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This month’s Journal features an article by 275.13 mg/day in responders (4 of 11) and 866.67 Ϯ 214.52 mg/day in nonresponders (7 of the future of clinical practice, whereby treat- 11). Ninety-five percent of the divalproex group ment development is guided by brain imaging.
achieved a serum valproate level higher than 75 Specifically, Pavuluri and colleagues sought to evaluate the effect of risperidone or divalproex At baseline and the end of the trial, partici- on brain circuits mediating affect and working pants completed a 7-minute fMRI scan paired memory in children and adolescents with bipolar with a two-back working memory task. Specifi- disorder (BD). To achieve this goal, they random- cally, angry, happy, or neutral faces were pre- ized youths with BD to receive risperidone plus sented for 3 seconds each in blocks of 10 faces of placebo or divalproex plus placebo and con- the same type. Participants pressed a button if ducted pre- and post-treatment functional mag- they saw the same face presented two trials netic resonance imaging (fMRI) scans.
previously. Between face-type blocks, partici- The study’s main finding was a differential pants had 20 seconds of rest for their brain effect of treatment on fMRI outcomes but not on activity to return to baseline. Typically develop- clinical outcomes. Specifically, compared with the ing controls (n ϭ 15; 14.5 Ϯ 2.8 years old) were divalproex group, the risperidone group, irrespec- recruited and underwent scanning twice as a tive of treatment response, had a greater change in baseline reference for the fMRI data.
the activation of the left ventral striatum—an area The results indicated that the risperidone rich in dopamine-2 receptors that mediate reward treatment was associated with alterations in stri- processing. In contrast, the divalproex group, irre- atal activity, whereas the divalproex treatment spective of treatment response, had a greater acti- was associated with alterations in frontal and vation in the left inferior frontal gyrus and right temporal activities. What does this mean for middle temporal gyrus—areas implicated in atten- practitioners—now and in the near future? Two tion and memory. This suggests the possibility that medications may be used in a personalized medi- First, combining neuroimaging and treatment cine approach to target precise cognitive or emo- methods in the same study holds the potential to tional processes gone awry in a particular patient advance the understanding of how current treat- ments work by identifying the predictors of re- sponse (or nonresponse) and clarifying the cogni- (13.6 Ϯ 2.5 years old) who were in a manic or tive and emotional processes underlying specific mixed mood state. After a 1-week medication psychiatric disorders that could be used as targets washout period (4 weeks for fluoxetine or aripipra- for novel treatments. This is the same mechanistic zole), participants with BD underwent scanning biomarker approach that has yielded such success and were randomized to either treatment arm.
in cancer chemotherapy, most notably pediatric- onset acute lymphoblastic leukemia, where bio- provement of at least 50% in the Young Mania markers gleaned from tissue samples have trans- Rating Score. At the end, the risperidone dose formed the 5-year survival from nil to around 85% was 1.35 Ϯ 0.46 mg/day in the responders (six of 10) and 1.45 Ϯ 0.35 mg/day in the nonresponders Extrapolating to the extreme from the present (four of 10). The divalproex dose was 852.14 Ϯ study—and needing additional research—it is JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY possible that, in the future, youths with BD time when research funding remains flat or in whose pretreatment scans indicate abnormal re- decline. Although this study was supported by ward processing may be treated with risperidone the National Institutes of Mental Health, this may to address their aberrant neurocircuitry or those be more difficult in the future. Thus, future whose pretreatment scans indicate that impaired studies will require transparent and ethical col- attention and memory might be treated with laborations between academia and the pharma- divalproex. We are not there yet, and anyone ceutical industry, because drug development in promising that now is far over-reaching the the United States is primarily a private-sector bounds of the data. However, studies similar to venture. Unfortunately, there have been too that by Pavuluri and colleagues have begun to many recent examples of such relations gone elucidate the neural mechanisms of treatment not awry that not only attract media attention but only in pediatric but also in children or also erode patients’ trust. However, without such partnerships done right, we will remain stuck Moreover, this approach is not the exclusive Thus, our profession’s progress to improve province of medication trials. Studies pairing imag- treatment options hinges on our ability to do this ing and nonpharmacologic treatment have exam- task, to navigate these collaborations success- ined the effects of cognitive behavioral therapy, fully, today. This article suggests that we can such as a study of adolescents with obsessive- provide better, more data-driven treatments— cently been used to study cognitive remediation,for example, in adults with In the future, such studies may lead to the elucidation of Dr. Dickstein is with Bradley Hospital PediMIND Program, Alpert neural markers of treatment response (or nonre- sponse) that would guide a selection of nonmedi- Disclosure: Dr. Dickstein receives research support from the NationalInstitute of Mental Health.
cation or medication treatments in a personalized Correspondence to Daniel P. Dickstein, M.D., Division of Child and medicine approach common to cancer treatment.
Adolescent Psychiatry, E.P. Bradley Hospital, 1011 Veterans Second, it is important to note that such stud- Memorial Parkway, East Providence, RI 02915; e-mail: ies are becoming increasingly difficult to con- duct. Either methodology is expensive on its 0890-8567/$36.00/2012 American Academy of Child andAdolescent Psychiatry own, but the combination of a clinical trial plus neuroimaging requires significant resources at a 1. Pavuluri MN, Passarotti AM, Fitzgerald JM, Wegbreit E, 8. Maslowsky J, Mogg K, Bradley BP, et al. A preliminary investi- Sweeney JA. Risperidone and divalproex differentially engage gation of neural correlates of treatment in adolescents with the fronto-striato-temporal circuitry in pediatric mania: a phar- generalized anxiety disorder. J Child Adolesc Psychopharmacol.
macological fMRI study. J Am Acad Child Adolesc Psychiatry.
9. Forbes EE, Olino TM, Ryan ND, et al. Reward-related brain 2. Moghrabi A, Levy DE, Asselin B, et al. Results of the Dana-Farber function as a predictor of treatment response in adolescents with Cancer Institute ALL Consortium Protocol 95-01 for children with major depressive disorder. Cogn Affect Behav Neurosci. 2010;10: acute lymphoblastic leukemia. Blood. 2007;109:896-904.
3. Pui CH, Campana D, Pei D, et al. Treating childhood acute 10. Peterson BS, Potenza MN, Wang Z, et al. An FMRI study of the lymphoblastic leukemia without cranial irradiation. N Engl J effects of psychostimulants on default-mode processing during Stroop task performance in youths with ADHD. Am J Psychiatry.
4. Chang KD, Wagner C, Garrett A, Howe M, Reiss A. A prelimi- nary functional magnetic resonance imaging study of prefrontal- 11. Posner J, Maia TV, Fair D, Peterson BS, Sonuga-Barke EJ, Nagel amygdalar activation changes in adolescents with bipolar depres- BJ. The attenuation of dysfunctional emotional processing with sion treated with lamotrigine. Bipolar Disord. 2008;10:426-431.
5. Chang K, Karchemskiy A, Kelley R, et al. Effect of divalproex on stimulant medication: an fMRI study of adolescents with ADHD.
brain morphometry, chemistry, and function in youth at high-risk for bipolar disorder: a pilot study. J Child Adolesc Psychophar- 12. Huyser C, Veltman DJ, Wolters LH, de Haan E, Boer F. Functional magnetic resonance imaging during planning before and after 6. Pavuluri MN, Passarotti AM, Lu LH, Carbray JA, Sweeney JA.
cognitive-behavioral therapy in pediatric obsessive-compulsive Double-blind randomized trial of risperidone versus divalproex disorder. J Am Acad Child Adolesc Psychiatry. 2010;49:1238- in pediatric bipolar disorder: fMRI outcomes. Psychiatry Res.
13. Wykes T, Brammer M, Mellers J, et al. Effects on the brain of a 7. McClure EB, Adler A, Monk CS, et al. fMRI predictors of psychological treatment: cognitive remediation therapy: func- treatment outcome in pediatric anxiety disorders. Psychopharma- tional magnetic resonance imaging in schizophrenia. Br J Psychi- JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRYVOLUME 51 NUMBER 2 FEBRUARY 2012
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