While stimulants generally remain first-line medication for ADHD, alternatives are often needed due to side effects or ineffectiveness. Of the non-stimulant medications, guanfacine and its more recent extended release preparation (trade name Intuniv) is one possible alternative. Current FDA guidelines specify 4mg per day as the maximum dose, although much of this recommendation is based on younger children. There is some data suggesting that guanfacine may be less effective in adolescents, and this recent industry sponsored study set out to see if perhaps one reason was due to insufficient dose. Here the authors conduct a multi-center, double-blind placebo-controlled randomized trial of extended release guanfacine attempting to achieve a dose of between 0.05 and 0.12 mg/kg/day, which is about the typical dose in younger children on a per weight basis.
The subjects were 314 adolescents between the ages of 13 and 17 with a confirmed ADHD diagnosis. Psychiatric comorbidity other than oppositional defiant disorder (ODD) was exclusionary. Most of the sample had previously tried a stimulant. Subjects at risk for cardiovascular problems or who were taking medications that “have central nervous system effects” were excluded from the study. Extended release guanfacine was initially dosed at 1mg per day and titrated according to response and tolerability to a maximum of 4mg per day for patients weighing less than 41kg and up to 7mg per day for patients weighing more than 58kg. The medication was given once per day in the morning. The primary outcome measure was changes in scores on the ADHD Rating Scale IV, the Clinical Global Impressions scale and the Weiss Functional Impairment Rating Scale. Side effects and vital signs were also monitored during this 13-week study.
In terms of results, a total of 85% of the sample was able to achieve their optimal dose with nearly half the sample taking 5-7 mg per day. At the end of the study (using a last on-treatment assessment carry forward analysis), 66.9% of the guanfacine, compared to 45.8% of the placebo group were classified as responders, based on at least a 30% improvment in the ADHD Rating Scale. Improvement in ADHD symptoms with guanfacine was found to be statistically superior to placebo starting on week 7, although no significant group differences were found on any domains of the functional impairment scale. In terms of side effects, somnolence was reported in 44% of the guanfacine group with headache occurring in 27%. As might be expected, small but significant differences were found for heart rate and blood pressure changes compared to placebo. Nine subjects discontinued the medication because of side effects.
The authors concluded that extended release guanfacine at doses up to 7mg per day is more effective than placebo in treating ADHD and was generally well tolerated.
One thing that was a bit unusual for this study was the high placebo response rate. Conventional wisdom states that placebo response rates tend to be low in ADHD studies and generally this is true: however, there have been other studies with high placebo response rates particularly with adolescents.
In my own practice, guanfacine is also a medication I consider for youth who can be dysregulated and aggressive, particularly those whose aggression tends to be more reactive. In some cases I’ve been able to avoid what to me are riskier medications such as antipsychotics. This study suggests that if patients are tolerating this medication well, it may be worth considering pushing the dose further before giving up on the medication.
I should state that I don’t personally don’t receive any money from the manufacturers of extended release guanfacine. This study, however, was sponsored by a pharmaceutical company, and I know these days that tends to raise some skepticism about the results. The lead author is a well respected child psychiatrist who is currently the Director of Child Psychiatry at Massachusetts General Hospital.
Wilens T. A Randomized, Placebo-Controlled Trial of Guanfacine Extended Release in Adolescents With Attention-Deficit/Hyperactivity Disorder. JAACAP 2015;54(11):916–925.
Home – Child Mental Health Blog
Posted: February 4th, 2016 by David Rettew
Posted: January 28th, 2016 by David Rettew
On Thursday January 28, representatives from six Vermont medical organizations (VT chapters of the American Academy of Pediatrics, American Association of Child & Adolescent Psychiatry, Family Medicine, and American College of Physicians as well as the Vermont Psychiatric Association and the Vermont Medical Society) held a press conference at the Statehouse in Montpelier to outline concerns about the proposed legalization of marijuana.
All six groups endorsed a single document that can be found below which outlines known health risks associated with cannabis use, particularly with youth. The group expressed concern that legalization would likely only add to the current drug problem in the state and cautioned against making a permanent decision for Vermonters without knowing the true costs of legalization, as data from states like Colorado and Washington only slowly becomes available (with much of it so far not good news).
The press conference was attended by several media groups as well as by representatives of the legislature. The Judiciary committee is expected to approve the bill out of committee on Friday January 29 to be considered by the full Senate and House.
Posted: December 28th, 2015 by David Rettew
(Note: portions of this review were recently published in an article in Clinical Psychiatry News)
While it is known that stimulant medications used to treat ADHD might occasionally to lead to psychotic symptoms, this side effect is considered to be rare and usually associated with either medication abuse or very high dosages. A report just released today in the journal Pediatrics, however, now calls into question how rare psychotic symptoms from stimulants might actually be.
The data for this study come from the Families Overcoming Risks and Building Opportunities for Wellbeing study. The sample size was small but thoroughly evaluated. A total of 141 children in which at least one of the parents was diagnosed with a major mental illness, mainly major depressive disorder and bipolar disorder but also schizophrenia (5%). The mean age of the children was about 12 years old. Of these children, 24 (or 17%) had taken stimulant medication. Psychotic symptoms or psychotic like experiences were assessed through four different methods including an instrument called the “Funny Feelings” interview with psychotic symptoms counted as present any of their four ascertainment methods yielded a positive result. The main analysis was a logistic regression examining the association between lifetime use of stimulant and lifetime use of a psychotic or psychotic like experience. The analyses controlled for age, gender, and family history.
The major finding of the study was that psychotic symptoms were quite common, present in one-third of this sample overall, and were found to be more likely among those children taking stimulants. A total of 62.5% of children taking stimulants versus 27.4% of children who had not, reported some kind of psychotic symptoms. After account for some potential confounding variables, the odds ratio related to taking stimulants was 4.41 which was found to be statistically significant. The odds ratio related to ADHD itself and psychosis was 1.98 but this was not significant due to the small sample size. When looking at current stimulant use, the rate of current psychotic symptoms was 27%. The type of psychotic symptoms ranged widely and included a number of children with auditory and visual hallucinations.
The authors concluded that psychotic symptoms may be more likely to occur among children with a family history of mental illness, particularly when taking stimulant medications. They urge close monitoring of these symptoms during treatment.
It is likely that many practicing clinicians are going to be quite stunned to see rates of psychotic symptoms this high. While the study will surely activate the current anti-medication fervor common among those who don’t see patients, many practicing physicians will likely find that these rates simply don’t fit with clinical experience. Indeed, there may be some reason to be cautious in interpreting these results. As mentioned, the sample size was quite small, and psychotic symptoms were almost exhaustively assessed. Yet strangely, association between psychosis and stimulant dose were not examined. Perhaps most limiting, overall level of psychiatric symptoms in children was not controlled for in the analysis. As a result, it is hard to know whether the group taking stimulants was more impaired from the start.
Nevertheless, this study suggests that more vigilance and perhaps more rigor is needed when querying for possible psychotic symptoms among children who take stimulant medications, particularly among youth who have a family history of major mental illness.
Ironically, while the intent of the study certainly is to advise caution in the use of psychiatric medications, the article could lead to the opposite, if more antipsychotic medications are used to treat these more subtle symptoms. This would be unfortunate, in my view, until these results are more thoroughly replicated using a randomized design. Studies like this remind us to maximize many non-pharmacological treatments that can be effective in ADHD.
MacKenzie LE, et al. Stimulant Medication and Psychotic Symptoms in Offspring of Parents With Mental Illness. Pediatrics 2015; epub ahead of print.
Posted: December 11th, 2015 by David Rettew
It is probably safe to say that melatonin has become the go-to agent for the treatment of children who struggle to fall asleep. According to a recent article in the Wall Street Journal, melatonin is now a 260 million dollar market in this country where it is sold over the counter, unlike some European countries where a prescription is still required.
Melatonin is a hormone that is synthesized from the amino acid tryptophan in the pineal gland. Its release is controlled by the suprachiasmic nucleus of the hypothalamus with the level peaking in the evening. The fact that our body makes melatonin naturally has been one factor related to many primary care physicians and psychiatrists alike giving the hormone a “pass” when it comes to
scrutiny, but questions about both is efficacy and safety remain.
Recently, a selective review (which reads more like a commentary) about melatonin use in youth was published in the Journal of Paediatrics and Child Health. While the article certainly seems to be trying to persuade as much as inform, the author makes some important and surprising points. One is that animal studies have shown a range of effects on the reproductive system for melatonin that have not been well understood. Indeed, there still exists a registered use for melatonin in animals to increase fertility. These effects on reproduction or puberty in humans have yet to be demonstrated, although the few studies that have examined this issue have been small and contain significant limitations. It is also worth noting that melatonin is metabolized in the liver by the enzymes CYP1A2 and CYP2C19 which can be inhibited by antidepressants such as fluvoxamine and citalopram, respectively. As melatonin is often used in conjunction with psychiatric medications, these potential interactions need to be considered.
With regard to efficacy, studies seem to support its usefulness, although perhaps not to the extent one might expect. Two recent controlled trials in children found that melatonin increased sleep onset by about 30 to 45 minutes but it does not generally increase total amount of sleep.
The author concluded that the research on melatonin in children is inadequate, especially given the effects on the reproductive system documented in animal studies. He urged much more research before governing bodies decree melatonin as safe and effective.
The review was later criticized in a letter to the editor for omitting studies from melatonin prescription products such as Circadin which is approved in Europe (although not for kids). In the USA, there is also the melatonin receptor agonist remelton (Rozerum) which also has some data but, again, is not approved for pediatric ages.
Counter-balancing the concern of melatonin is the large body of literature that demonstrates the negative effects of poor and inadequate sleep. In trying to balance these concerns, I’m not sure I’m ready to take melatonin out of my bag (particularly in comparison to other sleep medications that are used). At the same time, however, it is important not to use melatonin or any other sleep-aid as a shortcut to addressing behavioral measures. Many children benefit from consistent routines that gradually wind down stimulation and prepare a child to settle down for the night, and families that try to circumvent this process often run into problems. Exercise (or lack thereof) can also be a major player in why some kids just don’t feel tired at night. Nevertheless, it is also certainly true that many children will struggle with sleep no matter how good the bedtime routine is.
Kennaway D. Potential safety issues in the use of the hormone melatonin in paediatrics. J Paediatrics Child Health. 2015: 51(6):584-589.
Posted: December 9th, 2015 by David Rettew
The Vermont Center for Children, Youth and Families at FAHC/UVM, in partnership with VCHIP, is entering our fourth year of the Child Psychiatric Phone and Email Consultation Program. The goal of this program is to provide healthcare providers with free curbside phone and email consultation to assist in the management of emotional and behavioral problems in primary care settings. Examples of these consultations include assisting in assessment, diagnosis, medication management and Family Wellness recommendations.
Results taken from a questionnaire given before and after PCP’s have accessed our consultation service show that users confirm an increased ability to quickly access expert psychiatric consultation as well as experience an increase in confidence in diagnosing and treating children’s mental health issues.
Whether you are already familiar with our consultation services, or hearing about them for the first time, please review the below commitment.
- Designate a child psychiatric specialist (MD or NP) to return your phone call/e-mail within 24 hours during the regular work week (weekend coverage is already available through the on call system).
- Provide you and your staff with phone and E-mail access to our experienced Family Wellness Coach, Eliza Pillard, LICSW, who can help guide your practice in the search for evidence based interventions for emotional and behavioral problems on behalf of your patients.
- Connect you to our VCCYF Primary Care blog http://blog.uvm.edu/drettew/ and VFBA (Vermont Family Based Approach) blog http://blog.uvm.edu/vfba/ which deliver regular postings on topics that may be relevant for your patients, such as updates on child mental health and family wellness research and interventions.
- Update all participants with news of access to our services (e.g., our Autism Assessment Clinic), educational opportunities, and advances in our field.
Please note that this program will not serve as a rapid conduit for assessment and consultation at the VCCYF. As you know, we have a long waiting list and feel obligated to serve families on a first-come-first-serve basis.
If you are interested in accessing a consult, please contact Eliza at firstname.lastname@example.org or (802) 847-9759. We look forward to hearing from you.
Jim Hudziak, MD, Director Eliza Pillard, LICSW
Vermont Center for Children, Youth, and Families Family Wellness Coach
Posted: December 3rd, 2015 by David Rettew
Despite the fact the we spend nearly a third of our life asleep, many fundamental questions, such as how much sleep we really need, remain debated. One popular view is that most of us living in modern cultures are chronically sleep deprived and this may be one of the causes of many health problems, from obesity to depression.
To try and get a better handle on natural sleep habits, some researchers recently published a study that examined the sleep patterns of three pre-industrial societies in Tanzania, Bolivia, and Namibia that were mainly hunter-gatherer or hunter-horticulturalist groups. None of the three groups used modern conveniences to alter light or temperature. Of chief interest were the basic statistics regarding sleep onset and duration and their relations to environmental variables such as light and temperature. Sleep was measured using watch like devices worn on the wrists for 6 to 28 days.
Interestingly (and fortunately for the researchers trying to synthesize their data), there were many similarities between the three societies with regards to sleep habits. The total sleep duration was found to range between 5.7 to 7.1 hours per day, with about 1 hour more of sleep occurring during the winter. Initiation of sleep tended to occur about 3 hours after sunset with awakening occurring generally before sunrise. Somewhat unexpected was that these patterns seemed to be as much related to temperature as light, with sleep onset occurring during the period of rapid temperature decline and awakening occurring around the time temperature is at its lowest.
Contrary to some data suggesting that our ancestors slept in two waves with a period of quiet wakefulness in between, extended periods of nocturnal awakening were rare. Napping was also not particularly common but did occur in about 7% of days during the winter and 22% of days in the summer (this was an estimate and may have counted periods of rest without sleeping). Interviews with subjects revealed that, despite none of the three cultures having a word for insomnia, the problem was reported by some, albeit at levels typically lower than that of industrialized societies.
The authors concluded that their data suggest, contrary to some popular opinions, that sleep in industrial societies has not been artificially reduced below natural levels due to the pressures of modern culture. At the same time, however, there was evidence that modern sleep schedules have veered in some different ways, possibly due to all the artificial light and temperature controls we now enjoy.
While definitely an interesting study, the clinical takeaway is not immediately clear. One possible implication might be to relax our pushing of people to get at least 8 hours of sleep per night. There could also be benefit for people with sleep problems to try and shift their schedules somewhat or create light and temperature variations that more closely mirror the natural world.
Yetish G, et al. Natural Sleep and Its Seasonal Variations in Three Pre-industrial Societies. Current Biology 2015; 25:1-7.
Posted: November 19th, 2015 by David Rettew
The medical community was disappointed, but perhaps not shocked, several years ago when it was revealed that the efficacy of antidepressant medications in the treatment of adolescent depression might not be as strong as we thought. This bias was due to the fact that the clinical trials, most of which were funded by pharmaceutic companies, that showed a positive effect for the medication were published prominently in journals while negative trials got much less publicity and often were not published at all. A deliberate effort to downplay unfavorable studies of antidepressants was generally suspected, although some people have argued that other factors may also be at work, such as journals being less enthusiastic to publish negative findings and researchers not wanting to devote lots of time and energy describing hypotheses that did not pan out.
With regard to depression, the publication bias for antidepressants made some clinicians think more strongly about recommending psychotherapy. Now, however, a new study recently published in PLOS One, examines whether or not a similar bias may be present in psychotherapy studies of depression.
The authors looked back at grants awarded by the NIH for controlled psychotherapy studies for depression conducted between the years 1972 to 2008. They found the publications for these studies and examined the effect size by which the therapy improved symptoms relative to placebo. If they found a funded grant but no publication, the authors contacted the investigators and calculated the effect size for those studies. Studies of children and adolescents, unfortunately, were excluded for these analyses.
Surprisingly, nearly a quarter (23.6%) of the 55 funded studies did not result in publication and two studies were never started at all. Most of the unpublished studies were never submitted for publication in the first place (rather than it being written up and rejected over and over by different journals). Most notably, the effect size of unpublished trials was less than half that of published trials. When these unpublished studies were added to the published ones, the effect size for psychotherapy dropped by 25%.
The authors concluded that there is strong evidence to conclude that a publication bias exists for psychotherapy trials for depression and that our understanding of how effective psychotherapy is, at least for depression, may need to be adjusted somewhat. That said, the evidence continues to show that psychotherapy generally works for depression and there is no reason to alter the general recommendation of psychotherapy as a first line treatment.
This study is useful in reminding us that bias can exist in many domains and for many reasons. Most of us are now quite primed to recognize potential bias and conflict when it comes to the pharmaceutical industry, but we need to be vigilant about some of the less obvious sources as well.
Driessen E, et al. Does Publication Bias Inflate the Apparent Efficacy of Psychological Treatment for Major Depressive Disorder? A Systematic Review and Meta-Analysis of US National Institutes of Health-Funded Trials. PLOS One, epub ahead of print, 2015.
Posted: November 4th, 2015 by David Rettew
(Editor’s Note: I’m pleased to share this guest post by one of our first year child psychiatry fellows, Dr. Winston Chung.)
More recently, one of the hot topics in Pediatrics, Neurology, and Psychiatry is the impact of concussion(s) on the developing mind. It came into the public consciousness due to the highly publicized death of beloved NFL football players like Junior Seau, and the tragic accident of 13yo Zackery Lystedt who collapsed after a football game and later required neurosurgery to alleviate the pressure produced by the swelling in his brain. Increasingly, we’re forced to confront the difficult decision of whether we should allow our kids to play football, hockey, or soccer, and the morality of supporting billion dollar industries that produced a product where men launch themselves at one another destroying their body and mind.
The American Academy of Neurology defines concussion as a biomechanically induced clinical syndrome leading to alteration of brain function, affecting memory, and orientation, and may involve loss of consciousness. Though definitions vary, many clinicians define concussion as a subset of mild Traumatic Brain Injury which is defined as Glasgow Coma Scale score of 13-15, loss of consciousness of less than 30 minutes (if present), and posttraumatic amnesia of 24 hours (if present). There are between 1.5-3.8 million sport-related TBIs in the US each year, the majority of which are mild TBI and concussions. Concussions lead to 100,000 Emergency Room visits each year for school-aged children and represents 9% of all high school sports injuries.
Concussions are produced by acceleration and deceleration forces on the brain, whether linear or rotational. When these forces act on the brain, it stretches and deforms, doing the same to the individual components that make up the brain such as neurons, and blood vessels. The axons that make up the white matter tracts are especially vulnerable to injury given their length. The disruption of the neuronal membranes leads to disruption of neurotransmitters and electrolytes that are neatly sequestered, causing the brain to go into a hypermetabolic state (thus requiring glucose) to return it to its former equilibrium. This leads to a widened gap between the increased energy needs of the neurons and the decreased blood flow to the brain, resulting in an energy crisis.
The result of this disruption are headaches, fatigue, dizziness, slowed mentation, drowsiness, difficulty concentrating, nausea, light sensitivity, noise sensitivity, forgetfulness, blurry vision, sleep disturbance, irritability, depression, vomiting, and tinnitus. Usually the symptoms are self-limiting and they resolve after 7-10 days. However, symptoms in children may resolve more slowly. The mean duration of post-concussion symptoms among patients age 8-23 years who were referred to a concussion clinic was 43+/- 55 days. A minority of the patients reports post-concussion symptoms that persist for months, sometimes years. Repeated head trauma appears to lead to one of two presentations. Mood and behavioral symptoms usually appearing in third decade of life, and cognitive impairment and memory loss developing in fifth decade of life. The majority of subjects who present initially with behavior or mood symptoms progress to have cognitive symptoms before passing away, whereas those who present with cognitive impairment less commonly develop mood symptoms.
One topic that hasn’t been discussed enough in the press is the potential health effects of subconcussive injuries. Subconcussive impact is defined as biomechanically induced injuries to the brain that do not result in clinical symptoms, but may have a cumulative effect leading to chronic traumatic brain injury in some adult patients. Recently, a small study showed white matter microstructure changes in professional soccer players who did not have a history of concussions when compared to age-matched swimmers. And it’s been reported that an offensive lineman in American football can experience over 1,000 subconcussive hits over the level of 10g in the course of a single collegiate season.
(Of note, for further information, please see an excellent presentation on the topic by Dr. Jim Hudziak who discussed concussions at a recent Community Medical School talk at the University of Vermont College of Medicine. The video will soon be available and can be accessed here.)
Posted: November 4th, 2015 by David Rettew
There is a widely held concern that psychostimulants when used to treat ADHD can induce or exacerbate anxiety. This belief has led many clinicians to hesitate about using stimulants in patients who already suffer from high level of anxiety, prompting some prescribers to try, as first-line agents, nonstimulant medications that supposedly have less risk but may be less effective against core ADHD symptoms. The actual data about stimulants and anxiety, are more mixed. Recently, a meta-analysis was published with the hopes of coming to a more definitive answer on this questions.
The study reviewed 23 different placebo-controlled trails and encompassed nearly 3000 children and adolescents. Clinician rated side effect measures of anxiety, when available, was utilized to assess patient anxiety. Subgroup analyses and meta-regression techniques were carried out to examine differences between medication types and doses.
In terms of results, there was overall a decreased risk of anxiety in patients treated with stimulants versus controls. This global finding, when analyzed more closely, held particularly with methylphenidate preparations (e.g. Ritalin, Concerta, etc) while amphetamine derivatives (e.g. Adderall) did not separate statistically from placebo. There was also some indication that short versus long-acting stimulants and higher versus lower doses were associated with this reduced anxiety risk. No evidence of publication bias was found, although a number of stimulant trials did not meet the authors’ inclusion criteria.
The authors concluded that, contrary to conventional wisdom and some FDA labelling, the risk of anxiety is actually lower compared to placebo in patients treated with stimulant medications.
In the Discussion section, the authors commented about the possible mechanism of their main finding and hypothesized that the reduced anxiety risk was likely not a direct antianxiety effect of the stimulant rather an indirect effect of improving ADHD symptoms.
While the study certainly doesn’t exclude the possibility of some patients experiencing worsening anxiety with stimulant treatment, the article should be somewhat reassuring to those who might otherwise be reluctant to prescribe stimulants to the large number of youth with ADHD who also experience significant anxiety.
Coughlin CG, Cohen SC, et al. Meta-Analysis: Reduced Risk of Anxiety with Psychostimulant Treatment in Children with Attention-Deficit/Hyperactivity Disorder. J Chi Adolesc Psychopharm. 2015;25:611-617.