POSTER PRESENTATIONS

POSTER PRESENTATIONS The following are summaries of posters presented at the American Psychiatric Association Annual Meeting held in Philadelphia, Pennsylvania, May 18-23, 2002 DOES STIMULANT THERAPY FOR ATTENTION- DEFICIT/ HYPERACTIVITY DISORDER BEGET LATER SUBSTANCE ABUSE? A META-ANALYTIC REVIEW OF THE LITERATURE Wilens T, Faraone S, Biederman J, Gunawardene S, Prince J Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. A team of investigators at the Clinical Research Program in Pediatric Psychopharmacology, Massachusetts General Hospital and Harvard Medical School have conducted a meta-analysis of the medical literature in order to quantify the relationship between stimulant therapy and subsequent substance use disorders (SUDs) in attention-deficit/hyperactivity disorder (ADHD) youth. Their objective was to review cumulative findings regarding the putative association between prior exposure to stimulants and SUD. With the support of a grant from the US Public Health Service, the investigators undertook a review of 5 studies, including 2 with follow-up in adolescence and 3 in young adulthood, comprising 576 medicated subjects and 339 unmedicated subjects who were followed for at least 4 years. 1-5 They reported the following odds ratios (listed as protective effect of stimulant therapy) and 95% confidence intervals (CI) for the studies by meta-analysis: These findings suggest that stimulants have a protective effect against SUD, with 7 of the odds ratios (from 4 studies) being >1.0; 5 of these odds ratios are statistically significant. Two of the odds ratios (from 1 study) are <1, suggesting an adverse impact of stimulants, but these are not statistically significant. The pooled estimate of the odds ratio from the meta-analysis was 2.3, and was statistically significant (z = 2.3; P =.02; 95% CI for odds ratio: 1.1, 4.6). This odds ratio indicates a 2.3-fold reduction in risk for SUD in youth who are treated pharmacologically, compared with youth not receiving pharmacotherapy for ADHD. The study design effect indicated that studies of treated and untreated youth with ADHD who had similar baseline severity resulted in larger odds ratios (ORs) than studies that had dissimilar baseline severity. As a group, the data from studies that had similar baseline severity showed a statistically significant protective effect (OR = 3.5 [2.2, 5.8]). The 2 data points from the 1 study that did not have similar baseline severity between treatment groups both suggest that stimulants increased the risk of SUD outcomes (OR = 0.5 [0.34, 0.88]). The study had a number of limitations in that it included a small number of overall studies (N = 5), some published and others only presented, including a total of 915 subjects who were predominantly male. Moreover, the naturalistic, nonrandomized nature of these studies may have created confounds (eg, severity of illness, comorbidity, family history of SUD) that may have independently affected outcome. Although the subject of inquiry was the effect of stimulant therapy on SUD, 4% of all study subjects were taking other medications. In addition, the duration and adequacy of treatment were not delineated; definitions of substance abuse or dependence varied from study to study; and SUD outcomes were determined by subjective reports of patients or parents. Despite these limitations, this meta-analysis indicates that the pharmacotherapy of ADHD does not increase the risk for subsequent SUD. In contrast, the available Advanced Studies in Medicine 925

data suggest that stimulant medication has a protective effect on later SUD. Of special note are the investigators findings of a less robust protective effect of stimulant treatment in reducing SUD in adulthood (1.6 fold relative to adolescence [5.8 fold]). An important finding for child psychiatry is the fact that stimulants offer a protective effect against SUD in youth with ADHD. However, further study is needed to investigate the long-term SUD outcome and putative mechanisms of reduced SUD risk in male and female youth with ADHD who are treated pharmacologically. REFERENCES 1. Lambert NM, Hartsough CS. Prospective study of tobacco smoking and substance dependencies among samples of ADHD and non-adhd participants. J Learn Disabil. 1999;31(6):533-544. 2. Biederman J, Wilens T, Mick E, Spencer T, Faraone S. Pharmacotherapy of attention-deficit/hyperactivity disorder reduces risk for substance use disorder. Pediatrics. 1999;104(2):20; 3. Wilens T, Biederman J, Mick E, Spencer T. Pharmacotherapy reduces substance use disorders in ADHD in midadolescence. Paper presented at: College of Problems with Drug Dependence, 1999; Acapulco, Mexico. 4. Molina B, Pelham W, Roth J. Alcohol and other substance use and abuse in ADHD adolescents: patterns of use compared to controls and prediction from childhood. Paper presented at: International Society for Research in Child and Adolescent Psychiatry; 1999; Barcelona, Spain. 5. Huss M. ADHD and substance abuse. Paper presented at: IX Annual European Congress of Psychiatry; 1999; Hamburg, Germany. PTSD AND ADHD: COMORBIDITY, SYMPTOM OVERLAP, AND SIGNIFICANCE OF AGE AT FIRST TRAUMA Irene Powch, PhD Portland VA Medical Center and Oregon Health Sciences University The child literature reports significantly higher rates of attention-deficit/hyperactivity disorder (ADHD) in traumatized populations 1 and traumatized populations with posttraumatic stress disorder (PTSD) than in controls. 2,3 There is evidence that early trauma may cause neurobiological changes that could manifest as hyperactivity in the context of limbic dysregulation. 4 There are no published studies on trauma history or PTSD comorbidity with ADHD in adults. It is not known whether adults with a history of trauma before 8 years of age report greater hyperactivity and childhood ADHD that persisted into late adulthood than those who were not traumatized until later in life. These unanswered questions relating to the relationship between PTSD and ADHD have gained particular relevance in our post-september 11 society, as large numbers of Americans, adults and children, are reporting PTSD symptomology. This suggests the possibility of a surge in ADHD in the years ahead. The purpose of the present study was to provide preliminary evidence in support of hypotheses that implicate early trauma in the etiology of ADHD. The hypotheses of the study were: Veterans who experienced early trauma (before 8 years of age) will evidence higher rates of hyperactivity present since childhood than veterans who first experienced trauma later in life; Childhood physical abuse (which, it could be argued, might be provoked by the hyperactive child) would not be more strongly associated with hyperactivity than childhood sexual abuse (which is less readily explained as being provoked by the child); Childhood hyperactivity will not be associated with greater exposure to subsequent trauma as measured by combat exposure and total traumatic life event exposure over the lifetime. The investigator also assumed that a different pattern of symptoms would be associated with childhood abuse than with combat trauma, and hyperactivity would be associated more often with childhood abuse. Investigators recruited veterans from outpatient mental health and domiciliary services at a Veterans Administration hospital. PTSD was diagnosed with the Clinician Administered PTSD Scale; ADHD was diagnosed with a structured clinical interview created to assess Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) ADHD symptoms in early childhood (to third grade) and in the present. Subjects also completed 5 other measures of trauma history, PTSD, and ADHD. The remaining 46 study subjects were aged 30 to 56 years. Nearly half (44%) of the subjects reported an experience of childhood trau- 926 Vol. 2, No. 25 November 2002

ma, and nearly half (47%) reported moderate to extreme combat exposure. Investigators found that subjects who experienced child physical abuse were not more inclined toward hyperactivity than those who experienced sexual abuse. In fact, the multiple regression beta weight between child sexual abuse and hyperactivity was higher than that between child physical abuse and hyperactivity (.35; P<.05 vs a nonsignificant.13). Table 1 summarizes the trauma histories and psychiatric diagnoses for this sample. Table 2 indicates that subjects who experienced trauma early in life reported a significantly greater number of ADHD symptoms across the lifespan (18.5 symptoms vs 12.8 symptoms; P<.05). They also reported significant elevations in current depression, anxious arousal, dissociation, and anger/irritability compared with those who were first traumatized later in life. Childhood hyperactivity was not found to predispose the subjects in this sample to more combat exposure (r = -.24) or to a greater number of traumatic life events (r =.19), both nonsignificant correlations. Combat exposure and traumatic life events were, however, significantly correlated with a current diagnosis of PTSD (r =.40; P<.01, and r =.34; P<.05, respectively). ADHD symptoms appear to be a more persistent sequela of childhood sexual abuse than PTSD symptoms (r =.32; P<.05 vs a nonsignificant r = -.01). In addition, the patterns of correlations between PTSD symptoms and ADHD symptoms found in this study provide a compelling argument to seriously consider trauma in the etiology of at least some subtypes of ADHD. Opportunities for future research in this area abound, including replication of the study presented here with other adult populations. Moreover, a longitudinal study could more definitively address questions of causation (Does trauma increase the risk of developing ADHD, or does ADHD increase the risk of exposure to trauma in early childhood?), as well as questions of remission rates (Is ADHD a more persistent consequence of early trauma than is PTSD?). Another area for investigation is whether patients with trauma-induced ADHD experience a differential treatment response than do those with other subtypes of ADHD. In addition, experimental cognitive testing techniques may be applied to ascertain the role of different types of impulsivity among early trauma sur- Table 1.Trauma Histories and Psychiatric Diagnoses in Study Sample* History/Diagnosis Percentage Affected First trauma before 8 years of age (average age 6 years) 44% First trauma after 8 years of age (average age 18 years) 56% Physically abused moderately to extremely 44% Sexually abused moderately to extremely 40% Combat exposure moderate to extreme 47% Current PTSD diagnosis 70% Current ADHD diagnosis 13% ADHD diagnosis in childhood, but not current 24% Childhood hyperactivity 30% Childhood inattention 33% Current hyperactivity 15% Current inattention 48% *N = 46. PTSD = post-traumatic stress disorder; ADHD = attention-deficit/ hyperactivity disorder. Table 2. Symptom Severity Depending on Age of First Trauma* Early Trauma Late Trauma (n = 20) (n = 22) ADHD total (child and adult) 18.5 12.8 Child hyperactivity 4.5 2.4 Child inattention 4.2 2.8 Adult hyperactivity 4.3 3.1 Adult inattention 5.7 4.5 Anxious arousal (TSI) 15.5 12.2 Depression (TSI) 15.7 10.7 Dissociation (TSI) 13.5 9.2 Anger/irritability (TSI) 15.0 12.7 Tension-reduction behavior (TSI) 6.5 3.3 Lifetime traumatic events exposure 28.5 16.7 *Analysis of variance (ANOVA) was used to compare means. P<.05; P<.005. ADHD = attention-deficit/hyperactivity disorder; TSI = test for severe impairment. Advanced Studies in Medicine 927

vivors with ADHD, without ADHD, and those with ADHD and no history of trauma. REFERENCES 1. Putnam FW. Developmental pathways following sexual abuse. Paper presented at: The Annual Meeting of the Society for Adolescent Psychiatry; 1994; San Francisco, Ca. 2. Famularo R, Fenton T, Kinscherff R, et al. Psychiatric comorbidity in childhood post traumatic stress disorder. Child Abuse Negl. 1996;20:953-961. 3. Glod CA, Teicher MH. Relationship between early abuse, posttraumatic stress disorder, and activity levels in prepubertal children. J Am Acad Child Adolesc Psychiatry. 1996;35:1384-1393. 4. Yutaka I, Teicher MN, Glod CA, et al. Increased prevalence of electrophysiological abnormalities in children with psychological, physical, and sexual abuse. J Neuropsychiatry Clin Neurosci. 1993;5:401-408. EFFICACY OF ATOMOXETINE IN CHILDREN AND ADOLESCENTS WITH ATTENTION- DEFICIT/HYPERACTIVITY DISORDER Brown WJ, Wernicke J, Allen AJ, Michelson D, Harder D, Milton D, Kelsey D Eli Lilly and Company, Indianapolis, Indiana A poster presented at the 2002 American Psychiatric Association APA Annual Meeting demonstrates promising results for the investigational drug atomoxetine, a potent inhibitor of the presynaptic norepinephrine transporter that plays an important role in modulating the brain systems that control attention and activity. If approved, atomoxetine will be the first nonstimulant therapy available for the treatment of attention-deficit/hyperactivity disorder (ADHD). Originally called tomoxetine, the drug s name was changed to atomoxetine in order to avoid any confusion with tamoxifen, the drug marketed for breast cancer therapy. The safety of atomoxetine was demonstrated in a separate poster presentation. The atomoxetine efficacy analysis presented at the APA annual meeting included data from 2 randomized, double-blind, placebo-controlled studies. One study was a dose-finding trial (placebo and atomoxetine 0.5 mg/d, 1.2 mg/d, and 1.8 mg/d) that utilized a twice-daily dosing regimen (placebo and atomoxetine 1.2 mg/d and 1.8 mg/d were included in the analysis). The second study was a dose-titration trial that utilized a once-daily dose. The study s patient population included children (296) and adolescents (120) who met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for ADHD with a baseline severity score measured by ADHD Rating Scale (ADHD RS) at least 1.5 standard deviations above the age and gender norms for their diagnostic subtype. Excluded from the study were children and adolescents with serious medical illness, comorbid psychosis or bipolar disorder, history of seizure disorder, or ongoing use of psychoactive medication other than the study drug. Primary efficacy measure for the study was the ADHD RS-IV Parent Version, with the Conners Parent Rating Scale-Revised Short Form (CPRS-R) and Clinical Global Impressions of Severity (CGI-S) used as secondary efficacy measures. Efficacy was measured by comparing improvement in mean scores from baseline to last observation between atomoxetine and placebo. Statistical comparisons were performed using an analysis of variance including a model with study, treatment, age category (children/adolescents), and treatment-byage category interaction. The figure demonstrates that in the ADHD total score, no significant change in efficacy from baseline was demonstrated between children and adolescents for either atomoxetine (P =.963) or placebo (P =.291). In the component of the ADHD RS relating specifically to inattentiveness, no significant difference was found between children and adolescents for either atomoxetine (P =.942) or placebo (P =.305). Both children and adolescents in the drug treatment group were found to experience a mean change from baseline of approximately -7.0 (P<.001 and P =.012, respectively), as compared with -2.34 to -3.59 in the placebo study arm. Similar results were reported for children and adolescents treated with atomoxetine compared with placebo in the Hyperactive/Impulsive Subscale Score (P<.001, P =.024, respectively), CGI-S (P<.001, P =.002, respectively), and the CPRS-R ADHD Index (P<.001, respectively). Significant improvements from baseline for subjects undergoing drug therapy were reported in ADHD RS Total Score (-13.31, children; -13.32, adolescents); Inattentive Subscale Score (-7, children; -6.9, adolescents); Hyperactive/Impulsive Subscale 928 Vol. 2, No. 25 November 2002

Score (-6.31, children; -6.42, adolescents); and CPRS-R Index Score (-8.42, children; -8.41 adolescents). Changes from baseline were more modest in the CGI-S subscale (-1.25, children; -1.36, adolescents). In all measures, scores were consistent for both children and adolescents. The data from these 2 clinical trials suggest that atomoxetine is equally efficacious in children and adolescents with ADHD, as measured by significant improvement in the ADHD RS (total and subscale scores), CPRS-R ADHD index, and CGI-S. These studies suggest that atomoxetine will provide an efficacious alternative to psychostimulants in the treatment of child and adolescent ADHD. However, to date, the drug s efficacy has not been directly studied in comparison with psychostimulant therapy. Figure. SUD Outcomes in Stimulant Treated Youths *P<.05. SUD = substance use disorder. LONG-TERM SAFETY OF ATOMOXETINE IN CHILDREN AND ADOLESCENTS WITH ATTENTION-DEFICIT/HYPERACTIVITY DISORDER Based on a poster presentation by Wernicke JF,* Kratochvil C, Milton D,* Dunn D, Spencer T, Heiligenstein J,* and Michelson D* *Eli Lilly and Company; Psychopharmacology Research Center, University of Nebraska Medical Center, Omaha, Nebraska; Indiana University/Riley Hospital, Indianapolis, Indiana; Joint Program in Pediatric Psychopharmacology, Massachusetts General Hospital, Boston, Massachusetts. This study of the long-term safety of atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) is among the largest studies of ADHD drug safety to be undertaken, consisting of 325 patients (258 children, 67 adolescents) who were exposed to extended atomoxetine treatment for an average of approximately 78 weeks. The open-label trial enrolled patients aged 7 to 17 years who met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for ADHD. The study population had no serious medical illnesses, comorbid psychoses or bipolar disorders, history of seizures, no ongoing use of psychoactive medications other than the study drug, and no history of substance abuse. Although the study is ongoing, the mean number of days on therapy at the time of this interim analysis was 313, with 143 patients completing 1 year of therapy. Among study participants, 3.7% (n = 12) discontinued the study due to an adverse event. Adverse events were rare; those most frequently reported included headache, rhinitis, abdominal pain, pharyngitis, and vomiting. These adverse events, as well as decreased appetite and weight loss sometimes associated with atomoxetine treatment, were reported primarily during initiation of drug therapy, and then tended to decrease significantly over time. Interestingly, this study reported an increase in weight and height among study subjects over time: mean weight increased 2.6 kg and height increased 4.4 cm. The finding is significant, since a source of concern for existing ADHD therapies is appetite suppression and its potential impact on childhood growth. Although atomoxetine is not a stimulant, its use nonetheless resulted in a slight increase in diastolic blood pressure (3.6 mm Hg), systolic blood pressure (3.5 mm Hg), and pulse (3.9 bpm). In addition, a decrease of Advanced Studies in Medicine 929

4.8 msec in mean Fridericia-corrected QT interval from baseline to endpoint was observed. This study demonstrates long-term safety of an investigational new class of drug therapy available for the treatment of ADHD, showing atomoxetine to be generally well tolerated. In contrast to acute studies where mean weight loss was observed, this study revealed mean weight increases during long-term therapy. No evidence of a drug-related QTc prolongation was observed. Although adverse events occurred infrequently during the study, those that did occur decreased over time, and new adverse events did not appear later in the treatment of study subjects. According to study author David Michelson, MD, little long-term data has been reported for stimulants to date. These data therefore represent one of the first systemic, prospective studies of the safety of any ADHD medication over an extended period of time. ADHD SUBTYPES CHANGE DRAMATICALLY WITH AGE AND GENDER Based on a poster presentation by Turgay A,* Ansari R, Zafar M, and the Scarborough Hospital ADHD Institute Study Group *University of Toronto, Ontario, Canada; The Scarborough Hospital, Ontario, Canada The Scarborough Hospital attention-deficit/hyperactivity disorder (ADHD) Clinic, Training and Research Institute was established in 1994. The institute allowed a large database to be studied by a multidisciplinary team consisting of child, adolescent, and adult psychiatrists with representatives from other medical disciplines as well as social workers and child development specialists. Using the existing database from Scarborough Hospital, researchers investigated the relationships between ADHD, subtypes, age, and gender. The study sample consisted of all patients who were consecutively referred to the Scarborough Hospital ADHD Clinic, Training and Research Institute and who had completed evaluations according to the inclusion criteria between September 1, 1994, and December 31, 2001. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria were used to establish diagnoses for ADHD and comorbid disorders. The study included 2298 male subjects and 635 female subjects (N = 2933) with ADHD who were aged 2 to 68 years; most subjects were in the 6- to 18-year-old age group (n = 2277). Subjects were systematically assessed to determine ADHD subtypes, age, and gender relationships. Evaluations included Gadow-Sprafkin general psychopathology screening scales, DuPaul ADHD scales, and semistructured interviews. Although community-based studies reported 2 decades ago established a 2.5:1 male:female ratio, 1,2 the male:female ratio in this study was 3.6:1 (P<.001), indicating an underidentification of females in the existing literature. As age increased, male:female ratio decreased: Among children aged 2 to 5 years (n = 359), the male:female ratio was 5.18:1; for patients older than 19 years (n = 297), the ratio was very close to the community sample s ratio of 2.5:1. ADHD subtypes changed as age increased. In the 2- to 5-year-old age group, the ratio of ADHD combined type vs ADHD predominantly inattentive type (ADHD:attention-deficit disorder [ADD]) was 38:1. In the group consisting of subjects older than 19 years, the ADHD:ADD ratio was 0:89. ADHD predominantly inattentive type was more common in female than male subjects (30.47% vs18.9%). In every age group, ADHD hyperactive-impulsive type (HI) was the least common subtype, representing 2.08% of male subjects and 1.73% of female subjects. The study conclusions were that ADHD-HI type was rare in every age group studied and in both genders. The proportion of ADHD combined type cases decreased as a function of age, and the percentage of females identified with ADHD increased with age. In this sample, ADHD was underidentified in children younger than 6 years, females, adolescents, adults, and ADHD inattentive type. Community screening with practical, valid, reliable, and sensitive questionnaires is essential. REFERENCES 1. Offord DR, Boyle MH, Racine Y. Ontario Child Health Study: Correlates of disorder. J Am Acad Child Adolesc Psychiatry. 1988;28:856-860. 2. Szatmari P, Offord DR, Boyle MH. Ontario child health study: Prevalence of attention deficit disorders with hyperactivity. J Child Psychol Psychiatry. 1989;30:219-230. 930 Vol. 2, No. 25 November 2002