Treatment-resistant depression (TRD) is a chronic illness characterized by persistent depressive symptoms despite multiple treatments. TRD can also be viewed as chronic depression with incomplete symptomatic remission. TRD accounts for a significant portion of health expenditures related to depression,1 as depression becomes more recognized as a debilitating disease with marked functional impairment that spans all social, familial, and financial demographics. Finally, the interplay between depression and deterioration in physical health is starting to be recognized, and the sequelae of untreated depression on physical health cannot be overstated. Additionally, comorbidity of TRD with maladaptive personality traits or disorders is recognized but often not systematically addressed.2
The challenges in treating TRD have led to multiple innovations in integrative treatment approaches, often encompassing modalities that go above and beyond pharmacologic treatment. Psychotherapeutic modalities are the area of focus in this article.
As described in studies that examine pharmacologic interventions for TRD, there is evidence that supports the efficacy of antidepressant medications,3,4 but with significant limitations, and other evidence that suggests that an adjunctive treatment strategy combining different classes of psychotropic medications produces the best results.5 However, for many patients, treatment interventions based solely on medication compliance are not feasible due to factors such as side effects, high costs of medications, and religious, cultural, or personal beliefs regarding pharmacologic interventions.6 For these reasons, it is important to identify nonpharmacologic interventions for the treatment of TRD, such as psychotherapy. Not only is it important to avoid biologic reductionism with the treatment of depression, but it is also essential to appreciate how effective psychotherapy and psychosocial treatments can be in a wide range of personal and social issues. Psychotherapy is still, however, woefully underused despite its efficacy; the number of visits that involved psychotherapy as well as medication management has dropped since 2002,7 whereas the number of people on antidepressant medications has drastically increased in the past decade.8 Interestingly, although TRD represents a subset of people with refractory depressive symptoms and significant difficulties in social and occupational functioning, lack of appreciation of symptom severity remains a barrier to obtaining (and staying in) mental health care in at least one-quarter of patients with severe symptoms.9 According to the National Comorbidity Replication study,9 25% of people with symptoms in the severe range report low perceived need for treatment. In this patient subpopulation, proper identification and referral to therapy would be paramount.
How Can Psychotherapy Be Integrated into the Management of TRD?
Psychotherapy is the cornerstone of nonpharmacologic interventions that are effective in reducing or managing symptoms of TRD. The primary alternative to the pharmacologic treatment of TRD is the use of individual psychotherapy, although group therapy can be used as well. Overall, research in this area is limited but promising,10 as discussed later in this article. Most studies have focused on psychotherapy as an adjunct to pharmacologic management, and this reflects prevailing practices in depression treatment at this point, as the vast majority of patients receive antidepressant medications from a nonspecialist, nonpsychiatrist provider.
For the clinician managing a patient with TRD, some shifts in perspective may be needed for optimal integration of psychotherapy and other management modalities. The first is viewing TRD as a chronic disease that requires longitudinal, comprehensive treatment planning; this is where most of the opportunities for care integration with pharmacologic management and psychotherapy (or other treatment modalities) can happen. For this perspective to be cemented, clinicians need to be aware that TRD often does not respond to a single, evidence-based treatment (eg, a single medication), because TRD is often comorbid with other issues, such as personality disorders, substance use, or medical issues. Inadequately treated depression, misdiagnosed bipolar disorder, underlying subthreshold psychosis, and substance use can also be significant comorbidities.
The second shift in perspective needs to include an improved appreciation of target goals in TRD, which include psychosocial functioning and self-care, and not just a depressive symptom report; this would hopefully lead to a subsequently improved ability to select therapeutic measures that may fit individual patients. Clarity of diagnosis is key in treatment planning. TRD can be a reflection of misdiagnosis of bipolar disorder and latent psychotic symptoms, and can be comorbid with frequent suicidality (ideations or gestures), anxiety, poor distress tolerance, and decompensation in the face of seemingly mundane life events, as well as with elements of chronic pain, chronic fatigue, and limited adherence to necessary/prescribed treatments. Using psychotherapy for TRD may help with many, if not all, of these dimensions. Furthermore, having collaborative treatment may assist in making a correct diagnosis.
In the management of TRD, a flexible approach may be most helpful (as outlined further in this article). When selecting psychotherapy for a patient with TRD, it is important for the clinician to recognize that therapy measures share a common core of efficacy, despite apparent discrepancies in methodology and theoretical backgrounds. Nonspecific factors in psychotherapy include therapeutic alliance, therapist competence, and adherence to therapeutic modality.11,12
Psychotherapy has gone through many cycles of evolution over the past decades, with conceptual and technical differences.13,14 It may be challenging for the clinician to refer or determine which modality to choose for their patients. The first-wave psychotherapies, consisting mostly of psychodynamic, psychoanalytic, and family-of-origin work, were past-focused, sometimes trauma-focused, and often theory-driven. First-wave psychotherapies use the therapist as the expert. Second-wave psychotherapies (exemplified by cognitive-behavioral therapies, gestalt therapies, family-systems therapy), in contrast, are present-focused, problem-focused, and also theory-driven. Third-wave therapies are more solution-focused, much more heterogeneous in terms of technique, and focus on building competence in dealing with life stressors, and sometimes with acceptance of what cannot be easily changed. More importantly, these therapies may be more patient-driven. All psychotherapeutic modalities aim at increasing cognitive flexibility, although they may approach it differently. As eloquently summarized by Ngo,15 second-wave therapies assist the patient in viewing the world and describing it differently, thus processing it differently, whereas third-wave therapies enhance conscious action, acceptance of the present, and assist in decreasing avoidance.
Specific Psychotherapeutic Modalities in TRD
Several modalities of individual psychotherapy have been evaluated in adults with TRD, the most common being cognitive-behavioral therapy (CBT). Individual psychotherapy, in particular cognitive and behaviorally oriented modalities, addresses the maladaptive thoughts and behaviors that can contribute to and exacerbate chronic depressive symptoms. Maladaptive thoughts and behaviors can be divided into cognitive distortions versus negative core beliefs. Cognitive distortions are negative automatic thoughts, whereas core beliefs pertain to deeper self-image and long-held expectations. Both types of thinking “errors” benefit from intervention in TRD. Low levels of activity and engagement in life can also be the focus of CBT, via behavioral activation. As people are taught to increase (and balance) both mastery and enjoyment activities in life, depression symptoms may subside as life satisfaction improves.
Therapeutic interventions that teach patients to identify and correct cognitive distortions, increase behavioral activation, and ways to more effectively manage acute stressors are especially helpful for patients who experience TRD.10 For instance, in one study that directly compared the efficacy of antidepressant medications versus CBT in patients, the authors randomly assigned patients to either a medication group, 16 weeks of CBT, or 8 weeks of a placebo. CBT was determined to be as effective as medications for the initial treatment of moderate to severe major depression, but without any unwanted side effects.16 It should be noted that several studies also suggest that the combination of medication and psychotherapy is most effective in the treatment of TRD.17–19 For example, in a study that looked at the impact of the combination of antidepressants and CBT on TRD, researchers found that after 6 months of prospective treatment, 469 patients who received CBT (plus antidepressants) saw at least a 50% reduction in depressive symptoms compared to patients who only received antidepressants.20 Beneficial outcomes, including remission, were maintained over 12 months. However, participants in this study noted CBT was “difficult,” highlighting that the need for effort and commitment on behalf of the patients is necessary for successful symptomatic resolution.
More recently, TRD has also been effectively managed with “third-wave psychotherapies.” This group of psychotherapies is comprised of a heterogeneous group of treatments that includes Acceptance and Commitment Treatment (ACT), Cognitive Behavioral Analysis System of Psychotherapy (CBASP), Dialectical Behavioral Therapy (DBT), and Mindfulness-Based Cognitive-Behavioral Therapy (MBCBT).21
One of the ways that ACT helps patients with TRD is by working with patients to help them acknowledge and accept their negative thoughts and emotions and by discouraging experiential avoidance, improving psychologic flexibility, and improving self-care.22
CBASP is different from other third-wave psychotherapies in that it is a psychotherapy model that was specifically designed to treat chronically depressed patients. Through this form of psychotherapy, patients learn how their thoughts and behaviors create interpersonal problems that contribute to or exacerbate their depression, but they also learn to develop strategies to change maladaptive patterns of interpersonal behavior.17 CBASP has been found to be at least as effective as other evidenced-based treatments in reducing the rate of remission of depression in patients who suffer from TRD.23 Underlying assumptions for CBASP include that refractory depressive symptoms stem from helplessness and avoidance-based patterns, and that managing interpersonal interactions, while maintaining affective control, leads to improved interactions with the general environment and significant others who are pertinent in the patient's life. Anecdotal data that patients with TRD are often perceived as alternating between hostility and submissive attitudes was substantiated in more rigorous scientific analysis, and success of CBASP in people with TRD is accompanied by a change in patients' interpersonal impact on their therapists.24 Such findings substantiate how psychotherapies such as CBASP sustain change in patient's lives via changes in interactions with significant others around them.
DBT and MBCBT are third-wave psychotherapies that have not only been adapted to treat patients with TRD, but these therapies have also been implemented in group format. DBT covers four dialectical behavior therapy skill sets: mindfulness, interpersonal effectiveness, emotion regulation, and distress tolerance. Given the high comorbidity between TRD and personality disorders, especially borderline personality disorder, using DBT as a tool for TRD has much logical backing, as it targets both conditions. Harley et al.25 developed a 16-session, DBT skills group that was modified specifically to treat patients with TRD, and found that although both wait-list participants and skills-group participants demonstrated improvement of depressive symptoms over time, patients in the modified DBT skills group demonstrated significantly greater reduction in depressive symptoms. The Radically Open Dialectical Behaviour Therapy study, currently ongoing, will evaluate a more widespread use of DBT for TRD.
Similarly, MBCBT was not originally designed to specifically treat TRD; however, given its effectiveness in helping prevent relapse of depression for people in complete remission, it has been offered in group format for patients who suffer from TRD and has demonstrated effectiveness in reducing depressive symptoms in participants.26
In addition to psychotherapies that are based on CBT or third-wave psychotherapies, TRD patients have also benefited from psychodynamic therapies. Research suggests that the benefits of short-term psychodynamic therapies are similar to the effects of antidepressants and CBT. Results suggest that the benefits of CBT may be recognized more quickly than short-term psychodynamic therapies; however, they may not continue to provide symptom relief after treatment like they do with psychodynamic therapies. As for longer-term psychodynamic treatments, results suggest that they not only decrease depressive symptoms in TRD, they may also improve social and personal functioning. The aim of psychoanalytic interventions is helping patients to gradually internalize and improve their psychologic capacity to handle stressors, personal experiences, feelings, and relationships.27 Psychodynamic therapy is best practiced in a longer-term format, unlike CBT. The Tavistock Adult Depression Study, currently underway, reports observing patients with TRD for 18 months and using manualized, weekly psychoanalytic therapy.28 Results are eagerly awaited.
Would Patients with TRD Benefit from Alternate Means of Delivery of Psychotherapy?
Although TRD remains a therapeutic challenge, new modes of treatment offer hope to many patients. In this section, we look at novel methods of treatment delivery that can enable patients to receive the optimal care that they need despite obstacles. Of these, the most promising is telemedicine (specifically telepsychiatry), defined by the American Telemedicine Association29 as “the use of medical information, exchanged from one site to another by means of electronic communication to improve a patient's health.” None of these options have been specifically studied in TRD, but as they represent an evolving and promising field for depression, they may grow into adjunctive treatments in TRD in the future.
Psychiatry lends itself naturally to this treatment modality because of the limited nature of “hands-on” work that is required in a typical patient encounter. Even with more invasive, hands-on treatment that may be required for TRD (such as electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagal nerve stimulation), psychiatrists can provide effective guidance to practitioners in distant settings who can do the actual treatment under supervision. Telepsychiatry can also help with ensuring compliance, monitoring for relapse, and rapid intervention in patients who might not otherwise be able to access psychiatric services. This modality is also being increasingly used internationally for providing psychiatric services (including psychotherapy) across national borders, thus making advanced psychiatric and psychologic expertise available to patients in countries where psychiatric services are still in their infancy. This includes countries in Asia, the Middle East, and Africa.
There is evidence now available that telepsychiatry is comparable to in-person treatment for a variety of conditions, including depression, in most populations (adult, child, geriatric, ethnic).30 In a meta-analysis of 30 studies, Linde et al.31 reported on “face-to-face CBT in 7 treatment groups, face-to-face problem-solving therapy in 4, face-to-face interpersonal psychotherapy in 2, other face-to-face psychological interventions in 6 (5 variable counseling interventions and 1 psychoeducational intervention), remote therapist-led CBT in 3, remote therapist-led problem-solving therapy in 2, guided self-help CBT in 4, and no or minimal contact CBT in 4 treatment groups.” In their meta-analysis, telepsychiatry interventions were more useful in patients with major depressive disorders than in patients with mild symptomatology (eg, dysthymia), which is a paradoxic finding when compared to mainstream literature on face-to-face depression treatments. The authors' explanation is that more intense treatments may be more effective than less intense ones, and that more studies are needed in this area.31
Although there remain significant challenges to the widespread implementation of telepsychiatry, primarily licensing/oversight and reimbursement issues, the advantages that this treatment modality offers make it all but inevitable that it will become a standard of care in the near future, especially in underserved areas. Telepsychiatry can increase treatment access for patients with depression (including TRD) who live in remote/rural areas or are unable, for any number of reasons, to make an in-person visit. In addition, the time saving that can be achieved with doctors not having to drive to remote locations can allow us to spread our services over a greater patient pool and ease the acute (and increasing) shortage of psychiatrists in many areas. Studies also show that it may be easier to engage younger patients and families with telepsychiatry.32
Several studies support the use of telephone-based psychotherapy for depression,33 and there has been interest in exploring online methods of delivering therapy services. A recent study on the use of computerized CBT using a commercially produced program (Beating the Blues34) as well as a free-to-use CBT program (“MoodGYM35) showed that these methods did not substantially improve depression outcomes compared to usual general practitioner care alone.36
The findings from such studies have to be interpreted with caution, as several meta-analyses have found the effectiveness of internet CBT interventions to be intermediate in effect sizes between wait-list interventions and face-to-face interventions.37 However, as examined below, success in treatment of acute depressive disorders may or may not translate into success of treating TRD because of limited patient engagement and adherence to necessary regimen. Ongoing work into predictors of dropout from online treatment, which is typically high,38 indicates dropout is related to nonrandom factors that may become the targets of interventions if online therapy is to become more popular. Results from small pilot studies focusing on online delivery of mindfulness-based, psychodynamic,39 or acceptance/commitment therapies40 are promising but not yet sufficient for large-scale implementation.
Non–real-time methods of providing psychiatric expertise, including email, instant messaging, social media, and others, such as smartphone applications, are also growing, although scarce evidence exists regarding their efficacy. These methods are so far more focused on screening for, rather than treating, depression. The advantage and draw of such methods relies mainly on their ability to provide just-in-time interventions, with potentially rapid feedback as events unfold in a person's life. Although there is some evidence that automated emails promoting self-help behaviors may help with subthreshold depression symptoms,41 the severe nature of TRD, delays in responding to email with its attendant risks to the patient, and the non-secure nature of most email communication may preclude use of this modality in TRD on routine basis. The same may be true of most social media, where confidentiality cannot be adequately assured. For now, the effectiveness of smartphone applications is limited to screening general populations, and to self-report (patients inputting mood levels in the app), although studies are currently being conducted in using smartphone apps to track mood and assist in clinical diagnosis (N. Moukaddam and A. Sabarhwal, unpublished data, 2016).
Obstacles to Using Psychotherapy in TRD
Despite the potential benefits of using psychotherapy on its own or in conjunction with medication for TRD, widespread application faces a number of barriers. Trivedi et al.10 elucidate these barriers in their systematic review of psychotherapy for patients with TRD. They reported that the primary barrier to psychotherapy is access, particularly to those who live in underserved areas. The second barrier to utilization of psychotherapy is the relative cost compared to the cost of medications. The authors suggest that patients tend to look at the immediate costs of therapy (including time, money, effort), as opposed to the potential long-term benefits of therapy.
These authors suggest one strategy that may increase access and reduce costs for psychotherapy may be to move toward a more collaborative model of care where non-mental health professionals (eg, nurses) provide some brief psychotherapeutic interventions.11 There is evidence that suggests that this model could not only improve patient education, but also better integrate mental health providers and other health disciplines.42 Recently, there has also been more support toward using more multifaceted interventions to improve depression care.43
Widespread implementation of psychotherapeutic interventions in TRD faces obstacles that are knowledge- and attitude-related stemming from patients and clinicians, as well as financial and access factors. However, psychotherapeutic interventions have proven to be efficient in treating TRD, successful in bringing about symptomatic remission in a significant number of patients, and often a life-changer for many. Strength of evidence varies, but the panoply of available therapies that have shown some success in TRD ranges from psychodynamic to third-wave therapies, and choices abound for referrals. Based on available accumulated evidence as well as clinical experience, we strongly recommend that referral to therapy be made as soon as TRD is identified, and that a multipronged, comprehensive treatment plan be discussed with patients early to minimize symptom chronicity and promote functional recovery.
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- DeRubeis RJ, Hollon SD, Amsterdam JD, et al. Cognitive therapy vs medications in the treatment of moderate to severe depression. Arch Gen Psychiatry. 2005;62(4):409–416. doi:10.1001/archpsyc.62.4.409 [CrossRef]
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