A Single-Blind, Placebo Controlled Trial of Triple Beaded Mixed Amphetamine Salts in DSM-5 Adults With ADHD Assessing Effects Throughout the Day.

OBJECTIVE: To examine the effects of triple beaded mixed amphetamine salts (TB MAS) on ADHD and executive dysfunction symptoms throughout the day in adults with DSM-5 ADHD. METHOD: This was a 6 week, single-blind, placebo-lead in trial of TB MAS (12.5-37.5 mg/day); all participants received 2 weeks of single-blind placebo); one individual was a placebo responder and was discontinued. One of these 18 dropped after 1 week on 12.5 mg/day, while all others completed the trial and received 37.5 mg/day TB MAS. RESULTS: There were significant effects of TB MAS on all clinical measures, including investigator overall symptoms (AISRS); self-report overall (ASRS), time-sensitive ADHD (TASS) scores throughout the day, impairment (CGI) and executive function scores (BRIEF-A). TB MAS was generally well tolerated. CONCLUSIONS: This study extends prior findings of TB MAS to adults with DSM-5 ADHD; it further re-validates findings of efficacy of TB MAS throughout the day.

Pilot Study of Prism EFP NeuroFeedback in Adult ADHD.

OBJECTIVE: A pilot study to preliminarily examine the effects of Prism EFP NeuroFeedback (NF) in adult ADHD. METHOD: Prism EFP NF is a form of NF specifically designed to target emotional dysregulation (ED) through down regulation of amygdala activity. Prism EFP NF has been shown to improve other disorders with significant ED. Nine participants with adult ADHD received an open trial of Prism EFP NF consisting of fifteen sessions over 8 weeks; all completed at least 5 weeks of treatment with seven completing all 8 weeks. Outcomes were assessed by change in ADHD symptoms from baseline to End of Treatment. RESULTS: About two-third reduction was seen in total DSM ADHD symptom scores (primary outcome measure) with improvement observed in all other clinical measures. No significant adverse events were seen. CONCLUSION: This preliminary trial found substantial effects of Prism EFP NF on ADHD/ED symptoms and global impairment.

A Placebo-Controlled Trial of Lisdexamfetamine in the Treatment of Comorbid Sluggish Cognitive Tempo and Adult ADHD.

Objective: To examine the efficacy of lisdexamfetamine (LDX) versus placebo on behavioral attributes of sluggish cognitive tempo (SCT) in adults with attention-deficit/hyperactivity disorder (ADHD) and SCT.Methods: In a randomized crossover trial conducted January 2016-April 2018, 38 adults with DSM-5 ADHD (via the Adult ADHD Clinical Diagnostic Scale v1.2) and SCT were recruited at 2 academic medical centers and assessed for symptoms of ADHD, SCT, executive function deficits, and functional impairment at baseline and weekly during treatment. Participants received 4 weeks of treatment with either LDX (30-70 mg/d; mean = 59.1 ± 14.8 mg/d) or matching placebo (mean = 66.6 ± 9.1 mg/d) with a 2-week washout before switching to the other arm. The ADHD Rating Scale and Barkley Adult ADHD Rating Scale-IV SCT subscale were coprimary outcome measures.Results: There were moderately large treatment effects of LDX vs placebo on SCT ratings in both treatment periods (block 1 effect size = 0.68; block 2 effect size = 0.61), which reached significance only in block 1 owing to carryover effects of the first treatment epoch into the second. Significant effects were also seen for LDX over placebo in ADHD, executive function deficit, and functional impairment ratings, without order effects; no site differences were seen except on the Global Executive Complex score of the Behavior Rating Inventory of Executive Function-Adult Version. No moderating effects of sex, age, race, and ethnicity were seen.Conclusions: Adults with ADHD and comorbid SCT had significant improvement after LDX vs placebo in ratings of SCT, ADHD, executive function deficits, and functional impairment. This is the first study to show improvement in SCT after stimulant therapy in adults with ADHD.Trial Registration: ClinicalTrials.gov identifier: NCT02635035.

The Relationship Between Executive Function Deficits and DSM-5-Defined ADHD Symptoms.

Objectives: To identify the relationship between the core Diagnostic and Statistical Manual of Mental Disorders (5th ed.) ADHD symptoms and executive function deficits (EFDs), to evaluate ADHD characteristics of those with executive dysfunction (ED), and to examine the predictive utility of the Adult ADHD Investigator Symptom Rating Scale (AISRS) in identifying those with adult ADHD and ED. Method: Two samples (referred and primary care practice) were pooled together for present analysis. Results: Final analysis included 297 respondents, 171 with adult ADHD. Spearman correlation coefficients and binary logistic regressions demonstrated that ADHD inattentive (IA) and hyperactive-impulsive (H-I) symptoms were moderately to strongly correlated with and highly predictive of EFDs. Receiver operating characteristic curve analysis showed that an AISRS DSM 18-item score of ⩾ 28 was most predictive of clinical ED. Conclusion: ADHD symptoms were strongly correlated with and predictive of EFDs, clinicians should screen adults with ADHD for EFDs and ADHD treatment providers should track EFD improvement in addition to DSM-5 ADHD symptoms.

Validation of the Expanded Versions of the Adult ADHD Self-Report Scale v1.1 Symptom Checklist and the Adult ADHD Investigator Symptom Rating Scale.

Objective: The aim of this study is to validate the Adult ADHD Self-Report Scale (ASRS) and Adult ADHD Investigator Symptom Rating Scale (AISRS) expanded versions, including executive function deficits (EFDs) and emotional dyscontrol (EC) items, and to present ASRS and AISRS pilot normative data. Method: Two patient samples (referred and primary care physician [PCP] controls) were pooled together for these analyses. Results: Final analysis included 297 respondents, 171 with adult ADHD. Cronbach's alphas were high for all sections of the scales. Examining histograms of ASRS 31-item and AISRS 18-item total scores for ADHD controls, 95% cutoff scores were 70 and 23, respectively; histograms for pilot normative sample suggest cutoffs of 82 and 26, respectively. Conclusion: (a) ASRS- and AISRS-expanded versions have high validity in assessment of core 18 adult ADHD Diagnostic and Statistical Manual of Mental Disorders (DSM) symptoms and EFD and EC symptoms. (b) ASRS (31-item) scores 70 to 82 and AISRS (18-item) scores from 23 to 26 suggest a high likelihood of adult ADHD.

Pharmacokinetic and Pharmacodynamic Properties of Lisdexamfetamine in Adults with Attention-Deficit/Hyperactivity Disorder.

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.

Neural Correlates of Symptom Improvement Following Stimulant Treatment in Adults with Attention-Deficit/Hyperactivity Disorder.

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 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.

Clinical effects of lisdexamfetamine and mixed amphetamine salts immediate release in adult ADHD: results of a crossover design clinical trial.

OBJECTIVES: To examine the clinical effects of equivalent doses of single-blind (SB; patient-blind) lisdexamfetamine (LDX) and mixed amphetamine salts-immediate release (MAS-IR) on adult attention-deficit/hyperactivity disorder (ADHD) in a placebo (PBO)-controlled, crossover design. METHODS: Twenty-four subjects were treated sequentially in a fixed order with (1) SB PBO (matching LDX) for 1 week, (2) SB LDX (up to 70 mg/day) for 5 weeks, (3) SB PBO washout for 3 weeks, and (4) open-label treatment MAS-IR (tid up to 45 mg/day) for 5 weeks. Clinical effects on ADHD and executive function were assessed weekly throughout the trial with the ADHD Rating Scale with adult prompts, the Clinical Global Impression Severity Scale (CGI-S), and the Behavior Rating Inventory of Executive Function (BRIEF). RESULTS: Lisdexamfetamine and MAS-IR were generally well tolerated. Significant and equal reductions on ADHD clinician ratings were seen. Significantly greater reductions in CGI-S and selected BRIEF subsets were observed in LDX over MAS-IR treatment. However, in general, baseline scores for MAS-IR treatment did not fully return to the LDX baseline. Adherence in this structured and monitored clinical trial was good for once daily LDX and 3 times a day MAS-IR. CONCLUSIONS: In this crossover study, both LDX and MAS-IR had significant effects on ADHD clinician ratings and measures of executive function (with response rates of about 80%); patients in this monitored clinical trial were adherent with once daily LDX and 3 times a day MAS-IR, which may not be the case in real-world clinical practice. The findings of some superiority of LDX over MAS-IR on the CGI-S and BRIEF ratings may be influenced by the variability in the baselines used, but nevertheless should be further investigated in larger scale, parallel-design clinical trials.

Abnormal gene expression in cerebellum of Npc1-/- mice during postnatal development.

Niemann-Pick Type C (NPC) disease is an autosomal recessive neurodegenerative disorder with abnormal lipid storage as the major cellular pathologic hallmark. Genetic analyses have identified mutations in NPC1 gene in the great majority of cases, while mutations in NPC2 account for the remainders. Yet little is known regarding the cellular mechanisms responsible for NPC pathogenesis, especially for neurodegeneration, which is the usual cause of death. To identify critical steps that could account for the pathological manifestations of the disease in one of the most affected brain structures, we performed global gene expression analysis in the cerebellum from 3-week old Npc1+/+ and Npc1-/- mice with two different microarray platforms (Agilent and Illumina). Differentially expressed genes identified by both microarray platforms were then subjected to KEGG pathway analysis. Expression of genes in six pathways was significantly altered in Npc1-/- mice; functionally, these signaling pathways belong to the following three categories: (1) steroid and terpenoid biosynthesis, (2) immune response, and (3) cell adhesion/motility. In addition, the expression of several proteins involved in lipid transport was significantly altered in Npc1-/- mice. Our results provide novel molecular insight regarding the mechanisms of pathogenesis in NPC disease and reveal potential new therapeutic targets.