Robert H. Farber

Inhibitory deficits in ocular motor behavior in adults with attention-deficit/hyperactivity disorder

BACKGROUND Many of the symptoms of attention-deficit/hyperactivity disorder (ADHD) have been attributed to deficits in behavioral inhibition mediated by the frontostriatal system. The ability to suppress unwanted saccadic eye movements is mediated by prefrontal cortex-basal ganglia circuitry and thus constitutes a useful measure of inhibitory ability. METHODS To evaluate the functional integrity of this circuitry in ADHD, adult ADHD subjects unmedicated for at least 48 hours and normal comparison adults were studied by means of a comprehensive battery of ocular motor paradigms. RESULTS On a prosaccade task, in which subjects were required to generate saccades toward a peripheral visual target after a short stimulus-free interval, ADHD subjects generated significantly more of anticipatory (premature) saccades (reaction time <90 msec) and of saccades toward the target on catch trials, in which they were supposed to inhibit eye movements. On the antisaccade task, in which they were required to inhibit gazing toward the target while moving their eyes in the opposite direction, ADHD subjects made significantly more directional errors than normal adults. The performance of ADHD adults was consistent with deficits in saccadic inhibition. CONCLUSIONS Given the recent evidence for the interdependence between the brain systems mediating visual attention and ocular motor behavior, these findings support the notion that deficits in inhibitory mechanisms might underlie the inattention characteristic of ADHD. These results also implicate abnormalities in prefrontal cortex-basal ganglia circuitry in ADHD.

A pharmacokinetic evaluation of five H1 antagonists after an oral and intravenous microdose to human subjects

AIMS To evaluate the pharmacokinetics (PK) of five H(1) receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). METHODS Five H(1) receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy. RESULTS The median clearance (CL), apparent volume of distribution (V(d)) and apparent terminal elimination half-life (t(1/2)) of diphenhydramine after an i.v. microdose were 24.7 l h(-1), 302 l and 9.3 h, and the oral C(max) and AUC(0-infinity) were 0.195 ng ml(-1) and 1.52 ng h ml(-1), respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2. CONCLUSIONS Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.

Saccadic performance characteristics and the behavioural neurology of Tourette’s syndrome

OBJECTIVE To better understand the neuropathological correlates of Tourette’s syndrome (TS), measures of saccadic eye movement performance were examined among patients with TS. METHODS A case-control design was used. Twenty one patients with DSM-IV TS (mean age 40.6 years (SD 11.0); 38% female) mainly recruited from UCSD Psychiatry Services, and a community based sample of 21 normal subjects (mean age 34.6 years (SD 13.4); 43% women) participated in this study. Participants were administered ocular motor tasks assessing visual fixation, and the generation of prosaccades, predictive saccades, and antisaccades. Saccadic reaction time, amplitude, duration, and mean and peak velocity were computed. Intrusive saccades during visual fixation and the proportion of correct antisaccade responses were also evaluated. RESULTS The groups had similar visual fixation performance. Whereas patients with TS generated prosaccades with normal reaction times and amplitudes, their saccade durations were shorter and their mean velocities were higher than in normal subjects. During a prosaccade gap task, patients with TS exhibited an increased proportion of anticipatory saccades (RTs<90). The proportion of “express” saccades (90<RTs<135) did not differ between groups. Patients with TS had fewer correct antisaccade responses than did normal subjects, an effect accounted for by 19% of the patients. Antisaccade reaction times among patients with TS were increased during an overlap version of the task. Conclusion—These findings suggest that TS mildly affects the ocular motor control circuitry associated with saccade inhibition.

Symptoms in Obsessive-Compulsive Disorder and Tourette Syndrome: A Spectrum?.

There is clear overlap in the clinical symptoms of obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). As a result, OCD (with or without tics) and TS (with or without obsessive-compulsive symptoms [OCS]) have been conceptualized to form a disorder spectrum—an overlapping set of phenotypes reflecting presumed commonality at the level of the underlying genetics and neuropathology. We identified the characteristics of a research sample of patients with OCD or TS, based on information obtained in semistructured clinical interviews, to examine the similarities and differences in the clinical symptoms across this spectrum. This sample conformed to known age-of-onset and sex distribution patterns for OCD and TS. Previously reported patterns of predominant aggressive and sexual obsessions and touching compulsions were observed in subjects with tic-related OCD, compared with non—tic-related OCD (ie, OCD alone). The majority of patients with tic-related OCD experienced horrifically violent obsessions that were less common in OCD alone and much less common in TS. Nonetheless, symptomatic and functional impairment in TS subjects was clearly related to the intensity of their OCS. The specific obsessions and compulsions associated with clinical impairment in TS differed from those associated with impairment in OCD. These results suggest that, despite the many overlapping dimensions of these disorders, the symptoms and associated impairment in “pure” OCD, tic-related OCD, and TS do not form a simple continuous spectrum.

Single-Dose Study of a Corticotropin-Releasing Factor Receptor-1 Antagonist in Women With 21- Hydroxylase Deficiency

CONTEXT Treatment of 21-hydroxylase deficiency (21OHD) is difficult to optimize. Normalization of excessive ACTH and adrenal steroid production commonly requires supraphysiologic doses of glucocorticoids. OBJECTIVES We evaluated the safety and tolerability of the selective corticotropin releasing factor type 1 (CRF1) receptor antagonist NBI-77860 in women with classic 21OHD and tested the hypothesis that CRF1 receptor blockade decreases early-morning ACTH and 17α-hydroxyprogesterone (17OHP) in these patients. PARTICIPANTS The study enrolled eight classic 21OHD females, ages 18-58 years, seen at a single tertiary referral university setting. DESIGN This was a phase Ib, single-blind, placebo-controlled, fixed-sequence, single-dose trial. During three treatment periods separated by 3-week washout intervals, patients sequentially received placebo, NBI-77860 300 mg, and NBI-77860 600 mg at 10 pm; glucocorticoid therapy was withheld for 20 hours. We evaluated ACTH, 17OHP, androstenedione, and testosterone as well as NBI-77860 pharmacokinetics over 24 hours. RESULTS Dose-dependent reductions of ACTH and/or 17OHP were observed in six of eight subjects. Relative to placebo, NBI-77860 led to an ACTH and 17OHP reduction by a mean of 43% and 0.7% for the 300 mg dose, respectively, and by 41% and 27% for the 600 mg dose, respectively. Both NBI-77860 doses were well tolerated. CONCLUSION The meaningful reductions in ACTH and 17OHP following NBI-77860 dosing in 21OHD patients demonstrate target engagement and proof of principle in this disorder. These promising data provide a rationale for additional investigations of CRF1 receptor antagonists added to physiologic doses of hydrocortisone and fludrocortisone acetate for the treatment of classic 21OHD.

Post-bedtime dosing with indiplon in adults and the elderly: results from two placebo-controlled, active comparator crossover studies in healthy volunteers.

ABSTRACT Objective: To assess the effects of post-bedtime dosing with indiplon on next-day function in adults and the elderly. Research design and methods: Two randomized, double-blind, placebo-controlled crossover studies were conducted in two groups of healthy volunteers: an adult study (18–45 years) and an elderly study (65–80 years). In adults, a single post-bedtime dose of indiplon 10 mg and 20 mg was compared to placebo, with zolpidem 10 mg and zopiclone 7.5 mg included as controls. In the elderly, a single post-bedtime dose of indiplon 5 mg and 10 mg was compared to placebo, with zopiclone 3.75 mg included as a control. Next-day residual effects were evaluated in the morning at 4 and 6 h post-dose in adults, and 4, 6, and 8 h in the elderly, by a Visual Analog Scale of sleepiness (VAS-sleepiness), Digit Symbol Substitution Test (DSST), and the Symbol Copying Test (SCT). Results: In adults, there were no statistically significant differences between indiplon and placebo on the VAS-sleepiness, DSST, or SCT at any timepoint for either dose. In contrast, a significant increase versus placebo in VAS-sleepiness was observed for both zopiclone (at 4 and 6 h post-dose; p < 0.0001 and p = 0.002, respectively) and zolpidem (at 4 h post-dose; p = 0.042). In the elderly, there were no statistically significant differences between indiplon 5 mg and placebo on the VAS-sleepiness, DSST, or SCT at any timepoint. DSST was significantly reduced for indiplon 10 mg versus placebo at 4 h only ( p = 0.022), compared with a significant reduction in DSST for zopiclone at both 4 and 8 h post-dose ( p = 0.002 and p = 0.003, respectively). In adults, the overall incidence of adverse events was higher on zopiclone compared to indiplon, zolpidem, and placebo. In the elderly, the incidence of adverse events was similar for indiplon, zopiclone, and placebo. Potential limitations of the current study include recruitment of healthy volunteers and the use of a limited pharmacodynamic battery. Conclusions: Indiplon, at doses of 10 mg in adults and 5 mg in the elderly, was not associated with next day residual sedation or impairment in simple cognitive and psychomotor tasks when administered during the night 4 h prior to awakening.