Letters to the Editor Long-Term Effects of Prenatal SSRI Exposure on Child Growth: Weighing the Evidence To the Editor: We read with interest the article by Wisner et al. (1) evaluating the effect of in utero exposure to selective serotonin reuptake inhibitors (SSRIs) or maternal depression on infant growth in the first year of life. While this study represents an important contribution to the literature, we feel that several issues warrant further clarification to improve interpretation of the results. First, a previously identified issue relates to the potential for sex-specific differences when investigating long-term outcomes (2). There is strong evidence that prenatal exposure to both SSRIs and maternal depression is associated with a variety of sex-specific outcomes, including postnatal growth (2). We have previously investigated the effect of prenatal SSRI exposure on risk for children who are overweight at 4–5 years old. In this study, we observed that girls of SSRI-exposed mothers were less likely to be overweight compared with girls of mothers with an untreated psychiatric illness (adjusted prevalence ratio, 0.23; 95% confidence interval [CI]50.05–0.98) and girls of unexposed mothers (adjusted prevalence ratio, 0.27; 95% CI50.07–0.99). In contrast, no association with being overweight was observed among boys of exposed mothers compared with boys of mothers with an untreated psychiatric illness (adjusted prevalence ratio, 1.17; 95% CI50.54–2.51) and boys of unexposed mothers (adjusted prevalence ratio, 0.93; 95% CI50.52–1.67) (3). It would be useful to know whether any analyses were undertaken to examine potential interactions between exposure and the child’s sex and if so, if any differences were observed. Second, much like percentiles are standardized for age and sex, it may be beneficial to assess patterns of growth in childhood by taking into account the relationship between a child’s height and weight (4). It would be useful to know whether the use of weight-for-length or body mass index-for-age-adjusted percentiles were considered and whether any assessments were undertaken using welldefined international cutoffs to examine growth at either extreme. While studies such as this emphasize the need for looking beyond birth outcomes and considering long-term effects of prenatal exposure on child development and well-being, an often understudied aspect of medication use in pregnancy, addressing the issues outlined above would enable us to more appropriately weigh the evidence. References 1. Wisner KL, Bogen DL, Sit D, McShea M, Hughes C, Rizzo D, Confer A, Luther J, Eng H, Wisniewski SW: Does fetal exposure to SSRIs or maternal depression impact infant growth? Am J Psychiatry 2013; 170:485–493 2. Grzeskowiak LE, Gilbert AL, Morrison JL: Long term impact of prenatal exposure to SSRIs on growth and body weight in childhood: evidence from animal and human studies. Reprod Toxicol 2012; 34:101–109 3. Grzeskowiak LE, Gilbert AL, Morrison JL: Prenatal exposure to selective serotonin reuptake inhibitors and risk of childhood overweight. J Dev Orig Health Dis 2012; 3:253–261 4. Gillman MW: The first months of life: a critical period for development of obesity. Am J Clin Nutr 2008; 87:1587–1589
1364
ajp.psychiatryonline.org
LUKE E. GRZESKOWIAK, PH.D., B.PHARM. (HONS). JANNA L. MORRISON, PH.D., B.SC. (HONS).
From the Robinson Institute, the University of Adelaide, Adelaide, South Australia, and the School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide. Supported by a Heart Foundation South Australian Cardiovascular Research Network Fellowship (CR10A4988). The authors report no financial relationships with commercial interests. This letter (doi: 10.1176/appi.ajp.2013.13040472) was accepted for publication in August 2013.
Response to Grzeskowiak and Morrison To the Editor: Drs. Grzeskowiak and Morrison suggested conducting sex-specific analyses to augment our findings (1). These investigators reported that fetal exposure to selective serotonin reuptake inhibitors (SSRIs) was associated with a significantly lower risk for girls who were overweight at ages 4 or 5 years compared with girls exposed prenatally to maternal psychiatric illness or to neither illness nor SSRI (2). Were any sex differences observed with respect to the impact of SSRI exposure on growth? The impact of fetal exposure to SSRI, major depressive disorder, or neither was modeled for male and female infants with longitudinal mixed-effect regression analyses. No significant associations were found in male infants (weight, p50.37; length, p50.27; or head circumference, p50.63) or in female infants (weight, p50.53; length, p50.07; or head circumference, p50.54). Did weight-for-length-adjusted percentiles from international standards for growth at either extreme differ by sex? We evaluated the proportion of male and female infants at the ,15th and .85th percentiles for weight-for-recumbent length according to both Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) standards. In 2010, the CDC convened with representatives from NIH and the American Association of Pediatrics and recommended WHO standards for children from birth through 2 years (http:// www.cdc.gov/growthcharts/who_charts.htm). The WHO standards reflect growth patterns among predominantly breastfed children and were designed specifically to create growth standards for children under optimal conditions. Utilizing the CDC standards, the proportions of male infants at the ,15th percentile or the .85th percentile did not differ by exposure. Similarly, no difference by exposure was observed for female infants. According to WHO standards, the proportions of male infants at the ,15th and the .85th percentiles did not differ by exposure. However, a significant difference was identified for female infants at the ,15th percentile. At birth, female infants exposed prenatally to major depressive disorder were more likely to be at the ,15th percentile for weight-for-length (p50.039) than female infants exposed to either SSRI or neither (58% compared with 17% compared with 36%, respectively). However, by 12 weeks old, the proportions of female infants in all groups were approximately 15%. No difference in female infants for the .85th percentile was observed.
Am J Psychiatry 170:11, November 2013
LETTERS TO THE EDITOR
Our findings and study design differ from those of Grzeskowiak et al. (2). Our prospective investigation had a relatively small sample size, but it incorporated detailed exposure information, including laboratory documentation of SSRI exposure, diagnostic interviews for major depressive disorder, and urine drug screens. Grzeskowiak and colleagues’ retrospective study of a larger cohort was based on dispensed prescriptions for SSRI in women with unspecified psychiatric illness. Our data span the first year of life compared with their findings at ages 4–5 years. We look forward to this evolving literature. References 1. Wisner KL, Bogen DL, Sit D, McShea M, Hughes C, Rizzo D, Confer A, Luther J, Eng H, Wisniewski SW: Does fetal exposure to SSRIs or maternal depression impact infant growth? Am J Psychiatry 2013; 170:485–493 2. Grzeskowiak LE, Gilbert AL, Morrison JL: Prenatal exposure to selective serotonin reuptake inhibitors and risk of childhood overweight. Developmental Origins of Health and Disease 2012; 3:253–261
KATHERINE L. WISNER, M.D., M.S. STEPHEN R. WISNIEWSKI, PH.D. CARA L. ECKHARDT, PH.D., M.P.H. JAMES F. LUTHER, M.A. HEATHER F. ENG, B.A. DEBRA L. BOGEN, M.D.
From the Asher Center for the Study and Treatment of Depressive Disorders, Departments of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology, Northwestern University, Chicago; the Department of Epidemiology, Graduate School of Public Health, and the Department of Pediatrics, University of Pittsburgh; and the School of Community Health, Portland State University, Portland, Ore.
cognitive therapists had only 1.7 years of clinical experience and many would still be trainees. In our clinic, cognitive therapy for social anxiety disorder achieves greater effects when delivered by fully trained therapists. Third, the average competency with which cognitive therapy was delivered seems to be low. Mean ratings of therapy videotapes on the cognitive therapy competence scale (unpublished 2013 paper of U. Stangier) suggest a substantial number of sessions fell below the “redline” minimum of 3.5 (out of 6.0). This is important because there is good evidence that competence predicts outcome in cognitive therapy for social anxiety disorder (4). Fourth, behavioral experiments in which therapists leave the office with patients to test their beliefs in real life are a central feature of cognitive therapy. To make such experiments feasible, the standard cognitive therapy protocol recommends 90-minute sessions. Almost all Leichsenring and colleagues’ sessions were 55 minutes, making it unlikely that such experiments were used regularly. Comparisons between previously published trials (2) show that cognitive therapy is associated with approximately 50% more improvement in social anxiety when sessions are 90 minutes compared with 55–60 minutes. In summary, Leichsenring and colleagues’ conclusion that cognitive therapy and psychodynamic therapy are both efficacious (superior to no treatment) is justified, as is the conclusion that cognitive therapy is superior to psychodynamic therapy. However, one might reasonably question their estimate of the relative effects of cognitive therapy and psychodynamic therapy. A further trial in which cognitive therapy is delivered as recommended and at an adequate level of competence would be required to clarify matters. References
The authors’ disclosures accompany the original article. This reply (doi: 10.1176/appi.ajp.2013.13040472r) was accepted for publication in August 2013.
Psychodynamic Therapy or Cognitive Therapy for Social Anxiety Disorder To the Editor: I read with interest the article by Leichsenring et al. (1) in the July issue of the Journal. Cognitive therapy was significantly more effective than psychodynamic therapy on four of five social anxiety measures, including all those mentioned in the trial registration document (ISRCTN53517394). As one of the developers of cognitive therapy, I was naturally delighted to see the trial extend the range of credible psychological therapies to which cognitive therapy has been shown to be superior (2). However, several design features suggest the trial is likely to have underestimated the benefit of cognitive therapy relative to psychodynamic therapy. Readers may wish to bear these in mind when considering the relatively small differences in outcome that are reported. First, to match psychodynamic therapy, the time over which cognitive therapy was delivered was extended from the usual 3–4 months to 8–9 months. There is good evidence that slowing down the delivery of cognitive-behavioral treatments for social anxiety disorder reduces their effectiveness (3). Second, “type of treatment” is confounded with “therapist experience.” On average, psychodynamic therapists were qualified and had 8.0 years of clinical experience, whereas
Am J Psychiatry 170:11, November 2013
1. Leichsenring F, Salzer S, Beutel ME, Herpertz S, Hiller W, Hoyer J, Huesing J, Joraschky P, Nolting B, Poehlmann K, Ritter V, Stangier U, Strauss B, Stuhldreher N, Tefikow S, Teismann T, Willutzki U, Wiltink J, Leibing E: Psychodynamic therapy and cognitivebehavioral therapy in social anxiety disorder: a multicenter randomized controlled trial. Am J Psychiatry 2013; 170:759–767 2. Stott R, Wild J, Grey N, Liness S, Warnock-Parkes E, Commins S, Readings J, Bremner G, Woodward E, Ehlers A, Clark DM: Internetdelivered cognitive therapy for social anxiety disorder: a development pilot series. Behav Cogn Psychother 2013; 41:383–397 3. Herbert JD, Rheingold AA, Gaudiano BA, Myers VH: Standard versus extended cognitive behavior therapy for social anxiety disorder: a randomized-controlled trial. Behav Cogn Psychother 2004; 32:131–147 4. Ginzburg DM, Bohn C, Höfling V, Weck F, Clark DM, Stangier U: Treatment-specific competence predicts outcome in cognitive therapy for social anxiety disorder. Behav Res Ther 2012; 50:747–752
DAVID M. CLARK, D.PHIL.
Department of Experimental Psychology, University of Oxford, United Kingdom. The author reports no financial relationships with commercial interests. This letter (doi: 10.1176/appi.ajp.2013.13060744) was accepted for publication in September 2013.
Response to Clark To the Editor: Dr. Clark raises several concerns concerning our trial (1). First, cognitive therapy was implemented by
ajp.psychiatryonline.org
1365
Copyright of American Journal of Psychiatry is the property of American Psychiatric Publishing, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
1364
ajp.psychiatryonline.org
LUKE E. GRZESKOWIAK, PH.D., B.PHARM. (HONS). JANNA L. MORRISON, PH.D., B.SC. (HONS).
From the Robinson Institute, the University of Adelaide, Adelaide, South Australia, and the School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide. Supported by a Heart Foundation South Australian Cardiovascular Research Network Fellowship (CR10A4988). The authors report no financial relationships with commercial interests. This letter (doi: 10.1176/appi.ajp.2013.13040472) was accepted for publication in August 2013.
Response to Grzeskowiak and Morrison To the Editor: Drs. Grzeskowiak and Morrison suggested conducting sex-specific analyses to augment our findings (1). These investigators reported that fetal exposure to selective serotonin reuptake inhibitors (SSRIs) was associated with a significantly lower risk for girls who were overweight at ages 4 or 5 years compared with girls exposed prenatally to maternal psychiatric illness or to neither illness nor SSRI (2). Were any sex differences observed with respect to the impact of SSRI exposure on growth? The impact of fetal exposure to SSRI, major depressive disorder, or neither was modeled for male and female infants with longitudinal mixed-effect regression analyses. No significant associations were found in male infants (weight, p50.37; length, p50.27; or head circumference, p50.63) or in female infants (weight, p50.53; length, p50.07; or head circumference, p50.54). Did weight-for-length-adjusted percentiles from international standards for growth at either extreme differ by sex? We evaluated the proportion of male and female infants at the ,15th and .85th percentiles for weight-for-recumbent length according to both Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) standards. In 2010, the CDC convened with representatives from NIH and the American Association of Pediatrics and recommended WHO standards for children from birth through 2 years (http:// www.cdc.gov/growthcharts/who_charts.htm). The WHO standards reflect growth patterns among predominantly breastfed children and were designed specifically to create growth standards for children under optimal conditions. Utilizing the CDC standards, the proportions of male infants at the ,15th percentile or the .85th percentile did not differ by exposure. Similarly, no difference by exposure was observed for female infants. According to WHO standards, the proportions of male infants at the ,15th and the .85th percentiles did not differ by exposure. However, a significant difference was identified for female infants at the ,15th percentile. At birth, female infants exposed prenatally to major depressive disorder were more likely to be at the ,15th percentile for weight-for-length (p50.039) than female infants exposed to either SSRI or neither (58% compared with 17% compared with 36%, respectively). However, by 12 weeks old, the proportions of female infants in all groups were approximately 15%. No difference in female infants for the .85th percentile was observed.
Am J Psychiatry 170:11, November 2013
LETTERS TO THE EDITOR
Our findings and study design differ from those of Grzeskowiak et al. (2). Our prospective investigation had a relatively small sample size, but it incorporated detailed exposure information, including laboratory documentation of SSRI exposure, diagnostic interviews for major depressive disorder, and urine drug screens. Grzeskowiak and colleagues’ retrospective study of a larger cohort was based on dispensed prescriptions for SSRI in women with unspecified psychiatric illness. Our data span the first year of life compared with their findings at ages 4–5 years. We look forward to this evolving literature. References 1. Wisner KL, Bogen DL, Sit D, McShea M, Hughes C, Rizzo D, Confer A, Luther J, Eng H, Wisniewski SW: Does fetal exposure to SSRIs or maternal depression impact infant growth? Am J Psychiatry 2013; 170:485–493 2. Grzeskowiak LE, Gilbert AL, Morrison JL: Prenatal exposure to selective serotonin reuptake inhibitors and risk of childhood overweight. Developmental Origins of Health and Disease 2012; 3:253–261
KATHERINE L. WISNER, M.D., M.S. STEPHEN R. WISNIEWSKI, PH.D. CARA L. ECKHARDT, PH.D., M.P.H. JAMES F. LUTHER, M.A. HEATHER F. ENG, B.A. DEBRA L. BOGEN, M.D.
From the Asher Center for the Study and Treatment of Depressive Disorders, Departments of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology, Northwestern University, Chicago; the Department of Epidemiology, Graduate School of Public Health, and the Department of Pediatrics, University of Pittsburgh; and the School of Community Health, Portland State University, Portland, Ore.
cognitive therapists had only 1.7 years of clinical experience and many would still be trainees. In our clinic, cognitive therapy for social anxiety disorder achieves greater effects when delivered by fully trained therapists. Third, the average competency with which cognitive therapy was delivered seems to be low. Mean ratings of therapy videotapes on the cognitive therapy competence scale (unpublished 2013 paper of U. Stangier) suggest a substantial number of sessions fell below the “redline” minimum of 3.5 (out of 6.0). This is important because there is good evidence that competence predicts outcome in cognitive therapy for social anxiety disorder (4). Fourth, behavioral experiments in which therapists leave the office with patients to test their beliefs in real life are a central feature of cognitive therapy. To make such experiments feasible, the standard cognitive therapy protocol recommends 90-minute sessions. Almost all Leichsenring and colleagues’ sessions were 55 minutes, making it unlikely that such experiments were used regularly. Comparisons between previously published trials (2) show that cognitive therapy is associated with approximately 50% more improvement in social anxiety when sessions are 90 minutes compared with 55–60 minutes. In summary, Leichsenring and colleagues’ conclusion that cognitive therapy and psychodynamic therapy are both efficacious (superior to no treatment) is justified, as is the conclusion that cognitive therapy is superior to psychodynamic therapy. However, one might reasonably question their estimate of the relative effects of cognitive therapy and psychodynamic therapy. A further trial in which cognitive therapy is delivered as recommended and at an adequate level of competence would be required to clarify matters. References
The authors’ disclosures accompany the original article. This reply (doi: 10.1176/appi.ajp.2013.13040472r) was accepted for publication in August 2013.
Psychodynamic Therapy or Cognitive Therapy for Social Anxiety Disorder To the Editor: I read with interest the article by Leichsenring et al. (1) in the July issue of the Journal. Cognitive therapy was significantly more effective than psychodynamic therapy on four of five social anxiety measures, including all those mentioned in the trial registration document (ISRCTN53517394). As one of the developers of cognitive therapy, I was naturally delighted to see the trial extend the range of credible psychological therapies to which cognitive therapy has been shown to be superior (2). However, several design features suggest the trial is likely to have underestimated the benefit of cognitive therapy relative to psychodynamic therapy. Readers may wish to bear these in mind when considering the relatively small differences in outcome that are reported. First, to match psychodynamic therapy, the time over which cognitive therapy was delivered was extended from the usual 3–4 months to 8–9 months. There is good evidence that slowing down the delivery of cognitive-behavioral treatments for social anxiety disorder reduces their effectiveness (3). Second, “type of treatment” is confounded with “therapist experience.” On average, psychodynamic therapists were qualified and had 8.0 years of clinical experience, whereas
Am J Psychiatry 170:11, November 2013
1. Leichsenring F, Salzer S, Beutel ME, Herpertz S, Hiller W, Hoyer J, Huesing J, Joraschky P, Nolting B, Poehlmann K, Ritter V, Stangier U, Strauss B, Stuhldreher N, Tefikow S, Teismann T, Willutzki U, Wiltink J, Leibing E: Psychodynamic therapy and cognitivebehavioral therapy in social anxiety disorder: a multicenter randomized controlled trial. Am J Psychiatry 2013; 170:759–767 2. Stott R, Wild J, Grey N, Liness S, Warnock-Parkes E, Commins S, Readings J, Bremner G, Woodward E, Ehlers A, Clark DM: Internetdelivered cognitive therapy for social anxiety disorder: a development pilot series. Behav Cogn Psychother 2013; 41:383–397 3. Herbert JD, Rheingold AA, Gaudiano BA, Myers VH: Standard versus extended cognitive behavior therapy for social anxiety disorder: a randomized-controlled trial. Behav Cogn Psychother 2004; 32:131–147 4. Ginzburg DM, Bohn C, Höfling V, Weck F, Clark DM, Stangier U: Treatment-specific competence predicts outcome in cognitive therapy for social anxiety disorder. Behav Res Ther 2012; 50:747–752
DAVID M. CLARK, D.PHIL.
Department of Experimental Psychology, University of Oxford, United Kingdom. The author reports no financial relationships with commercial interests. This letter (doi: 10.1176/appi.ajp.2013.13060744) was accepted for publication in September 2013.
Response to Clark To the Editor: Dr. Clark raises several concerns concerning our trial (1). First, cognitive therapy was implemented by
ajp.psychiatryonline.org
1365
Copyright of American Journal of Psychiatry is the property of American Psychiatric Publishing, Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
