Scope of problem
Major Depressive Disorder (MDD) is a common, often recurrent or chronic illness associated with significant morbidity. According to the World Health Organization, an estimated 4.4% of the global population suffers from depression. MDD is among the five leading causes of years lived with disability (YLDs) in 2016 ( ). Past-year depression prevalence increased significantly in the United States (U.S.) from 2005 to 2015 ( ). Few studies have estimated the prevalence of treatment-resistant depression (TRD) in primary care. Information is further limited by lack of uniform criteria for defining TRD as detailed in Chapter 1 . Using failure to respond to two antidepressants from different classes as definition for TRD, the InSight study conducted in Canada, found the prevalence of TRD in primary care to be about 22.0% ( ).
Treatment for major depression is often initiated by primary care providers (PCPs) in the form of antidepressants and/or referral to psychotherapy ( ; ; ; ). Only about 20.0%–30.0% of patients in clinical practice respond to initial antidepressant treatment ( ). The large STAR*D trial, which recruited patients from primary care and psychiatric clinics, showed that even with close follow-up and structured treatment, close to 30.0% of patients have TRD ( ).
Various clinical and psychosocial factors contributing to treatment resistance are relevant to primary care practices. Longer duration and severity of current depressive episode, previous failed trials of antidepressants and comorbid anxiety disorders have been associated with increased risk of treatment failure ( ).
Depression comorbid with physical health problems contributes to poor response to depression treatment and poor outcome of physical health problems. The physiological impact of medical illnesses, the presence of other medications, and the burden of physical health problems contributes to lack of response to depression treatment. Also, this relationship is bidirectional with MDD being associated with poor compliance with treatment recommendations for the management of physical health problems, poor self-care, greater functional impairment, and poor quality of life.
Bidirectional relationship between diabetes and depression is well established. A meta-analysis of long-term longitudinal studies found significantly higher risk of incident diabetes in depressed patients ( ). Diabetes patients with depression have poor self-management leading to increased risk of complications and mortality ( ; ). Another meta-analysis found that close top 40% of individuals with TRD met criteria for metabolic syndrome, with men being at significantly higher risk. Of the individuals with TRD, less than a third of patients with hypertension and dyslipidemia were treated for these conditions ( ). Similar to diabetes, prevalence of depression is higher in patients with cardiovascular disease ( ) and is a risk factor for incident cardiovascular illness ( ). Comorbid depression and cardiovascular disease is associated with poor outcomes for both ( ; ). Greater number of comorbid physical health problems has been associated with poor response to depression treatment ( ).
TRD has been consistently associated with high economic burden in the form increased utilization of health services; increased cost of care, poor health-related quality of life, and lost productivity. Compared with non-TRD, patients with TRD had more emergency department visits, more and longer inpatient hospitalizations and higher per person per year health care costs. These patterns have been observed in both government and commercially insured patients ( ). Both general medical and depression care-related costs increase with an increase in the severity of TRD, accounting for close to 30% increase in medical expenditures ( ; ; ; ; ).
Challenges of managing TRD in primary care settings
A major challenge to adequately addressing TRD is the limited number of mental health providers trained to adequately treat the condition. There are too few psychiatrists, advanced practice providers, and therapists to address TRD alone while continuing to treat the myriad other mental health conditions, and primary care providers (PCP) struggle to connect patients with existing mental health providers ( ; ). Thus, supporting PCPs in delivering depression care is the key to expanding their ability to treat TRD. PCPs currently identify and treat the majority of patients with depression, which, combined with their generally long-term relationships with patients, creates natural opportunities for increasing their ability to treat TRD while improving their comfort level in doing so. It also provides opportunities to address comorbid medical conditions that are less likely to be addressed in mental health settings. A number of studies have demonstrated challenges PCPs identify in providing mental health care to patients, including limited time, inadequate knowledge, and lack of resources ( ; ). Thus, it is important to incorporate strategies that help with efficiencies rather than simply adding more demands or requirements.
Collaborative care for management of depression in primary care ( Fig. 36.1 )
Integrating mental health services with general medical services to manage patients with chronic illnesses have been conclusively shown to improve outcomes for chronic physical and mental health problems. Collaborative care is a specific form of integration that provides team-based care including a behavioral health care manager, PCPs, and a psychiatric consultant. Other members, such as a pharmacist and social worker, can also be part of the team to address factors that may be contributing to the maintenance of TRD. Collaborative care teams conduct systematic case and population review using a registry facilitating timely, evidence- and measurement-based recommendations for patients’ PCP ( ; ; ).
The U.S. Preventive Services Task Force (UPSTF) recommends screening for depression in all adults. UPSTF further recommends that positive screens should lead to further assessments, which is often difficult to accomplish in busy primary care practices ( ). A large number of patients referred to mental health services, especially the most vulnerable, do not show up for initial appointment ( ; ). Having a behavioral health care manager available for warm handoffs improves the chances of further evaluation being completed ( ). In the collaborative care model, an initial assessment by the care manager includes the use of rating scales for measuring severity of depression; record of response to past treatment; and screening for comorbid conditions including bipolar disorder and substance use, which are all factors that can complicate treatment of depression. The collaborative care team then provides individualized treatment recommendations to the patient’s PCP. Frequency of monitoring is based on severity of illness, adverse effects, and treatment adherence. The care manager also provides education and support to improve adherence, may use motivational interviewing, and incorporates psychotherapeutic techniques. Routine follow-up allows for early identification of failure or intolerance to pharmacological interventions and treatment is subsequently modified. Structured, manualized cognitive behavior therapy (CBT) can also be integrated in the treatment plan ( ; ).
More than 80 randomized controlled trials have found significantly better response and remission rates for depression with collaborative care compared to usual care. A systematic review of 79 RCTs which included 24,308 participants, showed significantly greater improvement in depression outcomes for adults with depression treated with the collaborative care model in the short-term and medium-term ( ). A meta-analysis of 37 randomized studies that included 12,355 patients with depression in primary care settings showed that depression outcome benefits were maintained for up to 5 years ( ).
In addition, collaborative care programs have been adapted to address both depression and chronic medical conditions. The TEAMCare and subsequent Care Of Mental, Physical, And Substance-use Syndromes (COMPASS) studies delivered collaborative care to patients with depression and comorbid diabetes and/or coronary heart disease. The initial trial found that patients engaged in collaborative care reported greater improvements in depression symptoms; blood sugar, cholesterol, and systolic blood pressure readings; quality of life ratings; and care satisfaction compared to those receiving usual care ( ). Large-scale implementation reported similar, albeit somewhat less robust, results, indicating that such programs can be successfully translated into real-world practice ( ).
Components of collaborative care for depression
Pharmacotherapy
While pharmacotherapeutic strategies for TRD are covered in 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , there is evidence that the collaborative care model is associated with better implementation of available pharmacotherapy strategies with stepped intensification of care, resulting in a significantly greater number of antidepressant medication trials in patients enrolled in the intervention when compared to those under usual care ( ). Several large-scale collaborative care programs for depression have been implemented in primary care. Compared to those receiving usual care, patients with MDD who engaged in the collaborative care program reported greater medication adherence, quality of care, and improvement depressive symptoms. Importantly, greater improvement in depressive symptoms was observed among patients who required a medication adjustment, suggesting that collaborative care may be most impactful for patients who do not initially respond to treatment ( ). Large single-payer health care systems, such as the Veterans Administration (VA), have implemented collaborative care. The Translating Initiatives in Depression into Effective Solutions (TIDES) found high rates of medication adherence and treatment engagement among veterans enrolled in collaborative care. A significant decrease in depressive symptoms was reported over the course of treatment, which was similar in magnitude to veterans referred to mental health specialty ( ). The Telemedicine Enhanced Antidepressant Management (TEAM) study provided evidence for a telehealth-based collaborative care program delivered in rural VA clinics without on-site psychiatrists. Veterans participating in the program reported greater medication adherence, reductions in depression symptoms, and satisfaction of care compared to those receiving usual care ( ). This study provided preliminary evidence for telehealth-based collaborative care programs as a way to reach rural and underserved populations, which has since been expanded to other health care settings ( ; ).
Psychotherapy
The presence of psychological services in primary care has steadily grown over the past two decades ( ). Behavioral activation (BA) and problem-solving therapy (PST) are the most common psychotherapy interventions employed across primary-care–based collaborative care programs for depression. BA is based on a behavioral model of depression. This model proposes that individuals who develop depression experience low-levels of positive reinforcement due to limited access to, availability of, or ability to engage in pleasant activities, which results in depressed mood and avoidance. The very nature of depressive symptoms, such as loss of interest, lack of motivation, poor energy, and social withdrawal, serve to maintain this negative cycle. Ultimately, this perpetuates the problem and leads to continued low levels of positive reinforcement ( ). BA is a brief, structured psychotherapy that aims to increase engagement in pleasant, masterful, and/or valued activities and decrease avoidance. This is accomplished through a number of different strategies including activity monitoring, activity scheduling, and problem solving ( ). PST is based on a cognitive-behavioral model of depression. This model postulates that individuals with depression exhibit deficits in problem-solving skills ( ) including a negative problem-solving orientation and maladaptive problem-solving style ( ). PST is a brief psychotherapy approach that aims to teach effective problem-solving attitudes and skills. This is achieved through a step-by-step strategy in which the patient identifies the problem, generates potential solutions, selects and implements a solution, and evaluates the outcome with the option to trial another solution if necessary ( ).
The rationale behind selecting these two interventions include their strong evidence-base, short-term structure, and straight-forward theoretical framework and therapeutic techniques. The structure of these therapies aligns well with the population-based model of care practiced in primary care settings. While there are a number of different protocols available, both interventions typically consist of only 6–12 sessions ( ; ). The fact that these therapies are relatively easy to understand conceptually and implement practically enables care managers, often without specialized training in mental health, to deliver these interventions with high treatment fidelity.
While, BA and PST are evidence-based treatments for depression, these have not been extensively studied in patients with TRD. Rather, TRD trials have investigated the use of CBT, which often includes the same strategies used in BA and PST ( ; ).
The efficacy of CBT for TRD has begun to be evaluated in primary care. Only one large-scale psychotherapy trial has been conducted ( ). The Cognitive-Behavioral therapy as an Adjunct to pharmacotherapy for primary care patients with Treatment-resistant depression (CoBAulT) randomized clinical trial was conducted in primary care practices across the United Kingdom. Participants included primary care patients with TRD as operationalized as antidepressant medication adherent, but not responsive, for at least 6 weeks. Participants who engaged in individual CBT were significantly more likely to achieve response and remission at 6 ( ) and 46 months ( ) compared to those receiving treatment as usual. Older participants were found to benefit more from CBT while participants with more severe depressive symptoms at baseline benefited less; however, these differences were relatively small and resulted in the authors ultimately recommending CBT for all patients with TRD ( ). While these results are promising, this trial has not yet been replicated in other primary care settings. Various psychotherapeutic interventions for TRD are further detailed in Chapter 25 .
Collaborative model of care expands access to evidence-based psychotherapy to a larger proportion of the primary care population. Studies have employed a variety of providers as care managers including psychologists ( ; ), nurses ( ; ; ; ; ; ; ), other medical professionals ( ; ), and paraprofessionals ( ). While outcomes differ slightly across studies, collaborative care can be competently delivered by care managers from diverse backgrounds. This model of care can also expand access to mental health specialists such as clinical psychologists, master’s level clinicians, and clinical social workers for patients experiencing more severe or long-lasting depressive symptoms.
Advancing treatment in primary care settings
Improving capacity of primary care providers
Decision tools to assist PCPs, such as the Texas Medication Algorithm Project and the psychopharmacology algorithm project at the Harvard South Shore Program, have the potential to improve depression outcomes by facilitating systematic decision-making around evidenced-based treatments for TRD ( ; ). However, in studies of improving depression treatment in primary care by using algorithms, decision support, guideline implementation strategies, or education alone for PCPs the improvements have been limited ( ; ; ; ; ).
Project ECHO is a telementoring model of education in which participating clinicians remotely attend lecture and case-based learning sessions hosted by specialists at regular intervals to improve their capacity to manage complex medical conditions. It is intended to improve access to specialty care to communities that would otherwise have difficulty accessing specialty care, such as rural locations. As opposed to traditional telepsychiatry models in which one clinician interacts with one patient at a time, Project ECHO allows for dissemination of specialty expertise to many primary care clinicians simultaneously and incorporates time for practical discussion of cases submitted by participating clinicians. Project ECHO has not specifically been studied for TRD but has demonstrated positive outcomes for a number of behavioral health conditions ( ). Further research is needed to test this model of education and support for TRD.
Another approach to expand the capacity of PCPs to treat TRD is to make informal curbside consultation to psychiatric providers easily accessible ( ). That approach is often a component of collaborative care models, but can also be leveraged in clinics or systems which have not implemented collaborative care. The Massachusetts Child Psychiatry Access Project (MCPAP) is an example of such a program that offers mental health consultation services to enrolled PCPs across Massachusetts, usually by telephone ( ). It has been very well received by PCPs ( ). The model can be replicated on a smaller scale within medical systems or even by contracting with a consulting psychiatrist to provide education and assistance with coordination of care when needed. While not yet studied for TRD, it provides the opportunity to assist PCPs in taking additional steps to treat TRD than they might otherwise take with the guidance of a psychiatrist.
Integrating digital solutions
A variety of digital tools have become available in recent years to treat mental health conditions. Mental health applications have proliferated rapidly, and along with their availability has come claims of their efficacy for a variety of conditions ( ). Although some have been tested in randomized controlled trials and proven efficacious ( ; ), many do not incorporate evidence-based interventions, and even fewer have been studied to evaluate their outcomes ( ; ). There is great promise that, over time, they will be studied in clinical trials and be evaluated specifically for TRD, and there have been some initial efforts to do so. A 2017 Japanese study compared the effectiveness of a smartphone CBT app as an adjunctive treatment for patients who had not responded to initial treatment with at least one antidepressant ( ). While the study population did not meet commonly used definitions for TRD, the intervention group had low dropout rates and those in the treatment arm scored lower on standard measures of depression severity and side effects than the control arm. The accessibility and affordability of smartphone apps make them ideal vehicles for distribution of psychotherapy for patients with TRD treated in primary care, but the ability for them to be produced and marketed without proper evaluation raises concerns about their quality. Further trials are needed to identify those most effective for TRD.
Telemental health, the remote delivery of mental health care through telecommunication technology, has an evidence base dating back several decades and is widely accepted by patients and providers. Studies comparing synchronous telemental health with in person care in primary and specialty care settings have shown similar treatment outcomes and levels of patient satisfaction, adherence, and health care cost ( ; ; ; ). The ubiquity of telemental health renders it able to be delivered to patients in a variety of settings (e.g., home, work, primary care clinic) by clinicians in a range of locations and adds flexibility to how mental health treatment can be incorporated into primary care settings. A growing body of literature is emerging on the value of being deliberate in developing and managing virtual teams to improve their efficacy in delivering telemental health ( ). There is still a need to study telemental health specifically for TRD, but the studies that have shown it to be effective across a range of conditions including depression suggest it can be successful in treatment TRD as well.
Other digital solutions, such as asynchronous telemental health and e-consults, have been identified as ways to expand access to psychiatric care ( ). Similar to other digital modalities they have not been rigorously studied specifically for TRD in primary care. Early literature on asynchronous telemental health is promising, suggesting potential for it to be implemented by the clinical team, maintain patient satisfaction, and improve access to care ( ). Likewise, e-consults have been shown to improve access to care, especially for non-Native English speakers and vulnerable populations, but improvements in other treatment outcomes have not yet been demonstrated ( ; ).
Clinical summary ( Table 36.1 )
As is the case with most chronic illnesses, TRD requires the careful review of diagnosis, comorbidities, clinical, and psychosocial factors contributing to treatment failure. Long-term treatment with multiple medication trials, combination of antidepressants and augmenting agents along with psychotherapy is often required to manage TRD. If these measures fail, education and referral for use of novel agents such as ketamine or somatic therapies such as transcranial magnetic stimulation (TMS), electroconvulsive therapy (ECT), and deep brain stimulation (DBS) is required. This need for individualized treatment, as well as frequent medical and psychiatric comorbidity in patients with TRD, requires collaboration between mental health providers and PCPs. The collaborative care model allows PCPs to continue to manage depression even when it does not respond to initial treatment by providing them with additional treatment strategies that they might otherwise be less comfortable with or knowledgeable of, and offering back-up support and monitoring to assist patients proceeding with those treatments. Collaborative care is designed to focus intervention efforts toward those who are struggling or not responding to treatment and to help triage and refer such patients to a higher-step level of care when indicated, including to more specialized mental health services. Successful implementation of integrated care in primary care practices requires rigorous organizational change and involved collaborative care team, or intensive quality improvement programs ( ; ; ).