Letters Selected Pregnancy and Delivery Outcomes After Exposure to Antidepressant Medication
COMMENT & RESPONSE
Was Risk of Suicide Underestimated? To the Editor We carefully read the article by Khan and colleagues.1 The authors evaluated the mortality risk and risk of suicide among adult patients with a diagnosis of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder participating in clinical trials conducted by pharmaceutical companies. The trials were reported to the US Food and Drug Administration for approval to market pharmaceutical agents and to evaluate whether psychopharmacological agents worsen this risk. They found that compared with placebo all active compounds, except for heterocyclic antidepressants, significantly reduced the risk of suicide. However, the average duration of placebo exposure was significantly shorter than that for psychotropic agents being evaluated (Table 3 in the article by Khan et al1). It is well known that the first time after first contact to psychiatric services, 2,3 and the first period after discharge, is associated with increased suicide risk4 and that the risk of suicide is reduced as time passes. Could the positive results found in the study partly be explained by comparison of periods with different levels of risk in the treatment arms owing to different length of follow-up? A person-year is not just a person-year, and early periods seem to be associated with higher risk of suicide compared with later periods. Merete Nordentoft, MD, DMSc, PhD, MPH Thomas Munk Laursen, MSc, PhD Author Affiliations: Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark (Nordentoft); National Center for Register-Based Research, University of Aarhus, Aarhus, Denmark (Laursen). Corresponding Author: Merete Nordentoft, MD, DMSc, PhD, MPH, Mental Health Center Copenhagen, University of Copenhagen, Bispebjerg Bakke 23, Entrance 13A, Copenhagen, Denmark 2400 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Khan A, Faucett J, Morrison S, Brown WA. Comparative mortality risk in adult patients with schizophrenia, depression, bipolar disorder, anxiety disorders, and attention-deficit/hyperactivity disorder participating in psychopharmacology clinical trials. JAMA Psychiatry. 2013;70(10):1091-1099. 23986353 2. Nordentoft M, Mortensen PB, Pedersen CB. Absolute risk of suicide after first hospital contact in mental disorder. Arch Gen Psychiatry. 2011;68(10):10581064. 3. Nordentoft M, Wahlbeck K, Hällgren J, et al. Excess mortality, causes of death and life expectancy in 270,770 patients with recent onset of mental disorders in Denmark, Finland and Sweden. PLoS One. 2013;8(1):e55176. 4. Qin P, Nordentoft M. Suicide risk in relation to psychiatric hospitalization: evidence based on longitudinal registers. Arch Gen Psychiatry. 2005;62(4):427432. 15809410 716
To the Editor On behalf of the entire writing team, we are writing in reply to 2 letters recently published in response to our systematic review and meta-analysis of pregnancy and delivery outcomes after exposure to antidepressant medication.1 In their letter, Tufanaru and Jureidini2 questioned our conclusion of “no significant association” between antidepressant exposure and spontaneous abortion. We fully agree that the distinction between statistically significant or not significant at P = .055 is arbitrary. However, we disagree that a statistically significant finding necessarily implies a clinically meaningful finding. Indeed, the point we emphasized in our discussion regarding preterm birth and low birth weight was that despite being statistically significant, these associations were likely not clinically significant considering their very small magnitude.1 In the context of the limited and poor-quality data linking spontaneous abortion to prenatal antidepressant exposure, it would be premature to warn the public of an increased risk for spontaneous abortion associated with prenatal antidepressant exposure. The comparison of our data on antidepressant exposure with data on smoking is totally inappropriate, considering that antidepressants are therapeutic while smoking is only hazardous. As such, a much lower threshold for establishing risk is clearly appropriate to advance public education regarding the dangers of smoking. Although we disagree that broad public education is appropriate at this time, we feel strongly that women making decisions about antidepressant use during pregnancy should have access to all relevant information to guide their decision. Indeed, making the best-quality information available to women and their physicians and other health care providers, such as midwives, is the goal of our research in this area. In the other letter, Mintzes3 disagreed with our conclusion that any harms associated with antidepressant exposure during pregnancy are small in magnitude and must be considered in light of the potential risks of untreated depression. Specifically, she stated that our study failed to demonstrate that antidepressant medications mitigate harm associated with depression during pregnancy. Our systematic review was not designed to address the question of whether antidepressant medications mitigate harm associated with depression—rather, where possible, we controlled for maternal depression to determine whether any associations between antidepressants and poor outcomes could be explained by exposure to depression. Our subsequent publication4 directly took up the question of the impact of depression on perinatal outcomes, finding that premature delivery and breastfeeding initiation in particular are associated with maternal depression. In this subsequent review, we highlighted that the literature in this area
JAMA Psychiatry June 2014 Volume 71, Number 6
Copyright 2014 American Medical Association. All rights reserved.
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Letters
suffers from many methodologic limitations affecting our ability to determine the impact of depression, in addition to not adequately addressing the potential risk for serious (although rare) outcomes, such as suicide, which are of concern to women and their physicians and other health care providers. It is critical to consider the potential risks of untreated depression in making decisions about the use of antidepressants during pregnancy. Nevertheless, we wish to emphasize that, where available and appropriate for the patient, nondrug treatment options should always be considered as part of this decision-making process. Lori E. Ross, PhD Sophie Grigoriadis, MD, MA, PhD, FRCPC Author Affiliations: Centre for Addiction and Mental Health, Toronto, Ontario, Canada (Ross); Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Grigoriadis). Corresponding Author: Lori E. Ross, PhD, Centre for Addiction and Mental Health, Social and Epidemiological Research Department, 33 Russell St, Room T-406, Toronto, ON M5S 2S1, Canada ([email protected]). Conflict of Interest Disclosures: Dr Grigoriadis received a New Investigator Award in Women’s Health Research from the Canadian Institutes of Health Research (CIHR) in partnership with the Ontario Women’s Health Council, Award NOW-88207 during the time of this work. She has also received honoraria as a consultant, member of an advisory committee, or lecturer during
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the past 5 years from Wyeth Pharmaceuticals, GlaxoSmithKline, Pfizer, Servier, Eli Lilly Canada, and Lundbeck. No other disclosures were reported. Funding/Support: Dr Grigoriadis has received research grant support from the CIHR, Ontario Ministry of Health, Ontario Mental Health Foundation, and the C. R. Younger Foundation. Dr Ross is supported by a New Investigator Award from the CIHR and the Ontario Women’s Health Council Award NOW-84656. Funding for the original study was provided by Research Syntheses grant KRS-83127 from the CIHR and grant 2008-005 from the Ontario Ministry of Health and Long-term Care through the Drug Innovation Fund. In addition, support to the Centre for Addiction and Mental Health for salary of scientists and infrastructure was provided by the Ontario Ministry of Health and Long-term Care. Role of the Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. Disclaimer: The views expressed here do not necessarily reflect those of the Ontario Ministry of Health and Long-term Care. 1. Ross LE, Grigoriadis S, Mamisashvili L, et al. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. JAMA Psychiatry. 2013;70(4):436-443. 2. Tufanaru C, Jureidini J. Antidepressant medication and spontaneous abortion: “no significant association”? clinically significant association! JAMA Psychiatry. 2013;70(12):1373-1374. 3. Mintzes B. A leap of faith in antidepressant treatment? JAMA Psychiatry. 2013;70(12):1373. 4. Grigoriadis S, VonderPorten EH, Mamisashvili L, et al. The impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis. J Clin Psychiatry. 2013;74(4):e321-e341.
JAMA Psychiatry June 2014 Volume 71, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Tufts Univ. Hirsh Health Sciences Library User on 11/24/2015
717
COMMENT & RESPONSE
Was Risk of Suicide Underestimated? To the Editor We carefully read the article by Khan and colleagues.1 The authors evaluated the mortality risk and risk of suicide among adult patients with a diagnosis of schizophrenia, depression, bipolar disorder, anxiety disorders, or attention-deficit/hyperactivity disorder participating in clinical trials conducted by pharmaceutical companies. The trials were reported to the US Food and Drug Administration for approval to market pharmaceutical agents and to evaluate whether psychopharmacological agents worsen this risk. They found that compared with placebo all active compounds, except for heterocyclic antidepressants, significantly reduced the risk of suicide. However, the average duration of placebo exposure was significantly shorter than that for psychotropic agents being evaluated (Table 3 in the article by Khan et al1). It is well known that the first time after first contact to psychiatric services, 2,3 and the first period after discharge, is associated with increased suicide risk4 and that the risk of suicide is reduced as time passes. Could the positive results found in the study partly be explained by comparison of periods with different levels of risk in the treatment arms owing to different length of follow-up? A person-year is not just a person-year, and early periods seem to be associated with higher risk of suicide compared with later periods. Merete Nordentoft, MD, DMSc, PhD, MPH Thomas Munk Laursen, MSc, PhD Author Affiliations: Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark (Nordentoft); National Center for Register-Based Research, University of Aarhus, Aarhus, Denmark (Laursen). Corresponding Author: Merete Nordentoft, MD, DMSc, PhD, MPH, Mental Health Center Copenhagen, University of Copenhagen, Bispebjerg Bakke 23, Entrance 13A, Copenhagen, Denmark 2400 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Khan A, Faucett J, Morrison S, Brown WA. Comparative mortality risk in adult patients with schizophrenia, depression, bipolar disorder, anxiety disorders, and attention-deficit/hyperactivity disorder participating in psychopharmacology clinical trials. JAMA Psychiatry. 2013;70(10):1091-1099. 23986353 2. Nordentoft M, Mortensen PB, Pedersen CB. Absolute risk of suicide after first hospital contact in mental disorder. Arch Gen Psychiatry. 2011;68(10):10581064. 3. Nordentoft M, Wahlbeck K, Hällgren J, et al. Excess mortality, causes of death and life expectancy in 270,770 patients with recent onset of mental disorders in Denmark, Finland and Sweden. PLoS One. 2013;8(1):e55176. 4. Qin P, Nordentoft M. Suicide risk in relation to psychiatric hospitalization: evidence based on longitudinal registers. Arch Gen Psychiatry. 2005;62(4):427432. 15809410 716
To the Editor On behalf of the entire writing team, we are writing in reply to 2 letters recently published in response to our systematic review and meta-analysis of pregnancy and delivery outcomes after exposure to antidepressant medication.1 In their letter, Tufanaru and Jureidini2 questioned our conclusion of “no significant association” between antidepressant exposure and spontaneous abortion. We fully agree that the distinction between statistically significant or not significant at P = .055 is arbitrary. However, we disagree that a statistically significant finding necessarily implies a clinically meaningful finding. Indeed, the point we emphasized in our discussion regarding preterm birth and low birth weight was that despite being statistically significant, these associations were likely not clinically significant considering their very small magnitude.1 In the context of the limited and poor-quality data linking spontaneous abortion to prenatal antidepressant exposure, it would be premature to warn the public of an increased risk for spontaneous abortion associated with prenatal antidepressant exposure. The comparison of our data on antidepressant exposure with data on smoking is totally inappropriate, considering that antidepressants are therapeutic while smoking is only hazardous. As such, a much lower threshold for establishing risk is clearly appropriate to advance public education regarding the dangers of smoking. Although we disagree that broad public education is appropriate at this time, we feel strongly that women making decisions about antidepressant use during pregnancy should have access to all relevant information to guide their decision. Indeed, making the best-quality information available to women and their physicians and other health care providers, such as midwives, is the goal of our research in this area. In the other letter, Mintzes3 disagreed with our conclusion that any harms associated with antidepressant exposure during pregnancy are small in magnitude and must be considered in light of the potential risks of untreated depression. Specifically, she stated that our study failed to demonstrate that antidepressant medications mitigate harm associated with depression during pregnancy. Our systematic review was not designed to address the question of whether antidepressant medications mitigate harm associated with depression—rather, where possible, we controlled for maternal depression to determine whether any associations between antidepressants and poor outcomes could be explained by exposure to depression. Our subsequent publication4 directly took up the question of the impact of depression on perinatal outcomes, finding that premature delivery and breastfeeding initiation in particular are associated with maternal depression. In this subsequent review, we highlighted that the literature in this area
JAMA Psychiatry June 2014 Volume 71, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Tufts Univ. Hirsh Health Sciences Library User on 11/24/2015
jamapsychiatry.com
Letters
suffers from many methodologic limitations affecting our ability to determine the impact of depression, in addition to not adequately addressing the potential risk for serious (although rare) outcomes, such as suicide, which are of concern to women and their physicians and other health care providers. It is critical to consider the potential risks of untreated depression in making decisions about the use of antidepressants during pregnancy. Nevertheless, we wish to emphasize that, where available and appropriate for the patient, nondrug treatment options should always be considered as part of this decision-making process. Lori E. Ross, PhD Sophie Grigoriadis, MD, MA, PhD, FRCPC Author Affiliations: Centre for Addiction and Mental Health, Toronto, Ontario, Canada (Ross); Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada (Grigoriadis). Corresponding Author: Lori E. Ross, PhD, Centre for Addiction and Mental Health, Social and Epidemiological Research Department, 33 Russell St, Room T-406, Toronto, ON M5S 2S1, Canada ([email protected]). Conflict of Interest Disclosures: Dr Grigoriadis received a New Investigator Award in Women’s Health Research from the Canadian Institutes of Health Research (CIHR) in partnership with the Ontario Women’s Health Council, Award NOW-88207 during the time of this work. She has also received honoraria as a consultant, member of an advisory committee, or lecturer during
jamapsychiatry.com
the past 5 years from Wyeth Pharmaceuticals, GlaxoSmithKline, Pfizer, Servier, Eli Lilly Canada, and Lundbeck. No other disclosures were reported. Funding/Support: Dr Grigoriadis has received research grant support from the CIHR, Ontario Ministry of Health, Ontario Mental Health Foundation, and the C. R. Younger Foundation. Dr Ross is supported by a New Investigator Award from the CIHR and the Ontario Women’s Health Council Award NOW-84656. Funding for the original study was provided by Research Syntheses grant KRS-83127 from the CIHR and grant 2008-005 from the Ontario Ministry of Health and Long-term Care through the Drug Innovation Fund. In addition, support to the Centre for Addiction and Mental Health for salary of scientists and infrastructure was provided by the Ontario Ministry of Health and Long-term Care. Role of the Sponsor: The funders had no role in the preparation, review, or approval of the manuscript, and the decision to submit the manuscript for publication. Disclaimer: The views expressed here do not necessarily reflect those of the Ontario Ministry of Health and Long-term Care. 1. Ross LE, Grigoriadis S, Mamisashvili L, et al. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. JAMA Psychiatry. 2013;70(4):436-443. 2. Tufanaru C, Jureidini J. Antidepressant medication and spontaneous abortion: “no significant association”? clinically significant association! JAMA Psychiatry. 2013;70(12):1373-1374. 3. Mintzes B. A leap of faith in antidepressant treatment? JAMA Psychiatry. 2013;70(12):1373. 4. Grigoriadis S, VonderPorten EH, Mamisashvili L, et al. The impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis. J Clin Psychiatry. 2013;74(4):e321-e341.
JAMA Psychiatry June 2014 Volume 71, Number 6
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpsyc.jamanetwork.com/ by a Tufts Univ. Hirsh Health Sciences Library User on 11/24/2015
717
