Meta-analysis Finds Strong Placebo Response in Treatment of ADHD, Mid-range Among Nine Neurological Disorders

ADHD is usually framed as a dopamine-and-norepinephrine condition, but recent studies have revealed that serotonin may also play a significant role. To delve deeper into this, we conducted a systematic literature review of studies looking at serotonin, its receptors, and the serotonin transporter (SERT) in relation to ADHD. The result: serotonin appears to be an important piece of the puzzle, but the overall picture is quite complex.

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‍An ADHD & Serotonin Literature Review:

‍The authors searched the literature without time limits and screened thousands of records to end up with 95 relevant publications. Those included animal/basic-science work, neuroimaging, pharmacodynamics, a couple of large genetic/transcriptomic studies (GWAS and a cortico-striatal TWAS), and a few clinical reports. Each paper was graded for quality: 17 high, 59 medium, and 19 low.

The Results:

• Most studies support a serotonergic role. About 81% (77/95) of the papers reported altered serotonin production, binding, transport, or degradation linked to ADHD or ADHD-like behaviors.
  
  
• Multiple lines of evidence: animal models frequently show that changing serotonin levels or receptor activity alters hyperactivity and impulsivity; human imaging and clinical studies provide supportive but smaller and sometimes mixed signals; genetic/transcriptomic work points to serotonin-related pathways among many implicated systems.
  
  
• Receptors and SERT matter: Multiple serotonin receptor subtypes (5-HT1A, 1B, 2A, 2C, 7) and SERT show associations with impulsivity, hyperactivity, attention, or brain activity patterns in ADHD models and some human studies.
  
  
• Mixed and conflicting data: Central measures (brain, CSF) more often show serotonin deficits, while peripheral measures (platelets, plasma) sometimes show higher serotonin — methodological differences likely explain some contradictions.
  
  
• Drugs used for ADHD can affect serotonin: Stimulants and non-stimulant drugs approved by FDA for treating ADHD (e.g., methylphenidate, atomoxetine, extended release viloxazine) or under investigation (centafafadine) have direct or indirect effects on serotonin systems, supporting the idea that monoamines interact rather than acting separately.  Because drugs that mainly affect serotonin are not useful for ADHD it seems likely that a pathway forward for ADHD drug development would be drugs that target multiple neurotransmitter systems.  A complex treatment for an etiologically complex disorder.
  
  

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The Role of Serotonin in ADHD: What's The Take-Away?

As the study points out, the idea that serotonin may play a role in the neurobiology of ADHD is not new, but this literature review “identified multiple individual strands of evidence gathered over several decades and brought them into a more coherent focus”. It concludes that serotonergic neurotransmission is implicated in ADHD.  This doesn’t mean variations in serotonin levels cause ADHD, but that serotonin may be a plausible target for future treatments and research.

ADHD is polygenic and multi-systemic. For now, clinicians and patients should view serotonin as part of a complex network that may contribute to ADHD symptoms.  More research is needed before making treatment decisions based on these findings. 

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Background:

A previous meta-analysis found that children born to mothers with diabetes had a 34% higher risk of developing ADHD compared to those born to non-diabetic mothers.  

However, previous studies suffered methodological limitations, such as small sample sizes, case-control or cross-sectional designs, and insufficient adjustment for key confounders such as maternal socio-economic status, mental health conditions, obesity, and substance use disorders.  

Moreover, many studies relied on self-reported maternal diabetes, and on non-clinical ADHD assessments, such as parental reports or screening tools, which are prone to bias and inaccuracies.  

Furthermore, the role of maternal antidiabetic medication use in relation to ADHD risk has rarely been examined. Antidiabetic medications are effective in controlling high blood sugar during pregnancy, but many can cross the placenta and the blood-brain barrier, raising concerns about potential effects on fetal brain development.  

Study:

To address these gaps, an Australian study team used a large cohort of linked health administrative data from New South Wales to investigate both the association between maternal diabetes and the risk of ADHD and the independent effect of prenatal exposure to antidiabetic medications. 

The study encompassed all mother-child pairs born from 2003 through 2005, with follow-up conducted through 2018 to monitor hospital admissions related to ADHD. That yielded a final cohort of almost 230,000 mother-child pairs. 

The team adjusted for potential confounders including maternal age, socioeconomic status, previous children, pregnancy-related hypertension, caesarean delivery, birth order and plurality, maternal anxiety, depression, schizophrenia, bipolar disorder, substance use (alcohol, tobacco, stimulants, opioids, cannabis), and child factors such as Apgar score, sex, prematurity, and low birth weight. 

Results:

For maternal diabetes overall, there was no significant association with offspring ADHD. That was also true when broken down into pre-existing maternal diabetes and gestational (pregnancy-induced) diabetes.  

In a subset of 11,668 mother-child pairs, including 3,210 involving exposure to antidiabetic medications, there was likewise no significant association with offspring ADHD. 

Conclusion:

The team concluded, “Our findings did not support the hypothesis that maternal diabetes increases the risk of ADHD in children. Additionally, maternal use of antidiabetic medication was not associated with ADHD.” 

This study highlights the importance of high-quality research. A previous meta-analysis linking ADHD and maternal diabetes did not appropriately adjust for confounders and cited many small studies that may have included biased self-report scales. This large, registry-based cohort study of nearly 230,000 mother–child pairs found no evidence that maternal diabetes—whether pre-existing or gestational—or prenatal exposure to antidiabetic medications was associated with subsequent offspring ADHD as measured by hospital-recorded ADHD outcomes. The study’s strengths include its population scale, prolonged follow-up, and extensive adjustment for maternal and perinatal confounders (including maternal mental health and substance-use disorders), which address many limitations of earlier, smaller studies that reported elevated risks.  

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Background: 

The COVID-19 pandemic brought environmental changes that may have influenced ADHD symptoms and contributed to higher diagnosis rates. School closures, the transition to remote learning, and restrictions on outdoor activities led to increased screen time and isolation, both of which can affect attention and behavioral regulation. Children and adolescents, who usually depend on social interactions and structured routines, experienced significant disruptions during this period.  

Method:

South Korea has a nationwide single-payer health insurance system that keeps detailed health records on virtually its entire population. To explore the impact of COVID-19 on ADHD, a Korean research team used a database established by the Korean government that tracked all patients with COVID-19 between 2020 and 2023, nationwide COVID vaccination records, and insurance claims. They included all participants aged 6 through 29 years old. 

The onset of ADHD was determined by diagnosis combined with the prescription of ADHD medication. 

Altogether, the study encompassed almost 1.2 million Koreans, including over 150,000 children (6-12), more than 220,000 adolescents (13-19), and almost 800,000 young adults (20-29). 

The team adjusted for age, sex, income, Charlson Comorbidity Index, and medical visits. The Charlson Comorbidity Index predicts the mortality for a patient who may have a range of 17 concurrent conditions, such as heart disease, AIDS, or cancer. 

Results:

With these adjustments, young adults known to be infected with COVID-19 were about 40% more likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection. 

Adolescents known to be infected with COVID-19 were about twice as likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection. 

Children known to be infected with COVID-19 were 2.4 times as likely to be subsequently diagnosed with ADHD than their counterparts with no record of such infection. 

All these results were highly significant, and point to much greater impact on the youngest persons infected. 

Interpretation: 

The team concluded, “our nationwide study revealed that the COVID-19 pandemic significantly influenced ADHD incidence (raising incidence between 2020 and 2023), with SARS-CoV-2 infection identified as a critical risk factor,” and “In particular, early intervention and neurological evaluations are needed for children, adolescents, and young adults with a history of SARS-CoV-2 infection.” 

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