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1 Biomarker for Depression Polarity...53 CHILD & ADOLESCENT PSYCHIATRY ALERTS Duloxetine Pharmacokinetics...53 Non-Suicidal Self-Injury...49 Parent Goals for ADHD Treatment...52 Reference Guide...54 Stimulants and Cardiovascular Risk...51 Transcranial Stimulation in ADHD...50 Volume XVI / September 2014 / Number 9 NEW... Online CME Now Available! Call us for details. Mechanisms of Non-Suicidal Self-Injury Adolescents engage in non-suicidal self-injury (NSSI) to regulate their emotions or to communicate with and influence others. According to results of a cross-sectional study, the 2 functions of NSSI automatic/intrapersonal and social/interpersonal are influenced by different factors. Methods: Study participants were part of a community sample of Swedish young people, aged years, who completed anonymous questionnaires in school. Of >3000 sampled youths, 1088 confirmed 1 episode of NSSI in the past year, and of these, 816 gave complete responses to the questionnaires, including the Functional Assessment of Self-Mutilation. This instrument assessed the methods, frequency, and function of different types of NSSI. The other questionnaires measured the occurrence of potentially traumatic life events such as childhood abuse, family adversity, and bullying; and 6 categories of trauma symptoms: anxiety; depression; anger; posttraumatic stress; sexual preoccupation; and dissociation. The investigators assessed different statistical models for each of the 2 functions of NSSI. Results: Of the adolescents who engaged in NSSI in the past year, 70% showed moderately severe behavior (i.e., cutting/carving, burning, and self-tattooing) and nearly half reported 11 episodes. A total of 17% had a lifetime prevalence of suicide attempts, and 23% fulfilled all of the DSM-5 diagnostic criteria for NSSI disorder. Hierarchic multivariate models for the 2 functions of NSSI included 4 major domains found to be significant: NSSI frequency, female gender, maltreatment/family adversities, and trauma symptoms. Together these factors accounted for 62% of the variance in automatic NSSI. Individual items associated with automatic/intrapersonal NSSI were a past suicide attempt, physical abuse by an adult in the family, emotional abuse, a long-term illness or handicap, and symptoms of depression and dissociation. The hierarchical model of NSSI with a social/interpersonal function also found significant associations with NSSI frequency, female gender, maltreatment/adversities, and trauma symptoms, CHILD & ADOLESCENT PSYCHIATRY ALERTS (ISSN ) is published monthly by M.J. Powers & Co. Publishers, 45 Carey Avenue, Butler, NJ Telephone child@alertpubs.com. Periodical-class postage paid at Butler, NJ, and at additional mailing offices. Postmaster: Send address changes to Child & Adolescent Psychiatry Alerts, 45 Carey Avenue, Suite 111, Butler, NJ by M.J. Powers & Co. Publishers. Written permission from M.J. Powers & Co. is required to reproduce material from this publication. Subscription $99 a year in the U.S.; $ Canada; $ elsewhere; $151 institutional. Back issues and single copies are available for $10.00 each, prepaid. Subscribers may enroll in the 12-month CME program for $77.00 per year. M.J. Powers & Co. Publishers is fully independent and accepts no commercial support of any kind. 49

2 but this model explained only 28% of the variance. Predictive items were a past suicide attempt, physical abuse by an adult in the family, and symptoms of anxiety and dissociation. A mediation analysis was conducted to determine whether trauma symptoms acted as mediators between maltreatment and the functions of NSSI. The relationship between childhood emotional, physical, and sexual abuse and performing NSSI for automatic/intrapersonal reasons was mediated by depression and dissociation. The relationship between physical abuse and the social functions of NSSI was mediated by anxiety and dissociation. Discussion: In treating adolescent NSSI, it is useful to assess not only traumatic life events, but also current psychopathology, such as trauma symptoms, which mediate the relationship. Assessing the specific reinforcing functions of NSSI can help guide individual treatment strategies. Patients who have experienced emotional abuse and those with symptoms of depression may benefit most from a focus on emotion regulation skills because in the study these variables were associated with the need to engage in NSSI to regulate emotions, to self-punish, or to generate feelings. The presence of physical abuse, a suicide attempt, or symptoms of dissociation suggest a broad treatment approach because they were associated with performing NSSI to regulate both social and automatic experiences. Zetterqvist M, Lundh L-G, Svedin C: A cross-sectional study of adolescent non-suicidal self-injury: support for a specific distress-function relationship. Child and Adolescent Psychiatry and Mental Health 2014;8:23. From Linkoping University, Sweden; and other institutions. Source of funding not stated. The authors declared no competing interests. Transcranial Stimulation and Memory in ADHD In a small study in boys with ADHD, transcranial electrical stimulation during sleep was associated with improved memory consolidation. Although preliminary, this research supports the possibility of improving academic performance by enhancing sleep-dependent memory functions. Methods: The study investigated the use of transcranial oscillatory direct current stimulation (todcs), which is believed to improve sleep-dependent consolidation of declarative memory by increasing the power of oscillations during slow-wave sleep. Study participants were 12 boys, aged years, with ADHD and 12 healthy controls. Participants were excluded if they had low IQ, profound memory impairment, or self-reported sleep disturbances. The boys were tested with a memory task in which they played a concentration-type computerized card game that was terminated when the player correctly matched 60% of the card pairs. Patients were tested at 8 PM, and again with the same card layout the next morning. The boys with ADHD spent 3 separate nights in a sleep lab: 1 night for adaptation and diagnosis, followed by real and sham todcs in random order, separated by at least 1 week. After taking the evening memory test, they went to bed at about 9 PM, and were administered todcs shortly after entering the first period of stage 2 non-rem sleep. Participants were awakened at 7 AM, had breakfast, and then completed a retrieval memory session. Control participants were tested at home. They did not receive sham or real todcs, but had EEG monitored during sleep and completed the memory task. Results: The children with ADHD had significant overnight loss of memory during the sham condition but retained memory during the todcs session, confirming the hypothesis that sleepdependent memory consolidation is higher with stimulation. Boys with ADHD had worse memory consolidation after sham stimulation than healthy controls, but their performance improved to the level of controls after todcs. Polysomnographic studies showed significant enhancement of slow oscillations during todcs, but no other differences in sleep parameters. Discussion: Memory deficits in ADHD are often thought to result from deviant encoding rather than deficiencies during consolidation or retrieval, but these study results and a few others 50 C&A PSYCHIATRY ALERTS / September 2014

3 support the contributory role of sleep in memory performance. Brain stimulation is not widely available, but similar therapeutic benefits might be achieved with physical exercise during the day, which also increases slow wave activity during sleep. Prehn-Kristensen A, Munz M, Goder R, Wilhelm I, et al: Transcranial oscillatory direct current stimulation during sleep improves declarative memory consolidation in children with attention-deficit/hyperactivity disorder to a level comparable to healthy controls. Brain Stimulation 2014; doi /j.brs From the Christian-Albrechts-University, Kiel, Germany; and other institutions. Funded by German Research Funding. The authors did not include disclosure of potential conflicts of interest. Stimulants and Cardiovascular Risk Cardiovascular events in children with ADHD, while rare, occurred at twice the rate in those who received stimulants, according to results of a nationwide registry-based cohort study. Methods: The study was conducted in a cohort of >700,000 children born in Denmark between 1990 and All data were obtained from national registers. The population included 8300 children who had received a diagnosis of ADHD after the age of 5 years. Cardiovascular outcomes were any hospital contact (i.e., inpatient admission, outpatient clinic visit, or visit to an emergency department) with a cardiovascular-disease diagnosis. Stimulant treatment was defined as purchase of a drug containing amphetamine, dexamphetamine, or methylphenidate. The analysis was adjusted for early measures of perinatal and child health, psychiatric comorbidity, parental psychiatric diagnoses, and socioeconomic and demographic factors. Results: Among the entire population, >5700 individuals experienced a cardiovascular event over a mean of 9.5 years of follow-up. Risk of these events was increased in stimulant users compared with the general population of non-users (adjusted hazard ratio,* 1.83). When the analysis was limited to children with ADHD, risk remained increased with stimulant use (hazard ratio, 2.34). There were 111 cardiovascular events in children with ADHD: 170 per 100,000 person-years. The most common specified events were arrhythmias (23%), cerebrovascular disease (9%), and hypertension (8%). However, many of the events (40%) were identified as heart disease or cardiovascular disease not otherwise specified. The relationship between risk and stimulant dosage was complicated. Risk was elevated in children receiving the highest dosage category, >30 mg/day methylphenidate, 12 months prior to the event but not more recently. Risk was also elevated with more recent exposure to low doses only. Cardiovascular events were 2-fold more likely in children who received <15 mg/methylphenidate 3 months before the event and at the time of the event, compared with non-users of stimulants. Discussion: Of 7 previous studies of cardiovascular risks in children taking stimulants, only 1 found an association. The present study is believed to be the first large nationwide cohort study and has the additional advantages of long prospective follow-up and inclusion of children with other cardiovascular risk factors. The results support the suggestion that ADHD may be more common in children with cardiovascular disease. The dose-response relationship suggests a possible mechanism for the events. Compared with controls, drug-naive children with ADHD have higher heart rates and reduced heart-rate variability, which are normalized with stimulants. Discontinuation of stimulants or a decrease from a high dose may cause the reemergence of heart rate variability and may also shorten the QTc interval, leading to arrhythmias. Stimulants may also affect cardiac sympathetic function by altering striatal dopamine transporter levels in the brain. Dalsgaard S, Kvist A, Leckman J, Nielsen H, et al: Cardiovascular safety of stimulants in children with attentiondeficit/hyperactivity disorder: a nationwide prospective cohort study. Journal of Child and Adolescent Psychopharmacology 2014;24 (August): From Aarhus University, Denmark; and other institutions. Funded by the Lundbeck Foundation; and other sources. The authors declared no conflicts of interest. *See Reference Guide. C &A PSYCHIATRY ALERTS / September

4 Parent Goals for ADHD Care The American Academy of Pediatrics recommends assessing parents' goals as part of a collaborative care model for the treatment of ADHD. Doing so may help clinicians develop targeted treatments and improve patient outcomes. According to a survey, asking parents about their goals is likely to elicit new information, not duplicated by standardized ADHD questionnaires. Methods: Treatment goals were identified by asking 441 parents of children with ADHD to complete an open-ended questionnaire that asked, "What are the top 1 or 2 goals for improvement for your child?" The question was asked as part of a routine pretreatment computerized assessment that also included the Vanderbilt ADHD Diagnostic Parent Rating Scale (VADPRS). Participating medical practices were 14 general pediatric practices in southern Mississippi and 7 developmental and behavioral pediatricians in 3 different states. Parent responses to the goals question were coded to fit into 17 goal categories: 3 ADHD symptom domains; 8 categories aimed at reducing standard types of impairment; and 6 categories established by consensus of 3 expert reviewers. (See table.) These included time management/organization; emotional problems; switching between tasks; conduct problems; physical problems; and medication problems. Finally the goal categories were reduced to 7 goal composites and compared with patient demographics and ADHD symptoms reported on the VADPRS scale. Individual Parent Goal Categories Academics Classroom Conduct problems Emotional problems Family functioning Hyperactivity Impulsivity Inattention Medication problems Parents Peers Physical problems Self-esteem Siblings Switching tasks Teachers Time management Other Goal Composite Categories ADHD symptoms Emotion esteem Executive function Family well-being Medical Relationships School Results: The most frequent of the 17 problem categories reported by parents were inattention (37%), academics (35%), and emotional problems (21%). Thirteen percent of parents reported problems classified as "other" because they did not fit into 1 of the 17 categories. Of the 7 goal composites, the most frequently reported was related to ADHD symptoms (48%). Others, in descending order of frequency, were executive functioning; school; relationships; emotion and self-esteem; family well-being; and medical. Significant differences were found between children seen in offices of primary care physicians and developmental/behavioral pediatricians. In primary care offices, significantly more parents reported inattention (45% vs. 21%), academics (41% vs. 24%), ADHD symptoms (52% vs. 31%), executive functioning (51% vs. 32%), and school (48% vs. 32%). In developmental/behavioral pediatric practices, more parents reported conduct problems (11% vs. 2%) and emotion-esteem issues (42% vs. 24%). Treatment goals were only modestly related to VADPRS scores for ADHD symptoms. As expected, a parent goal of improving inattention was correlated with VADPRS inattention; a goal of improving academic performance was correlated with the VADPRS academic scale score; and so on for several other problems. However, correlation coefficients were modest. Discussion: The American Academy of Pediatrics recommends shared decision-making in ADHD care, addressing specific individualized behavioral, academic, and social goals. However, there is evidence that the level of shared decision-making in routine pediatric ADHD care is low. The study authors are now developing a structured goals questionnaire based on the data from this study. McGoron L, Sturner R, Howard B, Barry T, et al: Parents' goals for ADHD care in a clinical pediatric sample. Clinical Pediatrics 2014; doi / From Total Child Health, Inc., Baltimore, MD; and other institutions. Funded by the NIH; and other sources. Three study authors disclosed financial relationships with commercial sources. 52 C&A PSYCHIATRY ALERTS / September 2014

5 Potential Biomarker for Depression Polarity Anterior cingulate cortex total choline levels, measured using magnetic resonance spectroscopy (MRS), were an accurate predictor of bipolar versus unipolar depression in a group of adolescent women. Background: Choline was investigated as a candidate marker because its levels are elevated in adults with major depressive disorder, decrease with effective treatment, and are similar in patients with bipolar disorder and healthy controls. The anterior cingulate cortex (ACC) is an established region of interest, implicated in the pathophysiology of mood disorders. Methods: Study participants were 37 young women, aged years, who were enrolled in 2 clinical trials of treatment-resistant major depressive disorder and bipolar disorder. All patients were required to meet minimum symptom thresholds on the Children's Depression Rating Scale-Revised or the Montgomery-Asberg Depression Rating Scale. Results of MRS were calculated as the ratio of choline to creatinine resonance (tcho/cre). Results: Of the 37 participants, 28 had a diagnosis of resistant depression and 9 had a diagnosis of bipolar disorder (I, II, or NOS). There were no differences at baseline between the illness groups in mean age (17 years), depression scores, or the volume percentage of gray matter, white matter, or cerebrospinal fluid within the ACC. Average tcho/cre was significantly higher in patients with major depression than in those with bipolar disorder: 0.25 vs (p=0.0002). Using a cutoff of 0.233, the test showed high accuracy, with an area under the receiver-operator curve of 0.883, sensitivity* of 85.7%, and specificity* of 77.8%. Discussion: About 60% of patients with bipolar disorder have illness onset during childhood or adolescence, and bipolar disorder is frequently misdiagnosed as major depressive disorder, with a mean delay of more than 16 years before appropriate treatment. Because the evidencebased treatments for the 2 disorders differ, there is a great need for biomarkers to distinguish the illnesses in pediatric patients. ACC choline levels vary with mood state and can be influenced by antidepressant drugs. Although the results of this study are promising, they are limited to female patients experiencing treatment-resistant depression but not currently taking mood stabilizers. The results need to be replicated in more diverse samples. Shi X-F, Forrest L, Kuykendall M, Prescot A, et al: Anterior cingulate cortex choline levels in female adolescents with unipolar versus bipolar depression: a potential new tool for diagnosis. Journal of Affective Disorders 2014;167 (October): From the University of Utah; and the George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City. Funded by the Depressive and Bipolar Disorder Alternative Treatment Foundation; and other sources. Three study authors declared financial relationships with commercial sources; the remaining 7 authors declared no conflicts of interest. *See Reference Guide. Pharmacokinetics of Duloxetine in Pediatrics Duloxetine pharmacokinetics are similar in children and adolescents, with somewhat lower drug exposure relative to adults, according to results of an analysis of data from the duloxetine clinical development program. The present analysis contributes to the limited information on antidepressant pharmacokinetics in children and adolescents. Background: Numerous antidepressants, primarily of the SSRI class, have been investigated in the pediatric population, but only fluoxetine has FDA approval for treating depression in patients 18 years. Limited or lacking pharmacokinetic data prior to conducting phase III clinical trials may be a reason why antidepressants with proven efficacy in adults have not shown efficacy in children and adolescents. Duloxetine was investigated in 1 phase II and 2 phase III clinical trials in children and adolescents. The phase III trials' efficacy results were inconclusive because neither duloxetine nor the active comparator, fluoxetine, was superior to placebo. C &A PSYCHIATRY ALERTS / September

6 Methods: The present analysis was based on combined pharmacokinetic data from the 3 trials. The phase II trial was a 32-week open-label investigation of duloxetine at dosages ranging from 20 to 120 mg/day. The 2 phase III trials lasted 36 weeks and investigated flexible dosages of mg or fixed doses of 30 and 60 mg. Steady-state blood samples were obtained at regular intervals during the trials. Data from the 3 trials were pooled to construct a model of duloxetine pharmacokinetics. Results: The study population included in the pharmacokinetic model consisted of 428 patients, aged 7 18 years, of whom one-third were children (aged 11 years). About half were girls, 91% were nonsmokers, and 88% were extensive CYP2D6 metabolizers. Nearly 1600 samples were analyzed. Duloxetine pharmacokinetics were adequately characterized by a 1-compartmental model, which was anchored to a constant absorption rate. Oral clearance varied among patients by 69%, and volume of distribution by 100%. Within-patient measurements varied by a similar magnitude. Patient characteristics such as age; gender; body mass index; serum creatinine; CYP2D6 phenotype; and menarche did not affect duloxetine kinetics. Dose and body surface area had statistically significant effects on clearance, and race had effects on volume of distribution, but the effects of these covariates were small compared with the overall variability of the parameters. Duloxetine clearance and volume of distribution in pediatric patients were higher than values in adults. Overall variability was similar in young patients and adults. The median concentration-time profile was lower in children than adults, and peak drug concentrations were about 30% lower. Discussion: These observations suggest that the bioavailability of duloxetine may be lower and/or clearance more rapid in pediatric patients than adults. As with adults, specific dose recommendations based on patient-specific factors are not required. Lobo E, Quinlan T, Prakash A: Pharmacokinetics of orally administered duloxetine in children and adolescents with major depressive disorder. Clinical Pharmacokinetics /s y. From Lilly Research Laboratories, Indianapolis, IN. Funded by Eli Lilly and Company. All 3 authors are employees and own stock options in Eli Lilly and Company, the manufacturer of Cymbalta. Drug Trade Names: duloxetine Cymbalta; fluoxetine Prozac Reference Guide Hazard Ratio: A measure of the risk of an event relative to exposure, or the probability of an event occurring in an exposed group versus a non-exposed group. A hazard ratio of 0.5 indicates that one group has half the risk of the other group. Sensitivity and Specificity: Statistical measures of the performance of binary classification tests. Sensitivity measures the proportion of actual positives that are correctly identified (i.e., the percentage of sick people who are correctly identified as having the condition). Specificity measures the proportion of negatives that are correctly identified (i.e., the percentage of healthy people who are correctly identified as not having the condition). A perfect predictor would have 100% sensitivity and specificity. Contributing Editors: Kate Casano, MSHyg Bennett Silver, MD Consulting Editor: Theodore A. Petti, MD, Rutgers Robert Wood Johnson Medical School Executive Editor: Trish Elliott Associate Editor: Tara Hausmann Assistant Editor: Krista Strobel Founding Editor: Michael J. Powers Off-Label Drug Use Statement: Some drugs discussed for specific indications in Child & Adolescent Psychiatry Alerts articles may not be approved for labeling and advertising for those indications by the United States Food and Drug Administration. 54 C&A PSYCHIATRY ALERTS / September 2014