Concurrent Stimulant and Atypical Antipsychotic Drug Use in Children and Adolescents Diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD)

Background: Multiple psychotropic drug use is highly prevalent in children and adolescents despite the lack of sufficient safety and efficacy data for such use. Few studies evaluated the concurrent use of stimulant and atypical antipsychotic agents in children and adolescents diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD). Objectives: The goals of this study were 1) to examine the prevalence of and factors associated with concurrent use of long acting stimulant (LAS) and atypical antipsychotic agents, 2) to examine the impact of addition of atypical antipsychotic agents on the persistence of LAS treatment, and 3) to examine the risk of cardiovascular adverse events due to addition of the atypical antipsychotic agents already on the regimen of LAS in children and adolescents diagnosed with ADHD. Methods: The study involved retrospective longitudinal analysis of 2003-2007 Medicaid Analytical eXtract (MAX) data of four US states. The study mainly focused on children and adolescents aged 6 to 17 years who were diagnosed with ADHD and initiated ADHD treatment by using long acting stimulant (LAS) medications from July 2003 to December 2006. The continuous eligibility 6 months before and 12 months after the index LAS date was ensured for the study cohort. The study cohort was uniformly followed for one year after the initiation of LAS. Concurrent use of LAS and atypical antipsychotic medications were defined as receipt of both medications together at least for 14 days. The persistence of LAS was defined as number of days to discontinuation of index LAS treatment. The cardiovascular events were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes from inpatient and outpatient files. Descriptive analysis was performed to examine the utilization of LAS and atypical antipsychotic agents and compare the study groups. Multiple logistic regression analysis within the conceptual framework of Andersen behavioral model was used to examine the factors associated with concurrent use with LAS use only as reference group. Multivariate analysis was conducted by using accelerated failure time regression to examine the determinants of persistence of LAS. In order to examine cardiovascular safety typical antipsychotic use was further classified as current use (active atypical antipsychotic use), former use (days after the periods of current use), and nonuse (time before the first atypical antipsychotic use including the follow up of patients who were never exposed to atypical antipsychotics). The cardiovascular risks were compared among the study groups using time dependent Cox regression analysis. Results: Among the 61, 793 children and adolescents who were diagnosed with ADHD and initiated their ADHD treatment with LAS 11, 866 (19.20%) received LAS and atypical antipsychotic concurrently at least for 14 days. Risperidone was highly used concurrently and clozapine was least used (0.03%) among atypical antipsychotic users. The results of multiple logistic regression revealed that children and adolescents with male gender, black race, and foster care benefit recipients were more likely to receive LAS and atypical antipsychotic agents concurrently than their counterparts. Moreover, FDA approved indications such as schizophrenia, bipolar disorder, and psychosis and FDA non-approved indications such as oppositional defiant disorder, pervasive developmental disorder, tic disorder, and personality disorder determined the concurrent use of LAS and atypical antipsychotic agents. The mean duration of LAS treatment was longer (200 days; 95% Confidence Interval (CI), 197.6-202.9 days) among concurrent LAS and atypical antipsychotic recipients than only LAS users (143 days; 95% CI, 141.8-144 days). The accelerated failure time regression analysis found that concurrent users of LAS and atypical antipsychotic agents had 45% longer (Survival Time Ratio (STR), 1.45; 95% CI, 1.41-1.49) LAS treatment persistence than only LAS recipients. Similarly, adolescents and non-whites had shorter LAS treatment persistence than their counterparts. The numbers of cardiac events were 840, 202, and 45 during periods of atypical non-use, current use and former use, respectively. After controlling for demographic, service related, and clinical characteristics, the study found that current users and former users of atypical antipsychotics among the LAS users were not associated with cardiovascular events compared to no atypical users (Current use: (Hazard ratio (HR), 1.17; 95% CI, 0.98-1.40; Former use: HR, 1.24; 95% CI, 0.91-1.69). Patient characteristics obesity (HR, 1.63; 95% CI, 1.21-2.20), diabetes (HR, 1.94; 95% CI, 1.27-2.96) and receipt of mood stabilizers increased the risk of cardiovascular events (HR, 1.87; 95% CI, 1.08-3.24) in the study population. Conclusions: This study found that almost 1 in 5 children and adolescents received LAS and atypical antipsychotics concurrently. In addition to FDA approved indications such as schizophrenia, bipolar disorder, and psychosis, FDA non-approved indications such as oppositional defiant disorder, pervasive developmental disorder, tic disorder, and personality disorder determined the concurrent use of LAS and atypical antipsychotics. The recipients of LAS and atypical antipsychotic agents concurrently had longer LAS treatment continuity than recipients of only LAS. The study did not find any increased cardiovascular risk with addition of the atypical antipsychotics to LAS regimen in children and adolescents diagnosed with ADHD. The addition of the atypical antipsychotic agents along with LAS in ADHD patients may be beneficial in controlling ADHD symptoms. There is need to conduct head to head clinical trials of the 2 treatment groups in order to examine the efficacy of atypical antipsychotic agents and mechanism in the treatment of ADHD. Therefore there is urgent need of conducting head to head long term trials in order to examine the safety and efficacy of concurrent use of LAS and atypical antipsychotic agents in children and adolescents with ADHD and several other psychiatric disorders. Future studies with long term follow up are required to evaluate the long term effects of concurrent use of long acting stimulants and atypical antipsychotic agents.