1 Workshop on Adaptive Treatment Strategies Janet Levy, Ph.D. Jim McKay, Ph.D. Carl Pieper, Dr.Ph. Madhukar Trivedi, M.D.

2 Purpose EDUCATIONAL: What are “adaptive treatment strategies” (“dynamic treatment regimes”)? THOUGHT PROVOKING: How might they be applied within the community of treatment providers within our network?

3 Agenda Introductions: Janet Levy Experimental Designs: Carl Pieper Adaptive Treatment Strategies in: The Addictions: Jim McKay Mental Health: Madhukar Trivedi The CTN: Janet Levy Closing: Janet Levy

4 History Innovations in the design of clinical trials have been in the service of pharmaceutical companies to facilitate drug development. The results OFTEN do NOT inform clinical practice, especially in mental health. “A less considered aspect of the usual placebo-controlled non-equivalence design is the disparity between the decisions that it supports and those that pervade clinical practice” p. 3250, Dawson and Lavori(2004).

5 History Development of CTN0030, a trial for the treatment of prescription opioid dependence began in Team wanted to design a study which would be “practical” (i.e. inform clinical practice). Idea of re-randomizing those who relapse during “detoxification” surfaced quickly (to support inferences about which treatment is best following relapse). How to frame the primary hypothesis? Is it about the first phase (detoxification?) OR is it about what to do for those who relapse early? We struggled, the DSMB struggled!!

6 History Work illustrating how one might design trials to support the development of clinical strategies in addiction and mental health was just beginning to be published in 2004!! Dawson, R. and Lavori, P.W. (2004) Discuss the need for innovations in trial design to inform clinical practice. Murphy, S.A. (2005). Presents preliminary sample size formulae to test hypotheses about strategies in a trial using multiple randomizations. Presents actual simple trial designs. Murphy, S.A. et al, (with McKay, J.R.), (2006 and 2007). Provides further thinking around how to construct adaptive treatment strategies and how to design trials specifically for the development of long terms strategies.

7 The Promise of Adaptive Treatment Strategies Help with adherence/drop out in out trials!!! Treat adherence/drop out as another : Intermediate outcome Indication for a different “treatment” Opens up the potential for including MANY more patients in our trials Vehicle for “Integrated Care” Use psychosocial treatments to facilitate Meds ? Use meds to facilitate psychological effects? Vehicle for “Stepped Care”

8 Carl Pieper, Dr. Ph. Principal Investigator, Clinical Trials Network, National Institute on Drug Abuse Assistant Research Professor, Dept. of Biometry & Bioinformatics, Duke University Medical Center. Director and Chief, Computer and Statistics Laboratory, Center for Aging & Human Development, Duke University Medical Center Senior Fellow, Center for Aging & Human Development, Duke University

9 Jim McKay, Ph.D. Professor of Psychology in Psychiatry at the University of Pennsylvania. Director of the joint Penn--TRI Center on the Continuum of Care in the Addictions. Co-director of the Center of Excellence in Substance Abuse Treatment and Education (CESATE) at the Philadelphia Veterans Affairs Medical Center."

10 Madhukar Trivedi, M.D. Professor and director of the Mood Disorders Research Program and Clinic at the University of Texas Southwestern Medical Center in Dallas where he holds the Lydia Bryant Test Professorship in Psychiatric Research. Director for the depression algorithm for the Texas Medication Algorithm Project (TMAP). Co-director of the Dallas Coordinating Center of the NIMH funded project “Sequences Treatment and Alternatives to Relieve Depression (Star*D), of which he is co-principal investigator..

11 Questions about Clinical Decisioning in the CTN 1a. In your clinical practice, what clinical signs indicate that A client is not responding well to treatment?

12 Questions about Clinical Decisioning in the CTN 1b. In your program, what treatment options are available when the client is not responding to standard care, or the first treatment he/she is provided?

13 Questions about Clinical Decisioning in the CTN 1c. In your clinical practice, what clinical signs indicate that a client is responding well to treatment?

14 Questions about Clinical Decisioning in the CTN 1d. In your program, when the patient is doing well, what treatment options are available besides more of the same or discharge?

15 Questions about Clinical Decisioning in the CTN 2. Based on your own experience as a clinician, which clinical decisions about patient care are the most challenging (for any reason)?

16 Questions about Clinical Decisioning in the CTN 3. Based on your own experience as a clinician, which clinical decisions are in most need of empirical research (for any reason)?

17 Questions about Clinical Decisioning in the CTN 4. What do you do when a patient returns to treatment several times without a prolonged period of success between treatments?

18 Questions about Clinical Decisioning in the CTN 5. How long would you continue to apply a particular treatment to a client before determining whether or not the treatment is successful?

19 References Brooner, R. K. Behavioral contingencies improve counseling attendance in an adaptive treatment model. Journal of Substance Abuse Treatment. (2004), 27: Dawson, R. Lavori, P.W., Coryell, W.H., Endicott, J. Keller, M.B. Course of treatment received by depressed patients. Journal of Psychiatric Research. (1999), 33: Dawson, R., Lavori, P.W. Placebo-free designs for evaluating new mental health treatments: the use of adaptive treatment strategies. Statistics in Medicine. 2004, 23: Dawson R., Lavori, P.W. Comparison of designs for adaptive treatment strategies: baseline vs. adaptive randomization. Journal of Statistical Planning and Inference. (2003),117 : 365 – 385. Lavori, P.W., Dawson, R. A design for testing clinical strategies: Biased – coin adaptive within – subject randomization. Journal of the Royal Statistical Association : Lavori, P.W., Dawson, R. Rush, A.J. Flexible treatment strategies in chronic disease: clinical and research implications. Biological Psychiatry. (2000), 48: Lavori PW, Rush JA, Wisniewski SR,Alpert J, Fava M, Kupfer DJ, Nierenberg A, Quitkin FM, Sackeim HA, Thase ME, Trivedi M.(2001). Strengthening clinical effectiveness trials: equipoise- stratified randomization. Biological Psychiatry, 50:

20 References Lavori, PW, Dawson, R.(2004) Dynamic treatment regimes: practical design considerations. Clinical Trials. (2004), 1: McKay, J.R., Lynch, K.G., Shepard, D.S., et al. The effectiveness of telephone – based continuing care in the clinical management of alcohol and cocaine use disorders: 12 month outcomes. Journal of Consulting and Clinical Psychology, (2004), 72: McKay, J.R. Is there a case for extended interventions for alcohol and drug use disorders? (2005), 100: McKay, JR. Lynch, K.G., Shepard, D.S., Pettinati, H.M. The effectiveness of telephone-based continuing care for alcohol and cocaine dependence: 24 – month outcomes. Archives of General Psychiatry. (2005), 62: McKay, J.R. Continuing care in the treatment of addictive disorders. Current Psychiatry Reports. (2006), 8: McLellan, A.T. Have we evaluated addiction treatment correctly? Implications from a chronic care perspective. Addiction, (2002), 97, McLellan, A.T., Lewis, D.C., O’Brien, C.P., Kleber, H.D. Drug dependence, a chronic medical illness. Implications for treatment, insurance, and outcomes evaluation. Journal of the American Medical Association. (2000), 284, No.13, 1689 – 1695.

21 References Murphy, SA, Van Der Laan, MJ, Robins, JM and Conduct Problems Prevention Group. Marginal mean models for dynamic regimes. Journal of the American Statistical Association. (2001), 96, No. 456: 1410 – Murphy, SA. Optimal dynamic treatment regimes. Journal of the Royal Statistical Society. 2003, 65: Murphy, SA. (2005). An experimental design for the development of adaptive treatment strategies. Statistics in Medicine.24: Murphy, SA., Lynch, K.G., Oslin, D.A., McKay, J.R., Tenhave, T. Developing adaptive treatment strategies in substance abuse research. Drug and Alcohol Dependence. (2006). Murphy, SA., Oslin, D.W., Rush, A.J., Zhu, J. Methodological challenges in constructing effective treatment sequences for chronic psychiatric disorders. Neuropsychopharmacology. (2007) 32: O’Malley S.S., Rounsaville, B.J., Farren, C. Namkoong, K. Wu, R., Robinson, J. O’Connor, P.G.. Initial and maintenance naltrexone treatment for alcohol dependence using primary care vs specialty care. A nested sequence of 3 randomized trials. Archives of Internal Medicine.(2003), 163,

22 References Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME, Ritz L, Biggs MM, Warden D, Luther JF, Shores- Wisldon K, Niederehe G, Fava M, STAR*D Study team. Bupropion-SR, Sertaline, or Venlafaxine-XR after failure of SSRIs for Depression. The New England Journal of Medicine.(2006), 354:12: Thall, P.F., Wathen, J.K. Practical Bayesian adaptive randomization in clinical trials. European Journal of Cancer. (2007), 43: Trivedi, M.H. et al, Medication augmentation after failure of SSRIs for Depression. The New England Journal of Medicine. (2006), 354:12: Trivedi, M. H. Fava, M. Marangell, L.B. Osser, D.N., Shelton, R.C. Use of treatment algorithms for depression. Primary Care Companion to the Journal of Clinical Psychiatry (5).