Timothy Wigal - Academia.edu (original) (raw)

Papers by Timothy Wigal

Behavioral Neuroscience, 1985

The effect of hippocampal lesions was assessed in patterned (single) alternation (PA) and the par... more The effect of hippocampal lesions was assessed in patterned (single) alternation (PA) and the partial reinforcement extinction effect (FREE), the two reward-schedule effects that appear earliest in ontogeny. Three groups of rat pups, with appropriate controls, were tested for each effect: lesion as infant/ test as infant, lesion as infant/test as adult, and lesion as adult/test as adult. Hippocampal lesions had no effect on PA in any of the three conditions except for a suggestion that the effect was mildly attenuated in the animals given lesions as infants and tested as adults: The pups were able to discriminate rewarded from nonrewarded trials and to inhibit responding on nonrewarded trials. On the other hand, the FREE was eliminated under all conditions of testing, in each case because of an increase in persistence following continuously reinforced acquisition. The results are discussed in terms of the functional maturation of the hippocampus and a possible dissociation of mechanisms that mediate response suppression in PA and in the PREE in infant rats.

Behavioral Neuroscience, 1988

crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attentio... more crossover study of the efficacy and safety of lisdexamfetamine dimesylate in adults with attention-deficit/hyperactivity disorder: novel findings using a simulated adult workplace environment design

Journal of the American Academy of Child & Adolescent Psychiatry, 2018

Gender nonconforming and transgender youth experience higher rates of bullying and victimization,... more Gender nonconforming and transgender youth experience higher rates of bullying and victimization, resulting in greater mental health concerns. Parental support is one of the most significant determinants of risk for mental health problems and suicidality in this population. Interventions that support parents in understanding the challenges that their teenagers face and that increase parental sensitivity are needed to support the well-being of teenagers and their families. The study examines the acceptance, uptake, and caregiver satisfaction of an adapted version of Connect, which addresses the unique attachment-related challenges and concerns of caregivers of transgender and gender-nonconforming youth. Methods: Adaptations were completed in consultation with a panel of child and adolescent psychiatrists to address relevant themes expressed in these families and to modify experiential learning content. An overview of the attachment principles will be provided, and specific adaptations will be described. Results: Participants in the first 3 pilot groups were 20 caregivers (14 mothers, 6 fathers) of 16 gender-nonconforming youth (ages 12-18 years). All parents attended at least 80% of sessions and reported feeling respected, safe, and welcomed in the group. They indicated that learning about attachment was helpful in enhancing their understanding of their teenager and their understanding of themselves as parents. Parents also rated the group as helpful in increasing their understanding of their teenager's gender identity and transition. Qualitative themes from clinical interviews that were completed postintervention included feeling more confident in parenting and being able to empathize with their teenager more easily. Conclusions: Preliminary findings support the usefulness of this intervention, and feedback has informed further revisions of the program with the goal of co-creating a culturally adapted, safe, and helpful intervention.

Neuropsychiatric Disease and Treatment, 2020

Purpose: Two phase 2 studies evaluated the efficacy and tolerability of centanafadine sustained-r... more Purpose: Two phase 2 studies evaluated the efficacy and tolerability of centanafadine sustained-release (SR) for adults with attention-deficit/hyperactivity disorder (ADHD). Patients and Methods: In a phase 2a, flexible-dose, single-blind study, 41 male patients (aged 18-55 years) with a diagnosis of ADHD (based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were titrated with centanafadine-SR 200-300, 400, or 500 mg/d for 2 weeks, and then were treated with the titrated dose for 2 weeks. In a phase 2b, randomized, double-blind, placebo-controlled, crossover study, 85 male and female patients (aged 18-60 years) with a diagnosis of ADHD (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) were titrated to target doses of centanafadine-SR 400, 500, 600, or 800 mg/d over the course of 1 week, and then received their titrated dose for 3 weeks. The primary outcome in both studies was mean total ADHD Rating Scale-IV (ADHD-RS-IV) score. Results: In the phase 2a study, mean ADHD-RS-IV total score decreased by 21.41 (standard deviation 10.74) from the start of active centanafadine-SR treatment to the end of week 4 (P<0.001). In the phase 2b study, centanafadine-SR treatment resulted in a statistically significant improvement in ADHD-RS-IV from baseline to week 3 compared with placebo (least-squares mean −16.5 vs −8.4; P<0.001; effect size 0.66), with significant efficacy demonstrated as early as week 1. Centanafadine-SR was generally well tolerated at doses ≤400 mg. Most treatmentemergent adverse events (TEAEs) were mild or moderate; decreased appetite, headache, and nausea were the most frequently reported. In the 2 studies, 13 of 120 patients discontinued centanafadine-SR due to TEAEs; however, only 1 patient who received ≤400 mg discontinued due to a TEAE. No serious TEAEs were reported at any dose. Conclusion: These results support the continued development of centanafadine-SR at doses up to 400 mg/d.

Oxford Medicine Online, 2018

This chapter describes the long-term outcomes in the Multimodal Treatment study of ADHD (MTA), wh... more This chapter describes the long-term outcomes in the Multimodal Treatment study of ADHD (MTA), which began in 1994 and ended in 2014. First, we provide a short history of the origin of the MTA. Second, we review the design as a 14-month randomized clinical trial and the transition to a long-term follow-up. Third, we present findings from 12 key publications describing outcomes in four stages of the MTA from childhood to adulthood. Fourth, we discuss how the final adult assessments of the MTA address critical issues about symptomatic persistence of ADHD, functional outcomes outside the parental home, and cost-benefit analyses of residual effects of treatment with medication.

All Hazards Risk and Resilience: Prioritizing Critical Infrastructure Using the RAMCAP Plus

Submission to the Garnaut Climate Change Review-Update 2011 I am pleased to enclose The Institute... more Submission to the Garnaut Climate Change Review-Update 2011 I am pleased to enclose The Institute of Actuaries of Australia's submission to the Garnaut Climate Change Review-Update 2011.

Journal of Pharmaceutical Sciences, 2014

The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and perf... more The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.

Journal of Developmental & Behavioral Pediatrics, 2001

The dopamine D4 receptor has become the focus of attention for a number of genetic studies for ps... more The dopamine D4 receptor has become the focus of attention for a number of genetic studies for psychiatric disorders since the initial cloning of this gene (Van Tol et al., 1991). The dopamine D4 receptor gene (DRD4), located on chromosome 11p15.5, has a number of interesting polymorphisms identified in the noncoding (

Journal of Attention Disorders, 1997

As the largest randomized clinical trial conducted by the National Institute of Mental Health, th... more As the largest randomized clinical trial conducted by the National Institute of Mental Health, the Multimodal Treatment Study of Children with ADHD (MTA) will yield data on a diverse sample of 576 7.0- to 9.9-year-old children with attention-deficit hyperactivity disorder (ADHD), Combined type, regarding the relative and combined effectiveness of psychosocial and pharmacologic interventions. After delineating key challenges posed by such a multi-site investigation, we describe the MTA's multiple-gating procedures for recruitment, screening, and diagnosis of a diverse sample. We then discuss the cross-domain assessment battery for tracking the sample before, during, and after 14 months of active intervention. Throughout, we emphasize the guiding principles that shaped pertinent decision making. Highlighted are issues of psychometric adequacy; dimensional vs. categorical measurement; multi-method, multi-agent, and multi-domain coverage; plotting of individual trajectories of devel...

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008

Pharmacogenetic studies investigating the 40-bp VNTR polymorphism at SLC6A3 and methylphenidate r... more Pharmacogenetic studies investigating the 40-bp VNTR polymorphism at SLC6A3 and methylphenidate response have shown conflicting results and large differences in study design and efficacy endpoints. Our objective was to investigate the relation between the 3 0-VNTR at SLC6A3 and variability in methylphenidate response in a sample of 141 ADHD children and adolescents, assessed before and after methylphenidate treatment with both clinical and neuropsychological outcome measures. 10-R homozygotes were significantly overrepresented in the low response group, but no genotype effect was shown in cognitive variables improvement. A meta-analysis of pharmacogenetic studies with comparable data (responders vs. non-responders) on a total of 475 subjects showed a significant association between the 10-10 genotype and low rates of methylphenidate response (mean Odds Ratio ¼ 0.46; 95% CI [0.28-0.76]). Heterogeneity between these studies did not reach a significant level but, as publications with different endpoints were excluded from this meta-analysis, our results do not rule out a possible influence of study design.

American Journal of Hematology, 2014

This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2... more This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2dimethylbutyrate (HQK-1001), a fetal globin gene-inducing short-chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12-55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/b 0 thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK-1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1-1.6%) with HQK-1001 and 0.2% (95% CI: 20.7-1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK-1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK-1001 and 1.7 with placebo. The most common adverse events in the HQK-1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK-1001 at this dose and schedule are not recommended in SCD. Intermittent HQK-1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation.

The American Journal of Cardiology, 2010

An in-office linguistic study was conducted to assess physician-patient discussions of mixed dysl... more An in-office linguistic study was conducted to assess physician-patient discussions of mixed dyslipidemia. Naturally occurring interactions among 12 cardiologists, 12 primary care physicians, and 45 of their patients diagnosed with low levels of high-density lipoprotein cholesterol and being treated with prescription niacin extended-release were recorded. The participants were interviewed separately after the visit. The transcripts were analyzed using sociolinguistic techniques. Determined from the time at talk and the number of questions asked, the patients were moderately engaged in the visit conversations; however, most communication was physician-driven. Only 6% of the average visit was dedicated to disease education. Conversations about dyslipidemia were characterized by numerous laboratory values but rarely contained clear benchmarking or goal setting. In the postvisit interviews, the patients demonstrated a lack of understanding about their lipid levels and the next steps they should take. Both &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;HDL&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; [high-density lipoprotein] and &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;good cholesterol&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; were the most frequently mentioned aspects of dyslipidemia in these conversations; however, most physicians did not contextualize these components such that the patients were able to understand and retain the information after the visit. Although the conversations about treatment with niacin extended-release contained detailed information about how to manage the side effect of flushing, they lacked a clear description of this side effect. Also, missing from the dialogue was a balanced discussion of risks and benefits. Communication gaps were observed in the discussions regarding mixed dyslipidemia and its treatment with niacin extended-release. In conclusion, additional research is warranted to assess the efficacy of communication strategies to educate both physicians and patients about this condition and its treatment.

Behavioral and Neural Biology, 1989

A series of four experiments examined the effect of the presence of stimuli from the home nest on... more A series of four experiments examined the effect of the presence of stimuli from the home nest on the acquisition and retention of aversively motivated behaviors in preweanling and adult rats. In Experiment 1, training in the presence of home-nest shavings facilitated acquisition of a T-maze discrimination to escape footshock for 16-day-old rats but not for adults. Experiment 2 demonstrated that the extent to which preweanlings were familiar with the home shavings determines the degree to which these stimuli facilitate spatial discrimination learning. When clean shavings were made more familiar than soiled home-nest stimuli (by changing the shavings every day) clean shavings enhanced discrimination performance, whereas no enhancement of learning by home shavings was observed. Experiment 3 extended the generality of the enhancement effect to a conditioned location aversion and examined the extent to which this facilitative effect was due to the tendency for home-nest shavings to elicit approach responses. Expression of the conditioned aversion was enhanced in subjects conditioned in the presence of home shavings, regardless of whether the home shavings were presented with the CS+, the CS-, or both. Experiment 4 determined that the enhanced expression of learning in the context of home-nest stimuli observed for preweanlings did not occur among subjects trained shortly after weaning. Collectively, these data suggest that whereas the enhancement of learning and retention by familiar home-nest stimuli enjoys generality across a number of conditioning situations, the effect may be limited to a relatively brief period during ontogeny.

Behavioral and Brain Functions, 2010

eScholarship provides open access, scholarly publishing services to the University of California ... more eScholarship provides open access, scholarly publishing services to the University of California and delivers a dynamic research platform to scholars worldwide.

Background: Duration of efficacy and safety of lisdexamfetamine dimesylate (LDX) was assessed in ... more Background: Duration of efficacy and safety of lisdexamfetamine dimesylate (LDX) was assessed in adults (18-55 years) with attention-deficit/hyperactivity disorder (ADHD) using the simulated adult workplace environment. Methods: After open-label dose optimization (4-week) with LDX, 30-70 mg/d, subjects entered a 2-week randomized, double-blind, placebo-controlled crossover phase. Efficacy assessments included the Permanent Product Measure of Performance (PERMP) total score (attempted+correct) measured predose and from 2 to 14 hours postdose, averaged across postdose sessions (primary) and at each time point vs placebo (secondary), and ADHD Rating Scale IV (ADHDRS-IV) with adult prompts at baseline and crossover visits. Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms. Results: Of 127 randomized subjects, 105 were in the intention-to-treat population and 103 completed the study. While receiving LDX vs placebo, adults had great...

Postgraduate Medicine, 2018

Postgraduate medicine, Jan 31, 2017

Evaluate the efficacy, duration of effect, and safety of 25 mg SHP465 mixed amphetamine salts (MA... more Evaluate the efficacy, duration of effect, and safety of 25 mg SHP465 mixed amphetamine salts (MAS) extended-release versus placebo in adults with attention-deficit/hyperactivity disorder (ADHD). Adults (18-55 years) with ADHD and with ADHD Rating Scale-IV (ADHD-RS-IV) scores ≥24 were randomized to treatment in a double-blind, 2-period, 2-treatment crossover study utilizing the Adult Workplace Environment (AWE), as described by Wigal and Wigal (J Atten Disord 2006;10:92-111). On day 7 of each 7-day treatment period, efficacy was assessed during a 16.5-hour postdose period. The primary endpoint, Permanent Product Measure of Performance (PERMP) total score, was analyzed in the intent-to-treat population using a mixed linear model of analysis of variance. Secondary endpoints, for which the study was not powered, included PERMP problems attempted and answered correctly, ADHD clinician ratings based on counselor observations and inputs during the Time Segment Rating System (Co-ADHD-RS TS...