Dec 13, 2019 | Conference Blog
The annual meeting of APSARD is an opportunity to bring experts together to share knowledge and build collaborative relationships for improving research and clinical practice. In the symposium, “Are Differences in Long-Acting Stimulant Formulations Clinically Meaningful?,” Dr. Andrew Babiskin, Dr. Thomas Spencer, Dr. Roberto Gomeni, and Dr. Ann Childress will discuss the newest findings regarding the bioequivalency and clinical implications of brand and generic formulations of extended release methylphenidate drugs, and FDA product-specific guidance on bioequivalent drug development.
Clinician Takeaways:
Clinicians will gain an improved understanding of the clinical implications of differing pharmacokinetic (PK) profiles in extended release methylphenidate (MPH ER) formulations used for ADHD.
Researcher Takeaways:
Researchers will gain familiarity with FDA requirements for Bioequivalence in extended release methylphenidate (MPH ER) formulations.
The Talks:
Dr. Andrew Babiskin, will review the FDA product-specific guidances (PSGs) on how to develop generic drug products that are therapeutically equivalent to specific reference listed drugs. Although rate of absorption (Cmax) and extent of absorption (AUC) are sufficient to establish bioequivalence (BE) for many extended release drugs, MPH ER requires additional partial exposure/AUC (pAUC) measures. This presentation will 1) discuss general principle of BE assessment, 2) present the current BE recommendations in the published PSGs for MPH ER drug products, and 3) delineate the rationales for pAUC recommendations for these products.
Thomas Spencer, MD, will present results of an FDA sponsored study to address BE in pharmacodynamic (PD) effects between MPH ER formulations intended to be similar in PK (OROS MPH (Concerta), and Mallinckrodt generic) compared to a MPH ER formulation with a different PK profile (Quillivant XR). Findings showed similar PD effects for the two compounds with similar PK profiles and intended duration (Concerta and Mallinckrodt generic), but less robust PD effects for the compound with differing PK (Quillivant) and statistically different effects from Concerta in later hours.
Roberto Gomeni, PhD, will present a model based approach maximizing the clinical benefit of MPH formulations. The clinical benefit of a treatment is defined as the ratio between clinical improvement and risk of tolerability and safety. A drug-disease model is described that accounts for pharmacokinetics, the placebo response, the exposure-response relationship, and the tolerability and safety issues. The optimization of the clinical benefit was achieved based on a convolution-based model. The results of the analysis identified an optimized dose and in-vitro/in-vivo release suitable to provide a sustained clinical response and an improved control of the safety and tolerability issues with respect to conventional formulations.
Ann Childress, MD, will discuss pharmacodynamics differences of MPH ER products and impact on patients from a clinician’s perspective. MPH ER formulations contain an immediate-release (IR) MPH component. The percentage of IR to ER MPH varies from approximately 20% to 50% in marketed MPH ER products. Comparative data from MPH studies were compiled along with a list of available generics from the FDA website. Incidental reports from patients were collected. Not all MPH products behave the same, and formulation may have a significant impact on patient outcomes. It is important to know which generics the patients are receiving and to careful assess onset, duration and magnitude of drug effects to determine which generic is best for an individual.
Nov 19, 2019 | Research Updates
If we are to read what we believe on the Internet, dieting can cure many of the ills faced by humans. Much of what is written is true. Changes in dieting can be good for heart disease, diabetes, high blood pressure and kidney stones to name just a few examples. But what about ADHD? Food elimination diets have been extensively studied for their ability to treat ADHD. They are based on the very reasonable idea that allergies or toxic reactions to foods can have effects on the brain and could lead to ADHD symptoms. Although the idea is reasonable, it is not such an easy task to figure out what foods might cause allergic reactions that could lead to ADHD symptoms. Some proponents of elimination diets have proposed eliminating a single food, others include multiple foods and some go as far to allow only a few foods to be eaten so as to avoid all potential allergies. Most readers will wonder if such restrictive diets, even if they did work, are feasible. That is certainly a concern for very restrictive diets.
Perhaps the most well-known ADHD diet is the Feingold diet (named after its creator). This diet eliminates artificial food colorings and preservatives that have become so common in the western diet. Some have claimed that the increasing use of colorings and preservatives explains why the prevalence of ADHD is greater in Western countries and has been increasing over time. But those people have it wrong. The prevalence of ADHD is similar around the world and has not been increasing over time. That has been well documented but details must wait for another blog.
The Feingold and other elimination diets have been studied by meta-analysis. This means that someone analyzed several well controlled trials published by other people. Passing the test of meta-analysis is the strongest test of any treatment effect. When this test is applied to the best studies available, there is evidence that exclusion of fool colorings helps reduce ADHD symptoms. But more restrictive diets are not effective. So removing artificial food colors seems like a good idea that will help reduce ADHD symptoms. But although such diets ‘work’, they don’t work very well. On a scale of one to 10 where 10 is the best effect, drug therapy scores 9 to 10 but eliminating food colorings scores only 3 or 4. Some patients or parents of patients might want to this diet change first in the hopes that it will work well for them. That is a possibility, but if that is your choice, you should not delay the more effective drug treatments for too long in the likely event that liminating food colorings is not sufficient. You can learn more about elimination diets from: Nigg, J. T. and K. Holton (2014). “Restriction and elimination diets in ADHD treatment.” Child Adolesc Psychiatr Clin N Am 23(4): 937-953.
Keep in mind that the treatment guidelines from professional organization point to ADHD drugs as the first line treatment for ADHD. The only exception is for preschool children where medication is only the first line treatment for severe ADHD; the guidelines recommend that other preschoolers with ADHD be treated with non-pharmacologic treatments, when available. You can learn more about non-pharmacologic treatments for ADHD from a book I recently edited: Faraone, S. V. & Antshel, K. M. (2014). ADHD: Non-Pharmacologic Interventions. Child Adolesc Psychiatr Clin N Am 23, xiii-xiv.
Aug 28, 2019 | Research Updates
BLOG POSTING BY:
 |
Stephen Faraone, Ph.D.
SUNY Upstate Medical University |
The study team began with a representative sample of 69,972 U.S. adults aged 18 years or older who completed the 2012 and 2013 U.S. National Health and Wellness Survey. These adults were invited to complete the Validate Attitudes and Lifestyle Issues in Depression, ADHD and Troubles with Eating (VALIDATE) study, which included 1) a customized questionnaire designed to collect data on sociodemographic and clinical characteristics and lifestyle, and 2) several validated work productivity, daily functioning, self-esteem, and health-related quality of life (HRQoL) questionnaires. Of the 22,937 respondents, 444 had been previously diagnosed with ADHD, and 1,055 reported ADHD-like symptoms but had no previous clinical diagnosis.
There were no significant differences between the two groups in terms of age, education, income, health insurance, and most comorbid disorders. But those who had not been previously diagnosed were significantly more likely to be first-generation Americans (p<.001), nonwhite (p<.001), unemployed (p=.024), or suffer from depression, insomnia, or hypertension.
After matching the two groups for sociodemographic characteristics and comorbid conditions, covariate comparisons were made between 436 respondents diagnosed with ADHD and 867 previously undiagnosed respondents. Among respondents who were employed, diagnosed individuals registered a mean work productivity loss of 29% as opposed to 49% for the previously undiagnosed (p<.001). They also registered a 37% level of activity impairment versus a 53% level among the undiagnosed (p<.001). On the Sheehan Disability Scale, which ranges from 0 (no impairment) to 30 (highly impaired), the diagnosed group had a mean of 10, as opposed to a mean of 15 for the undiagnosed (p<.001). Diagnosed respondents also significantly outperformed undiagnosed ones on the Rosenberg Self-Esteem Scale (19 versus 15, on a scale of 0 to 30, p<.001), and on two quality-of-life scales (p<.001).
Applying a linear regression mixed model to the matched sets, the diagnosed still scored 16 points better than the undiagnosed on the WPAI:GH Productivity Loss scale (p<.001), 14 points better on the WPAI:GH Activity Impairment scale (p<.001), 4.5 points better on the Sheehan Disability Scale (p<.001), almost 4 points on the Rosenberg Self-Esteem Scale (p<.0001), with comparable gains on the two quality-of-life scales (p<.001 and p<.0001).
The authors concluded, “This comparison revealed that individuals who had been diagnosed with ADHD were more likely to experience better functioning, HRQoL [health related quality-of-life], and self-esteem than those with symptomatic ADHD. This result appears to be robust, withstanding several levels of increasingly rigorous statistical adjustment.” That points to substantial benefits from the treatment that follows diagnosis of adult ADHD.
REFERENCES:
Manjiri Pawaskar, Moshe Fridman, Regina Grebla, and Manisha Madhoo, “Comparison of Quality of Life, Productivity, Functioning and Self-Esteem in Adults Diagnosed With ADHD and With Symptomatic ADH,” Journal of Attention Disorders, Published online May 2, 2019 https://doi.org/10.1177/1087054719841129.
Apr 26, 2019 | Research Updates
Beth Krone, Ph.D. and Jessica Downes J.D.
The National Center for Complementary and Integrative Health (NCCIH) at the NIH places health and mental health products and practices in the context of rigorous science for reference of the public and professionals. Their April digest focused on non-pharmaceutical approaches to ADHD management, at https://nccih.nih.gov/health/providers/digest/adhd, and https://nccih.nih.gov/health/providers/digest/adhd-science. Here is an infographic of their findings for your reference:
| Treatment |
Evidence |
Effectiveness |
Caveats |
Safety |
| Omega-3 Fatty acids |
Inconclusive |
Not as good as stimulants. Better than DHA |
Possible utility for treating sub-population with deficiencies |
Prolonged bleeding time, shellfish allergy risks,
gastrointestinal complaints |
| Melatonin |
Limited:
CEBM* level-1 |
No effect on ADHD |
For sleep-onset only |
Drowsiness, headache, dizziness, nausea, nightmares |
| Pycnogenol French Pine Bark |
Insufficient |
Unknown |
Undetermined |
Unknown |
| Ginko biloba |
Insufficient |
Not as good as stimulants |
Not recommended for ADHD |
Headache, nausea, GI upset, diarrhea, dizziness, allergic rash, increased bleeding risk |
| St John’s Wort |
Ineffective |
No effect on ADHD |
Not recommended for ADHD may interact with ADHD medications |
Sensitivity to sunlight, anxiety, dry mouth, dizziness, GI problems, fatigue, headache, or sexual dysfunction, serious drug interactions |
| Acupuncture |
Insufficient |
Unknown |
Few Studies, limited evidence of benefit |
Improperly performed acupuncture can cause serious side effects |
| Meditation |
Insufficient |
Unknown possible benefit |
Many methodologically poor-quality studies |
Unknown |
| Yoga |
Insufficient |
Unknown Possible short-term benefit |
Too few and methodologically poor-quality studies |
Must work with experienced trainers to prevent injuries |
| Aerobic Exercise |
Insufficient |
Unknown Possible short-term benefit |
Too few studies |
Possible injuries |
| Neurofeedback |
Inconclusive |
Unknown
possible benefit |
fMRI studies show activation; recent sham controlled studies show no benefit |
Unknown |
| Zinc |
Inconclusive |
Unknown |
Used in populations with deficiencies |
Zinc toxicity |
| Dimethylamylamine (DMAA) |
Insufficient |
Unknown |
FDA warnings about serious side effects |
Elevated blood pressure, heart attack, shortness of breath, chest tightness |
* Center for Evidence-Based Medicine
Apr 26, 2019 | Research Updates
As an on-going feature of our blog forum, we invite members to submit brief write-ups about their current work and the programs they have to offer. In this spirit, we are happy to highlight an ongoing study of our colleagues in the Netherlands: Dr. Sandra Kooij, Dr. Denise Bijlenga, Dr. Suzan Vogel, and Dr. Emma van Andel at PsyQ Expertise Center Adult ADHD in The Hague, and prof. Dr. Aartjan Beekman at GGZ inGeest, Amsterdam UMC, VUmc, The Netherlands
The FASE Study: Best Treatment of Delayed Sleep Phase Syndrome in Adult ADHD
Dr. Emma van Andel, junior researcher at PsyQ Expertise Center Adult ADHD, The Hague, The Netherlands
Sleep problems are highly prevalent among adults with ADHD, of whom 78% in some samples suffer from Delayed Sleep Phase Syndrome (DSPS) [1,2]. Such sleep problems are often a source of worry and frustration for patients and can also aggravate ADHD symptoms. Sleep loss resulting from DSPS has been associated with increased risk of chronic diseases such as obesity, diabetes, hypertension, metabolic syndrome, cardiovascular disease, and even cancer [3,4]. ADHD has also been related to poorer health in some samples [5,6]. Even young and generally healthy people who suffer from both ADHD and DSPS may thus be at great risk to develop these chronic diseases.
The FASE study investigates whether this is indeed the case and if treatment focused specifically on DSPS can improve sleep, ADHD, and health. DSPS can be treated with sleep education, melatonin administration, and/or light therapy: relatively inexpensive and convenient interventions that may increase people’s well-being and perhaps lower the need for (high doses of) ADHD medication.
The FASE study offers 3 weeks of DSPS treatment to 51 adults (18-55y) with ADHD and DSPS. Treatment consists of sleep education plus either (1) melatonin, (2) placebo, or (3) melatonin and light therapy. A broad range of health variables is assessed at baseline, directly after treatment, and 2 weeks later.
This group of adults with ADHD and DSPS is expected to display a suboptimal health profile at baseline and improvements in sleep, ADHD symptoms, and physical as well as mental health after treatment. Preliminary baseline results already suggest suboptimal health outcomes at baseline. Inclusion is nearly complete, so the first results on the effects of the interventions are expected this summer.
The FASE study will give more insight into the relationship between ADHD and DSPS and their relation to health. It also evaluates which DSPS treatment can best improve people’s well-being and decrease their risk of developing chronic diseases.
More information about the FASE study can be found at https://www.trialregister.nl/trial/3831.
References
ADHD and DSPS
1. Van Veen et al., 2010: https://www.ncbi.nlm.nih.gov/pubmed/20163790
2. Bijlenga et al., 2019: https://www.ncbi.nlm.nih.gov/pubmed/30927228
Sleep loss and physical health
3. Knutson et al., 2010: https://www.ncbi.nlm.nih.gov/pubmed/21112022
4. Spiegel et al., 2005: https://www.ncbi.nlm.nih.gov/pubmed/16227462
ADHD and physical health
5. Instanes et al., 2016: https://www.ncbi.nlm.nih.gov/pubmed/27664125
6. Vogel et al., 2018: https://www.ncbi.nlm.nih.gov/pubmed/29940457
