Faculty Bibliography

OBJECTIVE:To investigate the informativeness of self-reports of ADHD symptoms in adults with ADHD in the clinical setting. METHOD/METHODS:Subjects were clinically referred adults aged 19 years to 67 years of age of both sexes ( N = 54). All subjects were on stable doses of stimulant and were considered responders to treatment. ADHD symptoms were assessed using the ADHD Investigator Symptom Rating Scale (AISRS) and the ADHD Self-Report Scale (ASRS). Spearman's rank correlations were used to assess the correlations between clinician-assessed ADHD and patients' self-reports. RESULTS:Spearman's rank correlation analysis found evidence of a strong, positive association between total scores on the AISRS and the ASRS ( rs = .65, df = 52, p< .001). CONCLUSION/CONCLUSIONS:Results have important implications for the management and monitoring of treatment response in the clinical setting through patients' self-report.

Objectives: Once-daily dosing with dasotraline, a novel dopamine and norepinephrine reuptakeinhibitor, achieves stable plasma concentrationsover 24 hours with once-daily dosing. This studyevaluated dasotraline in children aged 6-12 years(NCT02428088).
METHOD(S): Patients were randomized 1:1:1 to 6 weeks ofonce-daily, fixed-dose dasotraline 2 or 4 mg/day, or placebo.The primary efficacy endpoint was change from baseline(CFB) at Week 6 in ADHD Rating Scale Version IV-HomeVersion (ADHD RS-IV HV) total score, using a mixed modelfor repeated measures (MMRM) in the intent-to-treat (ITT)population. Secondary endpoints included Clinical GlobalImpression-Severity (CGI-S) score and safety endpoints.
RESULT(S): The mean age of 342 randomized patients was9.1 [SD: 1.9] years; 66.7% were male. Overall, 79% ofpatients completed the study. In the ITT population(N = 336), ADHD RS-IV HV total score improvedsignificantly with dasotraline 4 mg/day vs placebo(leastsquares [LS] mean [SE] CFB at Week 6:-17.53 [+/- 1.31]vs-11.36 [+/- 1.29], respectively, p < 0.001; effect size[ES]: 0.48). Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/dayvs placebo at Week 6 (p = 0.001, p = 0.003, respectively).Improvement in CGI-S score was statistically significantwith dasotraline 4 mg/day vs placebo(LS mean [SE] CFBat Week 6:-1.39 [+/- 0.12] vs-1.04 [+/- 0.12], respectively,p = 0.040; ES: 0.29). No significant improvement wasobserved on the ADHD RS-IV HV total score and theCGI-S score for dasotraline 2 mg/day vs placebo. Themost frequent treatment-emergent AEs (=5% and higherthan placebo) were (2 mg/day; 4 mg/day; placebo):insomnia (15.3%; 21.7%; 4.3%, all terms combined),decreased appetite (12.6%; 21.7%; 5.2%), weight loss(5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%),nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%;5.2%; 2.6%).
CONCLUSION(S): Compared with placebo, dasotraline4 mg/day significantly improved ADHD symptoms inchildren, as assessed by ADHD RS-IV HV total score andinattentiveness and hyperactivity/impulsivity subscalescores. Dasotraline was generally well tolerated; mostcommon AEs were insomnia, decreased appetite, weightloss and irritability

Cogmed Working Memory Training (CWMT), an online cognitive training program developed for children, is an increasingly popular non-pharmacological intervention for ADHD amongst all ages, despite limited supporting evidence. The initial objective of the present work was to examine the short- and long-term impacts of CWMT on brain function in adults with ADHD. However, during the conduct of our study, we experienced multiple levels of failures in recruitment and retention that signaled potential concerns about the suitability of CWMT for adults with ADHD. This perspective piece aims to describe the difficulties we encountered in the context of studies examining the efficacy of CWMT in comparable populations. We trace these difficulties to the limited tolerability of the current CWMT structure for adults with ADHD, and review similar limitations in the literature. We suggest that efficacy of CWMT in children may be due in large part to close monitoring and scaffolding provided by clinicians and caregivers. For CWMT to have viability for widespread use in adults, greater support and structure will be needed for users to improve the likelihood of adherence. We discuss implications and considerations for future efforts in both research and clinical practice.

Objective: To examine the level of agreement between self- and observer-reported ratings of ADHD symptoms and executive function (EF) behaviors in adults with moderate to severe ADHD and EF deficits. Method: During a 10-week, randomized, double-blind, placebo-controlled study, the effect of lisdexamfetamine dimesylate (LDX) on EF was assessed by self-report and informant report (Behavior Rating Inventory of Executive Function-Adult Version), and ADHD symptoms were assessed by clinician- and informant-rated scales (ADHD Rating Scale IV with adult prompts and Conners' Adult ADHD Rating Scales-Observer Report: Short Version, respectively). Post hoc analysis used Pearson correlations to assess relationships between self- and informant-rated EF and clinician- and informant-rated ADHD symptoms. Results: Correlations between self-ratings versus informant ratings and clinician versus informant ratings were greater at Week 10/early termination (EF: placebo [0.5231-0.6085], LDX [0.3543-0.5167]; ADHD symptoms: placebo [0.4169], LDX [0.4004]) versus baseline (EF: placebo [0.3208-0.5023], LDX [0.2852-0.3439]; ADHD symptoms: placebo [0.1511], LDX [-0.0408]). Conclusion: LDX improved EF and ADHD symptoms, based on participant, informant, and clinician ratings. Increased rater agreement over time may reflect improved symptom awareness. (J. of Att. Dis. XXXX; XX(X) XX-XX).

Reports an error in "The World Health Organization Adult Attention-Deficit/Hyperactivity Disorder Self-Report Screening Scale for DSM-5" by Berk Ustun, Lenard A. Adler, Cynthia Rudin, Stephen V. Faraone, Thomas J. Spencer, Patricia Berglund, Michael J. Gruber and Ronald C. Kessler (JAMA Psychiatry, 2017[May], Vol 74[5], 520-526). In the original article, there was an error in the Results section of the article. In the second paragraph of "Choosing the Optimal Number of Screening Questions," option 3 included the phrase "Criterion A2e, acts as if 'driven by a motor.'" The phrase should have been "Criterion A2d, difficulty playing quietly/leisure time." (The following abstract of the original article appeared in record 2017-32659-009). Importance: Recognition that adult attention-deficit/hyperactivity disorder (ADHD) is common, seriously impairing, and usually undiagnosed has led to the development of adult ADHD screening scales for use in community, workplace, and primary care settings. However, these scales are all calibrated to DSM-IV criteria, which are narrower than the recently developed DSM-5 criteria. Objectives: To update for DSM-5 criteria and improve the operating characteristics of the widely used World Health Organization Adult ADHD Self-Report Scale (ASRS) for screening. Design, setting, and participants: Probability subsamples of participants in 2 general population surveys (2001-2003 household survey [n = 119] and 2004-2005 managed care subscriber survey [n = 218]) who completed the full 29-question self-report ASRS, with both subsamples over-sampling ASRS-screened positives, were blindly administered a semistructured research diagnostic interview for DSM-5 adult ADHD. In 2016, the Risk-Calibrated Supersparse Linear Integer Model, a novel machine-learning algorithm designed to create screening scales with optimal integer weights and limited numbers of screening questions, was applied to the pooled data to create a DSM-5 version of the ASRS screening scale. The accuracy of the new scale was then confirmed in an independent 2011-2012 clinical sample of patients seeking evaluation at the New York University Langone Medical Center Adult ADHD Program (NYU Langone) and 2015-2016 primary care controls (n = 300). Data analysis was conducted from April 4, 2016, to September 22, 2016. Main outcomes and measures: The sensitivity, specificity, area under the curve (AUC), and positive predictive value (PPV) of the revised ASRS. Results: Of the total 637 participants, 44 (37.0%) household survey respondents, 51 (23.4%) managed care respondents, and 173 (57.7%) NYU Langone respondents met DSM-5 criteria for adult ADHD in the semistructured diagnostic interview. Of the respondents who met DSM-5 criteria for adult ADHD, 123 were male (45.9%); mean (SD) age was 33.1 (11.4) years. A 6-question screening scale was found to be optimal in distinguishing cases from noncases in the first 2 samples. Operating characteristics were excellent at the diagnostic threshold in the weighted (to the 8.2% DSM-5/Adult ADHD Clinical Diagnostic Scale population prevalence) data (sensitivity, 91.4%; specificity, 96.0%; AUC, 0.94; PPV, 67.3%). Operating characteristics were similar despite a much higher prevalence (57.7%) when the scale was applied to the NYU Langone clinical sample (sensitivity, 91.9%; specificity, 74.0%; AUC, 0.83; PPV, 82.8%). Conclusions and relevance: The new ADHD screening scale is short, easily scored, detects the vast majority of general population cases at a threshold that also has high specificity and PPV, and could be used as a screening tool in specialty treatment settings.

Objectives: This talk will review the clinical significance of symptoms of mood (emotional) dysregulation versus frank co-occurring mood disorders in adults with ADHD and examine evidence for the potential treatment of co-occurring mood disorders or symptoms of emotional dysregulation in adults with ADHD. Methods: Studies on co-occurring mood disorders and emotional dysregulation symptoms in adults with ADHD were surveyed and reviewed via PubMed search and cross-referencing from review articles/chapters. Results: Mood dysregulation has been shown to be a commonly occurring symptom in adults with ADHD and exists as a separate, unique factor compared with symptoms of inattention, hyperactivity/impulsivity, and executive dysfunction. The same factor analysis found that emotional dysregulation symptoms loaded highly on the combined subtype of ADHD or in cases that did not meet full ADHD criteria. Treatment studies have found that emotional dysregulation symptoms do generally respond to treatment with stimulants or with the nonstimulant, atomoxetine, but at approximately half the effect size of stimulants. Studies have shown high rates of mood disorders of bipolar disorder (10-15%), major depression (15-20%), and dysthymia (20%) in adults with ADHD. Furthermore, rates of ADHD are quite high in individuals with mood disorders. The available literature on treating ADHD and comorbid mood disorders is surprisingly scant. Bupropion has an extensive history of use as an antidepressant, and several studies have shown it to be an effective nonstimulant in ADHD, but studies have not systematically assessed its use when mood disorders or mood dysregulation co-occur with ADHD. A handful of studies have examined the addition of stimulant medications to patients with major depression treated with antidepressants. Conclusions: Clinicians should be aware of high rates of co-occurring mood disorders in adults with ADHD, and the reverse, as not identifying one of the comorbidities may result in incomplete treatment or negative outcomes. High rates of mood dysregulation symptoms have been reported in adults with ADHD, even though they are not part of the core ADHD symptoms in DSM-5

Objectives: Dasotraline, a novel dopamine and norepinephrine reuptake inhibitor, provides stable plasma concentrations over 24 hours with once-daily dosing. This study evaluated dasotraline in children aged 6-12 years meeting DSM-5 criteria for ADHD (NCT02428088). Methods: Patients were randomized to either six weeks of once-daily, fixed-dose dasotraline (2 or 4 mg/day), or placebo. The primary efficacy endpoint was change from baseline (CFB) in ADHD Rating Scale-IV Home Version (ADHD-RS-IV HV) total score at week six, using a mixed model for repeated measures in the intent-to-treat (ITT) population. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score and safety. Results: The mean age of 342 randomized patients was 9.1 ( 1.9) years; 66.7 percent were male. Overall, 79 percent of patients completed the study. In the ITT population (N = 336), ADHD RS-IV HV total score improved significantly with dasotraline 4 mg/day versus placebo [least squares (LS) mean CFB at week 6: -17.53 (95% CI: -20.12, -14.95) vs -11.36 (-13.89, -8.83), respectively, p < 0.001; effect size (ES): 0.48]. Inattentiveness and hyperactivity/impulsivity subscale scores significantly improved with 4 mg/day versus placebo at week six (p = 0.001, p = 0.003, respectively). The 2 mg/day arm did not significantly differ from placebo on ADHD RS-IV HV total score [LS mean CFB at week 6: -11.80 (-14.37, -9.22), p = 0.812; ES: 0.03). Improvement in CGI-S score was statistically significant with dasotraline 4 mg/day versus placebo [LS mean CFB at week 6: -1.39 (-1.63, -1.15) vs -1.04 (-1.28, -0.80), respectively, p = 0.040; ES: 0.29]. No significant improvement was observed on the CGI-S for dasotraline 2 mg/day versus placebo [LS mean CFB at week 6: -0.94 (-1.18, -0.70), ns]. The most frequent treatment-emergent AEs ( 5% and higher than placebo) were (2 mg/day; 4 mg/day; placebo): insomnia (15.3%; 21.7%; 4.3%, all terms combined), decreased appetite (12.6%; 21.7%; 5.2%), weight loss (5.4%; 8.7%; 0%), irritability (3.6%; 7.0%; 6.0%), nasopharyngitis (0.9%; 5.2%; 0.9%), and nausea (0%; 5.2%; 2.6%). Conclusions: Dasotraline 4 mg/day significantly improved ADHD symptoms in children compared to placebo, assessed by ADHD RS-IV HV total score and inattentiveness and hyperactivity/impulsivity subscale scores. Dasotraline was generally well tolerated; most common AEs included insomnia, decreased appetite, weight loss and irritability

Importance: Recognition that adult attention-deficit/hyperactivity disorder (ADHD) is common, seriously impairing, and usually undiagnosed has led to the development of adult ADHD screening scales for use in community, workplace, and primary care settings. However, these scales are all calibrated to DSM-IV criteria, which are narrower than the recently developed DSM-5 criteria. Objectives: To update for DSM-5 criteria and improve the operating characteristics of the widely used World Health Organization Adult ADHD Self-Report Scale (ASRS) for screening. Design, Setting, and Participants: Probability subsamples of participants in 2 general population surveys (2001-2003 household survey [n = 119] and 2004-2005 managed care subscriber survey [n = 218]) who completed the full 29-question self-report ASRS, with both subsamples over-sampling ASRS-screened positives, were blindly administered a semistructured research diagnostic interview for DSM-5 adult ADHD. In 2016, the Risk-Calibrated Supersparse Linear Integer Model, a novel machine-learning algorithm designed to create screening scales with optimal integer weights and limited numbers of screening questions, was applied to the pooled data to create a DSM-5 version of the ASRS screening scale. The accuracy of the new scale was then confirmed in an independent 2011-2012 clinical sample of patients seeking evaluation at the New York University Langone Medical Center Adult ADHD Program (NYU Langone) and 2015-2016 primary care controls (n = 300). Data analysis was conducted from April 4, 2016, to September 22, 2016. Main Outcomes and Measures: The sensitivity, specificity, area under the curve (AUC), and positive predictive value (PPV) of the revised ASRS. Results: Of the total 637 participants, 44 (37.0%) household survey respondents, 51 (23.4%) managed care respondents, and 173 (57.7%) NYU Langone respondents met DSM-5 criteria for adult ADHD in the semistructured diagnostic interview. Of the respondents who met DSM-5 criteria for adult ADHD, 123 were male (45.9%); mean (SD) age was 33.1 (11.4) years. A 6-question screening scale was found to be optimal in distinguishing cases from noncases in the first 2 samples. Operating characteristics were excellent at the diagnostic threshold in the weighted (to the 8.2% DSM-5/Adult ADHD Clinical Diagnostic Scale population prevalence) data (sensitivity, 91.4%; specificity, 96.0%; AUC, 0.94; PPV, 67.3%). Operating characteristics were similar despite a much higher prevalence (57.7%) when the scale was applied to the NYU Langone clinical sample (sensitivity, 91.9%; specificity, 74.0%; AUC, 0.83; PPV, 82.8%). Conclusions and Relevance: The new ADHD screening scale is short, easily scored, detects the vast majority of general population cases at a threshold that also has high specificity and PPV, and could be used as a screening tool in specialty treatment settings.

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.