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 Often studies showing no efficacy on the prestudy, defined primary outcome variable go unpublished.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.

The Ham-D is not Hamilton's Depression Scale.

Introduction: This article will demonstrate that the most widely used versions of the Hamilton Rating Scale for Depression (HAM-D) used in randomized clinical trials, the Guy 1976 HAM-D1 and the SIGH-D,2 have response options that deviate sharply from Max Hamilton's 19603 and 19674 guidelines. For example, difficulty in concentration, one of the diagnostic criteria for a Major Depressive Episode according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) since 1980, in editions III, IV, IV-TR and 5,5 is something that Hamilton wrote should be measured in his scale, yet it is not measured in either of the presently used HAM-Ds. Method: A review was conducted of the four key papers related to the development of the Hamilton Rating Scale for Depression: the 1960 and 1967 papers by Max Hamilton; the HAM-D chapter in the 1976 ECDEU Assessment Manual for Psychopharmacology edited by William Guy; and the 1988 article on the Structured Interview Guide for the HAM-D (SIGH-D) by Janet Williams. Additionally, the Janet Williams updated 2013 SIGH-D6 is also reviewed. Results: When comparing the HAM-D and the SIGH-D with the gold standard Hamilton guidelines from his 1960 and 1967 articles, 13 of the 17 items contain significant errors. Conclusion: Significant differences between the currently used HAM-Ds and the guidelines set forth by Max Hamilton in 1960 and 1967 will be demonstrated. These discrepancies may produce inconsistencies in administration and scoring, leading to unreliable measurements of subjects' and patients' depressive symptoms and unreliable measurement of their progress over time.