EDITORIAL
Combination Psychotropic Regimens in Community Practice Mark Olfson,
O
ne of the cross-cutting findings to emerge from the large federally funded clinical treatment trials of the common childhood psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD),1 adolescent depression,2 obsessive-compulsive disorder,3 and anxiety disorders,4 is that many children do not achieve remission from available pharmacologic or psychological monotherapies. When faced with patients who do not remit or even respond to standard treatments, physicians commonly venture into therapeutic territory that is uncharted by clinical research. Armed with their clinical experience and judgment, the patient’s treatment history and current clinical presentation, and an understanding of the principles of pharmacology, physicians set off in search of a medication regimen that is effective and well tolerated by their patients. In this issue of The Journal of American Academy of Child and Adolescent Psychiatry, Rubin and colleagues5 provide a valuable portrait of national trends (2004 to 2008) in the use of psychotropic medication combinations to treat children and adolescents in the Medicaid program. They focus primarily on treatment with antipsychotic medications in combination with other psychotropic classes, including stimulants, antidepressants, mood stabilizers, or a2-agonists. Given the recent overall increase in treatment of young people with antipsychotic medications6 and the ongoing review of new national quality measurements in this area,7 such a careful examination of antipsychotic prescribing practices arrives at an opportune time. We learn from Rubin et al. that these combination regimens are common, typically long in duration, and on the rise. The highest rates of use of antipsychotics with other medication classes occur in children and adolescents with severe mental disorders, such as schizophrenia, bipolar disorder, or autism, who
942
www.jaacap.org
MD, MPH
also have comorbid psychiatric disorders. Nevertheless, some of the patient groups with the fastest growth in treatment of these regimens have clinical diagnoses that are further removed from evidence-based targets for antipsychotic medications. Specifically, rapid growth is reported in the rate at which children and adolescents with intellectual disabilities without other mental disorders and those with ADHD without other mental disorders are treated with medication combinations including antipsychotics. Such trends raise the specter that treatments with antipsychotics concurrent with other psychotropic medications are spreading to young people with less complicated conditions who do not have psychotic features. Such trends heighten concerns over tradeoffs between risks and benefits. In evaluating the clinical significance of these new findings, it is important to bear in mind that clinical research with adults and children offers support for some combinations of antipsychotics and other psychotropic medications. Combining certain second-generation antipsychotics with mood stabilizers for adult bipolar disorder, for example, is more effective at preventing relapse than adding a placebo.8,9 Adding some low-dose second-generation antipsychotics to antidepressants also is helpful for adults with treatmentresistant major depressive disorder10,11 or obsessive-compulsive disorder.12 Unfortunately, less clinical research is available to guide the use of adjunctive antipsychotic medications for young people with psychiatric disorders who do not respond to standard treatments. In a recent trial of severely aggressive children with ADHD and oppositional-defiant disorder or conduct disorder, youth who received risperidone augmentation after optimization of stimulants and parent training showed a significantly greater decrease in aggressive and disruptive behaviors than similarly treated children who
JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
EDITORIAL
received placebo as the adjuvant.13 It remains unknown whether such encouraging results would be achieved in children with less-severe aggressive behaviors. For the great majority of drug combinations and specific conditions reported by Rubin et al., however, the academic literature offers no insights concerning safety or benefit. In contemplating the increase of complex pharmacologic regimens, one is left wondering how many children and adolescents who receive these medication combinations have been previously treated with and not responded to standard monotherapies at full dose and sufficient duration. In this regard, it is worth recalling that in the large Multimodal Treatment Study of Children with ADHD, use of combination medication regimens for ADHD was far more common in children treated by community physicians, occurring in 11% overall, including 16% who received ADHD medications, than in children treated in the medication management group by the investigators with carefully titrated methylphenidate (2%).1 Yet, compared with community care patients, the medication management patients showed superior outcomes in parent- and teacher-rated ADHD symptoms, presumably because they received higher doses and more consistent treatment with stimulants.14 It also is not known how frequently children and adolescents who receive medication combinations are re-evaluated to assess the benefits of their combination therapy. The long duration of combined antipsychotic and other medication treatment, which stretched on average to 146 days for treatment with stimulants and antipsychotics, suggests that such clinical reassessments are not occurring as often as one would hope. Long treatment episodes with antipsychotics and other psychotropic medications raise the possibility that insufficient consideration is being given to tapering antipsychotic medications, especially if the medications were added during a period of crisis or an inpatient admission. In practice, it can be difficult to disentangle true medication benefits from placebo effects or the natural fluctuating course of the disorder itself, which can bias clinical appraisals toward unnecessary continuation of adjuvant medications. One important related issue that is left for future research concerns antipsychotic dosing in community practice. A greater understanding of
the antipsychotic doses that are used as monotherapy and as part of combination regimens for various conditions would help to calibrate concerns raised by the evolving prescribing practices described by Rubin et al. A general sensitivity of children and adolescents to weight gain and other adverse metabolic effects from secondgeneration antipsychotics is well established.15 Yet much remains to be learned about the safety of second-generation antipsychotic medications at the lower doses that are commonly used for disruptive behavior disorders and often in combination with stimulants, rather than the higher doses more frequently used to treat young people with schizophrenia or bipolar disorder. In 1 study of first-time antipsychotic treatment for children and adolescents, risperidone at doses below 1.5 mg daily compared with higher doses resulted in significantly lower increases in weight and waist circumference.16 Because second-generation antipsychotic medication blockade of D2 receptors and their modulation of other important receptors, including 5-HT2A, a2-adrenergic, and 5-HT2C, are dose-dependent,17 understanding the influence of antipsychotic dosing and concomitant medications on safety and efficacy across target disorders and how variation in dosing plays out in community practice remain clinical research priorities. For the past several years, the use of complex pharmacologic regimens has increased in outpatient mental health care.18 Because medication combinations compound risks of adverse events and drug-drug interactions, prudence dictates that these regimens should be limited to fallback strategies that are considered only after there has been an inadequate response to evidence-supported monotherapies. In daily practice, however, child and adolescent psychiatrists confront the need to make management decisions in clinical situations for which there is little information from clinical trials to guide their selection of treatment. The prescribing practices uncovered by Rubin et al. suggest that in recent years greater weight has been given to decreasing symptoms than to decreasing the number of medications required to achieve the desired response. These new findings give urgency to expanding clinical research on commonly used medication combinations and focusing physician training on improving the management of children and adolescents who do not respond to first-line monotherapies. &
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
www.jaacap.org
943
OLFSON
Accepted June 6, 2014.
Correspondence to Mark Olfson, MD, MPH, The New York State Psychiatric Institute/Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, New York, NY; e-mail: [email protected]
Dr. Olfson is with the College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York. Work on this editorial was supported by grant U19 HS021112 from the Agency for Healthcare Research and Quality.
0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry
Disclosure: Dr. Olfson reports no biomedical financial interests or potential conflicts of interest.
http://dx.doi.org/10.1016/j.jaac.2014.05.018
REFERENCES 1. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999;56:1073-1086. 2. Treatment of Adolescents with Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA. 2004;292:807-820. 3. Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA. 2004;27:1969-1976. 4. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavior therapy, sertraline, or a combination in childhood anxiety. N Eng J Med. 2008;359:2753-2766. 5. Kreider A, Matone M, Bellonci C, et al. Growth in the concurrent use of antipsychotics with other psychotropic medications in Medicaid-enrolled children. J Am Acad Child Adolesc Psychiatry. 2014;53:960-970. 6. Ridout KK, Ridout SJ, Zhu J. Characteristics of antipsychotic users 2003-2010 in the United States. Presented at the 2014 Annual Meeting of the American Psychiatric Association, New York, NY. 7. Proposed New Measures for HEDIS 2015: safe and judicious antipsychotic use in children and adolescents. http://www.ncqa. org/Portals/0/HomePage/Antipsychotics.pdf. Accessed May 23, 2014. 8. Bowden CL, Vieta E, Ice KS, et al. Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J Clin Psychiatry. 2010;71: 130-137. 9. Marcus R, Khan A, Rollin L, et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to
944
www.jaacap.org
10.
11.
12.
13.
14.
15. 16.
17.
18.
JOURNAL
lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord. 2011;13:133-144. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980-991. Spielmans GI, Berman MI, Linardatos E, Rosenlict NZ, Perry A, Tsai AC. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Med. 2013;10:31001403. Dold M, Aigner M, Lanzemberger, Kasper S. Antipsychotic augmentation of serotonin reuptake inhibitors in treatmentresistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. Int J Neuropsychopharmacol. 2013;16:557-574. Aman MC, Bukstein OG, Gadow KD, et al. What does risperidone add to parent training and stimulant for severe aggression in child attention-deficit/hyperactivity disorder? J Am Acad Child Adolesc Psychiatry. 2014;53:47-60. Jensen PS, Hinshaw SP, Swanson JM, et al. Findings from the NIMH multimodal treatment study of ADHD (MTA): implications and applications for primary care providers. J Dev Behav Pediatr. 2001;22:60-73. Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med. 2011;17:97-107. Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302:1765-1773. Blier P, Blondeau C. Neurobiological bases and clinical aspects of the use of aripiprazole in treatment-resistant major depressive disorder. J Affect Disord. 2011;128(suppl 1):S3-S10. Mojtabai R, Olfson M. National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch Gen Psychiatry. 2010;67:26-36.
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
Combination Psychotropic Regimens in Community Practice Mark Olfson,
O
ne of the cross-cutting findings to emerge from the large federally funded clinical treatment trials of the common childhood psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD),1 adolescent depression,2 obsessive-compulsive disorder,3 and anxiety disorders,4 is that many children do not achieve remission from available pharmacologic or psychological monotherapies. When faced with patients who do not remit or even respond to standard treatments, physicians commonly venture into therapeutic territory that is uncharted by clinical research. Armed with their clinical experience and judgment, the patient’s treatment history and current clinical presentation, and an understanding of the principles of pharmacology, physicians set off in search of a medication regimen that is effective and well tolerated by their patients. In this issue of The Journal of American Academy of Child and Adolescent Psychiatry, Rubin and colleagues5 provide a valuable portrait of national trends (2004 to 2008) in the use of psychotropic medication combinations to treat children and adolescents in the Medicaid program. They focus primarily on treatment with antipsychotic medications in combination with other psychotropic classes, including stimulants, antidepressants, mood stabilizers, or a2-agonists. Given the recent overall increase in treatment of young people with antipsychotic medications6 and the ongoing review of new national quality measurements in this area,7 such a careful examination of antipsychotic prescribing practices arrives at an opportune time. We learn from Rubin et al. that these combination regimens are common, typically long in duration, and on the rise. The highest rates of use of antipsychotics with other medication classes occur in children and adolescents with severe mental disorders, such as schizophrenia, bipolar disorder, or autism, who
942
www.jaacap.org
MD, MPH
also have comorbid psychiatric disorders. Nevertheless, some of the patient groups with the fastest growth in treatment of these regimens have clinical diagnoses that are further removed from evidence-based targets for antipsychotic medications. Specifically, rapid growth is reported in the rate at which children and adolescents with intellectual disabilities without other mental disorders and those with ADHD without other mental disorders are treated with medication combinations including antipsychotics. Such trends raise the specter that treatments with antipsychotics concurrent with other psychotropic medications are spreading to young people with less complicated conditions who do not have psychotic features. Such trends heighten concerns over tradeoffs between risks and benefits. In evaluating the clinical significance of these new findings, it is important to bear in mind that clinical research with adults and children offers support for some combinations of antipsychotics and other psychotropic medications. Combining certain second-generation antipsychotics with mood stabilizers for adult bipolar disorder, for example, is more effective at preventing relapse than adding a placebo.8,9 Adding some low-dose second-generation antipsychotics to antidepressants also is helpful for adults with treatmentresistant major depressive disorder10,11 or obsessive-compulsive disorder.12 Unfortunately, less clinical research is available to guide the use of adjunctive antipsychotic medications for young people with psychiatric disorders who do not respond to standard treatments. In a recent trial of severely aggressive children with ADHD and oppositional-defiant disorder or conduct disorder, youth who received risperidone augmentation after optimization of stimulants and parent training showed a significantly greater decrease in aggressive and disruptive behaviors than similarly treated children who
JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
EDITORIAL
received placebo as the adjuvant.13 It remains unknown whether such encouraging results would be achieved in children with less-severe aggressive behaviors. For the great majority of drug combinations and specific conditions reported by Rubin et al., however, the academic literature offers no insights concerning safety or benefit. In contemplating the increase of complex pharmacologic regimens, one is left wondering how many children and adolescents who receive these medication combinations have been previously treated with and not responded to standard monotherapies at full dose and sufficient duration. In this regard, it is worth recalling that in the large Multimodal Treatment Study of Children with ADHD, use of combination medication regimens for ADHD was far more common in children treated by community physicians, occurring in 11% overall, including 16% who received ADHD medications, than in children treated in the medication management group by the investigators with carefully titrated methylphenidate (2%).1 Yet, compared with community care patients, the medication management patients showed superior outcomes in parent- and teacher-rated ADHD symptoms, presumably because they received higher doses and more consistent treatment with stimulants.14 It also is not known how frequently children and adolescents who receive medication combinations are re-evaluated to assess the benefits of their combination therapy. The long duration of combined antipsychotic and other medication treatment, which stretched on average to 146 days for treatment with stimulants and antipsychotics, suggests that such clinical reassessments are not occurring as often as one would hope. Long treatment episodes with antipsychotics and other psychotropic medications raise the possibility that insufficient consideration is being given to tapering antipsychotic medications, especially if the medications were added during a period of crisis or an inpatient admission. In practice, it can be difficult to disentangle true medication benefits from placebo effects or the natural fluctuating course of the disorder itself, which can bias clinical appraisals toward unnecessary continuation of adjuvant medications. One important related issue that is left for future research concerns antipsychotic dosing in community practice. A greater understanding of
the antipsychotic doses that are used as monotherapy and as part of combination regimens for various conditions would help to calibrate concerns raised by the evolving prescribing practices described by Rubin et al. A general sensitivity of children and adolescents to weight gain and other adverse metabolic effects from secondgeneration antipsychotics is well established.15 Yet much remains to be learned about the safety of second-generation antipsychotic medications at the lower doses that are commonly used for disruptive behavior disorders and often in combination with stimulants, rather than the higher doses more frequently used to treat young people with schizophrenia or bipolar disorder. In 1 study of first-time antipsychotic treatment for children and adolescents, risperidone at doses below 1.5 mg daily compared with higher doses resulted in significantly lower increases in weight and waist circumference.16 Because second-generation antipsychotic medication blockade of D2 receptors and their modulation of other important receptors, including 5-HT2A, a2-adrenergic, and 5-HT2C, are dose-dependent,17 understanding the influence of antipsychotic dosing and concomitant medications on safety and efficacy across target disorders and how variation in dosing plays out in community practice remain clinical research priorities. For the past several years, the use of complex pharmacologic regimens has increased in outpatient mental health care.18 Because medication combinations compound risks of adverse events and drug-drug interactions, prudence dictates that these regimens should be limited to fallback strategies that are considered only after there has been an inadequate response to evidence-supported monotherapies. In daily practice, however, child and adolescent psychiatrists confront the need to make management decisions in clinical situations for which there is little information from clinical trials to guide their selection of treatment. The prescribing practices uncovered by Rubin et al. suggest that in recent years greater weight has been given to decreasing symptoms than to decreasing the number of medications required to achieve the desired response. These new findings give urgency to expanding clinical research on commonly used medication combinations and focusing physician training on improving the management of children and adolescents who do not respond to first-line monotherapies. &
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
www.jaacap.org
943
OLFSON
Accepted June 6, 2014.
Correspondence to Mark Olfson, MD, MPH, The New York State Psychiatric Institute/Department of Psychiatry, College of Physicians and Surgeons of Columbia University, 1051 Riverside Drive, New York, NY; e-mail: [email protected]
Dr. Olfson is with the College of Physicians and Surgeons, Columbia University and the New York State Psychiatric Institute, New York. Work on this editorial was supported by grant U19 HS021112 from the Agency for Healthcare Research and Quality.
0890-8567/$36.00/ª2014 American Academy of Child and Adolescent Psychiatry
Disclosure: Dr. Olfson reports no biomedical financial interests or potential conflicts of interest.
http://dx.doi.org/10.1016/j.jaac.2014.05.018
REFERENCES 1. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999;56:1073-1086. 2. Treatment of Adolescents with Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. JAMA. 2004;292:807-820. 3. Pediatric OCD Treatment Study (POTS) Team. Cognitive-behavior therapy, sertraline, and their combination for children and adolescents with obsessive-compulsive disorder: the Pediatric OCD Treatment Study (POTS) randomized controlled trial. JAMA. 2004;27:1969-1976. 4. Walkup JT, Albano AM, Piacentini J, et al. Cognitive behavior therapy, sertraline, or a combination in childhood anxiety. N Eng J Med. 2008;359:2753-2766. 5. Kreider A, Matone M, Bellonci C, et al. Growth in the concurrent use of antipsychotics with other psychotropic medications in Medicaid-enrolled children. J Am Acad Child Adolesc Psychiatry. 2014;53:960-970. 6. Ridout KK, Ridout SJ, Zhu J. Characteristics of antipsychotic users 2003-2010 in the United States. Presented at the 2014 Annual Meeting of the American Psychiatric Association, New York, NY. 7. Proposed New Measures for HEDIS 2015: safe and judicious antipsychotic use in children and adolescents. http://www.ncqa. org/Portals/0/HomePage/Antipsychotics.pdf. Accessed May 23, 2014. 8. Bowden CL, Vieta E, Ice KS, et al. Ziprasidone plus a mood stabilizer in subjects with bipolar I disorder: a 6-month, randomized, placebo-controlled, double-blind trial. J Clin Psychiatry. 2010;71: 130-137. 9. Marcus R, Khan A, Rollin L, et al. Efficacy of aripiprazole adjunctive to lithium or valproate in the long-term treatment of patients with bipolar I disorder with an inadequate response to
944
www.jaacap.org
10.
11.
12.
13.
14.
15. 16.
17.
18.
JOURNAL
lithium or valproate monotherapy: a multicenter, double-blind, randomized study. Bipolar Disord. 2011;13:133-144. Nelson JC, Papakostas GI. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Am J Psychiatry. 2009;166:980-991. Spielmans GI, Berman MI, Linardatos E, Rosenlict NZ, Perry A, Tsai AC. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Med. 2013;10:31001403. Dold M, Aigner M, Lanzemberger, Kasper S. Antipsychotic augmentation of serotonin reuptake inhibitors in treatmentresistant obsessive-compulsive disorder: a meta-analysis of double-blind, randomized, placebo-controlled trials. Int J Neuropsychopharmacol. 2013;16:557-574. Aman MC, Bukstein OG, Gadow KD, et al. What does risperidone add to parent training and stimulant for severe aggression in child attention-deficit/hyperactivity disorder? J Am Acad Child Adolesc Psychiatry. 2014;53:47-60. Jensen PS, Hinshaw SP, Swanson JM, et al. Findings from the NIMH multimodal treatment study of ADHD (MTA): implications and applications for primary care providers. J Dev Behav Pediatr. 2001;22:60-73. Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med. 2011;17:97-107. Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302:1765-1773. Blier P, Blondeau C. Neurobiological bases and clinical aspects of the use of aripiprazole in treatment-resistant major depressive disorder. J Affect Disord. 2011;128(suppl 1):S3-S10. Mojtabai R, Olfson M. National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch Gen Psychiatry. 2010;67:26-36.
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 53 NUMBER 9 SEPTEMBER 2014
![[Psychotropic drugs in general practice].](/assets/img/hold.png)
