Meredith Gunlicks-Stoessel

Designing a pilot sequential multiple assignment randomized trial for developing an adaptive treatment strategy

There is growing interest in how best to adapt and readapt treatments to individuals to maximize clinical benefit. In response, adaptive treatment strategies (ATS), which operationalize adaptive, sequential clinical decision making, have been developed. From a patients perspective an ATS is a sequence of treatments, each individualized to the patients evolving health status. From a clinicians perspective, an ATS is a sequence of decision rules that input the patients current health status and output the next recommended treatment. Sequential multiple assignment randomized trials (SMART) have been developed to address the sequencing questions that arise in the development of ATSs, but SMARTs are relatively new in clinical research. This article provides an introduction to ATSs and SMART designs. This article also discusses the design of SMART pilot studies to address feasibility concerns, and to prepare investigators for a full-scale SMART. We consider an example SMART for the development of an ATS in the treatment of pediatric generalized anxiety disorders. Using the example SMART, we identify and discuss design issues unique to SMARTs that are best addressed in an external pilot study prior to the full-scale SMART. We also address the question of how many participants are needed in a SMART pilot study. A properly executed pilot study can be used to effectively address concerns about acceptability and feasibility in preparation for (that is, prior to) executing a full-scale SMART.

A Pilot SMART for Developing an Adaptive Treatment Strategy for Adolescent Depression

This pilot study was conducted to assess the feasibility and acceptability of 4 adaptive treatment strategies (ATSs) for adolescent depression to plan for a subsequent full-scale clinical trial. The ATSs aim to address 2 questions that arise when personalizing treatment: (a) For adolescents treated with Interpersonal Psychotherapy for depressed adolescents (IPT-A; Mufson et al., 2004), at what time point should therapists make the determination that the adolescent is not likely to respond if the initial treatment plan is continued (week 4 or week 8)? (b) For adolescents who are judged to need their treatment augmented, should the therapist increase the number of IPT-A sessions or add pharmacotherapy (fluoxetine)? A 16-week pilot sequential multiple assignment randomized trial (SMART) was conducted with 32 adolescents (M age = 14.9) who had a diagnosis of major depressive disorder, dysthymic disorder, or depressive disorder not otherwise specified. Adolescents were primarily female (75%) and Caucasian (84.4%). Data regarding the feasibility and acceptability of the study and treatment procedures and treatment response rates were collected. Week 4 was the more feasible and acceptable decision point for assessing need for a change to treatment. Adolescents, parents, and therapists reported a range of attitudes about medication and more intensive therapy as treatment options. Results from the pilot study have yielded additional research questions for the full-scale SMART and will improve our ability to successfully conduct the trial.

Early patterns of symptom change signal remission with interpersonal psychotherapy for depressed adolescents

Background: This study examined whether reductions in depression symptoms at different time points over the course of therapy predict remission for depressed adolescents treated with interpersonal psychotherapy (IPT‐A) or treatment as usual (TAU) delivered in school‐based health clinics. Methods: Participants were 63 adolescents (ages 12–18) drawn from a randomized controlled clinical trial examining the effectiveness of IPT‐A Mufson et al. [2004; Archives of General Psychiatry 61:577–584]. Adolescents were randomized to receive IPT‐A or TAU delivered by school‐based mental health clinicians. Assessments were completed at baseline and weeks 4, 8, 12, and 16 (or at early termination) and included the Hamilton Rating Scale for Depression (HRSD; Hamilton [1967; British Journal of Social and Clinical Psychology 6:278–2962]). Results: Receiver operating characteristic analysis was used to identify the time point and degree of reduction in HRSD that best predicted remission (HRSD <7) at the end of the trial (week 16). Week 4 was the best time point for classifying adolescents as likely to remit or not likely to remit for both IPT‐A and TAU. A 16.2% reduction in HRSD from baseline represented the best combined sensitivity and specificity in predicting week 16 remission status for adolescents treated with IPT‐A. A 24.4% reduction in depressive symptoms represented the best combined sensitivity and specificity in predicting remission status for TAU. Conclusions: These findings provide preliminary evidence of one early marker of remission with IPT‐A. Replication with larger samples would suggest that depressed adolescents who have not demonstrated at least a 16.2% reduction in their depressive symptoms after 4 weeks of IPT‐A may benefit from a change in the treatment plan. Depression and Anxiety, 2011.

Maternal Mood, Video-Mediated Cognitions, and Daily Stress During Home-Based, Family Interactions

This article presents an in vivo investigation of maternal negative mood, maternal video-mediated cognitions, and daily stressors in families with young children. Specifically, it was hypothesized that greater levels of maternal depressed, anxious, and hostile mood states immediately prior to a daily, reportedly routine, stressful parent-child interaction would be significantly associated with higher percentages of dysfunctional and lower percentages of functional cognitions. Forty-five mothers of 2- to 5-year-old children participated in this study by rating their mood before being videotaped in a daily routine with their child they reported as recurrent and stressful (e.g., mealtime). Using video-mediated recall (VMR) methodology, mothers were instructed to recall their cognitions upon immediate video review. Results indicated that greater levels of negative mood were associated with a greater percentage of dysfunctional cognitions and a smaller percentage of functional cognitions. Levels of maternal depressed mood were significantly and independently associated with greater rates of dysfunctional and lower rates of functional cognitions. Negative mood states were not consistently associated with the amount of maternal self-reported general irrationality, pointing to the utility of the VMR to elicit maternal cognitions specific to the observed interaction, which may have more implications for clinical intervention than more general irrationality measures. Evaluating maternal mood and using video-mediated maternal cognitions regarding daily family stressors can precipitate clinical interventions meant to reduce family-related stress and potentially improve maternal and child mental health outcomes.

Neural and neuroendocrine predictors of pharmacological treatment response in adolescents with depression: A preliminary study

Objective: Typically, about 30 to 50% of adolescents with depression fail to respond to evidence‐based treatments, including antidepressant medications such as selective serotonin reuptake inhibitors (SSRIs). Efforts for identifying predictors and moderators of treatment response are needed to begin to address critical questions relevant to personalized care in adolescent depression. In this pilot study, we aim to identify biological predictors of response to antidepressant treatment. Method: We used a multiple levels of analysis approach to evaluate threat system functioning (fronto‐limbic system and the associated hormonal cascade) to determine if key biological indexes at baseline could predict improvement in depressive symptoms after eight weeks of antidepressant treatment in adolescents with depression. Results: Neural predictors of favorable treatment response included lower amygdala connectivity with left supplementary motor area and with right precentral gyrus, and greater amygdala connectivity with right central opercular cortex and Heschls gyrus connectivity during rest. During an emotion task, neural predictors of treatment response were greater activation of the bilateral anterior cingulate cortex and left medial frontal gyrus. Additionally, different patterns of salivary cortisol obtained in the context of a modified Trier Social Stress Test were associated with those whose depressive symptoms remitted as compared to those whose symptoms persisted. Conclusions: This approach shows significant promise for identifying predictors of treatment response in adolescents with depression. Future work is needed that incorporates sufficiently powered, randomized control trials to provide the basis by which both predictors and moderators of treatment response are identified. The hope is that this work will inform the development of methods that can guide clinician decision‐making in assigning beneficial treatments for adolescents who are suffering from depression. HighlightsTreatments are available for adolescent depression.Few guidelines are available for guiding treatment selection.This study sets out to identify possible predictors of treatment response.Preliminary results support the use of neural circuitry and neuroendocrine indexes.The hope is to optimize the match between the individual and the treatment.

A Pilot Study of Stress System Activation in Children Enrolled in a Targeted Prevention Program: Implications for Personalization

Empirically validated interventions addressing childhood psychological problems are now readily available, but success likely depends in part on accurately identifying which children will benefit from which intervention. This pilot study examined the stress activation and response system, first as a way to differentiate high versus low-risk children, and second to explore indicators of the stress system associated with favorable intervention response. Method. Participants (N = 43, 58% male) were school-aged children who qualified for inclusion in the Early Risers “Skills for Success” Prevention Program based on their elevated levels of aggressive and/or socially withdrawn behavior and a normally developing comparison group. Compared to the normally developing group, children who were participants in the intervention exhibited a more blunted cortisol response to the stress paradigm. However, for the children in the intervention group, elevated cortisol levels at the start of the stress paradigm were concurrently associated with internalizing problems and predictive of improvement in internalizing problems over time. These findings provide preliminary evidence that hypothalamic pituitary adrenal (HPA) axis biological variables may be helpful tools for identifying children who would benefit from intervention and personalizing interventions.

Innovative child and adolescent treatment research for anxiety and depressive disorders.

‘‘Taking it to the Streets: Advancing the Dissemination of CBT’’ was the theme of the annual meeting of the Association for Behavioral and Cognitive Therapies (ABCT) held in Orlando, Florida in November 2008. ABCT is an interdisciplinary organization comprising researchers, clinicians, and trainees who are committed to development, implementation, and dissemination of behavioral, cognitive, and other evidence-based interventions. Historically, the ABCT annual meetings have had a preponderance of presentations focused on the treatment of anxiety and depressive disorders, and the 2008 meeting was no exception. Below are some of the highlights of this year’s convention. Treatments for childhood anxiety were evaluated in the Child/Adolescent Anxiety Multimodal Treatment Study (CAMS), a multisite National Institute of Mental Health (NIMH)-supported trial comparing the efficacy of cognitive-behavior therapy (CBT), sertraline, pill placebo, and a combination of CBT and sertraline for treating children and adolescents with Generalized Anxiety Disorder, Social Phobia, and/or Separation Anxiety Disorder. Study investigators presented a symposium focused on the primary outcomes of CAMS, the largest (n5 488) and first ever randomized clinical trial for childhood anxiety. Results indicated that the combined intervention led to significantly better response rates than CBT alone or sertraline alone (81% versus 60% and 55%, Po.001), whereas the monotherapies were not significantly different from each other. All three active conditions were superior to pill placebo (23.7% response rate, Po.001). John Walkup, M.D. and colleagues emphasized that clinicians can recommend three options for treating child and adolescent anxiety based on treatment availability and family preferences. Paul Rohde, Ph.D. from the Oregon Research Institute presented the findings of the continuation and maintenance treatments provided in the multisite Treatments of Adolescents with Depression Study (TADS). TADS examined the impact of psychosocial and psychopharmacological interventions on the achievement and maintenance of sustained treatment response for depression, comparing the effectiveness of fluoxetine (FLX), CBT, combination therapy (COMB), and pill placebo with clinical management (PBO). Following 12 weeks of acute treatment, patients in the FLX, CBT, and COMB conditions received 6 weeks of continuation treatment (intensity based on degree of response to acute treatment) followed by three maintenance treatment sessions scheduled over 18 weeks. Patients continued in the same treatment conditions assigned during acute treatment. Among the 39% (n5 95) of patients who had not achieved a sustained response (two consecutive ratings of a full response in assessments conducted 6 weeks apart) at the end of the acute treatment, sustained response rates during continuation and maintenance treatments were as follows: 80% COMB, 62% FLX, and 77% CBT (difference not significant). These results indicate that for most depressed adolescents who do not achieve a sustained response during acute treatment, extra time and treatment will result in the desired treatment effect. Although CAMS and TADS studied treatments for either anxiety or depression, respectively, Robin Weersing, Ph.D. from San Diego State University and University of California, San Diego presented the results of a pilot effectiveness study of a brief, integrated cognitive-behavioral approach to treat children with anxiety and/or depressive disorders in a primary-care setting. The eight-session treatment adapted and combined two CBT protocols, one for anxiety and one for depression, with a focus on ‘‘graded engagement’’ (a combination of exposure and behavioral activation). Children aged 8–17 (n5 60) with diagnoses of depression and/or anxiety were randomized to receive either the brief behavioral treatment or outside referral. Results at 12 weeks indicated that children in the brief CBT condition demonstrated significantly greater clinical global improvement and symptom reduction than children in the control group. Children with comorbid diagnoses demonstrated significant reductions in both anxious and depressive symptoms, suggesting the feasibility of a

Global advances in interpersonal psychotherapy research: highlights from the biennial meeting of the International Society for Interpersonal Psychotherapy

The third biennial conference of the International Society for Interpersonal Psychotherapy (ISIPT) was held in March 2009 in New York, New York. The theme of this year’s conference was ‘‘Global Updates,’’ and international experts provided updates on interpersonal psychotherapy (IPT) treatment, training, and research in Europe, Africa, Asia, Australasia, and the Americas. It was the largest gathering of IPTclinicians, researchers, educators, and trainees to date, reflecting the IPTcommunity’s place at the forefront of efforts to develop and disseminate evidence-based psychotherapy for diverse populations. ISIPTwas formed in 2000 with the goal of promoting the dissemination of IPT, establishing IPT training and accreditation pathways, and promoting international cooperation in IPT treatment, research, and training. Below are some of the highlights of this year’s conference. Vikram Patel, M.D., Ph.D. a Welcome Trust Senior Clinical Research Fellow at the London School of Hygiene and Tropical Medicine who is based in Goa, India, delivered a keynote address entitled, ‘‘The process of scaling up services for mental disorders in developing countries.’’ His talk focused on the 2007 Lancet Series on Global Mental Health that was created to emphasize the growing need to target mental health problems and increase mental health service coverage around the world, particularly in low and middle-income countries. He noted that prior to the Lancet series, mental health had not been included as a major global health initiative since a World Health Report in 2001. While there is ample evidence regarding efficacious treatments for many psychiatric disorders, these disorders are often undetected in primary care settings. If they are identified, psychosocial treatments are rarely available, particularly those known to be effective. One major barrier to addressing global psychiatric needs is the low number of psychiatrists and psychologists within the public sector and outside of urban areas. Reorganizing mental health systems is a critical step in increasing world-wide psychiatric services, and face-to-face contact will not be sufficient in order to close gaps in treatment delivery. The concept of ‘‘task-shifting,’’ or rationally redistributing some intervention activities to less specialized professionals (e.g., community health workers), was recommended as a means of sustaining interventions. The Lancet series has led to international advocacy, including endorsements from the World Federation of Mental Health and the World Health Organization, a call to action from the United Nations secretary, and mental health reforms and funding in several lowand middle-income countries. In addition, Dr. Patel launched the ‘‘Movement for Global Mental Health’’ on October 10, 2008, which has become ‘‘World Mental Health Day’’ (for more information, see www.globalmentalhealth.org). Finally, Dr. Patel emphasized the need for political will and solidarity from public health and mental health professionals in the field in order to begin to translate evidence into action. Following Dr. Patel’s address, several IPT researchers presented findings from their research adapting, implementing, and disseminating IPT to improve mental health in countries around the world. Lincoln Ndogoni, M.A. from the University of Nairobi and World Vision International, spoke about the use of local non-mental health staff in the provision of Interpersonal Psychotherapy for Groups (IPT-G) in low resource settings in Kenya. He and his colleagues developed culturally appropriate and relevant depression and functioning measures, and conducted an open trial of IPT-G to assess the feasibility and preliminary effectiveness of delivering IPT-G in Kenya. Fifteen locally trained nonmental health staff provided 16–20 weeks of 1–2 hr IPT-G sessions to 150 participants presenting with ‘‘kuhinyiririka meciria’’ (‘‘squeezed brain’’). At the end of the treatment, participants demonstrated significant reductions in depression severity, and only 3% of group members met criteria for depression. They also reported