Study to Promote Innovation in Rural Integrated Telepsychiatry (SPIRIT) Study Protocol. PI John Fortney, PhD

Transcription

1 Study to Promote Innovation in Rural Integrated Telepsychiatry (SPIRIT) Study Protocol PI John Fortney, PhD Table of Contents Objective 2 Specific Aims 2 Background 3 Expertise and qualifications of the PI and Co-Investigators 6 Interventions Methodology Statistical Design Recruitment methods Inclusion/exclusion criteria and age range. Citations. Appendices..

2 OBJECTIVE A large proportion of patients with posttrauwatic stress disorder (PTSD) and Bipolar Disorder (BD) are seen exclusively in the primary care (PC) setting, where they are often prescribed medications for depression (a common comorbidity for PTSD and a common misdiagnosis for BD). However, few PC patients receive effective treatment for BD or PTSD. Many are unwilling or unable to seek specialty mental health (MH) treatment, and in rural PC settings there is typically little to no availability of such specialty care. Thus, while PTSD and BD were once viewed exclusively as disorders requiring specialty MH care, primary care providers (PCPs) are increasingly being challenged to care for patients with these disorders. 1 However, the complexity of these disorders and their treatments make PTSD and BD challenging to manage in PC settings, 2, 3 and experts currently recommend that PCPs work in close consultation with a psychiatrist when treating these disorders. 4-6 The objective of this research is to compare two innovative approaches to managing PTSD and BD in CHCs: Telepsychiatry Collaborative Care (TCC) and Telepsychiatry Enhanced Referral (TER). The central scientific question addressed by this comparative effectiveness trial is whether it is better to expand the scope of integrated care programs to treat patients with more complex psychiatric disorders or to facilitate successful referrals to specialty MH care. In Telepsychiatry Collaborative Care (TCC), patients will meet with the telepsychiatrist consultant via interactive video at the beginning of treatment to ensure an accurate diagnosis and treatment history and develop effective treatment recommendations for the PCPs. Telepsychiatry consultations with patients will be used to increase the local PCP s comfort level and ability to treat PTSD and BD. Patients will also have encounters with local care managers, either synchronously faceto-face or by phone, or asynchronously by smartphone. Telepsychiatry via ACIP AIMS BD CAB CATI CBT CC CHC CITI CMTS Co-I Co-PI CPT EHR HRSA IOM MH MHIP NIH PAB PC PCL PCP PER PI PHQ-9 PTSD RCT TCC TER VA Acronyms Academic Community Implementation Partnership (NIH grant # MH085104) Advancing Integrated MH Solutions Bipolar Disorder ConsUWer Advisory Board Computer Assisted Telephone Interviewing Cognitive Behavioral Therapy Collaborative Care Community Health Center Collaborative Institutional Training Initiative Care Management Tracking System Co-investigator Co-Principal Investigator Cognitive Processing Therapy Electronic Health Record Health Resources & Services Administration Institute of Medicine Mental Health Mental Health Integration Program National Institutes of Health Policy Advisory Board Primary Care PTSD Check List Primary Care Provider Phone-Psychiatry Enhanced Referral Principal Investigator Patient Health Questionnaire PosttraUWatic Stress Disorder Randomized Controlled Trial Telepsychiatry Collaborative Care Telepsychiatry Enhanced Referral Department of Veterans Affairs interactive video will also be used in the context of enhanced referral to increase patients access to MH care. In Telepsychiatry Enhanced Referral (TER), patients will remain in the nearby, and more acceptable, PC setting and receive ongoing pharmacotherapy and psychotherapy from distant MH specialists. Receiving MH specialty care in the PC setting should address geographical and cultural barriers to care. Telephones will also be used in the context of enhanced referral to further increase access for those patients who do not engage in TER. In Phone-psychiatry Enhanced Referral (PER), patients will receive ongoing treatment from MH specialists in the comfort of their own home, further mitigating geographical and cultural barriers to care. PER will be offered only to patients failing to engage in TER. Theoretically, the two main comparator treatments (TCC and TER) represent clinical equipoise, with TCC expected to have greater reach (i.e., a greater proportion of patients engaged in treatment), but lower effectiveness (for those patients who are reached) and TER expected to have lower reach, but greater effectiveness (for those patients who are reached). Similarly, PER is expected to have greater reach, but lower effectiveness (for those reached) than TER. SPECIFIC AIMS Specific Aim #1: To quantitatively compare the treatment experience, engagement, self-reported clinical outcomes, and recovery-oriented outcomes of patients initially randomized to TCC and TER. Hypothesis 1: Patients randomized to TCC will have better treatment experiences (access, therapeutic alliance, patient-centeredness, activation and satisfaction) and treatment engagement (appointments attended, medication adherence, psychotherapy homework) than patients randomized to TER.

3 Hypothesis 2: Patients randomized to TCC will have better self-reported clinical outcomes (e.g., symptoms, side-effects) and recovery-oriented outcomes (e.g., health related quality of life, progress towards life goals) than patients randomized to TER. Hypothesis 3: Patient treatment engagement, provider protocol adherence and clinical practice systems will completely mediate any observed differences in self-reported clinical outcomes and recovery-oriented outcomes between patients randomized to TCC and TER. Specific Aim #2: For the subset of patients randomized to TER who do not engage in treatment and are still symptomatic at 6 months, quantitatively compare the treatment experience, treatment engagement, self-reported clinical outcomes and recovery-oriented outcomes of patients randomized to continued-ter or PER. Exploratory Hypothesis 4: Patients randomized to PER will have a better treatment experience and engagement in care during the second 6 month period than patients randomized to continued-ter. Exploratory Hypothesis 5: Patients randomized to PER will have better patient-reported clinical outcomes and recovery-oriented outcomes during the second 6 month period than patients randomized to continued- TER. Specific Aim #3: To gain an in-depth understanding of patients and providers treatment experience, qualitatively compare those randomized to TCC, TER and PER. Research Question 6: How do the treatment experiences of patients randomized to TCC compare with the treatment experiences of patients randomized to TER and PER? Research Question 7: How does the treatment delivery experience of providers differ for their patients randomized to TCC compared to their patients randomized to TER and PER? Specific Aim #4: To examine treatment heterogeneity among subgroups of patients randomized to TCC and TER based on race/ethnicity, age and clinical severity. Hypothesis 8: Patient self-reported clinical outcomes and recovery-oriented outcomes will be moderated by minority race/ethnicity and older age (with better outcomes observed in TCC), and by high levels of symptom severity and comorbidity (with better outcomes observed in TER). BACKGROUND PTSD and BD are devastating MH disorders that often go undetected/untreated PTSD and BD are among the biggest contributors to disability/suicidality worldwide. 7, 8 While there are highly effective treatments for PTSD and BD, rural patients do not have access to these treatments. 9 Providing effective treatments for PTSD and BD in rural PC settings has the potential to make an enormous impact on the quality of life for hundreds of thousands of rural disadvantaged Americans. PTSD is prevalent in PC settings PTSD can develop in individuals exposed to trauwatic events such as rape, assault, serious accidental injury, natural disasters or combat. It is characterized by flashbacks, nightmares, avoidance of situations that induce trauwa memories, hypervigilance, anger, and sleep deprivation. The most prevalent trauwa among women with PTSD is rape, and the most prevalent trauwa among men with PTSD is combat. 10 The one year prevalence rate of PTSD is 4% in the general population. 11 However, the percentage of patients screening positive for PTSD in PC is much higher, ranging from 14%-23% In PC, 79%-88% of patients with PTSD also go on to develop clinical depression, 19, 20 further contributing to disability and complicating treatment. PTSD is associated with significant impairment - Individuals with PTSD are more likely to engage in unhealthy behaviors such as tobacco use, drug use, alcohol misuse, and have high rates of morbidity/mortality. 13, PTSD negatively impacts marriages, 25 educational attainment, 26 23, and occupational functioning. Use of specialty MH services for PTSD is low Only 34.4% of patients currently meeting clinical criteria for PTSD receive specialty MH care during the course of a year, and only 22.6% have a psychiatrist visit. 9 The quality of detection and treatment in PC is poor Without systematic screening, PTSD usually goes undetected in the PC setting. Only 11%-18% of patients currently meeting clinical criteria for PTSD have a diagnosis docuwented in their medical record. 18, 28 Patients with PTSD are often diagnosed with depression and prescribed antidepressants, but do not receive trauwa-focused

4 psychotherapy (a critical treatment for PTSD). Of those patients who are eventually diagnosed with PTSD, an average of 12 years elapses between onset and diagnosis. 30 In PC, only 13%-34% of patients with PTSD receive adequate care (e.g., 2 months of an antidepressant or evidence-based psychotherapy). 9, 31 Among a sample of Community Health Center (CHC) PCPs, 70% report that they do not have enough time to deal with PTSD, 54% report that their patients with PTSD cannot obtain a specialty MH appointment, 45% report that PTSD patients refuse to see a MH specialist, 37% report feeling uncomfortable prescribing medications for PTSD, and 30% report having insufficient clinical knowledge about diagnosing PTSD. 2 BD is prevalent in PC settings Patients with BD, formerly called manic depressive disorder, experience disabling abnormal mood states including mania, hypomania, depression, and mixed states. 32 Symptoms of mania, such as excessive energy, grandiosity, and irritability, often lead to high-risk behaviors and negative consequences. However, over the course of this chronic illness, depressive episodes are far more common than manic episodes, and the onset of BD typically involves one or more depressive episodes before the first episode of mania or hypomania. 33, 34 The one-year prevalence rates of BDs (bipolar I, bipolar II and sub-threshold) in the general population are 1%, 1% and 2% respectively. 35 However, the prevalence rates are much higher in PC settings Hirschfeld reported that 25% of PC patients receiving antidepressant treatment for depression screened positive for lifetime mania. 40 Olfson reported that 24% of PC patients in a low-income sample who screened positive on the Patient Health Questionnaire (PHQ-9) also screened positive for lifetime mania. 41 BD is associated with significant impairment - BD is associated with high morbidity/mortality. PC patients screening positive for BD have lower mental and physical functioning, greater social 38, 42 and family impairment, and more work loss than patients screening negative. Even among sub-threshold BD patients, 46% reported severe role impairment. 35 BDs are now thought to cause greater overall impairment to the general population than depression , 45 Suicide risk is also higher for BD than for depression. Use of specialty MH services for BD is low Patients with BD treated by a psychiatrist are more likely to be prescribed appropriate medications. 35 However, only 33.8% of patients meeting current clinical criteria for BD receive specialty MH care during the course of a year and only 22.5% have a psychiatrist visit. 9 The quality of detection and treatment in PC is poor - Das found that 0% of patients screening positive for BD in the PC setting had a docuwented BD diagnosis. 38 Of those eventually diagnosed with BD, an average of 6-8 years elapses between onset and diagnosis. 30, 46 The most common misdiagnosis for BD is depression. 47 The American Psychiatric Association practice guidelines strongly advise against antidepressant monotherapy for BD, which could lead to switching from depression to mania or mixed states or 48, 49 Nevertheless, cycle acceleration. the use of antidepressants in the absence of concomitant mood stabilizer use is common. 50 Among patients with BD treated by a PCP, 71%-73% received inappropriate medication (e.g., antidepressant in the absence of a mood stabilizer), and another 18% received no psychotropic medication. 35, 41 Given that the most common misdiagnosis is depression, there is substantial risk that PC patients with unrecognized BD will receive inappropriate treatment. 38 Given the clinical consequences associated with misdiagnosing BD as depression, the 1, 48, importance of detecting and treating BD among PC patients is increasingly recognized as being critical. Collaborative Care (CC) is a promising approach for managing PTSD and BD CC involves psychiatrists and care managers providing clinical support to PCPs treating patients with MH disorders. Evidence from 80 RCTs 55 demonstrate that CC improves depression/anxiety outcomes compared to usual care across a diverse range of settings and populations However, there have also been two negative CC trials for PTSD in the VA, both of which lacked a psychotherapy component. 62, 63 Two studies have demonstrated that the core principles of CC are effective for patients 64, 65 with BD. Enhanced Referral is also a promising approach for managing PTSD and BD Enhanced referral interventions use various strategies to increase the rate of successful referrals from PC settings to specialty MH settings and have been shown to be effective for older adults with depression. One large comparative effectiveness trial (PRISM-e) conducted in urban CHCs and VA PC clinics compared enhanced referral to integrated care (a treatment comparator similar to, but less effective, than CC). The enhanced referral intervention comprised: 1) timely appointments, 2) transportation services, and 3) telephone follow-up with patients missing appointments. About half (49%) of the patients randomized to the enhanced referral model received some MH care compared with 71% percent randomized to the integrated care model. 66 For patients with sub-threshold depression, the clinical outcomes were equivalent between enhanced referral and integrated care despite better engagement in integrated care. 66, 67 Patients with depression randomized to enhanced referral had significantly better depression outcomes than those randomized to integrated care. 67 Almost all the PCPs involved in the trial thought that integrated care resulted in less stigma for patients (93%), quicker

5 appointments (86%), and more convenient care (88%); however far fewer thought that integrated care led to better management of depression (64%). 68 In addition, the PRISM-e trial identified significant treatment heterogeneity effects. In an analysis focused just on the CHC clinics, patients with more severe depression randomized to enhanced referral had better depression outcomes than those randomized to integrated care. 69 Thus, despite the growing evidence base of CC for PTSD and BD, it is possible that policy makers and clinicians should focus on facilitating referral to specialty MH care for these patients rather than trying to manage them exclusively in PC. Telemedicine technologies can be used to improve access to specialty MH services Both the CC model and the enhanced referral model are difficult to implement in rural CHCs lacking onsite psychiatrists and psychologists. Telemedicine can improve access to evidence-based treatments delivered by highly trained MH specialists. Telemedicine addresses cultural barriers (i.e., stigma) because services can be delivered to patients in their familiar PC setting. Telemedicine also addresses geographical and transportation barriers, which have been docuwented to be a major obstacle to receiving specialty MH care. 66, Interactive Video With advances in interactive video technology and reductions in cost, telemedicine is a highly feasible and pragmatic approach to improving cultural and geographic access. Interactive video technology is widely available in rural CHCs. 73 Telepsychiatry is now considered routine care in the VA, which delivered 340,842 telepsychiatry/telepsychology encounters to rural veterans in 2012, including those with PTSD and BD. 74, 75 Patient and provider satisfaction with interactive video encounters with MH specialists is uniformly high Moreover, psychiatric and psychological services delivered via interactive video are equivalent to services delivered face-to-face Phone Telephones can also be used improve access to specialty MH care for patients who are unable or unwilling to engage in face-to-face or interactive video encounters. In an RCT, 63% of patients with depression offered Cognitive Behavioral Therapy (CBT) by telephone completed 7 sessions. 91 Similarly, in two trials, 88%-90% of Latino PC patients with depression offered CBT by telephone completed at least one session. 92, 93 Mobile Health 94, 95 Smartphone apps can also be used by patients to communicate with providers asynchronously (i.e., with a time lag). These asynchronous communications tend to be briefer and more focused than synchronous communication. For example, provider-to patient communications focus on reminders to take medications or complete psychotherapy homework. Similarly, patient-to-provider communications focus on reporting symptom severity or medication sideeffects for the PCP to review. Setting - Federally Qualified Health Centers, more commonly known as Community Health Centers (CHCs), are America s healthcare safety net and are key to addressing mental health disparities across the nation. CHCs are the nation s largest and fastest growing network of primary care (PC) providers. There are 1,200 grantees with 9,000 clinic locations that provide services to 21 million Americans. 96 Almost half (49%) of CHC patients live in rural areas, 93% live at or below the Federal Poverty Level (200%), and 62% are racial/ethnic minorities. Supported by $2.8 billion in federal funding from the Health Resources and Services Administration (HRSA), healthcare expenditures for CHC patients total $16 billion per year. 96 Yet, very little research occurs in this setting, especially in the smaller CHCs that serve disadvantaged rural populations. 73 Despite the relatively low annual health expenditures per patient ($721) 96, CHCs provide high quality care with the majority (88%) using Electronic Health Records and most (58%) achieving Patient Centered Medical Home recognition. 96 Compared to private practice, CHCs demonstrate equal or better performance on a range of quality metrics for physical health disorders. 97 Psychiatric disorders are highly prevalent among CHC patients, yet patients face substantial barriers to receiving specialty Mental Health (MH) care Because CHCs serve patients living in poverty, the prevalence of MH disorders in CHCs is substantially higher than in private practice. 98 Nationally, over one million CHC patients were diagnosed with a MH disorder in 2013, 96 and many more went undetected. However, the vast majority of CHCs do not have psychiatrists or psychologists practicing on site. 99 In 2012, there was 1 psychiatrist per 49,764 CHC patients and 1 psychologist per 43,505 CHC patients. 100 Moreover, the Institute of Medicine (IOM) describes the linkages between CHCs and Community Mental Health Centers (the nation s safety net MH setting) as weak. 101 A 102, 103 large proportion of CHC Medical Directors report that they are unable to obtain specialty MH referrals. With the projected growth in CHC patients, our partners at the National Association of Community Health Centers estimate that CHCs will need to double their nuwber of MH providers. 98 Meeting these staffing needs will be extremely challenging, especially for CHCs located in rural areas. 104, 105 Recruiting more MH specialists to practice in rural America is not feasible, and innovative solutions are needed to address this issue.

6 EXPERTISE AND QUALIFICATIONS OF THE PI AND CO-INVESTIGATORS TO BE COMPLETED BY PI INTERVENTIONS Initial Interventions Both interventions have been proven to be effective in RCTs and are routinely used to deliver healthcare services, and thus do not represent increased risk to patient compared to the care they received prior to study enrollment. Both interventions are intended to be time limited, such that patients are eventually discharged back to usual care in the PC setting. In TCC, CHC PCPs retain the primary responsibility for patient care and are supported by onsite CHC care managers and offsite telepsychiatrists stationed at the University of Arkansas for Medical Sciences. Telepsychiatrists will conduct patient consultations via interactive video and recommend medications for the PCPs to prescribe. Care managers closely monitor patient symptoms to ensure that care is measurement based 106 and telepsychiatrists recommend revisions to the treatment plan until the patient experiences significant clinical improvement (a principle called Treatment to Target ). Care managers also offer patients Behavioral Activation (BA), a brief evidence-based psychotherapy. In TER, offsite telepsychiatrists and telepsychologists stationed at the University of Arkansas for Medical Sciences take over the responsibility for patient care, and treatment is delivered to patients in the CHC setting via interactive video. PCPs support the telepsychiatrist and telepsychologist. The TER intervention will also be measurement based and follow treatment to target principles. Telepsychiatrists will follow medication algorithms. Telepsychologists will follow manualized, evidence-based psychotherapies. An offsite care coordinator stationed at the University of Arkansas for Medical Sciences will use phone-based Motivational Interviewing techniques to facilitate attendance at interactive video appointments. Clinicians in both TCC and TER will have flexibility to tailor treatments according to patient preference. Telepsychiatry Collaborative Care (TCC) The treatment protocol for TCC is included in Appendix?. Roles and Clinical Activities CHC PCPs prescribe all psychotropic medications. Trained CHC care managers will support the PCP by promoting adherence to treatment and assessing treatment response. Care manager encounters (either phone or faceto-face depending on patient preference) will be scheduled every two weeks to foster proactive communications between an activated informed patient and a coordinated care team. Care managers will provide psychoeducation, monitor symptom severity, promote adherence to medications and help manage side-effects. Patients with PTSD will be monitored using the 17-item PCL and patients with BD will be monitored using the five-item Altman Mania Rating Scale. Depression symptoms will be monitored for all patients using the PHQ-9. Comorbid alcohol abuse will be assessed using the Audit-C. Depending on patient preference, care managers will provide either Behavioral Activation (details below) or help setting self-management goals such as physical activities, enjoyable activities, social activities and/or strategies to cut down on substance misuse. A HIPAA compliant web-based Care Management Tracking System (CMTS) hosted at the University of Washington will be used by care managers to structure all encounters. 107 Care managers will have weekly provider-to-provider consultations with the telepsychiatrist to review treatment plans for patients not responding to treatment. The University of Arkansas for Medical Sciences telepsychiatrist will use CMTS to review patients severity scores, comorbidities and medications, and to record treatment recommendations for the PCPs. To maximize PCPs comfort treating PTSD and BD, the telepsychiatrist will also conduct consultations with patients via interactive video to establish the diagnosis and recommend medications for the PCP to prescribe. Pharmacotherapy - For PTSD, consulting telepsychiatrists will initially recommend a generic antidepressant medication, augmented with prazosin for nightmares or trazodone for insomnia. For BD, consulting telepsychiatrists will recommend (fluoxetine/olanzapine, lamotrigine, lithiuw, lurasidone, or quetiapine). Drug monotherapy will be emphasized. Behavioral Activation (BA) BA is feasible to deliver by care managers in PC in 6-8 sessions, 108 is highly patient-centric, and has a good evidence base for reducing both PTSD and depression symptoms (which tend to dominate in BD) Care managers will follow a BA treatment manual adapted to treat both depression and PTSD symptoms that includes a trauwa exposure element focusing on avoidance behaviors. 112 BA is patient-centric because patients therapy homework is to engage in activities that are important to them. According to behavioral theory, symptoms will improve as patients decrease their avoidance behaviors and become more involved in activities that are meaningful to them, thereby increasing their sense of mastery and pleasure. Each BA session will be recorded in CMTS, including which specific elements were discussed during a session. Patient-centered Mobile Health System - Because care manager follow-up encounters will occur during clinic hours, they can be difficult to schedule for some patients, leading to poor continuity of care. Mobile technology allows patients to check in with their care manager at any time by remotely reporting information about

7 how they are doing. Mobile technology can also be used as a personalized reminder system for important activities like appointments, taking medications or completing psychotherapy homework. A HIPAA compliant smartphone app developed for the study will be used to securely collect PHQ-9, PCL, and other clinical data from patients and upload it to CMTS for care managers to access. Telepsychiatry Enhanced Referral (TER) The treatment protocol for TER is included in Appendix?. Roles and Clinical Activities - The University of Arkansas for Medical Sciences telepsychiatrist and/or telepsychologist will deliver the PTSD and/or BD treatment via interactive video to patients located at the CHC. Telepsychiatrists/telepsychologists will administer symptom rating scales at the beginning of each session. PCPs at the CHC will support the telepsychiatrist as needed by monitoring relevant parameters, (e.g., body mass index, blood seruw levels, lipids, etc) and assisting in handling MH emergencies. Onsite CHC staff will facilitate scheduling appointments for interactive video encounters. A care coordinator at the University of Arkansas for Medical Sciences will use motivational interviewing to encourage engagement. The first encounter will be with the telepsychiatrist to establish diagnosis and develop a treatment plan consisting of algorithm-informed medication management and/or evidence-based psychotherapy. Pharmacotherapy - The telepsychiatrists will prescribe medications based on the most recently available algorithms published by the International Psychopharmacology Algorithm Project (2005) 119 and the Harvard Psychopharmacology Algorithm Project (2010). 120 These algorithms are state dependent such that the prescribing decision points are based on each patient s current and past treatment history. For PTSD, the medication algorithm recommends antidepressant medication as the first line of treatment. The algorithm recommends the use of Prazosin and trazodone as an augmentation strategy for those with nightmares or insomnia (first line of treatment) or those with residual sleep disturbance. The algorithm also considers other residual symptoms that are not responsive to current treatment, as well as comorbidities. For BD, the medication algorithm recommends lithiuw, quetiapine, or lamotrigine monotherapy as first line treatments. Lurasidone will be considered as a first line treatment based on its recent FDA approval for bipolar depression (although we will be sensitive to patient out-of-pocket cost). Olanzapine/ fluoxetine is not favored as a first line treatment because of metabolic side effects of olanzapine and the long half-life of fluoxetine. Given the large nuwber of recent drug trials and FDA approvals for BD, we will include both the current and emerging evidence about the effectiveness of specific mood stabilizers. For patients with both PTSD and BD, the telepsychiatrist will focus on prescribing for symptoms that are most bothersome to the patient. Psychotherapy - Patients will be offered either CPT for PTSD or CBT for BD. CPT contains elements of both exposure and cognitive restructuring and is effective for PTSD Psychologists will follow Resnick s Cognitive Processing Therapy: Therapist s Manual. For BD, psychotherapy is recommended as an augmentation to pharmacotherapy in the acute phase of treatment for depression (but not mania). 125 In a critical review of the literature, Miklowitz concluded that there is strong evidence that Cognitive Behavioral Therapy (CBT) improves depression outcomes in BD. 126 Psychologists will follow STEP-BD investigator a revised version (few sessions) of Otto s Managing Bipolar Disorder: A Cognitive Behavior Treatment Program Workbook. 127 Patients with both PTSD and BD may choose whichever psychotherapy best fits their needs and have the option of completing both forms of psychotherapy. Care Coordination - To increase engagement, the offsite care coordinator will telephone patients missing appointments. The care coordinator will use Motivational Interviewing techniques to help patients address ambivalence about treatment and overcome barriers to care. Potential barriers include logistic barriers (e.g., transportation, childcare), cultural barriers (e.g., stigma, stoicism, self-reliance), lack of acceptance of diagnosis, lack of perceived need for care, and lack of perceived treatment effectiveness and/or safety. Motivational interviewing is a non-judgmental and non-adversarial approach to facilitating behavior change. There are four simple principals to motivational interviewing: 1) express empathy, 2) develop discrepancy, 3) roll with resistance, and 4) support self-efficacy. This patient-centered approach will involve accepting the patient s ambivalence about treatment using reflective listening, helping the patient reframe their perceptions, and encouraging the patient to believe that they can successfully engage in treatment. There is good evidence that motivational interviewing can promote engagement in MH treatment Care coordinators will conduct up to four motivational interviewing telephone calls with patients. Adaptive Engagement Intervention: Phone-Psychiatry Enhanced Referral (PER) The adaptive engagement intervention involves delivering psychiatric and/or psychological treatment (either initially or exclusively) by telephone to patients in their home. Offsite care coordinators will call the patient to schedule appointments. The telepsychiatrist/telepsychologist will initiate the calls to the patient s home and deliver the treatment described above in TER. Home-based phone encounters will further increase patients geographical and cultural access to MH specialists beyond PC-based interactive video encounters, and thus should increase engagement. However, because the

8 therapeutic bandwidth associated with the phone is lower than interactive video, this approach may reduce clinical effectiveness. Although phone-based psychiatric and psychological treatments are not currently reimbursable and are not often used in routine care, results of this proposed trial may lead to policy changes in reimbursement for phone care. Training and Implementation To train clinicians, we will use methods developed and routinely used by the University of Washington s Advancing Integrated MH Solutions (AIMS) Center: The AIMS Center utilizes an evidence-based training approach designed to maximize clinicians knowledge and skill acquisition and effectively transfer the learning from the training environment to the practice setting. We will use a combination of in-person workshops, online modules with built-in learning assessments, and webinar-based follow-up sessions. Both University of Arkansas for Medical Sciences and University of Washington staff will be involved in these trainings. For TCC, training activities will focus on key individual and team tasks, team workflows and communication strategies. Care managers will be provided case-based BA training and ongoing consultation. For the telepsychiatrists, University of Washington staff will disseminate the prescribing guidelines and have quarterly calls to discuss their use. For the psychologists, we will provide web-based training in CBT and CPT and case consultation from the University of Washington for not already trained in these evidence-based manualized psychotherapies. When new clinicians are hired, they will be provided with access to online, self-paced training materials and individualized support for skill development as needed. Telemedicine Implementation The University of Arkansas for Medical Sciences s telepsychiatrists and telepsychologists will be credentialed and privileged to treat patients at the CHCs and have remote access to their EHRs. For TCC, the telepsychiatry consultation note will be entered directly into the CHC s EHR. For TER, the telepsychiatrists/telepsychologists will be given remote access to the CHC EHR to enter progress notes, as well as to request lab tests and access results. The University of Arkansas for Medical Sciences s telepsychiatrists/telepsychologists will visit CHCs at least once a year to cultivate a trusting relationship. METHODOLOGY The primary objective of this mixed-methods pragmatic comparative effectiveness trial is to compare TCC and TER from the patient and provider perspective. The secondary objective is to determine whether patients not engaging and responding to TER, improve with PER. We propose a pragmatic trial design with broad inclusion criteria and limited exclusion criteria. Only those few CHC patients who are already engaged in specialty MH care or whose PCP is not comfortable treating them will be excluded. Patients will be the unit of randomization. Intervention fidelity will be measured but not controlled. Patient engagement will also be measured but not required, and intent to treat analysis will be conducted. Thus, we are comparing TCC and TER with regard to their combined impact of engagement and clinical effectiveness in routine care. Telepsychiatrists and telepsychologists from the University of Arkansas for Medical Sciences will provide the specialty MH care. Mixed quantitative and qualitative methods will be used to assess selfreported outcomes. Telephone Survey - All patients will be administered surveys at baseline, 6 and 12 months by telephone to minimize patient burden and attrition. The telephone survey will be conducted by the coordinating center (University of Washington) and is not included as part of this research protocol. The following instruwents will be used to collect data during the baseline interview. Demographics, employment status, insurance Physical Health Comorbidities Written for SPIRIT Written for SPIRIT Mental Health Related Quality of Life SF Recovery Goals Recovery Assessment Scale 133 Depression SCL20 134

9 Mania Altman Mania Rating Scale modified , 137 Bipolar Disorder Internal State Scale modified Sleep Jenkins modified 138 PTSD PTSD Diagnostic Scale 139 Borderline Personality Disorder McLean Screening InstrUWent for Borderline Personality 140 Panic Disorder APA DSM5 Severity Measure for Panic Disorder Generalized Anxiety GAD Alcohol Use AUDIT 142 Drug Use DAST file:///c:/users/fortney/downloads/apa_dsm5_severity- Measure-For-Panic-Disorder-Adult%20(2).pdf Barriers to Care Perceived Stigma and Barriers to Care for Psychological Problems scale 144 Patient Preferences Quality Improvement for Depression 145 Service Utilization Treatment History NCS-R 11 Current Service Use Written for SPIRIT Medication Adherence SCAP-HQ 146 Side Effects Written for SPIRIT Experience of Care CAHPS ECHO 147 Patient Activation Patient Activation Measure, modified 148 Qualitative Interviews - A sub-sample of patients will be invited to participate in qualitative interviews to describe their treatment experience using their own words. Likewise, PCPs will be invited to participate in qualitative interviews to voice their perspective. Methods and interview guides for the qualitative interviews will be submitted as a modification to this protocol before recruitment and data collection activities being. STATISTICAL DESIGN We will use a Sequential, Multiple Assignment, Randomized Trial (SMART) design to compare TCC and TER, and to determine whether patients not engaging and responding to TER improve with PER (an adaptive engagement intervention). Adaptive interventions are used to customize the treatment for patients whose needs are not being met. Patients not engaging in TER by six months will be randomized a second time to either continued-ter or PER. See Figure. The first stage of a SMART is the same as a traditional RCT, in which patients are randomized to two (or more) initial interventions. However, in contrast to traditional RCTs, SMARTs specify a tailoring variable that is used to classify patients into sub-groups that are subsequently randomized to adaptive interventions in the second stage. 149, 150 SMARTs are particularly useful whenever there is substantial treatment heterogeneity (i.e., variation in treatment response across patients). Because we anticipate that a substantial percentage of study participants will not engage in specialty MH treatment in TER (initial intervention), we chose to test an adaptive engagement intervention that should promote engagement (PER), but which may be less clinically effective than TER because of the lower therapeutic bandwidth of phones.

10 Tailoring Variable Because acute medication management by a psychiatrist is often provided to patients at least on a quarterly basis, we chose to define non-engagement in TER as having 2 encounters with a telepsychiatrist or telepsychologist in the first 6 months. Randomization We will use a two-stage randomization scheme. First Stage Randomization The first stage randomization will be conducted at the patient level immediately before being administered the baseline research assessment. Randomization will be stratified by CHCs (i.e., for each CHC system, equal nuwbers of patients will be allocated to TCC and TER) to avoid bias due to site-level variation. In addition, we will stratify by disorder to ensure that equal nuwbers of patients with PTSD and BD are randomized to each group. Because patients with BD are often at elevated risk for experiencing trauwa, approximately 25%-32% of patients with BD will also screen positive for PTSD. 35, 151 For patients screening positive for both PTSD and BD (n 125), we will categorize them as BD for purposes of stratification because that disorder would likely be the one that drives the prescribing. Second Stage Randomization - The second level randomization will be conducted immediately after the completion of the 6 month follow-up research assessment. For patients initially randomized to TER, the use of telepsychiatry/telepsychology services as docuwented by the telepsychiatrist and telepsychologist will be used to determine whether each study participant meets nonengagement (the tailoring variable is defined above). Those patients meeting non-engagement will be randomized to PER or continued-ter. Randomization will again be stratified by CHC and disorder. AssUWing that 50% of the patients do not engage, there will be 250 patients randomized in the second stage to PER or continued-ter. Statistical Analysis The primary outcome measure is the Mental Health Related Quality of Life (Short Form 12 Mental Health Composite SUWmary (MCS)). The secondary outcome measures are: 1. Recovery-oriented outcomes (Recovery Assessment Scale)

11 2. Psychotherapy engagement (NUWber of self-reported Cognitive Behavioral Therapy, Cognitive Processing Therapy, or Behavioral Activation counseling sessions that were attended) 3. Medication Adherence (Schizophrenia Care and Assessment Program Health Questionnaire (SCAP-HQ)) 4. Satisfaction (Experience of Care and Health Outcomes Survey (satisfaction question)) 5. Depression Severity (Hopkins Symptom Check List (SCL)-20) 6. Mania Severity (for sub-sample screening positive for Bipolar Disorder) (Altman Mania Rating Scale (modified by the investigators for telephone delivery)) 7. Bipolar Severity (for sub-sampling screening positive for Bipolar Disorder) (Internal State Scale, Version 2) 8. PTSD Severity (for sub-sampling screening positive for PTSD) (PTSD Diagnostic Rating Scale) The other outcome measures are: 1. Perceived access to mental health services (Perceived Stigma and Barriers to Care for Psychological Problems scale (minus the 3 military-specific items). 2. Therapeutic Alliance (Kim Alliance Scale 152, 153 ) 3. Patient activation (Patient Activation Measure) 4. Use of health services 5. Patient Centeredness (Experience of Care and Health Outcomes Survey) 6. Psychotropic medication side effects 7. Alcohol misuse (Audit-C) 8. Drug misuse (Dast-10) The analysis for each hypothesis is described below in more detail. Hypothesis 1: Patients randomized to TCC will have better treatment experiences (access, therapeutic alliance, patient-centeredness, activation and satisfaction) and treatment engagement (appointments attended, medication adherence, psychotherapy homework) than patients randomized to TER. Hypothesis 2: Patients randomized to TCC will have better self-reported clinical outcomes (e.g., symptoms, sideeffects) and recovery-oriented outcomes (e.g., health related quality of life, progress towards life goals) than patients randomized to TER. For Hypotheses 1 and 2, the explanatory variable of interest will be group randomization status (e.g., TCC group versus TER group). Covariates will include patient socio-demographic and clinical casemix variables chosen using the method of purposeful selection. Regression models will be specified with the appropriate distribution and link functions to match the dependent variable (e.g., linear for the SCL-20 score, binomial for psychotherapy initiation, negative binomial for visits, ordinal for satisfaction level). Separate regressions will be estimated for 6 month outcomes and 12 months outcomes. For the full sample (n=1,000), the regression analyses will take into account stratification by clinic and disorder. For diagnostic specific samples (n=500), the regression analyses will take into account stratification by clinic. Given that randomization is at the patient level we will include clinic as a stratifying variable in the analyses (e.g. fixed effect). Attrition weights will be calculated and used in the regression analyses. Hypothesis 3: Patient treatment engagement and total clinical contact time will completely mediate any observed differences in self-reported and recovery-oriented outcomes between patients randomized to TCC and TER. For Hypothesis 3, we will use the method developed by the MacArthur Foundation. We will analyze only those outcomes found to be significant when testing Hypothesis 2. All analyses will be conducted separately for the 6 and 12 month outcomes. The mediator variables in the 6 month regression will represent the time period from baseline to the 6 month follow-up, whereas the dependent variables will represent the brief time period (e.g., two weeks) immediately prior to the 6 month follow-up. Likewise, the mediator variables in the 12 month regression will represent the time period from the 6 month follow-up to the 12 month follow-up, whereas the dependent variables will represent the brief time period immediately prior to the 12 month follow-up. Thus, all mediators represent the time period after baseline, but before the measurement of the dependent variable. The first phase of the analysis will be to examine whether there are differences in the hypothesized mediator variables across the TCC and TER groups at 6 and 12 months. Separate regression analyses will be estimate for each hypothesized mediator with group randomization status specified as the explanatory variable of interest. This analysis will already have been completed for the patient engagement mediators (Hypothesis 1). All potential mediators that are found to be significantly different between the TCC and TER groups will be included in the next phase of the analysis. The

12 second phase of the analysis will use the same regression specifications that were used to test Hypothesis 2. We will add the mediator variables as both main effects and interaction effects with the main explanatory variable (group randomization status). We will then assess the statistical significance of the potential mediator variables (jointly for main and interaction effects) and we will use a likelihood ratio test to determine whether the parameters for group randomization status estimated in the mediation analyses are significantly different than the parameter for group randomization status estimated by the regression analyses used to test Hypothesis 2. If one or more of the potential mediator variables is significant and the likelihood ratio test is significant, then we will conclude that there is mediation. We will conclude that there is full mediation If the group randomization parameter estimate is not significantly different than zero, and partial mediation if the group randomization parameter estimate is significant. Exploratory Hypothesis 4: Patients randomized to PER will have a better treatment experience and engagement in care during the second 6 month period than patients randomized to continued-ter. Exploratory Hypothesis 5: Patients randomized to PER will have better patient-reported clinical outcomes and recovery-oriented outcomes during the second 6 month period than patients randomized to continued-ter. For Hypotheses 4 and 5, the explanatory variable of interest will be randomization to the TER group versus PER group. Covariates will include patient socio-demographic and clinical casemix variables chosen using the method of purposeful selection. Regression models will be specified with the appropriate distribution and link functions to match the dependent variable. Only the 12 month follow-up data will be used for this analysis. Only patients originally randomized to the TER intervention will be used for this analysis. For the full sample (n=500), the regression analyses will take into account stratification by clinic and disorder. For diagnostic specific samples (n=250), the regression analyses will take into account stratification by clinic. Clinic will be specified as a fixed effect. Attrition weights will be calculated and used in the regression analyses. Hypothesis 8: Patient self-reported clinical outcomes and recovery-oriented outcomes will be moderated by minority race/ethnicity and older age (with better outcomes observed in TCC), and by high levels of symptom severity and comorbidity (with better outcomes observed in TER)]. Hypothesis 8 will also be tested using the method developed by the MacArthur Foundation. All analyses will be conducted separately for the 6 and 12 month follow-up data. The moderator variables in the 6 and 12 month regression analyses will represent the pre-baseline time period and will not change over time. The moderator analysis will use the same regression specifications that were used to test Hypothesis 2. The hypothesized moderators will be added as a group as both main effects (if they were not already specified as covariates in the regressions used to test Hypothesis 2) and as interaction effects (with group randomization status). The significance of the interaction effects will be used to determine whether the patient characteristic is a treatment moderator. A negative interaction term will be interpreted as a risk factor for experiencing a smaller TCC treatment effect and positive interaction term will be interpreted as protective factor for not experiencing a smaller TCC treatment effect. The presence of significant treatment moderators will be interpreted as evidence of treatment heterogeneity, and subgroup specific treatment effects will be estimated with associated confidence intervals and displayed using a funnel plot to characterize the degree of heterogeneity. RECRUITMENT METHODS CHC staff routinely screen patients for PTSD and Bipolar Disorder and we will recruit all patients screening positive for either disorder. To maximize the comfort level of potential study participants, CHC staff will recruit and consent patients. Participating CHCs will obtain a Federalwide Assurance designating the University of Arkansas for Medical Sciences IRB as having oversight of huwan subjects protection, allowing CHC staff to be fully engaged in research activities. Following completion of web-based CITI HUWan Subjects Protection Training, we will train all CHC staff in the recruitment and consenting processes, allowing for local flexibility in language and procedures to account for variations in community culture and PC workflow. Following a positive PTSD or BD screen, CHC staff will talk with the patient and their PCP to assess study eligibility prior to engaging the patient in the informed consent process. Once the patient is consented, CHC staff will upload contact and screening information to our survey group s web-interface, and the patient will be randomized after completing the baseline survey. CHC staff will upload the following information to the web-interface: 1) Scanned signed informed consent docuwent, 2) Screening results, 3) Clinic recruited from, 4) Patient contact information (name, telephone nuwber(s), address, 5) Alternate contact information and 6) Language preference