EDITORIAL Child/Adolescent Anxiety Multimodal Study Safety Floyd R. Sallee,
T
he article “Child/Adolescent Anxiety Multimodal Study: Evaluating Safety” by Rynn et al.1 presents an intensive analysis of adverse events (AEs) associated with the treatment of youth with anxiety disorders within the context of the largest controlled trial to date to assess the relative safety of antidepressant and cognitive-behavioral treatment and their combination. This report comes at a time when the impact of the Food and Drug Administration’s Public Health Advisory and subsequent black-box warning of 2004 concerning the risk of suicidal thoughts and associated behaviors in youth with antidepressants has dissipated.2 The additional reassurance provided by the research of Rynn et al. of short-term tolerability and safety coincides with ever-increasing prescribing rates for selective serotonin reuptake inhibitors (SSRIs) for children and adolescents with anxiety disorders among generalists and specialists treating these conditions.3 In the midst of greater usage of antidepressant therapies in anxious children, there needs to be a better understanding of what types of risks to monitor and what should comprise monitoring.4 Research has supported the standardization of AE assessment with a structured method of inquiry. In this regard, the AE assessment for the Child/Adolescent Anxiety Multimodal Study (CAMS) was revolutionary in using a scripted AE 2-step procedure supplemented by direct-harm–related inquiry and a self-report physical symptom checklist. Unfortunately in clinical practice, the tools to systematically monitor for side effects have not been widely disseminated or adopted. The present article, although contributing to our understanding of acute tolerability of SSRI antidepressants, has pointed to a heightened risk of behavioral activation in children that seems to be mirrored in other studies. In a systematic review of antidepressant trials by Offidani et al.5 involving 6,767 youth with depressive or anxiety disorders, the investigators found an increased AE risk of behavioral activation or emotional arousal at rates 3 to 10 times greater than with placebo. Importantly, behavioral activation risk appeared to be equivalently high in the depression and anxiety disorder trials. In the research reported by Rynn et al.,1 children who received SSRI reported higher rates of AEs overall, but the combination of cognitive-behavioral therapy (CBT) with SSRI did not offer a more favorable AE profile. The analysis of Rynn et al. suggests that children are particularly vulnerable to AE risk and “psychiatric AEs” involving disinhibition in particular compared with adolescents. Psychiatric AEs are known to contribute to discontinuation in trials and to have treatment and compliance implications in the clinic. The weight of available evidence suggests that SSRIs are highly effective in the acute treatment of different anxiety disorders, and the contribution of the CAMS cannot be overstated.6 What has been missing until this point has been
MD, PhD
longer-term outcomes and remission and relapse rates for youth with anxiety treated with SSRIs. Near-term outcomes at 24 and 36 weeks after the conclusion of the CAMS demonstrated that acute response is retained in more than 80% of patients based on the evidence of a subset of the total sample.7 Additional evidence from the Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS), a follow-up of 59% of the original CAMS sample, showed that acute-phase CAMS treatment responders at mean 6year follow-up were more likely to be in remission, to have less severe anxiety symptoms, and to be higher functioning.8 For treatment responders, the impact on family function can be overwhelmingly positive, with a significant decrease in family burden of illness.9 Although the benefit side of the risk-to-benefit consideration is becoming clearer, the risks remain at issue. Rynn et al. are reassuring in their better defining the tolerability and safety by age group and treatment assignment using AE assessment methodology that was well defined if limited in scope. It is interesting that for the CAMS, the absence of AEs led to more rapid improvement within treatments with the exception of CBT only, where AEs, perhaps positively associated with graded exposure tasks, seemed to be related to more rapid improvement. It will be left to the CAMELS group to evaluate risks for the longer term of the acute treatment strategies used in the CAMS. Although CAMS exposure to SSRI was limited to 12 weeks, SSRI treatments for anxiety disorder in youth typically continue for at least 1 year. In this regard, we have no answers to the long-term risk of SSRI exposure by age or stage of brain development. Although juvenile rodent studies are believed to be an adequate surrogate for sentinel risk and signal detection, it is important that we have long-term longitudinal studies that follow therapeutic outcomes and AEs over time in naturalistic settings.10 & Accepted December 22, 2014. This article was reviewed under and accepted by ad hoc editor Daniel Pine, MD. Dr. Sallee is with the College of Medicine, University of Cincinnati. Disclosure: Dr. Sallee has received grant support from the National Institute of Mental Health and has served as a consultant of Ironshore Pharmaceuticals, AstraZeneca, Impax Laboratories, Purdue Pharma, Otsuka Research and Development, and Reckitt Benckiser. He is a member of the board of directors and a stockholder of P2D Bioscience. Correspondence to Floyd R. Sallee, MD, PhD, College of Medicine, University of Cincinnati, Department of Psychiatry, ML 0559, 231 Albert Sabin Way, Cincinnati, OH 45267; e-mail: [email protected] 0890-8567/$36.00/ª2015 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.12.009
JOURNAL 162
www.jaacap.org
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 54 NUMBER 3 MARCH 2015
EDITORIAL
REFERENCES
1. Rynn MA, Walkup JT, Compton SN, et al. Child/Adolescent Anxiety Multimodal Study: Evaluating Safety. J Am Acad Child Adolesc Psychiatry. 2015;54:180-190. 2. FDA Launches a multi-pronged strategy to strengthen safeguards for children treated with antidepressant medications [public health advisory]. Silver Spring, MD: US Food and Drug Administration. http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm 108363.htm. Published October 15, 2004. Accessed September 15, 2014. 3. Lam D, Gorman DA, Patten S, Pringsheim T. The pharmacoepidemiology of selective serotonin reuptake inhibitors for children and adolescents in Canada from 2005 to 2009: a database analysis. Paediatr Drugs. 2013;15:319-327. 4. Greenhill LL, Vitiello B, Fisher P, et al. Comparison of increasingly detailed elicitation methods for the assessment of adverse events in pediatric psychopharmacology. J Am Acad Child Adolesc Psychiatry. 2004; 43:1488-1496. 5. Offidani E, Fava GA, Tomba E, Baldessarini RJ. Excessive mood-elevation and behavioral activation with antidepressant treatment of juvenile
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 54 NUMBER 3 MARCH 2015
6.
7.
8.
9.
10.
depressive and anxiety disorders: systematic review. Psychother Psychosom. 2013;82:132-141. Ipser JC, Stein DJ, Hawkridge S, Hoppe L. Pharmacotherapy for anxiety disorders in children and adolescents. Cochrane Database Syst Rev. 2009; 8:CD005-170. Piacentini J, Bennett S, Compton SN, et al. 24- And 36-week outcomes for the Child/Adolescent Anxiety Multimodal Study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53:297-310. Ginsburg GS, Becker EM, Keeton CP, et al. Naturalistic follow-up of youths treated for pediatric anxiety disorders. JAMA Psychiatry. 2014;71: 310-318. Keeton CP, Ginsburg GS, Drake KL, et al. Benefits of child-focused anxiety treatments for parents and family functioning. Depress Anxiety. 2013;30:865-872. Leckman JF. The risks and benefits of antidepressants to treat pediatriconset depression and anxiety disorders: a developmental perspective. Psychother Psychosom. 2013;82:129-131.
www.jaacap.org
163
T
he article “Child/Adolescent Anxiety Multimodal Study: Evaluating Safety” by Rynn et al.1 presents an intensive analysis of adverse events (AEs) associated with the treatment of youth with anxiety disorders within the context of the largest controlled trial to date to assess the relative safety of antidepressant and cognitive-behavioral treatment and their combination. This report comes at a time when the impact of the Food and Drug Administration’s Public Health Advisory and subsequent black-box warning of 2004 concerning the risk of suicidal thoughts and associated behaviors in youth with antidepressants has dissipated.2 The additional reassurance provided by the research of Rynn et al. of short-term tolerability and safety coincides with ever-increasing prescribing rates for selective serotonin reuptake inhibitors (SSRIs) for children and adolescents with anxiety disorders among generalists and specialists treating these conditions.3 In the midst of greater usage of antidepressant therapies in anxious children, there needs to be a better understanding of what types of risks to monitor and what should comprise monitoring.4 Research has supported the standardization of AE assessment with a structured method of inquiry. In this regard, the AE assessment for the Child/Adolescent Anxiety Multimodal Study (CAMS) was revolutionary in using a scripted AE 2-step procedure supplemented by direct-harm–related inquiry and a self-report physical symptom checklist. Unfortunately in clinical practice, the tools to systematically monitor for side effects have not been widely disseminated or adopted. The present article, although contributing to our understanding of acute tolerability of SSRI antidepressants, has pointed to a heightened risk of behavioral activation in children that seems to be mirrored in other studies. In a systematic review of antidepressant trials by Offidani et al.5 involving 6,767 youth with depressive or anxiety disorders, the investigators found an increased AE risk of behavioral activation or emotional arousal at rates 3 to 10 times greater than with placebo. Importantly, behavioral activation risk appeared to be equivalently high in the depression and anxiety disorder trials. In the research reported by Rynn et al.,1 children who received SSRI reported higher rates of AEs overall, but the combination of cognitive-behavioral therapy (CBT) with SSRI did not offer a more favorable AE profile. The analysis of Rynn et al. suggests that children are particularly vulnerable to AE risk and “psychiatric AEs” involving disinhibition in particular compared with adolescents. Psychiatric AEs are known to contribute to discontinuation in trials and to have treatment and compliance implications in the clinic. The weight of available evidence suggests that SSRIs are highly effective in the acute treatment of different anxiety disorders, and the contribution of the CAMS cannot be overstated.6 What has been missing until this point has been
MD, PhD
longer-term outcomes and remission and relapse rates for youth with anxiety treated with SSRIs. Near-term outcomes at 24 and 36 weeks after the conclusion of the CAMS demonstrated that acute response is retained in more than 80% of patients based on the evidence of a subset of the total sample.7 Additional evidence from the Child/Adolescent Anxiety Multimodal Extended Long-term Study (CAMELS), a follow-up of 59% of the original CAMS sample, showed that acute-phase CAMS treatment responders at mean 6year follow-up were more likely to be in remission, to have less severe anxiety symptoms, and to be higher functioning.8 For treatment responders, the impact on family function can be overwhelmingly positive, with a significant decrease in family burden of illness.9 Although the benefit side of the risk-to-benefit consideration is becoming clearer, the risks remain at issue. Rynn et al. are reassuring in their better defining the tolerability and safety by age group and treatment assignment using AE assessment methodology that was well defined if limited in scope. It is interesting that for the CAMS, the absence of AEs led to more rapid improvement within treatments with the exception of CBT only, where AEs, perhaps positively associated with graded exposure tasks, seemed to be related to more rapid improvement. It will be left to the CAMELS group to evaluate risks for the longer term of the acute treatment strategies used in the CAMS. Although CAMS exposure to SSRI was limited to 12 weeks, SSRI treatments for anxiety disorder in youth typically continue for at least 1 year. In this regard, we have no answers to the long-term risk of SSRI exposure by age or stage of brain development. Although juvenile rodent studies are believed to be an adequate surrogate for sentinel risk and signal detection, it is important that we have long-term longitudinal studies that follow therapeutic outcomes and AEs over time in naturalistic settings.10 & Accepted December 22, 2014. This article was reviewed under and accepted by ad hoc editor Daniel Pine, MD. Dr. Sallee is with the College of Medicine, University of Cincinnati. Disclosure: Dr. Sallee has received grant support from the National Institute of Mental Health and has served as a consultant of Ironshore Pharmaceuticals, AstraZeneca, Impax Laboratories, Purdue Pharma, Otsuka Research and Development, and Reckitt Benckiser. He is a member of the board of directors and a stockholder of P2D Bioscience. Correspondence to Floyd R. Sallee, MD, PhD, College of Medicine, University of Cincinnati, Department of Psychiatry, ML 0559, 231 Albert Sabin Way, Cincinnati, OH 45267; e-mail: [email protected] 0890-8567/$36.00/ª2015 American Academy of Child and Adolescent Psychiatry http://dx.doi.org/10.1016/j.jaac.2014.12.009
JOURNAL 162
www.jaacap.org
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 54 NUMBER 3 MARCH 2015
EDITORIAL
REFERENCES
1. Rynn MA, Walkup JT, Compton SN, et al. Child/Adolescent Anxiety Multimodal Study: Evaluating Safety. J Am Acad Child Adolesc Psychiatry. 2015;54:180-190. 2. FDA Launches a multi-pronged strategy to strengthen safeguards for children treated with antidepressant medications [public health advisory]. Silver Spring, MD: US Food and Drug Administration. http:// www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2004/ucm 108363.htm. Published October 15, 2004. Accessed September 15, 2014. 3. Lam D, Gorman DA, Patten S, Pringsheim T. The pharmacoepidemiology of selective serotonin reuptake inhibitors for children and adolescents in Canada from 2005 to 2009: a database analysis. Paediatr Drugs. 2013;15:319-327. 4. Greenhill LL, Vitiello B, Fisher P, et al. Comparison of increasingly detailed elicitation methods for the assessment of adverse events in pediatric psychopharmacology. J Am Acad Child Adolesc Psychiatry. 2004; 43:1488-1496. 5. Offidani E, Fava GA, Tomba E, Baldessarini RJ. Excessive mood-elevation and behavioral activation with antidepressant treatment of juvenile
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 54 NUMBER 3 MARCH 2015
6.
7.
8.
9.
10.
depressive and anxiety disorders: systematic review. Psychother Psychosom. 2013;82:132-141. Ipser JC, Stein DJ, Hawkridge S, Hoppe L. Pharmacotherapy for anxiety disorders in children and adolescents. Cochrane Database Syst Rev. 2009; 8:CD005-170. Piacentini J, Bennett S, Compton SN, et al. 24- And 36-week outcomes for the Child/Adolescent Anxiety Multimodal Study (CAMS). J Am Acad Child Adolesc Psychiatry. 2014;53:297-310. Ginsburg GS, Becker EM, Keeton CP, et al. Naturalistic follow-up of youths treated for pediatric anxiety disorders. JAMA Psychiatry. 2014;71: 310-318. Keeton CP, Ginsburg GS, Drake KL, et al. Benefits of child-focused anxiety treatments for parents and family functioning. Depress Anxiety. 2013;30:865-872. Leckman JF. The risks and benefits of antidepressants to treat pediatriconset depression and anxiety disorders: a developmental perspective. Psychother Psychosom. 2013;82:129-131.
www.jaacap.org
163
