Faculty Bibliography

BACKGROUND: Lisdexamfetamine (LDX) is a prodrug and consists of an active moiety, d-amphetamine, bound to lysine. Clinically, d-amphetamine becomes available postcleavage of the prodrug in the blood stream. Clinical effects of LDX in attention-deficit/hyperactivity disorder (ADHD) have been shown to persist up to 14 hours; however, pharmacokinetic (PK) data of LDX and amphetamine in ADHD adults are not currently available. OBJECTIVES: (1) To examine PK data of LDX and d-amphetamine in plasma and (2) to compare such PK data with Time-Sensitive ADHD Symptom Scale (TASS) ratings (PK vs. pharmacodynamic [PD]). METHODS: Plasma d-amphetamine/LDX levels and TASS ratings were obtained immediately before morning dosing and then 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdosing in 21 adults with ADHD treated with 5 weeks of single-blind LDX up to 70 mg/day (after 1 week single-blind placebo). ADHD Rating Scale scores were obtained at the beginning of the visit, before morning dosing. RESULTS: LDX levels peaked at 1.5 hours after administration (Tmax) and then rapidly declined (levels were negligible at 6 hours and area under the plasma concentration versus time curve, AUC = 45.9, Cmax = 25.0, and half-life [t1/2] = 0.5 hours). Levels of d-amphetamine peaked at (Tmax) 4.4 hours and then slowly declined (AUC = 641.6, Cmax = 67.9, and t1/2 = 17.0 hours). No statistically significant correlations were seen between d-amphetamine levels and TASS scores. CONCLUSIONS: (1) Prodrug LDX levels peaked fairly rapidly and declined, while d-amphetamine levels peaked 3 hours later than LDX levels and persisted throughout the day and (2) the absence of PK/PD correlations between PK data and TASS ratings may be due to the subjects being tested in a controlled nonattention demanding environment.

Objectives: (a) Evaluate the efficacy and duration of effect of lisdexamfetamine dimesylate (LDX) in adult ADHD. (b) Assess the reliability and validity of the Adult ADHD Medication Smoothness of Effect Scale (AMSES) and Adult ADHD Medication Rebound Scale (AMRS). Method: Adults (N = 40) with ADHD were treated with LDX for up to 12 weeks. The primary efficacy measure was the ADHD Rating Scale (ADHD-RS). The psychometric properties of the AMSES and AMRS are analyzed and compared with the ADHD-RS, ADHD Self-Report Scale (ASRS) v1.1 Symptom Checklist, and Time-Sensitive ADHD Symptom Scale (TASS). Results: ADHD-RS scores were significantly improved with LDX. The AMSES and AMRS had high internal consistency and were correlated with the ADHD-RS, ASRS v1.1 Symptom Checklist, and TASS. Conclusion: LDX is effective in treating adult ADHD and has a smooth drug effect throughout the day with limited symptom rebound. The AMSES and AMRS are valid and reliable measures. (J. of Att. Dis. 2013; XX(X) 1-XX).

OBJECTIVE: The purpose of this study was to assess the relative accuracies of the Conners' Brief Rating Scale, Parent Version, the Conners' Continuous Performance Test II (CPT II), and a novel interactive game called "Groundskeeper" to discriminate child psychiatric patients with and without attention-deficit/hyperactivity disorder (ADHD). METHODS: We administered the three assessments to 113 clinically referred ADHD and non-ADHD patients who had been diagnosed with the Kiddie-Schedule of Affective Disorders and Schizophrenia- Present and Lifetime (K-SADS-PL), Version 19. RESULTS: As measured by the area under the curve (AUC) statistic from receiver operating characteristic (ROC) analysis, the diagnostic accuracy of Groundskeeper (0.79) was as high as the accuracy of the Conners' parent rating of inattention (0.76) and better than the CPT II percent correct (0.62). Combining the three tests produced an AUC of 0.87. Correlations among the three measures were small and, mostly, not significant. CONCLUSIONS: Our finding of similar diagnostic accuracies between Groundskeeper and the Conners' inattention scale is especially remarkable given that the Conners' inattention scale shares method variance with the diagnostic process. Although our work is preliminary, it suggests that computer games may be useful in the diagnostic process. This provides an important direction for research, given the objectivity of such measures and the fact that computer games are well tolerated by youth.

OBJECTIVE: The purposes of this study were to examine the impact of 3 weeks of amphetamine administration on intrinsic connectome-wide connectivity patterns in adults with attention-deficit/hyperactivity disorder (ADHD) and explore the association between stimulant-induced symptom improvement and functional connectivity alteration. METHODS: Participants included 19 adults (age 20-55 years) diagnosed with ADHD using the Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) criteria (American Psychiatric Association 2000 ) per the Adult Clinician Diagnostic Scale taking part in amphetamine trials. For each patient, two 6-minute resting-state functional magnetic resonance imaging (R-fMRI) scans were acquired at baseline and after treatment. A fully data-driven multivariate analytic approach (i.e., multivariate distance matrix regression [MDMR]) was applied to R-fMRI data to characterize the distributed pharmacological effects in the entire functional connectome. Clinical efficacy was assessed using ADHD rating scale with adult prompts and the Adult Self-Report Scale v1.1 Symptom Checklist. We linked stimulant-induced functional connectivity changes to symptom amelioration using Spearman's correlation. RESULTS: Three weeks of administration of a stimulant significantly reduced ADHD symptoms. MDMR-based analyses on R-fMRI data highlighted the left dorsolateral prefrontal cortex (DLPFC, a key cognitive control region) and the medial prefrontal cortex (MPFC, the anterior core of default network) whose distributed patterns of functional connectivity across the entire brain were altered by psychostimulants. Follow-up intrinsic functional connectivity revealed that stimulants specifically decreased the positive functional connectivity between DLPFC-insula, DLPFC-anterior cingulate cortex, and MPFC-insula. Importantly, these functional connectivity changes are associated with symptom improvement. CONCLUSION: These results suggested that ADHD is associated with increased functional integration or decreased functional segregation between core regions of cognitive control, default, and salience networks. The apparent normalization of intrinsic functional interaction in these circuits (i.e., increased functional segregation) may underlie the clinical benefits produced by 3 weeks of amphetamine treatment.

The adult attention-deficit/hyperactivity disorder (ADHD) quality-of-life (AAQoL) scale was previously validated in adult patients in the USA; here, the AAQoL is validated in adult European patients. Data from a 12-week open-label acute treatment period with atomoxetine (80-100 mg/day) in adults with ADHD were used. Patients (>/=18 to /=2 on >/=6 items on the inattentive or hyperactive core subscales of Conners' Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV); a CAARS-Inv:SV 18-item total ADHD symptom score >/=20; and Conners' Adult ADHD Rating Scale-Observer: Screening Version 6-item inattentive or hyperactive core subscale scores >/=2. Data were stratified based on patients' geographic region (Europe vs USA). Scale validation psychometric properties results were very similar between European (n = 1,217; 57.7 % male; mean age 33.0 years) and US (n = 602; 62.1 % male; mean age 33.5 years) patients, including factor loading, internal consistency, convergent and discriminant validity, and responsiveness. Exploratory factor analysis confirmed four AAQoL subscales. Internal consistency was acceptable (Cronbach's alpha > 0.70 for all subscales). The AAQoL total score showed moderate convergent validity with CAARS-Inv:SV 18-item total ADHD symptom and clinical global impression-ADHD-severity (CGI-ADHD-S) scores; and strong convergent validity with Behavior Rating Inventory of Executive Function-Adult Version: Self-Report Global-Executive-Composite Index scores. Mean AAQoL total scores were significantly different among patients grouped by CGI-ADHD-S scores, suggesting good discriminant validity. The AAQoL total and subscale scores presented good responsiveness from baseline to 12 weeks. The AAQoL scale shows comparable validity in European and US adults with ADHD.