Letters
2. Brent DA, Gibbons R. Initial dose of antidepressant and suicidal behavior in youth: start low, go slow. JAMA Intern Med. 2014;174(6):909-911. 3. Wijlaars LPMM, Nazareth I, Whitaker HJ, Evans SJW, Petersen I. Suicide-related events in young people following prescription of SSRIs and other antidepressants: a self-controlled case series analysis. BMJ Open. 2013;3 (9):e003247-e003247. 4. Sinclair LI, Christmas DM, Hood SD, et al. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. 2009;194(6): 483-490. 5. Culpepper L, Davidson JRT, Dietrich AJ, Goodman WK, Kroenke K, Schwenk TL. Suicidality as a possible side effect of antidepressant treatment. Prim Care Companion J Clin Psychiatry. 2004;6(2):79-86.
In Reply We welcome the opportunity Petersen and Nazareth provide with their letter to emphasize the importance of assessing the likely direction and quantifying the likely magnitude of biases in our study,1 including confounding by indication. As we stated originally, although it is possible that unmeasured confounding accounts for the dose-response relationship we observed, it is not obvious what unmeasured factors might have led to meaningful confounding of our results. For example, our sensitivity analyses indicate that suicidal ideation prior to antidepressant therapy was not associated with the dose prescribed after adjusting for our propensity score, indicating that prior suicidality may be reasonably approximated by accounting for the patient characteristics at our disposal. Furthermore, our bias analyses demonstrate that an unmeasured confounder that could explain away the heightened risk of deliberate self-harm among youth initiating high-dose therapy would need to be more than 10-times as imbalanced across dose levels than were our measures of psychiatric comorbidity and more strongly associated with deliberate self-harm than our strongest predictor of deliberate self-harm (ie, a history of deliberate self-harm), even after accounting for the other risk factors included in our propensity score. Our bias analysis allows readers to speculate about the extent to which any purported unmeasured confounder satisfies these requirements. Petersen and Nazareth also question our findings because we found a higher risk of deliberate self-harm soon after initiating antidepressants than later during treatment and effect modification by age. Neither time-varying hazards nor effect measure modification, however, invalidate causal interpretations. Indeed, the potential for time-varying hazards and effect modification are core reasons for implementing new user designs2 and propensity scores, as we did in our study. Our findings also align with the differential effects by age group found in the meta-analyses of randomized trials by the US Food and Drug Administration.3 While our nonexperimental study is not decisive, it nevertheless suggests that whatever residual confounding exists, it is unlikely to materially change our finding that higher doses of antidepressants likely cause higher rates of suicidal behavior in children and young adults. The fact that this inference is based on observational data does not free clinicians and policy makers from the responsibility to grapple with the causal implications. Like all scientific knowledge, findings from our study are provisional and subject to revision in 464
light of new knowledge. Because our study was the first study to assess the relationship between dose and deliberate selfharm, triangulating our estimates with future studies using other data and/or other appropriate analytic techniques is surely warranted. There will always be clinical questions that, for practical or ethical reasons, cannot be answered using randomized trials and for which carefully conducted observational studies have the potential to provide actionable results. Considered in light of evidence that the efficacy of antidepressant therapy for youth appears to be modest4 and separate evidence that dose is generally unrelated to the therapeutic efficacy of antidepressants,5 our findings reinforce the recommendation6 that clinicians who believe their patients would benefit from antidepressant therapy start low, go slow, and monitor all patients starting antidepressant therapy, especially youth, for several months and regardless of history of deliberate self-harm. Matthew Miller, MD, MPH, ScD Sonja Swanson, ScD Til Stürmer, MD, PhD Author Affiliations: Department of Health Sciences, Bouvé College of Health Sciences, Northeastern University, Burlington, Massachusetts (Miller); Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts (Miller, Swanson); Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (Stürmer). Corresponding Author: Matthew Miller, MD, MPH, ScD, Department of Health Sciences, Bouvé College of Health Sciences, Northeastern University, 360 Huntington Ave, Room 316 RB, Boston, MA 02115 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Miller M, Swanson SA, Azrael D, Pate V, Stürmer T. Antidepressant dose, age, and the risk of deliberate self-harm. JAMA Intern Med. 2014;174(6):899-909. 2. Kramer MS, Lane DA, Hutchinson TA. Analgesic use, blood dyscrasias, and case-control pharmacoepidemiology: a critique of the International Agranulocytosis and Aplastic Anemia Study. J Chronic Dis. 1987;40(12):1073-1085. 3. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339. 4. Tsapakis EM, Soldani F, Tondo L, Baldessarini RJ. Efficacy of antidepressants in juvenile depression: meta-analysis. Br J Psychiatry. 2008;193(1):10-17. 5. Hansen RA, Moore CG, Dusetzina SB, Leinwand BI, Gartlehner G, Gaynes BN. Controlling for drug dose in systematic review and meta-analysis: a case study of the effect of antidepressant dose. Med Decis Making. 2009;29 (1):91-103. 6. Birmaher B, Brent D, Bernet W, et al; AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503-1526.
Advancing Medical Professionalism and the Choosing Wisely Campaign To the Editor In a recent Editorial by Grady et al,1 the authors criticized the methodological approach used by specialty societies in creating Choosing Wisely recommendations of tests and procedures that physicians and patients should question. Unfortunately, the article missed a major aspect of the campaign that we believe has contributed to its success. At its roots, the Choosing Wisely campaign2 is about advancing medical professionalism; this difference distinguishes it from other efforts to improve health care. It ap-
JAMA Internal Medicine March 2015 Volume 175, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
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Letters
peals to physician desires to provide the best care possible for their patients by avoiding unnecessary and even harmful interventions. The specialty society lists were a means to spur these conversations between physicians and patients about what care they truly needed. To engage societies in this process, we created a framework that gave them autonomy to determine their list creation process so long as they followed 4 requirements: the recommendations had to be evidence based; tests and procedures had to done frequently; they had to be within the control of specialty; and the development process had to be transparent. By structuring the campaign in that way, we activated professionalism by engaging the societies and appealing to their professional values. We respected their competency to develop lists based on their years of experience in developing clinical guidelines; many used existing quality and safety committees to do this work and polled their members. Autonomy, competency, and respect have been essential ingredients that have prompted the specialty societies to take ownership and lead this vital effort for appropriate care, in partnership with patients and caregivers. What we lost by not dictating a uniform process, we gained by promoting ownership and engagement by the profession. The methodology described by Schuur et al,3 in their accompanying article mirrors the process most specialties societies followed. We sought transparency with the inclusion of a section called “How This List Was Created” that appears on every list at www.choosingwisely.org. The lists are an important part of Choosing Wisely, but it is the focus on conversations between physicians and patients about appropriate care and the response of physicians in embodying ideals of professionalism that demonstrate the impact it is making in improving our health care system. Richard J. Baron, MD, MACP Daniel Wolfson, MHSA Author Affiliations: American Board of Internal Medicine and ABIM Foundation, Philadelphia, Pennsylvania. Corresponding Author: Richard J. Baron, MD, MACP, American Board of Internal Medicine and ABIM Foundation, 510 Walnut St, Philadelphia, PA 19106 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Grady D, Redberg RF, Mallon WK. How should top-five lists be developed? what is the next step? JAMA Intern Med. 2014;174(4):498-499. 2. American Board of Internal Medicine Foundation. Choosing Wisely home page. http://www.choosingwisely.org. Accessed December 22, 2014. 3. Schuur JD, Carney DP, Lyn ET, et al. A top-five list for emergency medicine: a pilot project to improve the value of emergency care. JAMA Intern Med. 2014; 174(4):509-515.
In Reply We did not intend to criticize the Choosing Wisely campaign of the American Board of Internal Medicine (ABIM) Foundation.1 In fact, we believe that Caring Wisely,2 in which many professional medical societies have created “top 5” lists of tests and procedures that should be avoided, has been a very effective intervention to prompt physicians, patients, and professional organizations to begin to address ways to minimize low-value health care. The approach of deferring how to crejamainternalmedicine.com
ate lists of low-value tests and procedures to the appropriate professional organizations was shrewd, resulting in engagement by many societies, peer pressure on those that did not engage, and the emergence of best practices. Many professional societies have done an excellent job, engaging their members in transparent, democratic, and methodologically sound processes to highlight activities to avoid that are common, harmful, and costly. But what are the next steps? We believe that we should be thinking about how to build on the success of Choosing Wisely by encouraging all professional societies to periodically revise and expand the “top 5” lists using best practices to choose activities—that we should begin to measure the effectiveness of Choosing Wisely and consider interventions to encourage avoidance of activities on the list. Deborah Grady, MD, MPH Rita F. Redberg, MD, MSc Author Affiliations: Department of Medicine, University of California, San Francisco (Grady, Redberg); San Francisco Veterans Affairs Medical Center, San Francisco, California (Grady); Deputy Editor, JAMA Internal Medicine (Grady); Editor, JAMA Internal Medicine (Redberg). Corresponding Author: Deborah Grady, MD, MPH, Department of Medicine, University of California, San Francisco, 550 16th St, San Francisco, CA 94158 ([email protected]). Conflict of Interest Disclosures: None reported. 1. American Board of Internal Medicine Foundation. Choosing Wisely home page. http://www.choosingwisely.org. Accessed December 22, 2014. 2. UCSF Center for Healthcare Value. Caring Wisely. http://healthvalue.ucsf.edu /caring-wisely. Accessed December 22, 2014.
Treatment of Borderline Elevated Thyrotropin Levels To the Editor In their retrospective report on the falling threshold for treatment of borderline elevated thyrotropin (TSH) levels in the United Kingdom, Taylor and colleagues1 show an increased annual rate of new levothyroxine prescriptions and a decline in the median TSH threshold at the time of an index levothyroxine prescription. During follow-up for 6 months to 5 years of patients treated with levothyroxine, the percentage of those with a TSH level less than 0.1 mIU/L increased from 2.7% to 5.8%. As noted by the authors, and paralleling their results, the Colorado thyroid disease prevalence study showed a greater frequency of subclinical hyperthyroidism among patients in the United States taking thyroid medication for thyroid hormone replacement or for suppression therapy.2 The authors of the UK study consider the possibility that greater use of confirmatory testing might reduce unnecessary prescriptions for levothyroxine.1 It is agreed that an initial patient presentation with mildly elevated TSH level may occur for several reasons, including nonthyroidal transitory causes, such that treatment should not be offered without further confirmation of persistence of TSH elevation and patient profile suggesting potential benefit.3 Although inappropriate decisions to initiate levothyroxine therapy may occur, we suggest that other causes may account for some cases of subsequent TSH suppression among treated patients. Even among patients having true autoimmune thyroid disease, after an interval of TSH elevation due (Reprinted) JAMA Internal Medicine March 2015 Volume 175, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 06/07/2015
465
2. Brent DA, Gibbons R. Initial dose of antidepressant and suicidal behavior in youth: start low, go slow. JAMA Intern Med. 2014;174(6):909-911. 3. Wijlaars LPMM, Nazareth I, Whitaker HJ, Evans SJW, Petersen I. Suicide-related events in young people following prescription of SSRIs and other antidepressants: a self-controlled case series analysis. BMJ Open. 2013;3 (9):e003247-e003247. 4. Sinclair LI, Christmas DM, Hood SD, et al. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. Br J Psychiatry. 2009;194(6): 483-490. 5. Culpepper L, Davidson JRT, Dietrich AJ, Goodman WK, Kroenke K, Schwenk TL. Suicidality as a possible side effect of antidepressant treatment. Prim Care Companion J Clin Psychiatry. 2004;6(2):79-86.
In Reply We welcome the opportunity Petersen and Nazareth provide with their letter to emphasize the importance of assessing the likely direction and quantifying the likely magnitude of biases in our study,1 including confounding by indication. As we stated originally, although it is possible that unmeasured confounding accounts for the dose-response relationship we observed, it is not obvious what unmeasured factors might have led to meaningful confounding of our results. For example, our sensitivity analyses indicate that suicidal ideation prior to antidepressant therapy was not associated with the dose prescribed after adjusting for our propensity score, indicating that prior suicidality may be reasonably approximated by accounting for the patient characteristics at our disposal. Furthermore, our bias analyses demonstrate that an unmeasured confounder that could explain away the heightened risk of deliberate self-harm among youth initiating high-dose therapy would need to be more than 10-times as imbalanced across dose levels than were our measures of psychiatric comorbidity and more strongly associated with deliberate self-harm than our strongest predictor of deliberate self-harm (ie, a history of deliberate self-harm), even after accounting for the other risk factors included in our propensity score. Our bias analysis allows readers to speculate about the extent to which any purported unmeasured confounder satisfies these requirements. Petersen and Nazareth also question our findings because we found a higher risk of deliberate self-harm soon after initiating antidepressants than later during treatment and effect modification by age. Neither time-varying hazards nor effect measure modification, however, invalidate causal interpretations. Indeed, the potential for time-varying hazards and effect modification are core reasons for implementing new user designs2 and propensity scores, as we did in our study. Our findings also align with the differential effects by age group found in the meta-analyses of randomized trials by the US Food and Drug Administration.3 While our nonexperimental study is not decisive, it nevertheless suggests that whatever residual confounding exists, it is unlikely to materially change our finding that higher doses of antidepressants likely cause higher rates of suicidal behavior in children and young adults. The fact that this inference is based on observational data does not free clinicians and policy makers from the responsibility to grapple with the causal implications. Like all scientific knowledge, findings from our study are provisional and subject to revision in 464
light of new knowledge. Because our study was the first study to assess the relationship between dose and deliberate selfharm, triangulating our estimates with future studies using other data and/or other appropriate analytic techniques is surely warranted. There will always be clinical questions that, for practical or ethical reasons, cannot be answered using randomized trials and for which carefully conducted observational studies have the potential to provide actionable results. Considered in light of evidence that the efficacy of antidepressant therapy for youth appears to be modest4 and separate evidence that dose is generally unrelated to the therapeutic efficacy of antidepressants,5 our findings reinforce the recommendation6 that clinicians who believe their patients would benefit from antidepressant therapy start low, go slow, and monitor all patients starting antidepressant therapy, especially youth, for several months and regardless of history of deliberate self-harm. Matthew Miller, MD, MPH, ScD Sonja Swanson, ScD Til Stürmer, MD, PhD Author Affiliations: Department of Health Sciences, Bouvé College of Health Sciences, Northeastern University, Burlington, Massachusetts (Miller); Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts (Miller, Swanson); Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina (Stürmer). Corresponding Author: Matthew Miller, MD, MPH, ScD, Department of Health Sciences, Bouvé College of Health Sciences, Northeastern University, 360 Huntington Ave, Room 316 RB, Boston, MA 02115 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Miller M, Swanson SA, Azrael D, Pate V, Stürmer T. Antidepressant dose, age, and the risk of deliberate self-harm. JAMA Intern Med. 2014;174(6):899-909. 2. Kramer MS, Lane DA, Hutchinson TA. Analgesic use, blood dyscrasias, and case-control pharmacoepidemiology: a critique of the International Agranulocytosis and Aplastic Anemia Study. J Chronic Dis. 1987;40(12):1073-1085. 3. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry. 2006;63(3):332-339. 4. Tsapakis EM, Soldani F, Tondo L, Baldessarini RJ. Efficacy of antidepressants in juvenile depression: meta-analysis. Br J Psychiatry. 2008;193(1):10-17. 5. Hansen RA, Moore CG, Dusetzina SB, Leinwand BI, Gartlehner G, Gaynes BN. Controlling for drug dose in systematic review and meta-analysis: a case study of the effect of antidepressant dose. Med Decis Making. 2009;29 (1):91-103. 6. Birmaher B, Brent D, Bernet W, et al; AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503-1526.
Advancing Medical Professionalism and the Choosing Wisely Campaign To the Editor In a recent Editorial by Grady et al,1 the authors criticized the methodological approach used by specialty societies in creating Choosing Wisely recommendations of tests and procedures that physicians and patients should question. Unfortunately, the article missed a major aspect of the campaign that we believe has contributed to its success. At its roots, the Choosing Wisely campaign2 is about advancing medical professionalism; this difference distinguishes it from other efforts to improve health care. It ap-
JAMA Internal Medicine March 2015 Volume 175, Number 3 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 06/07/2015
jamainternalmedicine.com
Letters
peals to physician desires to provide the best care possible for their patients by avoiding unnecessary and even harmful interventions. The specialty society lists were a means to spur these conversations between physicians and patients about what care they truly needed. To engage societies in this process, we created a framework that gave them autonomy to determine their list creation process so long as they followed 4 requirements: the recommendations had to be evidence based; tests and procedures had to done frequently; they had to be within the control of specialty; and the development process had to be transparent. By structuring the campaign in that way, we activated professionalism by engaging the societies and appealing to their professional values. We respected their competency to develop lists based on their years of experience in developing clinical guidelines; many used existing quality and safety committees to do this work and polled their members. Autonomy, competency, and respect have been essential ingredients that have prompted the specialty societies to take ownership and lead this vital effort for appropriate care, in partnership with patients and caregivers. What we lost by not dictating a uniform process, we gained by promoting ownership and engagement by the profession. The methodology described by Schuur et al,3 in their accompanying article mirrors the process most specialties societies followed. We sought transparency with the inclusion of a section called “How This List Was Created” that appears on every list at www.choosingwisely.org. The lists are an important part of Choosing Wisely, but it is the focus on conversations between physicians and patients about appropriate care and the response of physicians in embodying ideals of professionalism that demonstrate the impact it is making in improving our health care system. Richard J. Baron, MD, MACP Daniel Wolfson, MHSA Author Affiliations: American Board of Internal Medicine and ABIM Foundation, Philadelphia, Pennsylvania. Corresponding Author: Richard J. Baron, MD, MACP, American Board of Internal Medicine and ABIM Foundation, 510 Walnut St, Philadelphia, PA 19106 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Grady D, Redberg RF, Mallon WK. How should top-five lists be developed? what is the next step? JAMA Intern Med. 2014;174(4):498-499. 2. American Board of Internal Medicine Foundation. Choosing Wisely home page. http://www.choosingwisely.org. Accessed December 22, 2014. 3. Schuur JD, Carney DP, Lyn ET, et al. A top-five list for emergency medicine: a pilot project to improve the value of emergency care. JAMA Intern Med. 2014; 174(4):509-515.
In Reply We did not intend to criticize the Choosing Wisely campaign of the American Board of Internal Medicine (ABIM) Foundation.1 In fact, we believe that Caring Wisely,2 in which many professional medical societies have created “top 5” lists of tests and procedures that should be avoided, has been a very effective intervention to prompt physicians, patients, and professional organizations to begin to address ways to minimize low-value health care. The approach of deferring how to crejamainternalmedicine.com
ate lists of low-value tests and procedures to the appropriate professional organizations was shrewd, resulting in engagement by many societies, peer pressure on those that did not engage, and the emergence of best practices. Many professional societies have done an excellent job, engaging their members in transparent, democratic, and methodologically sound processes to highlight activities to avoid that are common, harmful, and costly. But what are the next steps? We believe that we should be thinking about how to build on the success of Choosing Wisely by encouraging all professional societies to periodically revise and expand the “top 5” lists using best practices to choose activities—that we should begin to measure the effectiveness of Choosing Wisely and consider interventions to encourage avoidance of activities on the list. Deborah Grady, MD, MPH Rita F. Redberg, MD, MSc Author Affiliations: Department of Medicine, University of California, San Francisco (Grady, Redberg); San Francisco Veterans Affairs Medical Center, San Francisco, California (Grady); Deputy Editor, JAMA Internal Medicine (Grady); Editor, JAMA Internal Medicine (Redberg). Corresponding Author: Deborah Grady, MD, MPH, Department of Medicine, University of California, San Francisco, 550 16th St, San Francisco, CA 94158 ([email protected]). Conflict of Interest Disclosures: None reported. 1. American Board of Internal Medicine Foundation. Choosing Wisely home page. http://www.choosingwisely.org. Accessed December 22, 2014. 2. UCSF Center for Healthcare Value. Caring Wisely. http://healthvalue.ucsf.edu /caring-wisely. Accessed December 22, 2014.
Treatment of Borderline Elevated Thyrotropin Levels To the Editor In their retrospective report on the falling threshold for treatment of borderline elevated thyrotropin (TSH) levels in the United Kingdom, Taylor and colleagues1 show an increased annual rate of new levothyroxine prescriptions and a decline in the median TSH threshold at the time of an index levothyroxine prescription. During follow-up for 6 months to 5 years of patients treated with levothyroxine, the percentage of those with a TSH level less than 0.1 mIU/L increased from 2.7% to 5.8%. As noted by the authors, and paralleling their results, the Colorado thyroid disease prevalence study showed a greater frequency of subclinical hyperthyroidism among patients in the United States taking thyroid medication for thyroid hormone replacement or for suppression therapy.2 The authors of the UK study consider the possibility that greater use of confirmatory testing might reduce unnecessary prescriptions for levothyroxine.1 It is agreed that an initial patient presentation with mildly elevated TSH level may occur for several reasons, including nonthyroidal transitory causes, such that treatment should not be offered without further confirmation of persistence of TSH elevation and patient profile suggesting potential benefit.3 Although inappropriate decisions to initiate levothyroxine therapy may occur, we suggest that other causes may account for some cases of subsequent TSH suppression among treated patients. Even among patients having true autoimmune thyroid disease, after an interval of TSH elevation due (Reprinted) JAMA Internal Medicine March 2015 Volume 175, Number 3
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a J H Quillen College User on 06/07/2015
465
