Treatment-Resistant Depression: Prevalence, Risk Factors, and Treatment Strategies

Michael E. Thase, MD

Departments of Psychiatry, University of Pennsylvania School of Medicine and Philadelphia Veterans Affairs Medical Center, and University of Pittsburgh Medical Center, Philadelphia and Pittsburgh

Difficulty of Achieving Remission

In the longitudinal treatment of MDD, the outcomes of interest are often classified as response, remission, recovery, relapse, and recurrence.1 Response, sometimes viewed as the first goal of treatment, may also be subdivided by the magnitude and duration of symptom relief. According to the DSM-IV-TR,2 full remission is the absence of significant signs or symptoms of the disorder during the past 2 months; partial remission occurs when symptoms are present but the full criteria for a major depressive episode are not met, or when a period without any significant symptoms occurs but lasts less than 2 months. Relapse is the return of a depressive episode following a response but before recovery, whereas the term recurrence is used to describe the return of a depressive episode at some point after recovery.

Because depression is recognized as a major public health problem and a leading cause of disease burden worldwide,3 contemporary treatment guidelines4,5 have adopted remission as the optimal outcome of an acute episode of depression.6 However, more than half of all patients with depression do not achieve remission after first-line antidepressant treatment, and about 30% may not reach remission after multiple treatment trials.7

Drawing by analogy from medical microbiology, an episode of depression may be referred to as treatment resistant when it has not responded to an adequate trial of an established therapy. Treatment resistance accounts for much of the disability and cost associated with depression.8 Compared with patients whose depression is fully remitted, patients with incomplete remission have increased risk of relapse,9 increased chronicity of depressive episodes with shorter durations between episodes,9 impairments in workplace performance and social function,10 and an increased risk of suicide.11

When initiating antidepressant therapy, clinicians should practice therapeutic candor by not overselling therapies; patients should not expect a silver bullet. Patients should be told that the majority of individuals do not reach remission quickly, and residual symptoms are common. Depending on the severity of residual symptoms and factors such as comorbidity and number of prior unsuccessful treatment trials, a strategy as simple as continuing the antidepressant therapy for a few more weeks may be all that is necessary to achieve remission. But, in many cases, switching medications or augmenting the original antidepressant with a second agent may be necessary. To successfully treat resistant depression, clinicians must first recognize resistance then employ various strategies to manage it.

Recognizing TRD

Physicians can recognize TRD by using a system of ongoing assessment to methodically monitor patient progress during treatment. The systematic use of assessment tools such as itemized symptom rating scales to garner information with which treatment modifications can be made is known as measurement-based care
(AV 1AV 1).12–17 Measurement-based care requires regularly monitoring symptom improvements, side effects, and medication adherence and using a treatment algorithm such as the one developed for the Texas Medication Algorithms Project (TMAP) to guide clinical decisions based on the results of the assessments. However, although the use of this algorithm substantially increased the chances of remission in TMAP, a majority of the patients treated in this important demonstration project did not achieve remission.18

Although there is little disagreement about TRD as a concept, no single agreed-upon definition of TRD exists at this time. A review19 of randomized controlled trials of therapeutic strategies for TRD found that the criteria for determining treatment resistance varied greatly. For regulatory purposes (ie, to study novel interventions for TRD), one widely used definition is an inadequate response after at least 2 antidepressant trials of adequate dose, duration, and treatment adherence.

If TRD is suspected, both the accuracy of the primary diagnosis of a major depressive episode and the depressive subtype must be confirmed. Sometimes, what appears to be TRD is the result of another undiagnosed condition that has gone untreated, such as an occult malignancy or endocrine disorder. Other times a careful evaluation will reveal that the patient is suffering from a specific subtype of depression that does not respond well to antidepressants alone, such as psychotic or bipolar depression. The potential impact of psychiatric and medical comorbidities must also be carefully reassessed. Some factors associated with nonresponse to antidepressant therapies, such as anxiety disorders and early onset, are shown in
AV 2AV 2.20 Comorbid substance use dependence or disorder21 and comorbid medical illness22 can also contribute to TRD. Other factors that might contribute to apparent treatment resistance include unusual pharmacokinetics (ie, slow or fast patient metabolism)23 and noncompliance with treatment, which, at times, is attributable to intolerable adverse events that have not been addressed in therapy.24



Managing TRD

For patients who have not responded to an adequate trial of antidepressant medication, the next step is usually switching to another treatment or augmenting the current treatment. When a patient has been unable to tolerate the current antidepressant and/or has experienced little reduction of depressive symptoms, clinical experience has traditionally suggested that switching may be the best option. Conversely, augmentation strategies are generally employed when the current agent is well tolerated or there has been a partial remission of symptoms. Switching has some advantages over augmentation, such as less risk of harmful drug interactions, and usually can be accomplished with a lower cost and better adherence than multi-drug strategies. Switching options supported by efficacy data include switching from an SSRI to another SSRI or to bupropion, venlafaxine, or mirtazapine.25 A within-class switch may offer less risk of intolerance, but an across-class switch may provide better efficacy (AV 3AV 3).25,26 The advantages of augmentation and combination strategies compared with switching include avoiding the loss of the current agent’s partial efficacy and avoiding the withdrawal symptoms that may occur when the current agent is discontinued. Additionally, an augmenting agent can possibly be selected that will not only help resolve the major depressive episode but also target specific residual symptoms, such as anxiety or insomnia, or side effects of the current antidepressant, such as sedation.

Although a variety of augmentation strategies have been widely employed for several decades, until recently, most of the augmentation studies have been small or would not qualify as well-controlled randomized clinical trials. However, the second generation of antipsychotics has been very well studied, and is now the most rigorously studied augmentation option for TRD. For example, there are multiple randomized clinical trials testing the efficacy of olanzapine in combination with fluoxetine and of quetiapine, risperidone, and aripiprazole in combination with a number of antidepressants. When these studies are taken together, it is clear that adjunctive atypical antipsychotic therapy has demonstrated efficacy in reducing depressive symptoms; however, the atypical antipsychotics are relatively expensive and carry risks for a variety of adverse events, some fairly serious.27,28 Also, although efficacy during acute phase therapy has been demonstrated, the optimal duration of therapy has not been established and it is unclear how long, when effective, the second-generation antipsychotics should be used as adjunctive therapies. Thus, definitive longer-term studies are still needed, and this research must take into account issues pertaining to the cost-benefit and cost-effectiveness of this strategy. Other augmentation options with efficacy data include lithium,29 thyroid hormone,30 and omega-3 fatty acids.31 Selection of an augmentation agent requires considering the current drug regimen and potential interactions, the patient’s symptom and comorbidity profile, and potential adverse events.

Sometimes a second antidepressant is combined with the first to try to enhance antidepressant efficacy; although not technically an augmentation strategy, bupropion is commonly used in combination with SSRIs and SNRIs for this purpose,7 as are the sedating antidepressants mirtazapine32 and, outside of the US, mianserin.33 Such combined therapies have the same relative advantages and disadvantages of other augmentation strategies, though it is true that the efficacy of each of these medications has been established.

An effective treatment for depression, whether a medication or a focused form of psychotherapy, not only reduces symptoms acutely but also should protect against relapse over time. The major difference between pharmacotherapy and psychotherapy in this regard is that the former needs to be continued to exert relapse prevention effects, whereas the latter may have a more enduring benefit after termination of therapy for at least a subset of patients (AV 4AV 4).34 Although the participants in the STAR*D study were less accepting of cognitive therapy as a second-step option than either of the augmenting or switching medication options, those who did agree to accept randomization to cognitive therapy were as likely to benefit as were those who received medication strategies. Thus, for some patients with TRD, switching to or adding psychotherapy to medication treatment may be preferable to a change in medication. To effectively prevent relapse and recurrence for patients who do achieve remission, with or without residual symptoms, clinicians should proactively anticipate and immediately address factors that increase the risk of depressive relapse. Understanding the importance of relapse prevention will help the patient and the clinician to work together in managing the disorder. By adapting therapy over time to meet the patients’ changing needs, clinicians may help them maintain remission from depression.

For Clinical Use

  • Employ therapeutic candor and convey accurate information so that patients will have realistic expectations regarding antidepressant therapy
  • Use standardized measurement tools and treatment algorithms to select treatment strategies and track patients’ symptoms
  • If TRD is suspected, confirm the diagnosis and rule out untreated primary disorders
  • Consider augmentation with a second medication or psychotherapy instead of switching treatment when the patient has had a response and tolerability is acceptable

Drug Names

aripiprazole (Abilify), bupropion (Aplenzin, Wellbutrin, and others), mirtazapine (Remeron and others), olanzapine/fluoxetine (Symbyax), quetiapine (Seroquel), risperidone (Risperdal and others), venlafaxine (Effexor and others)


BDI=Beck Depression Inventory; BMQ=Brief Medication Questionnaire; DSM-IV-TR =Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision; FIBSER=Frequency, Intensity, and Burden of Side Effects Ratings; HDRS=Hamilton Depression Rating Scale; MDD=Major depressive disorder; PHQ-9=9-item Patient Health Questionnaire; QIDS-C=Quick Inventory of Depressive Symptomatology–Clinician rated; QIDS-SR=Quick Inventory of Depressive Symptomatology–Self Report; SSRI=selective serotonin reuptake inhibitor; STAR*D=Sequenced Treatment Alternatives to Relieve Depression; TRD = treatment-resistant depression; TMAP=Texas Medication Algorithm Project

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