels); 10% of patients dropped out due to side effects. The numerical advantage of T3 over lithium augmentation was not statistically significant. Buspirone. Buspirone augmentation (at doses ranging from 10 to 60 mg/day) has a mixed database supporting antidepressant efficacy (largely comprising open-label studies). One placebocontrolled trial (N 119) found no statistically significant benefit for buspirone augmentation in patients not responding to an SSRI (30). A second placebo-controlled trial (N 102) also found no overall augmentation benefit for buspirone but did identify statistically significantly greater antidepressant effects in patients with severe depression (31). Buspirone augmentation was used in the second level of STAR*D (for patients not achieving remission with citalopram) and compared with bupropion augmentation. Remission rates were virtually identical with the two agents (roughly 30%), although bupropion was associated with a greater reduction in self-rated depression severity and a lower dropout rate due to side effects. Atypical antipsychotics. Atypical antipsychotic medications have previously shown benefit as augmentation agents for a number of SSRIresistant nonpsychotic anxiety disorders (32–36). A recent meta-analysis of placebo-controlled trials found that atypical antipsychotic augmentation of an antidepressant medication was associated with statistically significantly greater response and remission rates, with a pooled response rate of 44% compared with 30% for placebo (37). Discontinuation due to side effects was greater for the antipsychotics compared with placebo. Aripiprazole is currently U.S. Food and Drug Administration (FDA)-approved for the treatment of depression not responding to an SSRI or a serotonin-norepinephrine reuptake inhibitor (SNRI). Quetiapine monotherapy and the combination agent olanzapine/ fluoxetine have each received FDA approval for the treatment of bipolar depression. Combining antidepressants. The most common combination of antidepressants is the addition of bupropion to an SSRI or SNRI (38, 39), despite a limited database with no placebo-controlled studies (40). As described above, bupropion augmentation of citalopram had a remission rate similar to that of buspirone augmentation in STAR*D, although there was some evidence for greater antidepressant effectiveness of bupropion overall. The efficacy of adding mirtazapine to an SSRI/SNRI is supported by a small database including at least one placebo-controlled trial (41, 42). The combination of an SSRI/SNRI with a TCA is somewhat supported by a limited dataset (43– 46).