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Home – Child Mental Health Blog

Study Links Chemical BPA to ADHD Diagnosis

Posted: August 25th, 2016 by David Rettew

Bisphenol A (BPA) is a petrochemical used in the manufacturing of a number of commonly used products including such as reusable water bottles, sports equipment, dental sealants, food cans linings, and adhesives.  There has been a lot of recent attention about BPA due to mounting concerns about possible links between BPA and a number of health problems including cancer, reproductive problems and neurodevelopmental difficulties.  Government agencies have maintained that BPA is safe at low levels, but the public scrutiny has been enough to push the production of many “BPA free” products.  The concern over the neurodevelopmental effects of BPA comes from someBPA animal data suggesting that the chemical can alter dopaminergic activity in the brain.  There have also been a few human studies that have linked BPA and behavioral problems, but these have had some limitations regarding things like sample characteristics and rigor of behavioral assessment.  This new study tries to take the research forward using an older and nationally representative sample and a more stringent assessment for ADHD.

The data for this study comes from the 2003-2004 National Health and Nutrition Examination survey which queries a nationally representative population-based sample that oversampled some minority groups.  For about 30% of the sample, both urinary BPA levels and ADHD diagnoses were available, resulting in a group of 460 children between the ages of 8 and 15.   ADHD was assessed using a structured diagnostic interview, but could also count if a parent reported that the diagnosis had been made by a medical professional.   A total of 17.3% of the sample met at least one of these two criteria. The association between ADHD and BPA exposure was analyzed using logistic regressions, and the analyses controlled for many potential confounds such as income, prenatal smoke exposure, and blood lead level.

Detectable BPA was found in 97.1% of the sample at widely varying concentrations.  Dividing the sample by mean BPA level (3.9 ug/l), those with higher levels were found to be significantly more likely to have an ADHD diagnosis (11.2% vs 2.9% if assessed through the structured interview).   Looking at a more quantitative association using regression analyses that controlled for confounding variables, children with higher levels of BPA were found to be more than five times as likely to have an ADHD diagnosis (OR 5.86).  This association was found much more strongly in boys with the link in girls being less significant or statistically non-significant in girls, depending upon how ADHD was assessed.

The authors concluded that higher BPA concentrations is associated with ADHD, particularly among boys.

After the study’s release, the article received some publicity but not as much as one might expect given the findings.  This might have occurred because it was published in the less well-known journal, Environmental Research, in the summer.  One certainly might be interested to know if the authors tried to publish the report in a more prominent journal and if they did, why it was not accepted.  I myself can’t see any fatal flaws, although the authors do acknowledge that they only measured BPA once in the study which is probably not the best way to assess its long term presence when it has a half-life of about 6 hours.  Also of interest would be additional analyses to determine if there is some cutoff point beyond which the risk for ADHD is much higher, as the authors in this study used a fairly arbitrary median split for their main result.  At the same time, the fact that these findings were present given the way they divided the sample is somewhat concerning as it suggests that there may be risk associated with BPA levels that are very commonly found.


Tewar S, et al.  Association ofBisphenolAexposureandAttention-Deficit/HyperactivityDisorderinanationalsampleofU.S.children.  Environmental Research.  2016: June 6 epub ahead of print.

Infant Sleep Training Methods Compared

Posted: July 21st, 2016 by David Rettew

The longstanding debate over sleep training methods, in particular those that include some aspect of  “crying it out,” picked up a new chapter recently after a new study was published in the journal Pediatrics.  What was more unique about this study was its head to head comparison of two methods, one using graduated extinction (the technical term for parents delaying their giving comfort to infants for designated periods of time) to what might be described as a more gentle method that does not involve extinction.  These alternative methods have increasingly cropped up due to lingering concerns that extinction-based methods might be experienced as traumatic and disrupt

photo from freedigitalphotos.net

photo from freedigitalphotos.net

parent-child despite there being no direct evidence of this.

In this Australian study,  a total of 43 infants around 10 months of age, all of whom were experiencing sleep problems, were recruited and randomized to one of three groups. One was taught a graduated extinction approach in which parents returned to the crib at progressively longer intervals over the course of a week. Another group used an approach called “bedtime fading” in which the infant’s bedtime was moved forward or backwards until the child sleep latency time was consistently less than 15 minutes. After that, parents were told to do what they normally do for nighttime awakenings. There was also a control group that received sleep educational materials. Sleep was assessed using both questionnaires and more objectively using ankle monitors, and saliva cortisol levels were also ascertained at follow-up as a measure of physiological stress. Attachment status was also assessed with the Strange Situation procedure.

At 3 month follow-up, significant improvements were found for both treatment conditions relative to controls with regard to length of sleep latency time and time to waking after sleep onset. The graduated extinction technique showed improvements relative both to the control and bedtime fading condition for reducing the number of nighttime awakenings, while total sleep time increased for the graduated extinction and control conditions. In terms of markers of stress, afternoon infant cortisol levels and levels of maternal stress were found to decrease for the two behavioral treatment groups relative to controls.  When the sample was assessed again at 12 month follow-up, no group differences were found related to attachment or levels of behavioral problems.

The authors concluded that their data support the effectiveness of brief behavioral sleep interventions without causing long-term stress or behavioral problems.

Will this study end the debate on sleep training?  For sure it will not, but the study does add some additional evidence that such techniques can work and do not represent traumatic experiences for children that result in harm.  At the same time, what might be more novel to some parents and primary care physicians alike is the realization that there are other evidence-based methods out there that have been shown to be effective and may be more palatable to parents than techniques that involve some aspect of crying it out.


GradisarM, et al.  Behavioral Interventions for Infant Sleep Problems: A Randomized Controlled Trial.  Pediatrics 2016; 137(6): epub ahead of print

Stimulant Treatment Linked to Cardiovascular Events in ADHD

Posted: June 30th, 2016 by David Rettew

The debate over whether or not stimulant medications like methylphenidate raise the risk of cardiovascular diseases and events has been going back and forth for years.  Many clinicians will remember the famous comment of Dr. Steven Nissan in a New England Journal of Medicine editorial in 2006 when he hoped that a physician’s hand would “tremble” before writing a stimulant prescription.   Then there was the American Heart Association’s recommendation in 2008 that all children get an ECG before stimulants are started only to have the group backtrack on this shortly thereafter.

photo by cooldesign and freedigitalphotos.net

photo by cooldesign and freedigitalphotos.net

Lately the question has been raised again with this report published in the Journal of Child and Adolescent Psychopharmacology.  To address some limitation of previous studies, the authors not only compared cardiovascular risk in stimulant users versus non-users but also did this analysis among patients who have received an ADHD diagnosis.  The study used a Danish registry to follow prospectively a group of over 700,000 children.  The main outcome variable was the presence of a cardiovascular disease or event.  This was a somewhat broad designation with the most common diagnoses coded being  cardiovascular disease not otherwise specified (40%) followed by an arrhythmia (23%).  Hypertension was the diagnosis in 8% of those identified as having a cardiovascular event.

Overall, the use of stimulants was found to roughly double the risk of a cardiovascular events both among ADHD patients (hazard ratio=2.20) and compared to the general population (hazard ratio=1.83).  Cardiovascular events were rare, with 170 events occurring among ADHD patients per 100,000 person years compared to 84 events per 100,000 person years for the overall population.

The association between risk and dose was a bit odd.  When looking at the dose taken 12 months prior to the cardiac “event,” higher doses (defined as over 30mg/day of methylphenidate) were found to be associated with higher risk.  When looking at doses taken more closely around the event, however, lower doses (less than 15mg perday) were associated with increased risk.  In addition, among children with known cardiovascular risk, stimulant treatment did not convey significantly increased risk beyond these other factors.  The authors also note that among the 5 ADHD children that experienced a serious cardiovascular event, none had been treated with stimulants.

In trying to put this all together, the authors concluded that stimulant treatment is associated with an increased risk of cardiovascular events compared both to the general population and to patients with ADHD who do not receive stimulant treatment.

The authors did try to sort out some of their puzzling findings with regard to dose.  While admitting that this was speculative, they wondered if there might be a slight danger in dropping someone from a high stimulant dose to a low one, perhaps via a shortening of the QTc interval via which in turn might be mediated through dopamine transporters that are found on the myocardium.

While the study is important in documenting this association with stimulant even among individuals with ADHD, many questions remain about clinical significance.  It is difficult to know exactly what is meant by “cardiovascular disease not otherwise specified” and other broad terms, especially since some prior studies that used more serious cardiac outcomes have not supported a link with stimulants.  In addition, the nagging questions about increased screening also are not answered with these data.  Of course, one could simply not prescribe stimulants, but then there are also studies linking stimulant treatment with reduced emergency department admissions.  This will very likely not be the last chapter in this important issue.


Dalsgaard S, et al. Cardiovascular Safety of Stimulants in Children with Attention-Deficit/Hyperactivity Disorder: A Nationwide Prospective Cohort Study. J Child Adolsc Psychopharmacology 2014; 24(6):302-310.


Breastfeeding May Boost Child IQ By Increasing Subcortical Grey Matter

Posted: June 2nd, 2016 by David Rettew

While many the medical benefits of breastfeeding such as improved immune function have been clearly established, its effect on child behavior and cognition has somewhat more difficult to determine.  This has been due to a variety of reasons.  Because randomization is not possible for breastfeeding studies, researchers have had to rely on naturalistic study designs.  Since mothers who breastfeed are, on average, more highly educated and tend to have higher income levels than mothers who don’t breastfeed, it can be challenging to tease out the

photo by JompHong and freedigitalphotos.net

photo by JompHong and freedigitalphotos.net

independent effect of breastfeeding from these other variables.  In addition, there remains much that is not known about any possible mechanisms that underlie this link.  To address some of these issues, a new study by Luby and colleagues was recently published in the Journal of the American Academy of Child and Adolescent Psychiatry.

The data from the study come from the Preschool Depression Study that has followed a sample of children for 11 years since around age 3.  Admittedly, this study was not designed to look at breastfeeding and the authors had to piece together the necessary components with what they already had.  As would be expected, the study oversampled children with emotional-behavioral problems, and a total of 63% of the subjects had experienced significant depression or anxiety at the last follow-up (and this was one of the variables controlled for in the analyses). Between the ages of 9 and 14, a total of 148 of these subjects underwent a structural MRI scan.  General linear models and process mediation models were used to test the hypothesis that breastfeeding was associated with significantly higher IQ, after controlling for important factors such as caregiver level of education.  They also tested the hypothesis that any association was mediated through the association between breastfeeding and brain grey matter volume.  Breastfeeding was scored as a dichotomous yes or no variable.  IQ was assessed through two different tests when children were between the ages of 8 and 15.

The authors found that, after statistically controlling for some potential confounds, breastfed infants had both significantly higher IQs as well as increased volumes of whole grey matter and subcortical and cortical grey matter.  In terms of raw numbers, the mean IQ for breastfed infants was 109 versus 99 in the nonbreastfed infants.  However, after accounting for caregiver education levels, breastfeeding added a more modest 3% of the variance to the model.   Their mediation analyses demonstrated that the increase in IQ was mediated through an increase in subcortical grey matter.

The authors concluded that their data support the link between breastfeeding and increased IQ and, going further, they suggested that the mechanism of this association might involve an increase in subcortical grey matter. In the Discussion section, the authors go into some hypotheses regarding how all this might work, including direct effects of the breastmilk long-chain polyunsaturated fatty acids on neurodevelopment combined with positive effects that stem from the close physical contact and stimulation that occurs during breastfeeding.  The authors urge greater efforts to encourage breastfeeding as a public health priority.


Luby J, et al.  Breastfeeding and Childhood IQ: The Mediating Role of Gray Matter Volume. JAACAP 2016: epub ahead of print.

Prescribing Exercise for Adolescent Depression

Posted: May 23rd, 2016 by David Rettew

Depression in children and adolescents can be a serious and sometimes deadly problem.  With renewed concern about the over-reliance of antidepressant medication, effective nonpharmacological interventions are highly welcome.  Psychotherapy has been shown to be an important treatment for many, but availability and patient follow-up can be challenging.    Exercise has been shown to be a promising treatment for adults; however, the literature for younger patients has been somewhat unsettled.  To get a more definitive sense of these Exercisestudies, a recent meta-analysis on the subject was recently published in the Journal of the American Academy of Child & Adolescent Psychiatry.

The authors searched for randomized controlled trials of adolescents between 13 and 17 years of age that used exercise promotion strategies or specific exercise protocols.  As some but certainly not all of the studies were performed with nonclinical samples, the primary outcome for this meta-analysis were scores on quantitative depression-related rating scales. A total of 11 trials encompassing 1,449 participants were identified from as early as 1982.  While the specific exercise regimen varied across studies, the majority involved some kind of supervised group aerobic and/or strength training around three times per week for 6 to 40 weeks.

Overall, exercise was found to have a moderate and statistically significant effect on reducing depressive symptoms.  The overall effect size was about one-half of a standard deviation which is considered moderate.  When the authors divided the sample between clinically depressed and community samples, they found continued support for the benefits of exercise for the clinical group but not from samples taken from the general population (although the effect size was roughly the same for both groups, suggesting that perhaps sample size and/or response variability was the problem in studies done with community samples).

The authors concluded that exercise appears to be a promising strategy to diminish depressive symptoms in adolescents.  While certainly not a miracle cure, it is difficult to see why clinicians would not want  to include exercise in his or her treatment plan for depression, given its many other benefits.

Despite these optimistic reports, a number of important issues need further study.  One of them is determining the optimal exercise regimen to maximize the antidepressant effect.  While many of these studies used 3 times per week of low to moderate intensity programs, it is certainly possible that other approaches might work just as well if not better, particularly those that encouraged daily exercise.  Another important question relates to medication.  While many of us are eager to find effective alternatives to antidepressant medications, this study unfortunately has no direct data on how exercise might be used instead of or in addition to other treatments.

As a practical support of these principles, Vermont will once again be offering the Vermont Parks Prescription program supported by the Governor’s Council on Physical Fitness and Sports and The Vermont Department of Forest Parks and Recreation.  It allows Vermont clinicians to distribute “prescriptions” for exercise which then allow free access to a Vermont State Park.   Physicians and other health care professionals who would like more information or would like to receive some of these vouchers can contact vermontfitness@vermont.gov .


Carter T. The effect of exercise on depressive symptoms in adolescents:  A systematic review and meta-analysis.  JAACAP 2016; Epub ahead of print.


Enhancing Behavioral Screens and Guidance in Primary Care Visits

Posted: April 20th, 2016 by David Rettew

Photo by Hin255 and freedigitalphotos.net

Photo by Hin255 and freedigitalphotos.net

How to cover the ever expanding list of important but time consuming screens and counseling topics now recommended at patient well checks has become a real challenge for primary care clinicians.  In response, there are beginning to emerge different approaches and models for the delivery of this care.  One of them, developed in Los Angeles, is called PARENT and stands for Parent-focused Redesign for Encounters, Newborns to Toddlers. This program involves several components including 1) families working with a non-MD parent coach at each well-visit for about 20 minutes, 2) completion of an online well-visit planner prior to each visits, and 3) periodic health messages delivered via text messages, all of which is designed to allow a child’s primary care physician the ability to have a relatively short problem-focused visit.  A recent study in the journal Pediatrics examines some initial quality metrics of this approach.

For this study, two independent pediatric practices encompassing 8 clinicians in the Los Angeles area were examined.  Subjects were 251 parents who had a child less than 12 months of age and who were randomized to either the PARENT program or primary care as usual.  Of interest were completion rates of various preventative screenings, patient satisfaction, and use of emergency care.

Results showed that indeed Children in the PARENT group were more likely to receive various preventative care measures and screenings and had parents who had more positive impressions of their care. These families were also were less likely to utilize at least 2 emergency department visits during the 12-month study compared to the usual care group (although the rationale for why the bar was set at 2 visits wasn’t well explained and seemed a bit odd).

The authors concluded that initiatives such as the PARENT program are promising in enhancing the delivery of important behavioral screens and guidance and may reduce the cost of emergency treatment.  Of note, a full cost analysis wasn’t performed to examine how shifting some components of well-child care away from the physician and towards a health educator or family coach affected the bottom line. It is also important to point out that whether or not actual improvement in child health and behavior occurred was not examined in this study.

Closer to home, a more comprehensive trial is being performed here at the University of Vermont Medical Center in which trained family coaches are meeting with families with young children in primary care offices in an effort to promote wellness and prevent later emotional-behavioral problems.  Unlike the Pediatrics study, the Vermont project comes with resources in the form of therapists, mentors, and a child psychiatrist to offer additional interventions for those who could benefit from them.

All of these efforts are valuable in helping primary care clinicians develop strategies that can help them perform the critical early behavioral guidance and interventions that have been shown to improve outcomes and save money in the long run while not creating undue burdens on one’s ever dwindling time.


Coker TR, et al. A Parent Coach Model for Well-Child Care Among Low-Income Children: A Randomized Controlled Trial.  Pediatrics 2016; 137:3, epub ahead of print.

Toxoplasma Gondii Infection Linked to Aggression and Intermittent Explosive Disorder

Posted: March 31st, 2016 by David Rettew

A new study creating lots of both media attention and puzzled looks explores the link between psychiatric disorders, particularly those that involve aggression and irritability, and latent infection with the protozoan parasite toxoplasma ghondii (T gondii).  In hearing about this study, the first reaction of many might be why anyone bothered to look at this link in the first place.  Cats are known hosts of the parasite, but infection can occur in humans from infected cat feces in addition to eating

photo by BK images and freedigitalvideos.net

photo by BK images and freedigitalvideos.net

undercooked meat or drinking contaminated water.  Human infection is common but usually not dangerous, unless someone is immunosupressed.   While not an agent with a huge literature behind it in terms of behavioral health, there have been previous associations found between latent toxoplasmosis infection and psychiatric symptoms, including a larger study in 2015.  There also exists a literature on the behavioral effects of T gondii in animals.  Thus, this study did not just come totally out of the blue.

For this investigation, the authors assessed three groups of adults (total n=358), including healthy controls, a group with well diagnosed intermittent explosive disorder (IED: characterized by episodes of severe impulsive aggression), and another group who met criteria for DSM-5 psychiatric disorders other than IED.  Aggression and impulsivity were assessed with various known rating scales, and toxoplasmosis status was assessed using a blood test for IGG antibodies.    

The overall rate of T. Gondii seropositive subjects was 15.9% which evidently (and a little unsettlingly to be honest) is close to national norms.  Statistically higher overall scores on aggression and impulsivity scores were found among subjects who were seropositive for T. Gondii, while, contrary to some previous work, no differences were found related to suicide or self-directed aggression.  In terms of the three diagnostic groups, the percentage of subjects with IED who were seropositive for T. Gondii was 21.8%, which was significantly higher than controls (9.1%) but not psychiatric controls (16.7%).

The authors concluded that their data support others that suggest a link between T. Gondii and aggression.  (Actually, in the abstract they say it supports the link with self-directed aggression but I think that is a mistake).

In the discussion section, the authors go into some speculation about why this link might exist, including possible low grade chronic inflammation in the brain, alterations of corticolimbic circuits, or even via increased production of testosterone, based on some animal studies.  Other than once mentioning that T Gondii infections are treatable, the article gives no advice about assessing or treating the infection in aggressive people, likely because their cross sectional data require further investigation using other designs.  I haven’t heard any official response from the cat lobby.


Coccaro EF, et al.  Toxoplasma gondii infection:  Relationship with aggression in psychiatric patients.  J Clin Psychiatry 2016; 77:334-341



Mental Health of Transgender Children Who Have Socially Transitioned

Posted: March 15th, 2016 by David Rettew

While it has been shown in many studies that transgender youth frequently struggle with significant emotional-behavioral problems, the million dollar question behind this association is the degree to which these symptoms are driven by the intense stigma, lack of acceptance, and

Photo from imagerymajestic and freedigitalphotos.net

Photo from imagerymajestic and freedigitalphotos.net

even outright maltreatment that many of these children and adolescents suffer.  This question is relevant not only to point the way for optimal intervention but also for the controversy surrounding the continued inclusion of gender dysphoria, previously known as gender identity disorder, in the DSM5.

To examine this issue further, a group of researchers from the TransYouth Project followed a sample of 73 prepubescent transgender children between the ages of 3 and 12 who had socially transitioned at both home and school.  This group was compared cross-sectionally to a sample of nontransgender children as well as a subset of siblings of the trangender children.  The main outcome variables were levels of anxiety and depression as measured by the seldom used parent-report questionnaires, the National Institutes of Health Patient Reported Outcomes Measurement Information System. Of note, the transgender children included in this study needed to believe, and not simply wish, that they were actually of the “opposite” gender.   Also, none of the subjects, 70% of whom were natal boys who now identified as female, had received any hormonal treatment at the time.

Relative to the control groups or to national norms for the rating scales, the transgender children showed no elevations on depression scores. Some statistically significant differences were found, however, with the transgender group with regard to anxiety, although the mean score for the transgender group (at 54) was not in the clinical (above 63) or even preclinical range (above 60).   This finding did not vary according to natal sex.

The authors concluded that their data support the idea that psychiatric symptoms are not inherent in transgender children and that supporting parents and schools in their social transition can result in improved mental health.

While informative, the study does have some limitations.  First, one definitely gets that the sense the TransYouth Project was hoping to find the results they did to better advocate for transgender children.  While it is probably true that most researchers hope to find a specific result in their studies, this fact probably does have an impact in how the study is interpreted (for example, highlighting the lack of depression rather than the increased anxiety they found).  The results also would have been a bit more compelling if the researchers used more widely known rating scales and gathered information from sources other than parents, who might be motivated to demonstrate that their efforts were successful.  It would also have been very helpful to present the percentage of children in each group in the clinical and preclinical range for depression and anxiety rather than just the group means.

These problems aside, this study provides some important data, suggesting that transgender children who are provided support and acceptance in their social transition can often be spared much of the anguish that unfortunately befalls many others.


Olson KR, et al. Mental Health of Transgender Children Who Are Supported in Their Identities.  Pediatrics 2016, epub ahead of print.


Prevention Efforts at Suicide Hotspots

Posted: February 17th, 2016 by David Rettew

As reported recently in the Vermont Digger, there is a bill (H. 593) in the Vermont Legislature that would require some sort of suicide prevention action to be taken at the Quechee George Bridge, where there have been 8 suicides since 2008 (more than all other Vermont bridges combined).

While there are few people opposed to preventing suicide, there remain some legitimate questions about the bill and the effectiveness of similar efforts at other suicide “hotspots” such as the Golden Gate Bridge in San Francisco or several bridges around Cornell University in Ithaca, New York.  People wonder about how effective such measures really are since people who are suicidal could simply go somewhere else.  There are also concerns over spoiling the access or view of many people who gain benefit from being in these often beautiful places.Quechee Bridge

What is actually known about the value of trying to deter suicides at these particular places?  A  recent article in Lancet Psychiatry used meta-analytic techniques to provide a more definitive answer.   The authors searched for scientific studies that assessed the effectiveness of hotspot suicide prevention.   They point out that, while most people think of prevention efforts mainly in terms of restricting access through fences or nets, other types of interventions also can be implemented.  Among these are efforts to encourage help-seeking (e.g. placing help lines phones at the site) and increasing the possibility of intervention by a third party (e.g. having more personnel near the site).  In examining whether or not suicide prevention works, the authors divided the studies they found based on the type of intervention that was used (although some places had more than one).   The primary outcome variable was a pooled incidence rate ratio (IRR) that reflected the change in number of suicides after the intervention was introduced.  The length of time suicides were assessed prior and after the intervention ranged widely from 5 months to 22 years.

A total of 18 studies were identified, most of them related to efforts designed to prevent suicides at bridges and cliffs.  By far the most common type of intervention were those that did restrict access.  Overall, suicide rates dropped from 5.8 suicides per year to 2.4.   In terms of intervention type, restricting access and increasing the possibility of third party involvement were significantly related to suicide reduction.  For measures that encouraged help-seeking, there was also support for this intervention but this positive result required the removal of one outlier study.

The authors concluded that interventions at suicide hotspots are effective.  Furthermore, they state that their finding of effectiveness for interventions other than restricting access supports the notion that these improvements are not simply the result of individuals substituting one place for another.


Pirkis J, et al.  Interventions to reduce suicides at suicide hotspots: a systematic review and meta-analysis.  Lancet Psychiatry 2015 Nov;2(11):994-1001


Higher Guanfacine Doses Found Effective for Adolescent ADHD

Posted: February 4th, 2016 by David Rettew

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 Guanfacineexclusionary.  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.

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