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Hyperactivity Disorder: The World According to the Caudate
EDITORIAL Individual Variability and Medications to Treat Attention-Deficit/Hyperactivity Disorder: The World According to the Caudate Tonya White,
W
hen considering medication options to treat childhood psychiatric disorders, clinicians acquire a wealth of information to assist in making the best choice. Important questions arise, such as: What are the primary and comorbid disorders? What is the standard of care for the disorder? Has the child been on any medications in the past? Were these medications effective? What is the family history? Have any family members been on medications that were helpful? Clinicians fit together an array of puzzle pieces and make an educated decision regarding the best medication to prescribe for each individual patient. However, despite the best information obtained and application of standards of care, some children just do not respond to the initial medication. It is not really their fault, nor is it the clinician’s; it is just that there is so much hidden individual variability that cannot be determined via a thorough clinical interview and mental status examination. It is this individual variability, which, although tremendously beneficial from an ontological perspective, sometimes thwarts our best treatment plans. Thus, studies with the goal to better understand the underlying neurobiological differences associated with psychopathology will move us closer toward precision medicine, selecting the right medication for each patient on the first go-round. Because differential response to medication is integrally tied to individual variation in the neurobiology and neurochemistry of the brain, it was the primary goal of the study by Schulz et al.1 to predict differential response to either methylphenidate or atomoxetine in children with attentiondeficit/hyperactivity disorder (ADHD) using baseline brain activity measures. This is where the caudate nucleus comes into play, which you were probably wondering, from this editorial’s title. The dorsal striatum consists of the caudate nucleus and putamen, and the caudate is highly innervated by dopaminergic neurons and is also implicated in ADHD.2 Although methylphenidate and atomoxetine inhibit the norepinephrine transporter, only methylphenidate blocks the dopamine transporter.3 Thus a study that focuses on brain activation in the dorsal striatum and, specifically, the caudate nucleus could potentially reveal differential effects in brain activation based on the different binding properties between methylphenidate and atomoxetine; atomoxetine may wave as it passes by all the rich dopamine neurons in the caudate, whereas methylphenidate will stop, shake hands, and stick around for a while.
544
www.jaacap.org
MD, PhD
In this study, Schulz et al. did not assess changes in caudate function associated with treatment but, rather, asked the question whether baseline striatal function obtained using a functional magnetic resonance imaging (MRI) go/no-go paradigm could predict response to treatment. In other words, does the activation in the striatum to a task that is dopamine-dependent (go/no-go)4 predict treatment response between a dopaminergic medication (methylphenidate) versus a non-dopamine medication (atomoxetine)? Although most children will respond to methylphenidate, there is a distinct subset of children who respond preferentially to atomoxetine. Schulz et al. embedded their functional MRI study into a double-blind, placebo-controlled, crossover design study comparing methylphenidate and atomoxetine.5 Interestingly, the authors found that baseline elevated functional brain activation in the right caudate elicited using the go/no-go task predicted response to methylphenidate over atomoxetine. Similar to many neuroimaging studies, there was not a perfect separation between differential response and activation in the right caudate. The authors showed that one in every two children with increased activation in the right caudate demonstrated preferential improvement to methylphenidate over atomoxetine. The right caudate activation predicted response to methylphenidate only when considered in combination with methylphenidate, whereas caudate activation did not predict response to methylphenidate alone. Thus, there is still considerable work to be performed before such an approach can be introduced into clinical practice. However, their study is interesting in showing some treatment response prediction in ADHD, and it would be very interesting to see a replication study. That said, even if the findings showed perfect prediction, I imagine that the thought of introducing MRI as a potential clinical tool for medication choice could raise some eyebrows. Some might argue, “Since 70% of children respond to methylphenidate on the first go, why would I take the time, cost, and effort to have a child undergo a functional MRI when a stimulant medication trial is quick, cost-effective, and has very little risk?” I would actually tend to agree with this comment if the process of scientific discovery were static, rather than being a highly dynamic process. New tools for better understanding the underlying neurobiology are constantly emerging, and having a better understanding of the underlying neurobiology of disorders—especially those with predictive power for treatment—will be extremely JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 56 NUMBER 7 JULY 2017
EDITORIAL
beneficial as new, cost-effective techniques emerge. Furthermore, because some children do not respond to the first trial, such precision medicine approaches, as opposed to trial and error, may be reassuring for both children and their parents, and could help with treatment choices for children who do not read the textbooks. Finally, although this study focused only on ADHD, it would be helpful to know the specificity of the findings, since “time is often the best diagnostician” in child psychiatry, and some children with ADHD may emerge with other problems later in life. &
The author is supported by the Sophia Children’s Hospital Research Foundation (SSWO), the Netherlands Organization for Health Research and Development (ZonMw) TOP project number 91211021, and from the Simons Foundation Autism Research Initiative (SFARI - 307280). Disclosure: Dr. White reports no biomedical financial interests or potential conflicts of interest. Correspondence to Tonya White, MD, PhD, Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia/Kp-2869, Postbus 2060, 3000 CB Rotterdam, The Netherlands; e-mail: t.white@ erasmusmc.nl
Accepted May 10, 2017.
0890-8567/$36.00/ª2017 American Academy of Child and Adolescent Psychiatry
Dr. White is with Erasmus University Medical Centre, Rotterdam, the Netherlands.
http://dx.doi.org/10.1016/j.jaac.2017.05.011
REFERENCES
1. Schulz KP, Bedard A-CV, Fan J, et al. Striatal activation predicts differential therapeutic responses to methylphenidate and atomoxetine. J Am Acad Child Adolesc Psychiatry. 2017;56:602-609. 2. Volkow ND, Wang G-J, Newcorn J, et al. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007;64:932. 3. Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS. Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci. 1996;58:231-239.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 56 NUMBER 7 JULY 2017
4. Vrshek-Schallhorn S, Wahlstrom D, Benolkin K, White T, Luciana M. Affective bias and response modulation following tyrosine depletion in healthy adults. Neuropsychopharmacology. 2006;31: 2523-2536. 5. Schulz KP, Fan J, Bedard A-C V, et al. Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2012;69: 952-961.
www.jaacap.org
545
W
hen considering medication options to treat childhood psychiatric disorders, clinicians acquire a wealth of information to assist in making the best choice. Important questions arise, such as: What are the primary and comorbid disorders? What is the standard of care for the disorder? Has the child been on any medications in the past? Were these medications effective? What is the family history? Have any family members been on medications that were helpful? Clinicians fit together an array of puzzle pieces and make an educated decision regarding the best medication to prescribe for each individual patient. However, despite the best information obtained and application of standards of care, some children just do not respond to the initial medication. It is not really their fault, nor is it the clinician’s; it is just that there is so much hidden individual variability that cannot be determined via a thorough clinical interview and mental status examination. It is this individual variability, which, although tremendously beneficial from an ontological perspective, sometimes thwarts our best treatment plans. Thus, studies with the goal to better understand the underlying neurobiological differences associated with psychopathology will move us closer toward precision medicine, selecting the right medication for each patient on the first go-round. Because differential response to medication is integrally tied to individual variation in the neurobiology and neurochemistry of the brain, it was the primary goal of the study by Schulz et al.1 to predict differential response to either methylphenidate or atomoxetine in children with attentiondeficit/hyperactivity disorder (ADHD) using baseline brain activity measures. This is where the caudate nucleus comes into play, which you were probably wondering, from this editorial’s title. The dorsal striatum consists of the caudate nucleus and putamen, and the caudate is highly innervated by dopaminergic neurons and is also implicated in ADHD.2 Although methylphenidate and atomoxetine inhibit the norepinephrine transporter, only methylphenidate blocks the dopamine transporter.3 Thus a study that focuses on brain activation in the dorsal striatum and, specifically, the caudate nucleus could potentially reveal differential effects in brain activation based on the different binding properties between methylphenidate and atomoxetine; atomoxetine may wave as it passes by all the rich dopamine neurons in the caudate, whereas methylphenidate will stop, shake hands, and stick around for a while.
544
www.jaacap.org
MD, PhD
In this study, Schulz et al. did not assess changes in caudate function associated with treatment but, rather, asked the question whether baseline striatal function obtained using a functional magnetic resonance imaging (MRI) go/no-go paradigm could predict response to treatment. In other words, does the activation in the striatum to a task that is dopamine-dependent (go/no-go)4 predict treatment response between a dopaminergic medication (methylphenidate) versus a non-dopamine medication (atomoxetine)? Although most children will respond to methylphenidate, there is a distinct subset of children who respond preferentially to atomoxetine. Schulz et al. embedded their functional MRI study into a double-blind, placebo-controlled, crossover design study comparing methylphenidate and atomoxetine.5 Interestingly, the authors found that baseline elevated functional brain activation in the right caudate elicited using the go/no-go task predicted response to methylphenidate over atomoxetine. Similar to many neuroimaging studies, there was not a perfect separation between differential response and activation in the right caudate. The authors showed that one in every two children with increased activation in the right caudate demonstrated preferential improvement to methylphenidate over atomoxetine. The right caudate activation predicted response to methylphenidate only when considered in combination with methylphenidate, whereas caudate activation did not predict response to methylphenidate alone. Thus, there is still considerable work to be performed before such an approach can be introduced into clinical practice. However, their study is interesting in showing some treatment response prediction in ADHD, and it would be very interesting to see a replication study. That said, even if the findings showed perfect prediction, I imagine that the thought of introducing MRI as a potential clinical tool for medication choice could raise some eyebrows. Some might argue, “Since 70% of children respond to methylphenidate on the first go, why would I take the time, cost, and effort to have a child undergo a functional MRI when a stimulant medication trial is quick, cost-effective, and has very little risk?” I would actually tend to agree with this comment if the process of scientific discovery were static, rather than being a highly dynamic process. New tools for better understanding the underlying neurobiology are constantly emerging, and having a better understanding of the underlying neurobiology of disorders—especially those with predictive power for treatment—will be extremely JOURNAL
OF THE
AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 56 NUMBER 7 JULY 2017
EDITORIAL
beneficial as new, cost-effective techniques emerge. Furthermore, because some children do not respond to the first trial, such precision medicine approaches, as opposed to trial and error, may be reassuring for both children and their parents, and could help with treatment choices for children who do not read the textbooks. Finally, although this study focused only on ADHD, it would be helpful to know the specificity of the findings, since “time is often the best diagnostician” in child psychiatry, and some children with ADHD may emerge with other problems later in life. &
The author is supported by the Sophia Children’s Hospital Research Foundation (SSWO), the Netherlands Organization for Health Research and Development (ZonMw) TOP project number 91211021, and from the Simons Foundation Autism Research Initiative (SFARI - 307280). Disclosure: Dr. White reports no biomedical financial interests or potential conflicts of interest. Correspondence to Tonya White, MD, PhD, Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC-Sophia/Kp-2869, Postbus 2060, 3000 CB Rotterdam, The Netherlands; e-mail: t.white@ erasmusmc.nl
Accepted May 10, 2017.
0890-8567/$36.00/ª2017 American Academy of Child and Adolescent Psychiatry
Dr. White is with Erasmus University Medical Centre, Rotterdam, the Netherlands.
http://dx.doi.org/10.1016/j.jaac.2017.05.011
REFERENCES
1. Schulz KP, Bedard A-CV, Fan J, et al. Striatal activation predicts differential therapeutic responses to methylphenidate and atomoxetine. J Am Acad Child Adolesc Psychiatry. 2017;56:602-609. 2. Volkow ND, Wang G-J, Newcorn J, et al. Depressed dopamine activity in caudate and preliminary evidence of limbic involvement in adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2007;64:932. 3. Gatley SJ, Pan D, Chen R, Chaturvedi G, Ding YS. Affinities of methylphenidate derivatives for dopamine, norepinephrine and serotonin transporters. Life Sci. 1996;58:231-239.
JOURNAL OF THE AMERICAN ACADEMY OF C HILD & ADOLESCENT PSYCHIATRY VOLUME 56 NUMBER 7 JULY 2017
4. Vrshek-Schallhorn S, Wahlstrom D, Benolkin K, White T, Luciana M. Affective bias and response modulation following tyrosine depletion in healthy adults. Neuropsychopharmacology. 2006;31: 2523-2536. 5. Schulz KP, Fan J, Bedard A-C V, et al. Common and unique therapeutic mechanisms of stimulant and nonstimulant treatments for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2012;69: 952-961.
www.jaacap.org
545