September 13, 2024
A meta-analysis of short-term, placebo-controlled, randomized clinical trials (Cortese et al. 2018), looking at both efficacy and safety, supported prescribing stimulants – methylphenidate use in children and adolescents and amphetamine use in adults – as first-choice medications.
However, these were short-term studies, and they focused on relieving ADHD symptoms. What about longer-term outcomes, especially looking more broadly at functional impairment and overall quality of life?
Sweden has a single-payer health insurance system that encompasses virtually every resident and is linked to national registers that enable researchers to conduct nationwide population studies.
A joint Finnish-Swedish research team used Sweden’s registers to study outcomes for all individuals of working age, 16 to 65 years old, living in Sweden who had received a diagnosis of ADHD from 2006 through 2021. The resulting study cohort encompassed 221,714 persons with ADHD.
The team adjusted for the following confounding variables: Genetics, baseline severity of symptoms, baseline comorbidities, temporal order of treatments (which medication was used as first, second, third, and so forth, including also nonuse of ADHD medications), time since cohort entry, and time-varying use of psychotropic drugs, including antidepressants, anxiolytics, hypnotics, mood stabilizers (carbamazepine, valproic acid, and lamotrigine), lithium, antipsychotics, and drugs for addictive disorders.
With these adjustments, they discovered that amphetamine treatment was associated with a roughly 25% reduction in psychiatric hospitalization relative to unmedicated ADHD. Lisdexamphetamine was associated with a roughly 20% reduction, dexamphetamine with a 12% reduction, and methylphenidate with a 7% reduction. All four medications are stimulants.
None of the non-stimulant medications – atomoxetine, guanfacine, clonidine – had any significant effect on psychiatric hospitalization. Nor did modafinil a drug that is not FDA approved for ADHD but is sometimes used when other drugs fail.
Amphetamine was also associated with the greatest reduction in suicide attempts or deaths, with a roughly 40% decline relative to unmedicated ADHD. Dexamphetamine was associated with a roughly 30% decline and lisdexamphetamine with a roughly 25% decline. The stimulant methylphenidate was only associated with an 8% reduction, and modafinil had no significant effect.
Surprisingly, non-stimulant medications were associated with significant increases in suicide attempts or deaths: 20% for atomoxetine, 65% for guanfacine, and almost double for clonidine.
Amphetamine and lisdexamphetamine also reduced the risk of nonpsychiatric hospitalization by more than a third compared to unmedicated ADHD. Dexamphetamine was associated with a risk reduction of more than 25%, methylphenidate with 20% lesser risk.
The non-stimulant atomoxetine was associated with a roughly 15% reduction in risk of nonpsychiatric hospitalization. But neither guanfacine nor clonidine had any significant effect.
Turning to work disability, atomoxetine was the only ADHD medication associated with a reduction – a roughly 10% improvement. All other medications had no significant effect.
The team concluded, “In this cohort study of adolescents and adults with ADHD, the use of medications for ADHD, especially lisdexamphetamine and other stimulants, was associated with decreased risk of psychiatric hospitalizations, suicidal behavior, and nonpsychiatric hospitalizations during periods when they were used compared with periods when ADHD medication was not used. Non-stimulant atomoxetine use was associated with decreased risk of work disability.”
Heidi Taipale, Jakob Bergström, Katalin Gèmes, Antti Tanskanen, Lisa Ekselius, Ellenor Mittendorfer-Rutz, and Magnus Helgesson, “Attention-Deficit/Hyperactivity Disorder Medications and Work Disability and Mental Health Outcomes,” JAMA Network Open (2024), 7(3):e242859, https://doi.org/10.1001/jamanetworkopen.2024.2859.
Cortese S, Adamo N, Del Giovane C, et al., “Comparative efficacy and tolerability of medications for attention- deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis,” Lancet Psychiatry (2018) 5(9):727-738, https://doi.org/10.1016/S2215-0366(18)30269-4.
With the growth of the Internet, we are flooded with information about attention deficit hyperactivity disorder from many sources, most of which aim to provide useful and compelling "facts" about the disorder. But, for the cautious reader, separating fact from opinion can be difficult when writers have not spelled out how they have come to decide that the information they present is factual.
My blog has several guidelines to reassure readers that the information they read about ADHD is up-to-date and dependable. They are as follows:
Nearly all the information presented is based on peer-reviewed publications in the scientific literature about ADHD. "Peer-reviewed" means that other scientists read the article and made suggestions for changes and approved that it was of sufficient quality for publication. I say "nearly all" because in some cases I've used books or other information published by colleagues who have a reputation for high-quality science.
When expressing certainty about putative facts, I am guided by the principles of evidence-based medicine, which recognizes that the degree to which we can be certain about the truth of scientific statements depends on several features of the scientific papers used to justify the statements, such as the number of studies available and the quality of the individual studies. For example, compare these two types of studies. One study gives drug X to 10 ADHD patients and reported that 7 improved. Another gave drug Y to 100 patients and a placebo to 100 other patients and used statistics to show that the rate of improvement was significantly greater in the drug-treated group. The second study is much better and much larger, so we should be more confident in its conclusions. The rules of evidence are fairly complex and can be viewed at the Oxford Center for Evidenced Based Medicine (OCEBM;http://www.cebm.net/).
The evidenced-based approach incorporates two types of information: a) the quality of the evidence and b) the magnitude of the treatment effect. The OCEBM levels of evidence quality are defined as follows (higher numbers are better:
Non-randomized, controlled studies. In these studies, the treatment group is compared to a group that receives a placebo treatment, which is a fake treatment not expected to work.
It is possible to have high-quality evidence proving that a treatment works but the treatment might not work very well. So it is important to consider the magnitude of the treatment effect, also called the "effect size" by statisticians. For ADHD, it is easiest to think about ranking treatments on a ten-point scale. The stimulant medications have a quality rating of 5 and also have the strongest magnitude of effect, about 9 or 10.Omega-3 fatty acid supplementation 'works' with a quality rating of 5, but the score for the magnitude of the effect is only 2, so it doesn't work very well. We have to take into account patient or parent preferences, comorbid conditions, prior response to treatment, and other issues when choosing a treatment for a specific patient, but we can only use an evidence-based approach when deciding which treatments are well-supported as helpful for a disorder.
A Chinese research team performed two types of meta-analyses to compare the risk of suicide for ADHD patients taking ADHD medication as opposed to those not taking medication.
The first type of meta-analysis combined six large population studies with a total of over 4.7 million participants. These were located on three continents - Europe, Asia, and North America - and more specifically Sweden, England, Taiwan, and the United States.
The risk of suicide among those taking medication was found to be about a quarter less than for unmediated individuals, though the results were barely significant at the 95 percent confidence level (p = 0.49, just a sliver below the p = 0.5 cutoff point). There were no significant differences between males and females, except that looking only at males or females reduced sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications produced divergent outcomes. A meta-analysis of four population studies covering almost 900,000 individuals found stimulant medications to be associated with a 28 percent reduced risk of suicide. On the other hand, a meta-analysis of three studies with over 62,000 individuals found no significant difference in suicide risk for non-stimulant medications. The benefit, therefore, seems limited to stimulant medication.
The second type of meta-analysis combined three within-individual studies with over 3.9 million persons in the United States, China, and Sweden. The risk of suicide among those taking medication was found to be almost a third less than for unmediated individuals, though the results were again barely significant at the 95 percent confidence level (p =0.49, just a sliver below the p = 0.5 cutoff point). Once again, there were no significant differences between males and females, except that looking only at males or females reduced the sample size and made results non-significant.
Differentiating between patients receiving stimulant and non-stimulant medications once again produced divergent outcomes. Meta-analysis of the same three studies found a 25 percent reduced risk of suicide among those taking stimulant medications. But as in the population studies, a meta-analysis of two studies with over 3.9 million persons found no reduction in risk among those taking non-stimulant medications.
A further meta-analysis of two studies with 3.9 million persons found no reduction in suicide risk among persons taking ADHD medications for 90 days or less, "revealing the importance of duration and adherence to medication in all individuals prescribed stimulants for ADHD."
The authors concluded, "exposure to non-stimulants is not associated with a higher risk of suicide attempts. However, a lower risk of suicide attempts was observed for stimulant drugs. However, the results must be interpreted with caution due to the evidence of heterogeneity ..."
Raising children is not easy. I should know.
As a clinical psychologist, I've helped parents learn the skills they need to be better parents. And my experience raising three children confirmed my clinical experience.
Parenting is a tough job under the best of circumstances, but it is even harder if the parent has ADHD.
For example, an effective parent establishes rules and enforces them systematically. This requires attention to detail, self-control, and good organizational skills. Given these requirements, it is easy to see how ADHD symptoms interfere with parenting. These observations have led some of my colleagues to test the theory that treating ADHD adults with medication would improve their parenting skills. I know about two studies that tested this idea.
In 2008, Dr. Chronis-Toscano and colleagues published a study using a sustained-release form of methylphenidate for mothers with ADHD. As expected, the medication decreased their symptoms of inattention and hyperactivity/impulsivity. The medication also reduced the mother's use of inconsistent discipline and corporal punishment and improved their monitoring and supervision of their children.
In a 2014 study, Waxmonsky and colleagues observed ADHD adults and their children in a laboratory setting once when the adults were off medication and once when they were on medication. They used the same sustained-release form of amphetamine for all the patients. As expected, the medications reduced ADHD symptoms in the parents. This laboratory study is especially informative because the researchers made objective ratings of parent-child interactions, rather than relying on the parents' reports of those interactions. Twenty parents completed the study. The medication led to less negative talk and commands and more praise by parents. It also reduced negative and inappropriate behaviors in their children.
Both studies suggest that treating ADHD adults with medication will improve their parenting skills. That is good news. But they also found that not all parenting behaviors improved. That makes sense. Parenting is a skill that must be learned. Because ADHD interferes with learning, parents with the disorder need time to learn these skills. Medication can eliminate some of the worst behaviors, but doctors should also provide adjunct behavioral or cognitive-behavioral therapies that could help ADHD parents learn parenting skills and achieve their full potential as parents.
Given the persistence of ADHD and its adverse effects on children and adolescents, one might expect caregivers to face greater parenting challenges, with potential effects on their own mental health.
To what extent do parenting stress, depression, and – at the extreme – even suicidal ideation manifest themselves among caregivers of ADHD patients as opposed to caregivers of children and adolescents without ADHD?
A pair of Korean researchers made use of their country’s single-payer health insurance system, which maintains records on virtually the entire population, to perform a nationwide population study. They used data from the Korean National Health and Nutrition Examination Surveys (KNHANES) covering the decade from 2011 to 2020. KNHANES is an annual survey using a sophisticated sampling design conducted by the Korean Ministry of Health and Welfare to represent the entire population of South Korea.
The analysis included 14,428 individuals who had children younger than 19 at the time of participation. All were asked whether their child had ever been diagnosed with ADHD by a physician. The mental health problems of the parents were assessed in terms of perceived stress, depressive symptoms, and suicidality.
Of the 14,428 participants, 8,298 (57.5 %) were mothers and 6,130 (42.5 %) were fathers. Of the mothers, 116 (1.4 %) had a child with ADHD, and of the fathers, 86 (1.4 %) had a child with ADHD.
The researchers adjusted for the following confounders: age of caregiver, education level, household income, area of residence, employment status, alcohol consumption, smoking status, cohabitation status, number of children, and child’s age.
After adjustment, mothers of ADHD patients fared significantly worse than mothers of typically developing children on all three categories of mental health problems. They were 67% more likely to report higher stress, three times as likely to report symptoms of depression, and 2.5 times more likely to report suicidal ideation.
Yet that pattern did not carry over to fathers, where there was no significant difference in mental health indicators between fathers of children with ADHD and fathers of children without ADHD.
The authors concluded, “Parents of children with ADHD, especially mothers, need community support and public health attention to help alleviate their mental health problems.”
Background:
ADHD is commonly accompanied by psychiatric comorbidities that complicate its diagnosis and treatment. Roughly two out of three affected children and adolescents have one or more comorbid psychiatric disorder.
Because the peak age of ADHD onset is typically a decade or more earlier than those for schizophrenia, depressive disorder, or bipolar disorder, it is essential to explore these comorbidities over an extended period. Populations studies help researchers identify broader patterns and trends within an entire population and includes adults as well as children. This type of study provides unique insights into the population at large, rather than a sample group.
In earlier studies the maximum follow-up period was twelve years, insufficient in view of the roughly ten years between onset of ADHD and onset of major psychiatric disorders. Also, previous nationwide population studies have included less than 150,000 participants.
This study, relying on data from South Korea’s universal single-payer health insurance system, included over one and a half million individuals. Persons previously diagnosed with depression, bipolar disorder, tic disorder, or schizophrenia were excluded.
382,434 individuals had been diagnosed with ADHD, while 1,169,279 were without an ADHD diagnosis.
Propensity score matching ensured that potential confounders, both sociodemographic and clinical, were equalized for the ADHD and control groups. After matching, there were 353,898 individuals in each group.
After these adjustments, individuals in the ADHD group were at least an order of magnitude more likely to subsequently be diagnosed with psychiatric disorders than their peers without an ADHD diagnosis:
Conclusion:
The Korean study team concluded, “Overall, our findings suggest that upon prolonged examination, the risk of subsequent diagnoses of other psychiatric disorders in individuals with ADHD appears to be higher than that reported previously. … Therefore, patients with ADHD should be carefully screened for the presence of other psychiatric symptoms on a regular basis from an earlier age … It is advisable to have a follow-up period extending beyond 10 years to sufficiently identify the occurrence of comorbid disorders in patients with ADHD.”
Children with ADHD often face challenges in social interactions, leading to long-term consequences if not properly addressed. While various interventions exist, many fail to consider the broader social context in which these children interact. A recent study conducted in Bergen, Norway, explored how primary school teachers perceive their role in supporting children with ADHD who struggle socially and the strategies they use to assist them.
Researchers conducted semi-structured interviews with five focus groups of primary school teachers. Using reflexive thematic analysis, they identified two major themes:
Rather than relying on standardized interventions, teachers tailored their strategies to foster an inclusive and supportive social environment. Their methods included both active participation in social situations and behind-the-scenes efforts to encourage peer inclusion and understanding.
This study underscores the need to move beyond labels and recognize children with ADHD as individuals with distinct social needs. Teachers play a crucial role in shaping these children’s experiences, using flexible and personalized approaches to promote positive social interactions. By integrating social context and individualized support, educators can help children with ADHD build meaningful connections and navigate their social world more effectively.
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