The Use of Brexpiprazole Combined With a Stimulant in Adults With Treatment-Resistant Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: This is the first controlled pharmacologic study in either adults or children with uncomplicated, treatment-resistant attention-deficit/hyperactivity disorder (ADHD). This study augmented stimulant therapy with the atypical antipsychotic brexpiprazole. The Food and Drug Administration preapproved primary outcome measure (Conners' Adult ADHD Rating Scale [CAARS]) showed no drug-placebo differences. Often studies showing no efficacy on the prestudy, defined primary outcome variable go unpublished. While this is decried, publishing studies with equivocal results remains rare. This reanalysis highlights trends in secondary measures having implications for treatment and research regarding treatment resistant ADHD. METHODS: Initially, 559 stimulant-naive and 174 prior stimulant nonresponders received methylphenidate osmotic-release oral system, dexmethylphenidate hydrochloride, lisdexamfetamine, or mixed amphetamine salts. After 5 weeks, 168 stimulant-naive patients and 68 prior stimulant nonresponders who failed treatment were randomized to brexpiprazole or placebo in a 2:1 ratio while the remaining were on the stimulant. Outcome was measured with the CAARS, Montgomery-Asberg Depression Rating Scale, Beck Depression Inventory, Clinical Global Impression, and the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). The WRAADDS contains 2 factors: attention and emotional dysregulation. RESULTS: Stimulant-naive patients showed no improvement with adjunctive brexpiprazole. Prior stimulant nonresponders displayed no brexpiprazole effect on the CAARS, Montgomery-Asberg Depression Rating Scale, or Beck Depression Inventory. In contrast, the WRAADDS detected a trend in treatment benefit, primarily through emotional dysregulation symptoms. Adverse effects on brexpiprazole and placebo were equivalent. CONCLUSIONS: Brexpiprazole might be effective in ADHD adults who are nonresponders to 2 or more stimulants. Future trials in treatment-resistant ADHD should use a 1:1 randomization and use a measure of ADHD symptoms that includes emotional dysregulation.

Psychometric data and versions of the Wender Utah Rating Scale including the WURS-25 & WURS-45.

Our associated paper presented a psychometric evaluation of the Wender Utah Rating Scale (WURS) and its abbreviated version, the WURS-25. Instead of actual factors scores, we employed "item averages" calculated by the average score of each item comprising that factor. We did not present a factor analysis of the WURS-25. Herein we identify items of the full WURS that are redundant or not part of any of the scale's five factors. Removing these items produced a shortened version, the WURS-45. We performed a logistic regression using actual factor loadings as well as factors based on item averages, and compared major depressive disorder (MDD) to generalized anxiety disorder (GAD) patients in the same analysis. We performed exploratory factor analysis with the WURS-45 items. We then performed logistic regressions and Receiver Operating Characteristics (ROC) analyses with the WURS-45 and WURS-25 factors. No increase in specificity or sensitivity arose when actual factors scores were used as opposed to factor scores from item averages. MDD and GAD ROC curves were very similar, supporting combining MDD with GAD patients into a single group. WURS-45 factors paralleled those derived from the full WURS. ROC curves, logistic regression and confusion tables showed the WURS-45 preserved the excellent diagnostic separation produced by the full WURS. Similar analyses showed WURS-25 scoring using its three factors improved its diagnostic utility. The WURS-45 has reduced redundancy with minimal loss in discriminatory power. Analysis of the WURS-25 using factor scores boosts its performance. Both versions of the scale provide clinical information describing childhood ADHD and are useful in separating adult patients with ADHD from those with MDD or GAD.

Wender Utah Rating Scale: Psychometrics, clinical utility and implications regarding the elements of ADHD.

The Wender Utah Rating Scale (WURS) is a self-report instrument completed by adults assessing a range of childhood symptoms and behaviors consistent with ADHD persisting into adulthood. Many items reflect emotional dysregulation. Although over 30 publications have examined its psychometric properties, reliance on non-clinical samples has limited conclusions from these reports, as have sub-optimal statistical approaches in most previous publications. None compared the full WURS to the abbreviated WURS-25. We evaluated both versions with adults presenting for treatment: 137 with ADHD and 230 with GAD or MDD, along with 120 normal controls. Factor analysis was performed on the full WURS using the clinical cohorts. The WURS versions were compared using ANOVA, logistic regression, ROC and confusion matrices. Consistent with two previous reports, the full WURS generated five factors: Disruptive mood & behavior, ADHD, Anxiety/dysphoria, Social and Academic. The ADHD factor correlated r > 0.8 with the Disruptive mood/behavior and the Academic factor. ADHD patients scored higher than GAD/MDD subjects (p < .001) on the Disruptive mood & behavior, ADHD, and Academic factors. The WURS-25 produced good separation of ADHD subjects from normal controls with ROC (AUC = 0.974) and logistic regression (Sensitivity = 91%, Specificity = 92%). Conversely, the full WURS better separated ADHD subjects from psychiatric controls with both ROC (AUC = 0.995) and logistic regression (Sensitivity = 84%, Specificity = 94%). Use of the full WURS with its five factors proved more successful at distinguishing ADHD from MDD and GAD than did the WURS-25. Its factors identify symptoms, including those of emotional dysregulation, critical to understanding ADHD.

Types of Adult Attention-Deficit/Hyperactivity Disorder: A Replication Analysis.

OBJECTIVE: Research supports the importance of emotional symptoms in adults with attention-deficit/hyperactivity disorder (ADHD), which are not reflected in the DSM-5 or ICD-10 criteria. The Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) assesses these symptoms, plus inattention, hyperactivity, and impulsivity. This scale allowed us to divide adult ADHD into 2 subtypes in a 2015 publication: ADHD inattentive presentation and ADHD emotional dysregulation presentation. The present study refines this observation using a larger, more diverse sample. METHODS: Eight double-blind adult ADHD clinical trials (encompassing 1,490 subjects) were selected because they included assessment with the WRAADDS; a second, alternative ADHD measure; and the Clinical Global Impressions-Severity of Illness scale (CGI-S). These data were subjected to confirmatory factor analyses, and ADHD presentations were compared, including treatment response. RESULTS: The original factor structure fit poorly with these new data. However, an alternative 2-factor solution fit both the original and the new subjects. ADHD inattentive presentation (n = 774) was defined by the inattention factor, and ADHD emotional dysregulation presentation (n = 620) was defined by additional elevation of the emotional dysregulation factor. The proportion of ADHD emotional dysregulation presentation ranged from 25% to 73% across the 8 studies. The emotional dysregulation presentation was associated with both a greater severity as measured by the CGI-S (P < .001) and more manifestations of childhood ADHD as measured by the Wender Utah Rating Scale (P < .001). CONCLUSIONS: Factor analytic results supported the validity of 2 adult ADHD presentations based on levels of emotional dysregulation. This system offers a more clinically relevant approach to the diagnosis of ADHD in adults than does the DSM system.

ADHD and Anxiety: Clinical Significance and Treatment Implications.

In comparison to the DSM formulation of ADHD, we have proposed that ADHD in adults should be divided into Inattentive and Emotional Dysregulation Presentations. Under both systems, there is potential overlap with generalized anxiety disorder (GAD). We compared data from four distinct populations: ADHD clinical trials, GAD clinical trials, an ADHD clinic, and a forensic clinic. Approximately 25% of patients in each population had comorbid ADHD and anxiety. Comorbid subjects reported more childhood ADHD symptoms and higher scores on ADHD scales and were more likely to fit criteria for ADHD Emotional Dysregulation Presentation or DSM-IV combined type. Comorbid subjects did not drop out at a higher rate and showed significant drug-placebo differences on ADHD symptoms, including Emotional Dysregulation. Conversely, although symptoms of anxiety decreased, there was no drug-placebo difference in improvement.

Personality Disorder in Adult Attention-Deficit/Hyperactivity Disorder: Attrition and Change During Long-term Treatment.

Personality disorders (PDs) are commonly found in adults with attention-deficit/hyperactivity disorder (ADHD) and are associated with increased ADHD symptoms and psychosocial impairment. To assess the impact of PDs or personality traits on retention rates in ADHD trials and whether treating ADHD affects the expression of PD, data were analyzed from 2 methylphenidate trials. Assessment of PDs and personality traits included using the Wisconsin Personality Disorders Inventory IV and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Personality Disorders. Attention-deficit/hyperactivity disorder symptoms were evaluated using the Wender-Reimherr Adult Attention Deficit Disorder Scale. Major findings were that subjects with cluster A, cluster B, passive-aggressive, or more than 1 PD showed more attrition. Subjects dropping out also had more schizoid and narcissistic traits. Attention-deficit/hyperactivity disorder symptoms (p < 0.001) and all personality traits (range, p = 0.03 to p = 0.001) improved, but there was almost no correlation between changes on these 2 measures. Conversely, of 11 Wisconsin Personality Disorders Inventory IV items that improved most, 8 resembled ADHD or oppositional defiant disorder symptoms.

Psychometric properties of the Self-Report Wender-Reimherr Adult Attention Deficit Disorder Scale.

BACKGROUND: The Self-Report Wender-Reimherr Adult Attention Deficit Disorder Scale (SR-WRAADDS) assesses the same 7 attention-deficit/ hyperactivity disorder (ADHD) domains as the interviewer-administered WRAADDS. METHODS: A normative sample was recruited, and additional participants came from trials involving ADHD, anxiety, or depression. Using the investigator-administered WRAADDS, participants in the ADHD sample were classified as ADHD inattentive presentation or ADHD emotional dysregulation presentation. RESULTS: In the ADHD sample, the SR-WRAADDS correlated with the investigator-rated version WRAADDS (P < .001). In comparing adults with ADHD with normal controls, all SR-WRAADDS domains demonstrated discriminate validity (P < .001); a cut point was identified yielding sensitivity of 97% and specificity of 89%. In comparison, in screening for ADHD in depression or anxiety disorders, sensitivity was 87% and specificity, 49%. Internal consistency was satisfactory (Cronbach α = 0.78; split-half reliability r = 0.92). Factor analysis yielded a 2-factor solution: one reflected emotional dysregulation; the other, inattention and disorganization. Detecting ADHD emotional dysregulation presentation within the ADHD sample, as the "disorder-of-interest," SR-WRAADDS and the investigator-rated WRAADDS agreement was 72% (sensitivity, 87%; specificity, 49%). The SR-WRAADDS detected a methylphenidate vs placebo treatment effect (P < .001). CONCLUSIONS: The psychometric properties of the SR-WRAADDS support its use in research and clinical practice. Emotional domains are integral to its assessment of adult ADHD.

Types of adult attention-deficit hyperactivity disorder (ADHD): baseline characteristics, initial response, and long-term response to treatment with methylphenidate.

Much recent research describes the importance of emotional symptoms in ADHD. While there is no accepted system for including emotionality in diagnosing ADHD, the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) provides a tool to facilitate this. It assesses a range of adult ADHD symptoms which load on two factors: inattentive and emotional dysregulation. The consistently high inattentive factor was used to define significant elevation on the more variable emotional dysregulation factor (which contains four WRAADDS domains: hyperactivity/restlessness, temper, affective lability, and emotional over-reactivity) allowing the definition of two ADHD diagnostic types. We compared these two types on a broad range of adult subject characteristics, including response to methylphenidate (MPH) treatment assessed during two clinical trials. Marked impairment in three of the four emotional domains reflected a symptom severity level equivalent to that of the inattentive factor. 59 % met this threshold, defining them as ADHD emotion dysregulation presentation, as opposed to 41 % with ADHD inattentive presentation. Cluster analysis validated these groups by generating similar clusters with 85 % agreement regarding membership. ADHD emotional dysregulation presentation subjects showed more childhood ADHD symptoms, adult symptoms of oppositional defiant disorder, and evidence of personality disorder. Both types showed similar improvement during the double-blind MPH arm of the trials and during a 6-month open-label phase. Based on the presence of symptoms of emotional dysregulation, ADHD in adults can be conceptualized as two types. Impairment and comorbidity in adults with ADHD are largely concentrated in ADHD emotional dysregulation presentation patients.

Effects of subtype of attention-deficit/hyperactivity disorder in adults on lateralized readiness potentials during a go/no-go choice reaction time task.

We studied 40 young adults with attention-deficit/hyperactivity disorder (ADHD; 18 predominantly inattentive type, 22 combined type) and 38 demographically comparable controls in a go/no-go choice reaction time task with 2 levels of difficulty. The ADHD/combined group was less accurate and had more variable reactions than controls. The ADHD/inattentive sample was slower than controls and had smaller early lateralized readiness potentials (LRPs). Compared with controls, both subtypes had (a) smaller early LRPs for no-go stimuli and (b) relatively earlier LRP onsets for difficult no-go events. The ADHD/combined sample also had smaller late LRP waves than controls. The results suggest that adults with ADHD, particularly those with the combined subtype, exhibit weaker central preparation to respond to both stimuli requiring a motor response and those prompting response inhibition.