Nationwide population studies: atomoxetine not associated with birth defects

The Background:

Down syndrome (DS) is a genetic disorder resulting from an extra copy of chromosome 21. It is associated with intellectual disability. 

Three to five thousand children are born with Down syndrome each year. They have higher risks for conditions like hypothyroidism, sleep apnea, epilepsy, sensory issues, infections, and autoimmune diseases. Research on ADHD in patients with Down syndrome has been inconclusive. 

The Study:

The National Health Interview Survey (NHIS) is a household survey conducted by the National Center for Health Statistics at the CDC. 

Due to the low prevalence of Down syndrome, a Chinese research team used NHIS records from 1997 to 2018 to analyze data from 214,300 children aged 3 to 17, to obtain a sufficiently large and nationally representative sample to investigate any potential association with ADHD. 

DS and ADHD were identified by asking, “Has a doctor or health professional ever diagnosed your child with Down syndrome, Attention Deficit Hyperactivity Disorder (ADHD), or Attention Deficit Disorder (ADD)?” 

After adjusting for age, sex, and race/ethnicity, plus family highest education level, family income-to-poverty ratio, and geographic region, children and adolescents with Down syndrome had 70% greater odds of also having ADHD than children and adolescents without Down syndrome. There were no significant differences between males and females. 

The Take-Away:

The team concluded, “in a nationwide population-based study of U.S. children, we found that a Down syndrome diagnosis was associated with a higher prevalence of ASD and ADHD. Our findings highlight the necessity of conducting early and routine screenings for ASD and ADHD in children with Down syndrome within clinical settings to improve the effectiveness of interventions.” 

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An estimated 150 million children and adolescents live on the streets worldwide. In the U.S., roughly 1.5 million experience homelessness annually. Homelessness increases the risk of health issues, violence, early pregnancy, substance use, vaccine-preventable diseases, mental disorders, suicidal behavior, and early death. 

Rates of anxiety, major depression, conduct disorders, and post-traumatic stress disorder are higher among school-age homeless children compared to their housed peers.  

However, there has been limited attention to ADHD, leading a French research team to conduct a systematic review and meta-analysis of its prevalence among homeless children and adolescents.  

The inclusion criteria required that participants be homeless, under 19 years of age at baseline, and have ADHD identified through a screening tool, self-report, or clinical assessment. 

Results:

Meta-analysis of 13 studies with a combined total of 2,878 individuals found indications of ADHD in almost one in four homeless children and adolescents. There was no sign of publication bias, but considerable variation in estimates across studies. 

The team found a dose-response effect. Meta-analysis of six studies with 1,334 participants under 12 years old reported 13% with indications of ADHD. Meta-analysis of five studies encompassing 991 individuals, 12 through 18 years old, found an ADHD rate of 43%. The ADHD rate among adolescents was 3.3 times greater than among children. 

There were no significant differences among countries. 

Moreover, limiting the meta-analysis to the seven studies with 1,538 participants that relied on clinical ADHD diagnoses, the gold standard,  resulted in an ADHD prevalence of 23%. 

The team concluded, “The review of 13 studies revealed that ADHD is common in homeless children and adolescents, suggesting that homelessness may contribute to the development or exacerbation of ADHD symptoms. Conversely, ADHD with other comorbidities may increase the likelihood of homelessness. Reintegrating these children and adolescents into care systems and ensuring access to public health interventions tailored for homeless families and youth is imperative for breaking the cycle of homelessness and improving long-term trajectories.” 

In other words, this review not only confirmed a strong link between homelessness and ADHD in children and youth, but also suggested a complex, cyclical relationship. Providing tailored health care and support for these vulnerable groups is crucial to interrupt this cycle and help improve their future outcomes.

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Background:

In Iceland, treatment with ADHD medication can only be initiated by psychiatrists or pediatricians with experience in diagnosing neurodevelopmental disorders. The diagnostic evaluation is most often carried out by a psychologist or psychiatrist, and must be confirmed by a psychiatrist. 

Some previous studies have suggested a small but significant increased risk of psychosis or mania associated with ADHD medication, while others have not. 

Iceland has a single-payer national healthcare insurance system that tracks virtually its entire population. An Icelandic research team accessed two administrative databases with nationwide coverage – the Icelandic Prescription Medicines Register and the Icelandic Hospital Discharge Register – to explore this relationship among all adults from 2010 through 2022. 

They included three categories of ADHD medications prescribed in Iceland: amphetamines, including dexamphetamine and lisdexamphetamine; methylphenidate; and atomoxetine. In Iceland, methylphenidate or atomoxetine must be prescribed and tried first before switching to lisdexamphetamine or dexamphetamine. 

Method:

Diagnoses of mania or psychosis recorded in electronic health records were used to identify individuals who were admitted to a psychiatric ward within one year of starting treatment with a specific class of ADHD medication. First-onset psychosis or mania was defined as the emergence of these conditions in individuals with no prior history, diagnosis, or hospitalization for psychosis or mania. 

A total of 16,125 adults began using an ADHD medication for the first time during the 13-year study period. 

Methylphenidate was the most used ADHD medication among those admitted for psychosis or mania (25 out of 61; 41%), reflecting its status as the most frequently prescribed stimulant during the study period. It was followed by amphetamines (21 out of 61; 34.4%) and atomoxetine (15 out of 61; 24.6%). 

Half of those hospitalized had previously received a diagnosis of substance use disorder. One in nine (11%) of those hospitalized acknowledged misuse of the type of ADHD medication they had been prescribed. 

Within a year of discharge, 42 out of the 61 patients (68.9%) had been prescribed an ADHD medication again. Among those, one in four (11 out of 42; 26%) were readmitted for psychosis or mania within the following year.  

The team noted, “It is concerning that most patients (68.9%) in our study resumed ADHD drug treatment within a year of hospital discharge … However, some studies have reported that the use of psychostimulants or atomoxetine to treat ADHD in individuals with psychotic disorders did not increase the risk of hospitalisation for psychosis if used concurrently with antipsychotic medication or that such use might even reduce this risk.”  

Findings: 

By comparison with the general population, adults initiating ADHD medications had eight times the relative risk of being admitted for psychosis or mania within the first year.  

The absolute risk was low: 0.38% overall for those initiating ADHD medication.  Adjusting for the general population risk of hospitalization for first-onset psychosis or mania, more than 300 patients would need to be initiated to ADHD medication to generate one hospital admission for psychosis or mania. 

The team conceded, “Confounders of real-life clinical settings, such as non-disclosed ADHD drug abuse or misuse or some degree of substance abuse, may have influenced our findings.” 

A further, unmentioned, limitation is that the team did not perform any of the usual adjustments for confounding variables, critically including co-occurring (comorbid) psychiatric disorders known to be common with ADHD, and likely to have a major effect on the relative risk of hospitalization. 

Given the very small increase in risk along with the methodological flaws, the team’s suggestion of a “potential causal role of ADHD drugs in the development of first-onset psychosis or mania” is unsubstantiated and speculative.  This is especially so given other studies suggesting no increased risk for psychosis due to these medications.  

In any event, causation cannot be established through observational studies.

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