ADHD Medication Abuse...49 CHILD& ADOLESCENT PSYCHIATRY ALERTS CBT for Suicide Prevention...50 CYP Genotypes and Treatment Outcome...52 Evidence-Based Psychopharmacology...53 Long-Term Depression Treatment...51 Pediatricians Treating ADHD...53 Suicide Predictors...49 Volume XI / September 2009 / Number 9 www.alertpubs.com ADHD Medication Abuse A review of national poison control center data shows that prescription of medications for ADHD has risen in recent years and that along with the increase came a rise in the abuse/ misuse of the agents. The National Poison Data System was queried to identify all calls received between 1998 and 2005 that involved intentional abuse/misuse of methylphenidate or amphetamine/ dextroamphetamine by adolescents aged 13 19 years. The total number of prescriptions for these medications was estimated based on physician surveys and manufacturer sales data. The annual number of prescriptions written for stimulant medications increased 80% over the study years. Prescriptions for ADHD-related amphetamine/dextroamphetamine rose 133%, but the number of calls received that pertained to misuse/abuse of these medications increased by 476%: from 71 in 1998 to 409 in 2005. In contrast, methylphenidate prescriptions for ADHD rose 52%, but related calls decreased by 30%. Setlik J, Bond R, Ho M: Adolescent prescription ADHD medication abuse is rising along with prescriptions for these medications. Pediatrics. Published online August 24, 2009 at www.pediatrics.org; doi 10.1542/peds.2008-0931. From the University of Cincinnati, Ohio. Funded by the Rocky Mountain Poison and Drug Center, a nonprofit government agency. The authors disclosed no potential conflicts of interest. Drug Trade Names: amphetamine/dextroamphetamine Adderall; methylphenidate Ritalin Predictors of Adolescent Suicide The multifaceted NIMH-funded Treatment of Adolescent Suicide Attempters Study (TASA) was designed to address the pressing need for effective suicide prevention strategies for adolescents. Patients: TASA included 124 adolescents (aged 13 19 years) with a major unipolar mood disorder who had attempted suicide in the 90 days before study entry and were currently experiencing at least moderate depressive symptoms. Substance abuse, psychosis, developmental disorders, and bipolar disorder were exclusion criteria. Assessments: Baseline evaluations collected information on the lethality and intent of the index and previous suicide attempts as well as the number of previous attempts. Patients underwent CHILD & ADOLESCENT PSYCHIATRY ALERTS (ISSN 1522-3817) is published monthly by M.J. Powers & Co. Publishers, 65 Madison Ave., Morristown, NJ 07960. Telephone 973-898-1200. e-mail: child@alertpubs.com. Periodical-class postage paid at Morristown, NJ, and at additional mailing offices. POSTMASTER: Send address changes to Child & Adolescent Psychiatry Alerts, 65 Madison Ave., Morristown, NJ 07960. 2009 by M.J. Powers & Co. Publishers. Written permission from M.J. Powers & Co. is required to reproduce material from this publication. Subscription $89 a year in the U.S.; $97.50 Canada; $107.50 elsewhere; $141 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. 49
structured diagnostic interviews and validated symptom ratings scales were administered. In the intent-to-treat analysis, the primary outcomes of interest were suicidal events including attempted or completed suicide, preparatory actions, suicidal behavior and/or ideation. A series of logistic regression analyses were used to identify potential predictors of suicidal events. Interventions: Initially the study was intended as a randomized controlled trial comparing a newly designed CBT program, a medication algorithm, and combination treatment. However, because of slow recruitment, patients were allowed to choose between randomization and selecting their own treatment. After creating a safety plan, patients received study treatment for 6 months. The CBT program is described in a separate article in this issue (see next story) and the medication algorithm will be covered in a future Child & Adolescent Psychiatry Alerts issue. Results: A total of 24 patients experienced a suicidal event during the 6 month study; risks were similar for less serious events and repeat attempts. The mean time to the event was <7 weeks, which may suggest therapies had not yet reached an adequate "dose." Strong clinical predictors of suicidal events included high levels of baseline suicidal ideation and self-reported depression, a history of physical or sexual maltreatment, having 2 previous attempts, lower lethality of the index episode, and poorer family cohesion. Discussion: Although the study design does not allow for efficacy comparisons between the treatment groups, factors predictive of suicidal events were identified. The authors suggest a randomized controlled trial of treatments targeting these factors. Brent D, Greenhill L, Compton S, Emslie G, et al: The treatment of adolescent suicide attempters study (TASA): predictors of suicidal events in an open treatment trial. Journal of the American Academy of Child and Adolescent Psychiatry. Published online August 26, 2009 at www.jaacap.com; doi 10.1097/CHI.0b013e3181b5dbe4. From the NIMH; and other institutions. Funded by the NIMH. Several study authors have disclosed commercial relationships that might pose conflicts of interest. CBT for Suicide Prevention The cognitive behavioral therapy for suicide prevention (CBT-SP) program used in the TASA study (see previous article) consists of newly developed treatment modules, some mandatory and others optional, designed to reduce risk factors, enhance coping strategies, and prevent suicide. A core feature of CBT-SP is its individualized nature, wherein physicians, patients, and family members collaborate to decide which modules would be most beneficial. The present report details the feasibility and acceptability of the program. Of the 124 TASA participants (aged 13 19 years), 110 participated in the CBT-SP program. These adolescents had relatively severe depression (baseline Children s Depression Rating Scale score, 51) and an average of 2.3 previous suicide attempts. The initial CBT-SP phase includes a chain of events analysis of the index suicide episode; creation of a stepwise safety plan that includes both internal and external strategies; psychoeducation about suicide and the role of underlying depression; a discussion of reasons to live and the creation of a "hope kit" with reminders of those reasons. Clinicians then develop an individualized case conceptualization for each patient and prioritized the skills training needed to prevent a future attempt. After the immediate crisis resolves, the optional individual and family behavioral and training modules are chosen based on patient needs tempered by the recognition of a limited time frame. Individual modules include behavioral activation; increasing pleasurable activity; mood monitoring; emotion regulation and distress tolerance techniques; cognitive restructuring; problem solving; goal setting; and assertiveness training. Family modules include behavioral activation, emotion regulation, problem solving, communication, and cognitive restructuring. The final component is a relapse prevention task during which the 50 C&A PSYCHIATRY ALERTS / September 2009
patient remembers the index episode and then applies the newly learned behavior to imagine a changed outcome. The CBT-SP appeared to be both feasible to use and acceptable to study participants. In spite of the difficult nature of the study population adolescents and suicidal patients are difficult to retain in treatment nearly three-fourths of patients completed at least the first phase of the CBT-SP. All patients who completed an exit interview reported that the treatment was helpful. Efficacy in suicide prevention was not addressed in this report and according to the authors should be evaluated in a controlled trial. Stanley B, Brown G, Brent D, Wells K, et al: Cognitive-behavioral therapy for suicide prevention (CBT-SP): treatment model, feasibility, and acceptability. Journal of the American Academy of Child and Adolescent Psychiatry. Published online August 26, 2009 at www.jaacap.com; doi 10.1097/CHI.0b013e3181b5dbfe. From Columbia University, New York, N.Y.; and other institutions. Funded by the NIMH. Several study authors have disclosed commercial relationships that might pose conflicts of interest. TADS Follow-Up The 4-stage multicenter randomized controlled TADS (Treatment for Adolescents with Depression Study) evaluated cognitive behavioral therapy, fluoxetine (Prozac) monotherapy, and combined treatment in adolescents with moderate-to-severe depression. In stage 4, long-term treatment was found to be associated with persistent improvement 1 year after study treatments were withdrawn. 1 Stage I. Adolescents with depression received 12 weeks of randomized treatment with flexibledose fluoxetine, CBT, combined treatment, or placebo. 2 Combined treatment was found to be the most effective option in terms of reduced depressive symptoms and suicidality. Response rates at 12 weeks were 71% with combined treatment, 61% with fluoxetine monotherapy, and 43% with CBT monotherapy. Stages II and III. Patients with partial response to initial treatment received unblinded continuation for an additional 24 weeks. Outcome evaluations were completed after a total of 18 and 36 weeks of treatment. At 18 weeks combination therapy remained superior to the other treatments with a response rate of 85%, compared with 69% with fluoxetine and 65% with CBT. 3 However, between 18 and 36 weeks, response rates converged and at the end of treatment there were no significant differences between the groups (86% for combined therapy and 81% for both fluoxetine and CBT monotherapy). Suicidal ideation was significantly more common in patients who received fluoxetine, and CBT appeared to have a protective effect. Regardless of treatment assignment, nearly 75% of patients who did not meet response criteria at 12 weeks did so by 36 weeks, and responses tended to be maintained. Patterns were similar for remission. 4 Stage IV of the TADS was a 1-year naturalistic follow-up during which patients received only community mental health treatments (i.e., no study treatment). A total of 215 patients completed at least 1 stage IV assessment. The benefits of acute and continuation treatment persisted during follow-up. According to Clinical Global Impression Ratings, 82% of TADS patients were "minimally impaired" at 36 weeks. In contrast to the deterioration usually seen after discontinuing short-term medication, during TADS follow-up 13% of patients deteriorated to mildly-to-extremely impaired with no significant differences between the treatment groups. Discussion: "The central findings from the TADS are as follows: 1) combined treatment meaningfully accelerates recovery from depression relative to CBT and fluoxetine, 2) longerterm treatment results in improved outcomes relative to short-term treatment, 3) longer-term treatment may decrease the chances of relapse or recurrence when treatment is discontinued, C&A PSYCHIATRY ALERTS / September 2009 51
and 4) adding CBT to fluoxetine minimizes persistent suicidal ideation and treatment-emergent suicidal events associated with medication monotherapy." Limitations include incomplete stage 4 data and no comparator treatment groups. 1 Treatment for Adolescents With Depression Study (TADS) Team: The treatment for adolescents with depression study (TADS): outcomes over 1 year of naturalistic follow-up. American Journal of Psychiatry. Published online September 1, 2009 at www.ajp.psychiatryonline.org; doi 10.1176/appi.ajp.2009.08111620. From Duke University Medical Center, Durham, N.C.; and other institutions. Funded by the NIMH. Several study authors have disclosed commercial relationships that might pose conflicts of interest. 2 Treatment for 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 (August 18):807 820. See Child & Adolescent Psychiatry Alerts 2004;6 (October):55 56. 3 TADS Team: The treatment for adolescents with depression study (TADS): long-term effectiveness and safety outcomes. Archives of General Psychiatry 2007;64 (October):1132 1144. See Child & Adolescent Psychiatry Alerts 2007;9 (November): 61 62. 4 Rohde P, et al: Achievement and maintenance of sustained response during the treatment for adolescents with depression study continuation and maintenance therapy. Archives of General Psychiatry 2008;65 (April):447 455. See Child & Adolescent Psychiatry Alerts 2008;10 (May):25 26. CYP Genotype Affects Treatment Outcome A retrospective study found that increased cytochrome P450 (CYP) metabolizing ability decreased both psychotropic efficacy and adverse effects in a group of hospitalized children. This finding adds to the suggestion that genotype can play an important role in individualizing and optimizing psychotropic drug therapy. Background: Polymorphic genes associated with 2 cytochrome enzymes, CYP2D6 and CYP2C19, underlie some of the variability in patients' response to psychotropic medications metabolized via the CYP pathway. The present study examined the effects of genotype on the antiaggression efficacy of psychotropics and on drug tolerability. Methods: A cohort of 279 consecutively hospitalized children and adolescents who underwent genotyping as part of their routine care were included in the study. Based on their genotype, patients were categorized into 4 groups: combined poor metabolizer phenotype; combined intermediate metabolizer phenotype; combined extensive metabolizer phenotype; combined ultrarapid metabolizer phenotype. Patients had a median age of 13 years (range, 3 18 years) and were treated with a variety of drugs metabolized via the CYP pathway, including commonly used antipsychotics, antidepressants, and stimulants. Most were taking 1 (36%) or 2 (29%) psychotropic drugs. The primary outcome measure, the Behavioral Intervention Score, was based on the number of interventions for disruptive or aggressive behavior, such as time outs or physical restraints. Results: Behavioral Intervention Scores were lowest, indicating greatest treatment efficacy, in poor metabolizers, who represented 20% of the total. Scores were higher in the 22% of patients with the intermediate genotype, still higher in the 52% who were extensive metabolizers for both enzymes, and highest in the 6% of patients with the highest metabolizing ability. A secondary analysis showed that the CYP2D6 phenotype was predictive of treatment response, while the CYP2C19 phenotype was not. Adverse drug effects followed a similar but inverted pattern. Poor metabolizers experienced the most side effects (mean, 1.44) and the strongest metabolizers the fewest (mean, 0.75). Prows C, Nick T, Saldana S, Pathak S, et al: Drug-metabolizing enzyme genotypes and aggressive behavior treatment response in hospitalized pediatric patients. Journal of Child and Adolescent Psychopharmacology 2009;19 (August):385 394. From Cincinnati Children's Hospital Medical Center, Ohio; and other institutions. Funded by the NIH; and other sources. Several study authors disclosed commercial relationships that could pose conflicts of interest. 52 C&A PSYCHIATRY ALERTS / September 2009
Pediatricians' Treatment of ADHD Improving A survey of American Academy of Pediatrics (AAP) fellows shows the educational materials and treatment guidelines issued in 2000 and 2001 have resulted in improved quality of care. Background: Following a 1999 survey of current practice, the AAP launched a widespread educational campaign on the assessment and treatment of ADHD by pediatricians. The educational tools included a practice guideline, continuing education materials, and parent/patient handouts. A follow-up survey was mailed 6 years later to evaluate changes in practice after the campaign. Methods: Surveys were mailed in 1999 and 2005 to randomly selected AAP pediatricians involved in patient care. The later survey included questions and language from the initial survey as well as additional queries about the educational campaign, and both asked for responses regarding patients aged 6 12 years. Individual responses on evaluable surveys (452 and 551, respectively) were compared. Results: A total of 77% of the 2005 respondents reported familiarity with the AAP guidelines and 33 55% reported familiarity with other components of the educational package. According to the 2005 survey, pediatricians were more likely than in earlier years to use formal diagnostic criteria and standardized parent and teacher rating scales than narrative reports in the initial evaluation of ADHD. In both survey years nearly all pediatricians reported assessing for comorbidity, but in the later period, the assessments appear to have been more structured. Regardless of the survey year, more than 90% of pediatricians who treated children with ADHD reported using pharmacotherapy, most often methylphenidate (Ritalin), at least sometimes. In 2005, rather than refer to a subspecialist, pediatrician prescribers were more likely to try a different agent or add a second medication (when comorbid disorders were absent) if response was inadequate. Classroom modification and parent training were often recommended in both survey years; recommendation of alternative therapies decreased over time. After the educational campaign, more survey respondents felt adequately trained to evaluate and treat patients with simple ADHD, however at both time points a large percentage (60 63%) were uncertain about their abilities. Discussion: These results suggest that practice patterns in the treatment of ADHD by pediatricians have improved and are now more in line with treatment guidelines. This could improve outcomes for a substantial number of patients, as half of all pediatricians surveyed in 2005 reported treating simple ADHD themselves. Wolraich M, Bard D, Stein M, Rushton J, et al: Pediatricians attitudes and practices on ADHD before and after development of ADHD pediatric practice guidelines. Journal of Attention Disorders. Published online August 25, 2009 at www.sagepub.com; doi 10.1177/1087054709344194. From the University of Oklahoma Health Sciences Center, Oklahoma City; and other institutions. Funded by the DHHS; and other sources. The authors did not include disclosure of potential conflicts of interest. Evidence-Based Psychopharmacology The American Academy of Child and Adolescent Psychiatry (AACAP) has released a practice parameter on the use of psychotropic medications in children and adolescents. The purpose is to promote the best practice principles of safe and appropriate psychotropic medication use for pediatric psychiatric disorders. Multiple steps are involved in the safe use of psychotropic medications. The first is to complete a thorough psychiatric evaluation. This should include interviews with both the patient and their parents or caregivers and is aimed at identifying symptoms and psychosocial factors that C&A PSYCHIATRY ALERTS / September 2009 53
may bear upon a medication trial. Obtaining a medical history and ordering appropriate targeted medical testing (e.g., height and weight for stimulants, lipid profiles for antipsychotics) are also critical before initiating pharmacotherapy. Communication with all professionals involved in the child s care (e.g., teachers, pediatricians) will enhance the ability to provide optimal therapy. Prescribers should next develop a comprehensive treatment plan based on the best available evidence and educate both the patients and caregivers about the disorder and the suggested treatments. The plan should include both pharmacological and psychosocial interventions when appropriate and should detail acute treatment goals, starting dosages, scheduled increases, and methods for monitoring improvement and adverse effects. Maintenance and discontinuation phases as well as a follow-up monitoring plan should also be mapped and discussed with the patient and caregivers. Caution must be exercised when there are barriers to appropriate monitoring that can lead to inappropriate medication use. Informed consent/ assent from patients and caregivers must be obtained before starting or changing medications and should be documented in the medical record. When pharmacotherapy is the agreed upon course of action, dosages and duration of treatment should be outlined at initiation. If adequate improvement is not evident in a prespecified time frame, the patient should be reevaluated to ensure the initial diagnostic assessment was accurate and to identify possible nonadherence and/or psychosocial impediments to effective pharmacotherapy. Although there is little empirical evidence to support combination medication strategies, some may offer advantages over monotherapy or address emergent adverse effects. The same procedures as initial pharmacotherapy should be followed when adding an additional medication. Information on starting medications in children and adolescents is abundant, but less is known about optimal treatment durations and discontinuation strategies. Discontinuing medication also requires a specific plan that must be fully disclosed to the patient and caregivers. This plan includes not only tapering strategies, but also schedules of follow-up, and education regarding withdrawal and rebound symptoms as well as warning signs of possible recurrence. The AACAP does not advocate restricting pediatric access to psychopharmacological treatment. Rather, they strive to ensure prescribers are able to provide high-quality assessment and planning and prescribing practices that will enhance patient outcomes. Specific treatment advice for individual disorders is available in the practice parameter for each disorder, which are available at www.aacap.org. Walkup J, et al for the Work Group on Quality Issues: Practice parameter on the use of psychotropic medication in children and adolescents. Journal of the American Academy of Child and Adolescent Psychiatry 2009;48 (September): 961 973. From the American Academy of Child and Adolescent Psychiatry. The primary author and several members of the workgroup have disclosed commercial relationships that might pose conflicts of interest. Correction: In the August 2009 issue, in the story titled, "Autism: Genetic Research," on page 48 the reference should read: Geschwind D: Advances in autism. Annual Review of Medicine 2009;60:367 380. From the Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles. The author is a volunteer on the Autism Speaks Scientific Advisory Council. Contributing Editor: Bennett Silver, MD, Kate Casano, MSHyg Consulting Editor: Theodore A. Petti, MD, UMDNJ Robert Wood Johnson Medical School Executive Editor: Michael J. Powers Associate Editor: Trish Elliott Assistant Editors: Mandie Stahl, Krista Strobel 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 2009