Posted: September 10th, 2014 by David Rettew
To keep in mind National Suicide Prevention Suicide Week as well as to offer some hopeful news, this week’s post summarizes a recent study from the American Journal of Psychiatry that claims to have found a gene that is related to suicidal behavior. It is somewhat of a complicated study with multiple samples (it’s hard to publish single gene studies anymore without an independent replication sample) and associations related both to the actual gene and its DNA code as well as epigenetic differences in the amount of methylation the gene has undergone: all of which in turn affects how much of the gene product is expressed. The gene under scrutiny is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis function: a key factor in a body’s response to stress. Previous research in both animals and humans has suggested that genes involved in this process might be an important place to look.
This study used prefrontal cortex tissue from several brain banks that included many individuals with depression, some of whom died by suicide. Possible candidate genes that emerged were then validated in tissue from other individuals as well as gene expression analyses from three groups of living patients (coming from blood not brain, obviously), where levels of anxiety and stress were assessed as well as concentrations of salivary cortisol.
The signal for suicide and suicidal behavior was found to be related to the SKA2 gene on chromosome 17. As mentioned, a significant association was found both related to DNA, specifically a single nucleotide polymorphism (SNP) at location rs7208505, and more strongly to epigenetic changes of that gene. Here, increased methylation was related to higher rates of suicide as well as higher rates of suicidal behavior. The accuracy of predicting suicidal behavior from these genetic and epigenetic variations in the living group was quite high at 80%, particularly the progression from suicidal ideation into attempt. However, this number comes from complicated statistical models and does not lend itself to an easy yes/no prediction of suicidal behavior based on the result of simple blood test.
The authors concluded that the SKA2 gene and its level of epigenetic changes may be an important biomarker for suicidal behavior. In saying this, however, it is important to remember that the term “suicide gene,” just like an “ADHD gene” or a “depression gene” is really a misnomer, as genes don’t code for diseases per se but rather for products involved in some kind of brain activity. In this case, the SKA2 gene is thought to help “chaperone” a glucocorticoid receptor (which may play an important step in regulating down the stress response) to the nucleus and can thus play a role in HPA axis function. While certainly an important and thought provoking study, the authors cautioned that their sample size was small and results should be considered preliminary. Lest people also start thinking that certain people are destined to be depressed and suicidal, it is also important to note that epigenetic changes to genes such as the ones found to be important in this study can be strongly related to the quality of one’s environment.
Guintivano J, et al. Identification and Replication of a Combined Epigenetic and Genetic Biomarker Predicting Suicide and Suicidal Behaviors. Am J Psychiatry 2014, epub ahead of print.
Posted: August 27th, 2014 by David Rettew
ADHD medications are some of the most common drugs given to children and adolescents. Most clinicians prescribe them within approved FDA indications. Moreover, the existence of an FDA approval often provides some comfort to the prescribing clinician that the medication has received rigorous testing for efficacy and safety. But has it? A recent study in PLOS One attempted to summarize how extensively ADHD medications were studied prior to the FDA approval with particular attention to the ability to detect rare side effects or safety over the long-term. Guidelines for the optimal testing of medications used for chronic conditions do exist from an organization called the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
The authors gathered data on all clinical trials performed on ADHD medications that have been approved by the FDA. Much of the information came from what are called FDA Drug Approval Packages that contain a large amount of data related to the approval process of a new drug. Key variables of interest for this study included the number of participants in the trials and the length of the studies.
A total of 32 trials were found that evaluated 20 different medications. Of interest, the oldest ADHD drug, Ritalin, was approved in 1955 based on clinical experience rather than a clinical trial. A total of seven drugs, including Adderall, were approved without a clinical trial of ADHD subjects. Only eight of the trials were published in the medical literature. The median number of participants per drug was 75 while the median length of a clinical trial was 4 weeks (the ICH recommends at least 300 patients studied for at least six months). For six medications, approval was contingent on collecting data post approval, although this occurred in only two cases.
The authors concluded that the amount of data collected in the process of obtaining FDA approval is inadequate to evaluate both for rare side effects or long-term safety. These trials fall well short of ICH recommendations, although the authors acknowledge that for many of these medications there now exists much more data from various sources.
In reading this study as a psychiatrist, I had two main take-away impressions. The first was some surprise at how small and short many of the trials were. While certainly one might expect similar efficacy and safety profiles for compounds that are so similar chemically, its probably safe to say that most clinicians assume a little more has been done to obtain FDA approval. The second impression (and this was the nagging question that kept coming into my mind as a read the article) was whether these holes in premarketing research were specific to ADHD medications versus being present for other classes of drugs. It was quite amazing to me how the authors barely addressed this obvious and important question, and its absence made the article seem more politically than scientifically motivated. Are asthma drugs any different? Probably not, and not acknowledging this adequately just fuels a fire against psychiatric medications that everyone knows is easily ignited.
Bourgeois FT, Kim JM, Mandl KD. Premarket Safety and Efficacy Studies for ADHD Medications in Children. PLOS One 2014: 9(7) e102249
Posted: August 19th, 2014 by David Rettew
It has been widely shown at this point that psychiatric problems in parents can negatively affect child behavior, but what about teachers? These days, many children spend as much if not more of their waking hours with teachers and other childcare providers than they do with parents. As such, it seems logical to extend the investigation of adult emotional-behavioral symptoms affecting children beyond studies involving just Mom and Dad. A recent study by Jeon and colleagues, published in the Journal of Consulting and Clinical Psychology, did just that.
The data come from the Fragile Families and Child Wellbeing Study in which 761 3-year-old children and their mothers (mainly from disadvantaged backgrounds) were assessed along with their preschool teachers. While teachers were not formally diagnosed or evaluated, they did report on their own mood using a short 6-item version of the Johns Hopkins Symptom Checklist. Child behavior, meanwhile, was assessed with our favorite instruments, namely the Teacher Report Form (teacher report) and Child Behavior Checklist (parent report). Path analyses were used to examine the link between teacher depressed mood and child internalizing and externalizing problems, and to test the possibility that any association is mediated through a lower quality of childcare as measured through observer ratings.
The results depended a bit on who rated the child’s behavior. When child behavior was assessed by teachers, a teacher’s self-reported depression score was both directly related to child internalizing and externalizing problems and indirectly related through a reduced quality of childcare. When child behavior was assessed by parents, however, only a direct significant association was found between teacher mood and child level of internalizing problems. While statistically significant, the magnitude of the effects were not overwhelming. For example, the raw correlation between teacher depression score and childcare quality was a fairly meager -.12.
The authors concluded that there was some evidence that depressive symptoms in teachers can be related to child behavior problems both through lower quality of childcare and through other means yet to be determined. They advocated for additional efforts to support the psychological well-being of teachers, both for its own sake and as a means to optimize the quality of childcare.
One important sidenote not addressed by the authors is that this study, in my view, strengthens the argument that parental mental health really does affect a child’s behavior because by looking at teacher effects, they remove the potential confound of shared genes that can muddy the waters in studies with parents. Some people might also be interested in how depressed the teachers actually were. Again, this was not focused upon in the paper other than reporting that their mean score was 8 on a scale that went from 0 to 18.
Jeon L, et al. Pathways From Teacher Depression and Child-Care Quality to Child Behavioral Problems. J Consult Clin Psychology 2014;82(2):225-235.
Posted: July 29th, 2014 by David Rettew
(Editor’s note: I’m very pleased to be able to present this guest post by one of our new child psychiatry fellows, Sean Ackerman, who recently published this important study – DR).
Sean Ackerman, MD
These days autism spectrum disorder (ASD) and assisted reproduction are both medical issues that frequently wind up in the media and are becoming ever more commonplace in our lives. Moreover, at times both issues have been lightning rods of controversy. Not surprisingly then – and in the context of ASD being linked to environmental factors – some have wondered if assisted reproduction and ASD were associated. There has even been some concern that some forms of assisted production – including in vitro fertilization, gamete intrafallopian transfer, or zygote intrafallopian transfer – could possibly even cause autism associated genetic events.
Researchers have looked at this question via a number of epidemiological studies, with mostly reassuring results. However, there has been some conflicting evidence and no genetic studies have been done… until now.
Via a large sample of almost 2,000 children with autism, we examined the use of assisted reproduction and any association with autism associated genetic events, publishing our results recently in the journal Fertility and Sterility. What we found was a completely negative result: no statistically significant differences in copy number variations or autism-associated gene-disrupting events were found when comparing ASD patients exposed to assisted reproduction with those not exposed to assisted reproduction.
Furthermore, in the context of assisted reproduction maternal age was identified as a potential contributor to ASD associated genetic events, meaning the characteristics of parents using assisted reproduction (not assisted reproduction itself) may explain any association previously found in epidemiological studies between ASD and assisted reproduction.
Overall, we believe this finding is important because when people consider assisted reproduction they often have many questions and anxieties. We hope that the above finding can help provide some important information to hopeful parents interested in assisted reproduction who are specifically concerned with the issue of autism.
Ackerman A, Wenegrat J, Rettew D, Althoff R, Bernier R. No increase in autism-associated genetic events in children conceived by assisted reproduction. Fertility and Sterility 2014; May 17 epub ahead of print.
Posted: July 21st, 2014 by David Rettew
It is easy to get stuck into territorial disputes, and one of the most common ones I hear in relation to child mental health is the question of whether a child with a trauma history should be thought of as having “real” ADHD or whether it is better to conceptualize the difficulties as being more directly related to trauma. A great illustration of what many consider to be an important diagnostic dilemma comes from a recent article in the The Atlantic by Rebecca Ruiz entitled “How Childhood Trauma Could Be Mistaken for ADHD.”
The main point of the article was to argue that many children who manifest behaviors of ADHD come from chaotic environments and have suffered many adverse child events. Experts quoted in this article advocated that it is important to recognize these events and address them, and that medications can’t fix a chaotic or abusive environment.
Nothing really to argue about so far. Certainly we can be guilty from time to time of getting overly focused on medications while not paying enough attention to the factors that might be driving or exacerbating the problem.
Unfortunately, where the article lost me was its repeated return to the us versus them, correct diagnosis versus incorrect diagnosis, good doc versus bad doc mentality that so pervasively permeates our field. When it comes to trauma and ADHD, this false dichotomy, in my view, would be similar to a physician stating something like, “He has a history of smoking so I don’t think this is real COPD but rather a reaction to the cigarettes.”
Let me offer a few other points for why I think some of these debates between the “biological” people and the “trauma” people are ultimately moot.
- Kids have only one brain that responds to both genetic and environmental factors. Attention and self-regulation skills begin to be learned early in life. When a negative environment impacts that developmental process, the brain physically changes. Thus, it shouldn’t be surprising that there is no evidence that kids who meet criteria for ADHD but also have trauma histories have a brain that is any less “ADHDish” than kids with ADHD who come from stable happy households. Yet somehow, a dualistic perspective that essentially implies separate brains for separate disorders continues to exist. While it is true that severe anxiety can sabotage attention, in my experience it is much more common that children who have suffered many adverse events, especially early in life, present with both real anxiety and real attention problems.
- You can’t ignore genetics. When it comes to children with trauma histories, many of their parents struggle with psychiatric disorders themselves including, not the of least of all, ADHD. This fact does not excuse parents of responsibility, but it is important to remember that these children can get a double dose of at-risk genes and at-risk environments. The vast majority of studies that link environmental trauma to negative child behavior do not take genetics into account, and the few that do paint a much more complex picture than is generally expressed in this article cited above.
- There is little evidence that doing “trauma work” fixes these supposedly misdiagnosed children, especially when the trauma is no longer occurring. While I would be one of the first to agree that a 15 minute “med check” for a child in a tumultuous environment is wildly inappropriate as a sole treatment, I would also have to add that a pleasant 45 minutes of play therapy while struggling parents sit outside in the waiting room is no better. Of course trauma and other environmental factors are incredibly important in the mental health of children. The point is that dismissive explanations of ADHD don’t hold water in study after study.
What can we do instead? The bottom line here is a need to throw out our “this or that” thinking and understand that reactions to adverse environments can contribute to ADHD or be part of ADHD rather than necessarily be mistaken for ADHD. These kids and the families who care for them deserve clinicians who can look at the big picture and proceed with comprehensive multi-faceted interventions. Looking at the world too narrowly through a particular lens (whether it be trauma or ADHD or many other things for that matter) holds everybody back and does not do justice to the amazing complexity of the brain.
Posted: July 1st, 2014 by David Rettew
Suicide remains a leading cause of death and is a major public health concern. Studies have demonstrated that many individuals who die by suicide often see their primary care physician soon before the event. Thus, it is important to know whether suicide screening might potentially prevent some of these tragic deaths. To that end, the U.S. Preventive Services Task Force, an organization that issues guidelines regarding prevention measure in medicine, looked at the evidence once again ten years after an earlier report when the said that they could not make a recommendation for or against the practice due to a lack of data.
Their analysis attempted to focus on adolescents, adults and older adults who were not at an elevated risk for suicide at baseline and did not have an identified psychiatric disorder. The task force attempted to find studies that addressed three areas, namely 1) the accuracy of suicide screening tests, 2) the effectiveness of interventions to decrease suicide, and 3) potential negative effects of suicide screening and treatment.
When it came to results, the authors found only four screening studies on suicide screening, all of which used a different instrument. Not enough data were available to determine if the screening was worthwhile, although the report didn’t really summarize these studies. The task force also found a general lack of evidence regarding the efficacy of treatment and any potential negative effects of suicide screening or treatment.
The overall conclusion of the task force was that, once again, the current database is insufficient to be able weigh the relative benefits and risk of preventive suicide screening in primary care. The task force recommended additional research to fill these significant gaps.
One might wonder in reading this often hard to follow report is why they chose to issue it again if the final conclusion of “insufficient data” remains unchanged. Perhaps it was to spur additional interest and attention. It is important to note that these recommendations (or lack thereof) do not suggest that there are no significant risk factors for suicide worth identifying. Indeed, the group has previously issued a recommendation that screening for depression, probably the strongest risk factor for suicide, be performed in primary care offices.
Lefevre M. Screening for Suicide Risk in Adolescents, Adults, and Older Adults in Primary Care: U.S. Preventive Services Task Force Recommendation. Annals of Internal Medicine 2014;160(10):719-727.
Posted: June 18th, 2014 by David Rettew
A new combined effort between the Vermont Department of Children and Families (DCF), the Vermont Department of Mental Health, and the Child & Adolescent Psychiatry Fellowship Program at the Vermont Center for Children, Youth, and Families (VCCYF) will support caseworkers who often need to make complex medical decisions regarding the children under their care.
While it has been well known that the number of youth who take antipsychotic medication has been increasing nationwide, the rate tends to be about five times higher among youth in state custody. Antipsychotic medications can be an important component of treatment for some, yet these medications also carry the potential for serious risks and side effects including movement disorders, obesity, diabetes, and high cholesterol. When kids enter state custody, DCF caseworkers become responsible for consenting to these and any other medications and medical decisions. This responsibility can be a challenge due to the large caseloads of the social workers and the fact that these children often move around to various placements around the state. Unlike most parents, DCF caseworkers are often unable to attend physician appointments with their children which is where the risks and benefits of medications are typically discussed. DCF caseworkers are also not clinically trained in pharmacology.
To support DCF caseworkers in this challenging task, a new program will begin next month that will help them in deciding whether or not a antipsychotic medication that is being considered for a child in custody is appropriate. This includes the following:
1. Additional training provided to the caseworkers about antipsychotic medications and their potential risks and benefits.
2. A more rigorous written informed consent process that will be required between the DCF caseworker and prescribing clinician to ensure that children in DCF custody who are being prescribed antipsychotics are getting these medications for the right reasons and being monitored according to best practice guidelines.
3. The opportunity for caseworkers who may have questions or concerns about the consideration of antipsychotic medications for one of their clients to get an independent opinion from one of the child psychiatry fellows in the VCCYF training program who is supervised by UVM child psychiatry faculty. These free consultations can occur whenever the caseworkers would like one and are required in certain situations (such as a child under six years old).
The project has been led at DCF by Cindy Walcott, Deputy Commissioner for Family Services. We are excited to be part of this effort both to help make sure these vulnerable children are getting the best care possible and to give our child psychiatry fellows a valuable educational experience. Vermont has already seen a decrease in the use of antipsychotic prescriptions among youth over the past several years. Improving access to evidence-based psychotherapy for oppositional and aggressive children, educating prescribers on when and how to reduce or discontinue these medications when appropriate, enhancing the flow of medical information between different practices, and using technology to remind physicians about the need for regular labwork can all help the prescribing of this class of medications to be closer to best practice recommendations.
The new policy begins on July 1. Primary care clinicians who prescribe antipsychotic medications to children in DCF custody can expect to be asked to complete this informed consent process with the child’s caseworker over the next few months.
Posted: June 2nd, 2014 by David Rettew
There have been many studies that have demonstrated links between excessive childhood screen time and negative outcomes including attention problems and aggression. Most of them imply causation but generally can’t prove it because the studies don’t measure child behavior before the screen time occurs. Yes playing Minecraft for 6 hours per day might cause problems, but it could also be true that kids whose have attention problems are drawn more to the bells and whistles of video games. A recent study published in the journal Pediatrics examined this question in relation to poor infant self-regulation and media usage at age 2.
The study comes from the Early Childhood Longitudinal Study – Birth Cohort and included 7450 children from the community, oversampled for higher rates of ethnic minorities. Infants were assessed for the regulatory abilities at an age of 9 months using a shortened version of the Infant Toddlers Symptom Checklist. Items involving fussiness, needing constant attention, and sleep problems loaded onto the overall score of regulation problems. Media usage was measured at age 2 by simply asking caregivers about average media use. Regression analyses were performed to examine the link between infant regulatory abilities and media use, controlling for other potential confounds. The authors examined the data both quantitatively (i.e. using the actual numbers of media time) and categorically dividing toddlers into groups that watched more or less than 2 hours per day (based on the AAP guidelines of two hours per day maximum of screen time).
Overall, a small but statistically significant link was found between infant regulatory abilities and age-two media use. The analyses showed that children with poorer regulatory skills (which was about 39% of the sample) consumed approximately 14 more minutes (9 minutes when adjusted for other variables) of media per day than those with good regulatory skills. At age 2, children averaged about 2.3 hours of media use per day with 40% of the sample going above the recommended 2 hours per day. The association between dysregulation and media use was stronger for children who remained dysregulated at age 2 and for children from English speaking and lower SES families.
The authors’ conclusions were somewhat unexpected. Despite showing evidence that dsyregulation might be a cause rather than a result of media use, the authors argued that the amount of use associated with infant dysregulation was too small to account for the finding from other studies that excessive screen time is linked to negative child behavior. They cautioned about a cycle in which fussier infants are more likely to be placed in front of screens (to give parents a break or occupy them in a safe place) which then in turn exposes them to the negative effects of increased screen time and thus reinforces the initial problem. While this is certainly a plausible hypothesis, it requires a study that assesses child behavior, parent behavior, and screen time at multiple time points. We are still waiting for that one, as far as I know.
Radesky JS, et al. Infant Self-Regulation and Early Childhood Media Exposure. Pediatric; online publication April 14, 2014