Departments & Divisions
Charles L. Bowden, Ph.D.
Dr. Charles Bowden, clinical professor in the departments of psychiatry and pharmacology who occupies the Nancy U. Karren Endowed Chair in Psychiatry, is an internationally respected authority on bipolar disorder and mood-stabilizing medications. He is recognized in the Psychiatry/Psychology category.
Dr. Bowden’s research has defined the symptoms and biology of bipolar disorders, and he has contributed major new understandings about the effectiveness and biochemical and physiological effects of mood-stabilizing drugs. He has studied many of the newest treatments for bipolar disorder in tightly designed, randomized, controlled clinical trials that have allowed their approval by the U.S. Food and Drug Administration and wide dissemination to patients.
- Recognized in Thomson Reuter’s “The World’s Most Influential Scientific Minds, 2014; and for 2015.” The honorees published the greatest number of highly cited papers (top one percent of citations by field) in 21 broad fields between 2014 and 2015.
- Dr Bowden is one of 110 scientists worldwide recognized in the Psychiatry/psychology category and one of 8 scientists recognized whose primary research work is on bipolar disorder.
- Received the Andrew C. Leon Distinguished Career Award, The International Society for CNS Clinical Trials and Methodology, in 2016
- Served as Councilor for the International Society for Bipolar Disorders Training, Education and Research Committee in 2005
- Served on Task Force on Nomenclature and Outcome, 2007-, Task Force Expert Panel on Use of Antidepressants in Bipolar Disorders, 2012-2013, Committee on Research Diagnostic Criteria (RDC) for Bipolar Disorder 2013-, Vice President of Research, 2015
- 1968 - Postdoctoral Fellowship - Candidate in Psychoanalytic Training - Columbia Psychoanalytic Clinic for Training and Research
- 1968 - Residency - Psychiatry - New York State Psychiatric Institute and Presbyterian Hospital
- 1965 - Internship - Medicine - Presbyterian-St. Luke's Hospital
- 1964 - MD - Medicine - Baylor College of Medicine
- 1960 - BS - Pre-med - The University of Texas at Austin
- 9/2018 - Professor Emeritus - UT Health San Antonio, Psychiatry, San Antonio
- 1/2011 - Graduate Faculty - Graduate School of Biomedical Science
- 1/1981 - Professor - The University of Texas Health Science Center at San Antonio, Pharmacology, San Antonio
Research & Grants
Nonlinear Computation Tool to Chart Trajectories of Bipolar Disorder
7/2010 - 6/2017
The goal of this project is to complete the development of a patient-centered software system and mobile app to assist in managing bipolar disorder. The applicants have developed a brief self-rating tool (KIOS) to determine the precise clinical state of a person with bipolar disorder. KIOS also produces advice specific to the patient?s condition to help manage the course of the disease. In the Phase II component of this work, we will conduct a randomized, open 16 week study to assess the performance of KIOS in identifying changes in clinical state, improving illness course, and facilitating both patient and clinician initiated changes in lifestyle, social relationships, medications for bipolar disorders, and overall well-being. This multi-site trial is being performed under the direction of Dr. Charles Bowden at the University of Texas Health Science Center at San Antonio with concurrent sites at the University of Louisville and the Lindner Center of HOPE/University of Cincinnati. The sample size for this study is 120 (40 per site) and the duration is 16 weeks. The Phase II work will also refine KIOS software to facilitate patient and clinician use of KIOS displays of the course of bipolar symptoms and the guidance on self-management.
National Institute of Mental Health (NIMH)
Optimizing Outcomes in Bipolar illness Interventions in Hispanic Communities
9/2011 - 6/2016
An Advanced Center for Interventions and/or Service Research was established to conduct research that will personalize community based treatment of bipolar disorders to improve outcomes. We will investigate interactions of cultural factors, adherence and engagement, behavioral domains and biological factors with outcomes, thereby providing a model that can transform current diagnostic and treatment paradigms for bipolar disorder. A major aim of this proposal is to better develop our understanding of bipolar disorder in the Hispanic American population, in particular the impact of acculturation on adherence to treatment programs. These efforts will equip us to serve as a national resource to advance the NIMH mission of reducing the burden of bipolar illness and improve outcomes through the efforts of research about treatments and their acceptability to patients, and broadly disseminate this research for the purposes of improving clinical care, public education and public health planning.
Bowden CL. Calcium Signaling Measurements in Lymphoblastoid Cell Lines (LCLs) of Patients with Bipolar Disorder (BD) as Diagnositc, Pronostic or Predictive Biomarkers Biol Psychiat; 2014 Jan.
Coelho RP, Walss-Bass C, Arnold J, Singh V, Bowden CL. Identification of a New Ecophenotypic Variant (EV) of Bipolar Disorder (BD): Potential Treatment Implications of Extreme Childhood Abuse (ECA); 2014 Jan. (Biol Psychiat; vol. 75, no. 129S).
Bowden CL. Valproate. In: Schatzberg AF, Nemeroff CB, eds. Textbook of Psychopharmacology, 5th edition. Arlington, VA: The American Psychiatric Association Publishing; 2017.
Kohler O, Sylvia LG, Bowden CL, Calabrese JR, Thase M, Shelton RC, McInnis M, Tohen M, Kocsis JH, Ketter TA, Friedman ES, Deckersbach T, Ostacher MJ, Iosifescu DV, McElroy S, Nierenberg AA. White blood cell count correlates with mood symptom severity and specific mood symptoms in bipolar disorder Aust N Z J Psychiatry 2017 Apr;51(4):355-365.
Kohler-Forsberg O, Sylvia L, Thase M, Calabrese JR, Deckersbach T, Tohen M, Bowden CL, McInnis M, Kocsis JH, Friedman ES, Ketter TA, McElroy S, Shelton RC, Nierenberg AA. Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol do not affect 6-month mood-stabilizing treatment outcome among 482 patients with bipolar disorder Depress Anxiety 2017 Mar;34(3):281-290.
Caldieraro MA, Walsh S, Rabideau D, McElroy S, Bowden CL, Kocsis J, Janos J, Bobo W, Ketter TA, Thase M, Shelton R, Gao K, Tohen M, Dufour, Kamali M, McInnis M, Reilly-Harrington, Calabrese J, Nierenberg A, Friedman E, Sylvia L, Deckersbach T. Clinical Correlates of Acute Bipolar Depressive Episode with Psychosis J Affective Disorders 2017 Jan;31:29-33.
Tohen M, Gold AK, Sylvia LG, Montana RE, McElroy SL, Thase ME, Rabideau DJ, Nierenberg AA, Reilly-Harrington NA, Friedman ES, Shelton RC, Bowden CL, Singh V, Deckersbach T, Ketter TA, Calabrese JR, Bobo WV, McInnis MG. Bipolar mixed features - Results from the Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study J Affect Disord 2017 Jan;.
Grunze H, Vieta E, Goodwin G, Bowden CL, Licht R, Azorin J, Moller H, Kasper S. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders: Acute and Long-term Treatment of Mixed States in Bipolar Disorder The World Journal of Biological Psychiatry 2017 Jan;.
Walss-Bass C, Fries G, Quevedo J, Zei C, Zunta-Soares G, Spiker D, Bowden CL, Soares J, Kazimi I. Integrated transcriptome and methylome analysis in youth at high risk for bipolar disorder, a preliminary analysis Translational Psychiatry 2017 Jan;.
Reilly-Harrington NA, Sylvia LG, Rabideau DJ, Gold AK, Deckersbach T, Bowden CL, Bobo WV, Singh V, Calabrese JR, Shelton RC, Friedman ES, Thase ME, Kamali M, Tohen M, McInnis MG, McElroy SL, Ketter TA, Kocsis JH, Kinrys G, Nierenberg AA. Tracking medication changes to assess outcomes in comparative effectiveness research: A bipolar CHOICE study J Affect Disord 2016 Nov;205:159-164.
Tohen M, Mintz J, Bowden CL. Analysis of bipolar maintenance treatment with lithium versus olanzapine utilizing Multi-state Outcome Analysis of Treatments (MOAT) Bipolar Disord 2016 May;18(3):282-287.
Reilly-Harrington NA, Shelton RC, Kamali M, Rabideau DJ, Shesler LW, Trivedi MH, McElroy SL, Sylvia LG, Bowden CL, Ketter TA, Calabrese JR, Thase ME, Bob WV, Deckersbach T, Tohen M, McInnis MG, Kocsis JH, Gold AK, Singh V, Finkelstein DM, Kinrys G, Nierenberg AA. A tool to predict suicidal ideation and behavior in bipolar disorder: The Concise Health Risk Tracking Self-Report J Affect Disord 2016 Jan;192:212-218.
Bowden CL, Mintz J, Tohen M. Multi-state outcome analysis of treatments (MOAT): application of a new approach to evaluate outcomes in longitudinal studies of bipolar disorder Molecular Psychiatry 2016 Jan;21:237-242.
Sylvia LG, Bowden CL, Calabrese JR, Thase M, Shelton RC, McInnis M, Tohen M, Kocsis JH, Ketter TA, Freidman ES, Deckersbach T, Ostacher MJ, Iosifescu DV, McElroy S, Nierenberg AA. White blood cell count correlates with mood symptom severity and specific mood symptoms in bipolar disorder Aust N Z J Psychiatry 2016 Jan;.
Arnold JG, Martinez C, Zavala J, Prihoda TJ, Escamilla M, Singh V, Bazan M, Quinones M, Bowden CL. Investigating symptom domains of bipolar disorder for Spanish- speakers using the Bipolar Inventory of Symptoms Scale J Affect Dis 2016 Jan;205:239-244.
Bowden CL, Singh V. The use of antidepressants in bipolar disorder patients with depression Expert Opinion on Pharmacotherapy 2016 Jan;17(1):17-25.
Nierenberg AA, McElroy SL, Friedman ES, Ketter TA, Shelton RC, Deckersbach T, McInnis MG, Bowden CL, Tohen M, Kocsis JH, Brody B, Reilly-Harrington NA, Sylvia KG, Shesler LW, Bernstein EE, Schoenfeld D, Rabideau DJ, Leon AC, Faraone S, Thase ME. Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder J Clin Psychiatry 2016 Jan;77:90-99.
Deckersbach T, Nierenberg AA, McInnis MG, Salcedo S, Bernstein E, Shelton RC, Kemp DE, Sylvia LG, Kocsis JH, Singh V, Tohen M, Bowden CL, Ketter TA, Calabrese JR, Thase ME, Reilly-Harrington NA, Rabideau DJ, Kinrys G, Kamali M. Baseline Disability and Poor Functioning in Bipolar Disorder Predict Worse Outcomes J Clin Psychiatry 2016 Jan;77:100-108.
Bowden CL, Mintz J, Tohen M. Multi-state outcome analysis of treatments (MOAT): application of a new approach to evaluate outcomes in longitudinal studies of bipolar disorder Molecular Psychiatry 2015 Mar;21:237-242.
Perugi G, Angst J, Azorin JM, Bowden CL, Mosolov S, Reis J, Vieta E, Young AH. Mixed features in patients with a major depressive episode: the BRIDGE-II-MIX study J Clin Psychiatry 2015 Mar;76(3).
Sylvia LG, Thase ME, Reilly-Harrington NA, Salcedo S, Brody B, Kinrys G, Kemp D, Shelton RC, McElroy SL, Kocsis JH, Friedman E, Tohen M, Bowden CL, Ketter TA, Singh V, Calabrese J, Nierenberg AA, Rabideau DJ, Elson CM, Deckersbach T. Psychotherapy use in bipolar disorder: Association with functioning and illness severity Australian and New Zealand Journal of Psychiatry 2015 Jan;49:453-461.
Gonzalez Arnold J, Salcedo S, Ketter TA, Calabrese JR, Rabideau DJ, Nierenberg AA, Bazan M, Leon AC, Friedman ES, Iosifescu D, Sylvia LG, Ostacher M, Thase M, Reilly-Harrington NA, Bowden CL. An exploratory study of responses to low-dose lithium in African Americans and Hispanics J Affect Disord 2015 Jan;178:224-228.
Bobo WV, Reilly-Harrington NA, Ketter TA, Brody BD, Kinrys G, Kemp DE, Shelton RC, McElroy SL, Sylvia LG, Kocsis JH, McInnis MG, Friedman ES, Singh V, Tohen M, Bowden CL, Deckersbach T, Calabrese JR, Thase ME, Nierenberg AA, Rabideau DJ, Schoenfeld DA, Faraone SV, Kamali M. Complexity of illness and adjunctive benzodiazepine use in outpatients with bipolar I or II disorder: results from the Bipolar CHOICE study J Clin Psychopharmacol 2015 Jan;35:68-74.
Popovic D, Vieta E, Azorin JM, Angst J, Bowden CL, Mosolov S, Young AH, Perugi G. Suicide attempts in major depressive episode: evidence from the BRIDGE-II-Mix study Bipolar Disorders 2015 Jan;17:795-803.
Ostacher MJ, Nierenberg AA, Rabideau DJ, Reilly-Harrington NA, Sylvia LG, Gold AK, Shesler LW, Ketter TA, Bowden CL, Calabrese JR, Friedman ES, Iosifescu DV, Thase ME, Leon AC, Trivedi MH. A clinical measure of suicidal ideation, suicidal behavior, and associated symptoms in bipolar disorder: Psychometric properties of the Concise Health Risk Tracking Self-Report (CHRT-SR) J Psychiat Research 2015 Jan;71:126-133.
McElroy SL, Kemp DE, Friedman ES, Reilly-Harrington NA, Sylvia LG, Calabrese JR, Rabideau DJ, Ketter TA, Thase ME, Singh V, Tohen M, Bowden CL, Bernstein EE, Brody BD, Deckersbach T, Kocsis JH, Kinrys G, Bobo WV, Kamali M, McInnis MG, Leon AC, Faraone S, Nierenberg AA, Shelton RC. Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder Acta Psychiatr Scand 2015 Jan;:1-10.
Bowden CL. Common sources of disparate results and experience in clinical practice vs. results from phase 2 registration studies: lamotrigine as a prototype Acta Psychiat Scand 2015 Jan;132:355-356.
Sylvia LG, Shelton LC, Bernstein EE, Friedman ES, Brody BD, McElroy SL, Singh V, Tohen M, Bowden CL, Thase ME, Reilly-Harrington NA, Nierenberg AA, Rabideau DJ, Kinrys DJ, Kocsis JH, Bobo WV, Kamali M, McInnis MG, Calabrese JR. Medical burden in bipolar disorder: findings from the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder study (Bipolar CHOICE) Bipolar Disorders 2015 Jan;17:212-223.
Friedman ES, Calabrese JR, Ketter TA, Leon AC, Thase ME, Bowden CL, Sylvia LG, Ostracher MJ, Severe J, Iosifescu DV, Nierenberg AA. Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: Contrasting LiTMUS baseline data with pre-existing placebo controlled trials J Affect Disord 2014 Jan;169:144-148.
Bowden CL. Providing assessable information on effectiveness of maintenance treatments for bipolar disorder to psychiatrists and patients Lancet Psychiatry 2014 Jan;1:351-359.
Sylvia LG, Dustin J, Rabideau DJ, Nierenberg AA, Bowden CL, Friedman ES, Iosifescu DV, Ketter T, CalabreseJR, Leon AC, Ostacher MJ, Reilly-Harrington NA. The effect of personalized guideline-concordant treatment on quality of life and functional impairment in bipolar disorder J Affect Disord 2014 Jan;169:144-148.
Friedman ES, Calabrese JR, Ketter TA, Leon AC, Thase ME, Bowden CL, Sylvia LG, Ostracher MJ, Severe J, Iosifescu DV, Nierenberg AA, Reilly-Harrington NA. Using comparative effectiveness design to improve the generalizability of bipolar treatment trials data: contrasting LiTMUS baseline data with pre-existing placebo controlled trials J Affective Disorders 2014 Jan;152:97-104.
Bowden CL. Expand the applicability and acceptability of CBT approaches in mood disorders World Psychiatry 2014 Jan;13:261-262.
Bobo WV, Reilly-Harrington NA, Ketter TA, Brody BD, Kinrys G, Kemp DE, Shelton RC, McElroy SL, Sylvia LG, Kocsis JH, Tohen M, Bowden CL, Deckersbach T, Calabrese JR, Thase ME, Nierenberg AA, Ribideau DJ, Schoenfeld DA, Faraone SV, Kamali M. Effect of adjunctive benzodiazepines on clinical outcomes in lithium- or quetiapine-treated outpatients with bipolar I or II disorder: Results from the Bipolar CHOICE trial J Affective Disorders 2014 Jan;161:30-35.
Sylvia LG, Reilly-Harrington NA, Kansky CI, Calabrese JR, Bowden CL, Ketter TA, Friedman ES, Iosifescu DV, Thase ME, Ostacher ME, Keyes M, Rabideau D, Nierenberg AA. Medication adherence in a comparative effectiveness trial for bipolar disorder Acta Psychiatrica Scandinavica 2014 Jan;129:359-365.
Kemp DE, Sylvia LG, Calabrese JR, Nierenbereg AA, Thase ME, Reilly-Harrington NA, Ostacher MJ, Leon AC, Ketter TA, Friedman ES, Bowden CL, Rabideau DJ, Pencina M, Iosifescu DV. General medical burden in bipolar disorder:findings from the LiTMUS comparative effectiveness trial. The LiTMUS Study Group Acta Psychiatr Scand 2014 Jan;129:24-34.
Beech RD, Leffert JJ, Lin A, Sylvia LG, Umlauf S, Mane S, Zhao H, Bowden CL, Calabrese JR, Friedman ES, Ketter TA, Iosifescu DV, Reilly-Harrington NA, Ostacher M, Thase ME, Nierenberg A. Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS) Pharmacogenomics 2014 Jan;14:182-191.
Singh V, Bowden CL, Arnold JG, Thompson PM, Prihoda TJ, Katz MM, Bernardo CG. Discriminating Primary Clinical States in Bipolar Disorder with a Comprehensive Symptom Scale Acta Psychiatr Scan 2013 Feb;127(2):145-152.
Bowden CL, Karayal ON, Schwartz JH, Gundapaneni BK, O'Gorman C. Characterizing relapse prevention in bipolar disorder with adjunctive ziprasidone: Clinical and methodological implications J Affect Disord 2013 Jan;144:171-175.
Perugi G, Angst J, Azorin JM, Bowden CL, Vieta E, Young AH. for the BRIDGE Study Group. The bipolar?borderline personality disorders connection in major depressive patients Acta Psychiatr Scand 2013 Jan;:1-8.
Angst J, Gamma A, Bowden CL, Azorin JM, Perugi G, Vieta E, Young AH. Evidence-based definitions of bipolar-I and bipolar-II disorders among 5,635 patients with major depressive episodes in the Bridge Study: validity and comorbidity Eur Arch Psychiatry Clin Neurosci 2013 Jan;263:6663-6733.
Grunze H, Vieta E, Goodwin GM, Bowden CL, Licht RW, Moller HJ, Kasper S. on behalf of the Task Force on Treatment Guidelines for Bipolar Disorders. The World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Biological Treatment of Bipolar Disorders The World Journal of Biological Psychiatry 2013 Jan;14:154-219.
Gamma A, Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, Young AH. Transcultural validity of the Hypomania Checklist?32 (HCL-32) in patients with major depressive episodes Bipolar Disord 2013 Jan;15:701-712.
Nery FG, Hatch JP, Monkul ES, Matsuo K, Zunta-Soares GB, Bowden CL, Soares JC. Trait impulsivity is increased in bipolar disorder patients with comorbid alcohol use disorders Psychopathology 2013 Jan;46(3):145-152.
Mitchell PB, Hadzi-Pavlovic D, Evoniuk G, Calabrese JR, Bowden CL. Factor analytic study in bipolar depression, and response to lamotrigine CNS Spectrum 2013 Jan;18:214-224.
Perugi G, Angst J, Azorin JM, Bowden CL, Vieta E, Young AH. BRIDGE Study Group. Is comorbid borderline personality disorder in patients with major depressive episode and bipolarity a developmental subtype? Findings from the international BRIDGE study J Affect Disord 2013 Jan;144:72-78.
Nierenberg AA, Friedman ES, Bowden CL, Sylvia LG, Thase ME, Ketter T, Ostacher MJ, Leon AC, Reilly-Harrington N, Iosifescu DV, Pencina M, Severe JB, Calabrese JR. Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium Am J Psychiatry 2013 Jan;170:102-110.
Sylvia LG, Iosifescu D, Friedman ES, Bernstein EE, Bowden CL, Ketter TA, Reilly-Harrington NA, Leon AC, Calabrese JR, Ostacher MJ, Rabideau DJ, Thase ME, Nierenberg AA. Use of Treatment Services in a Comparative Effectiveness Study of Bipolar Disorder Psychiatric Services 2013 Jan;64:1119-1126.
Pacchiarotti I, Bond DJ, Baldessarini RJ, Nolen WA, Grunze H, Licht RW, Post RM, Berk M, Goodwin GM, Sachs GS, Tondo L, Findling RL, Youngstrom EA, Tohen M, Undurraga J, Gonzalez-Pinto A, Goldberg JF, Yildiz A, Altshuler LL, Calabrese JR, Mitchell PB, Thase ME, Koukopoulos A, Colom F, Frye MA, Malhi GS, Fountoulakis KN, Vazquez G, Perlis RH, Ketter TA, Cassidy F, Akiskal H, Azorin JM, Valenti M, Mazzei DH, Lafer B, Kato T, Mazzarini L, Martinez-Aran A, Parker G, Souery D, Ozerdem A, McElroy SL, Girardi P, Yatham LN, Zarate CA, Nierenberg AA, Birmaher B, Bowden CL, Ghaemi SN, Lopez-Jaramillo , Rybakowski J, Ha K, Perugi G, Kasper S, Amsterdam JD, Hirschfeld RM, Kapczinski F, Vieta E. The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders Am J Psychiatry 2013 Jan;170:1249-1262.
Sylvia LG, Freidman ES, Kocsis JH, Bernstein EE, Brody BD, Kinrys G, Kemp DE, Shelfton RC, McElroy SL, Bobo WV, Kamali M, McInnis MG, Tohen M, Bowden CL, Ketter TA, Deckersbach T, Calabrese JR, Thase ME, Reilly-Harrington NA, Singh V, Rabideau DJ, Nierenberg AA. Association of exercise with quality of life and mood symptoms in a comparative effectiveness study of bipolar disorder J Affect Disord 2013 Jan;151:722-727.
Reilly-Harrington NA, Sylvia LG, Leon AC, Shesler LW, Ketter TA, Bowden CL, Calabrese JR, Friedman ES, Ostacher MJ, Iosifescu DV, Rabideau DJ, Thase ME, Nierenberg AA. The Medication Recommendation Tracking Form: a novel tool for tracking changes in prescribed medication, clinical decision making, and use in comparative effectiveness research J Psychiatr Res 2013 Jan;47:1686-1693.
Rabideau DJ, Nierenberg AA, Sylvia LG, Friedman ES, Bowden CL, Thase ME, Ketter TA, Ostacher MO, Reilly-Harrington N, Iosifescu DV, Calabrese JR, Leon AC, Schoenfeld DA. A novel application of the Intent to Attend assessment to reduce bias due to missing data in a randomized controlled clinical trial Clinical Trials 2014 Jan;:1-9.
Nierenberg AA, Sylvia LG, Leon AC, Reilly-Harrington NA, Shesler LW, McElroy SL, Friedman ES, Thase ME, Shelton RC, Bowden CL, Tohen M, Singh V, Deckersbach T, Ketter TA, Kocsis JH, McInnis MG, Schoenfeld D, Bobo WV, Calabrese JR. Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE): a pragmatic trial of complex treatment for a complex disorder Clinical Trials 2014 Jan;11:114-127.