August 15, 2024

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

A placebo is a pill that does not contain any active medication.  It is given to patients who form the control group in clinical trials.  Comparing the effects of a treatment with placebo is essential because some patients will improve with the passage of time and some will get better due to the expectation of benefit they have from being enrolled in a clinical trial.

In studies of psychiatric conditions, patients in placebo groups typically show improvement. This can be induced by combinations of hope, suggestion, expectation, and consumption of what are presented as medications. It is reinforced by the context of receiving compassionate care from others, with supportive conversations. 

A 2005 study found that placebo response is unequally distributed across psychiatric disorders, but did not address several disorders (including bipolar disorder) examined in the present meta-analysis conducted by a German research team. 

Using only high-quality randomized clinical trials (RCTs) across major psychiatric diagnoses, the team quantified differences in the change of disorder symptoms within placebo groups.  

They selected nine common and clinically significant psychiatric conditions: major depressive disorder (MDD), mania (bipolar disorder), schizophrenia, obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), generalized anxiety disorder (GAD), panic disorder, posttraumatic stress disorder (PTSD), and social phobia. For each of these, they selected the ten most recent high-quality RCTs of medicationsfor meta-analysis. 

Of the ninety included RCTs, the team only looked at placebo groups. Because RCTs for the different diagnoses used differing established psychopathology rating scales, standardized pre-post effect sizes were used to compare outcomes across diagnoses. 

Meta-analysis of the ten ADHD RCTs with a combined total of 1,189 participants reported large effect size improvements in symptoms, with no variation (heterogeneity) across RCTs and no sign of publication bias. 

By contrast, the placebo effect size improvements in symptoms of major depressive disorder (10 RCTs, 1,598 participants) and generalized anxiety disorder (10 RCTs, 1,457 participants) were very large, well above those for ADHD, and with no overlap of 95% confidence intervals. 

At the other end of the spectrum, the placebo effect size improvements in symptoms of schizophrenia (10 RCTs, 888 participants) were moderate, well below those for ADHD, and with no overlap of 95% confidence intervals. 

There were absolutely no indications of publication bias. 

The team noted, “In all diagnoses, there were improvements in symptom severity during placebo treatment (ie, the lower limit of the 95% CIs of the pooled pre-post placebo effect sizes were >0).” Although they stated, “The large and robust improvements observed in ADHD studies have not been reported to our knowledge.”  they seemed to have missed this article by me and my colleagues:  https://pubmed.ncbi.nlm.nih.gov/34232582/. 

They also concluded, “Comparing the courses of different disorders under placebo indirectly may assist in understanding disease etiology, possibly providing insights into the proportionate influence of organic and psychogenic factors. Conditions with presumed substantial hereditary and biological components, such as schizophrenia, exhibited modest placebo responses in our analysis. Conversely, disorders with potentially less biological contribution, eg, depression and GAD, showed stronger responses. Our study may serve as an initial framework for incorporating the comprehensive insights derived from placebo groups of controlled trials into the etiopathogenetic exploration of mental illnesses.”

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Yanli Zhang-James, John W.S. Clay, Rachel B. Aber, Hilary M. Gamble, Stephen V. Faraone,
Post–COVID-19 Mental Health Distress in 13 Million Youth: A Retrospective Cohort Study of Electronic Health Records,
Journal of the American Academy of Child & Adolescen

Tom Bschor, Lea Nagel, Josephine Unger, Guido Schwarzer, and Christopher Baethge, “Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis,” JAMA Psychiatry (2024), https://doi.org/10.1001/jamapsychiatry.2024.0994. 

Faraone, S. V., Newcorn, J. H., Cipriani, A., Brandeis, D., Kaiser, A., Hohmann, S., Haege, A. & Cortese, S. (2021). Placebo and nocebo responses in randomised, controlled trials of medications for ADHD: a systematic review and meta-analysis. Mol Psychiatry 27, 212-219.

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Meta-analysis Finds ADHD Associated with Higher-Risk of Dementia

The Background:

Dementia is a rapidly growing public health problem affecting more than 50 million people worldwide. Nearly 10 million new cases are diagnosed each year, and that number is expected to almost triple by 2050. The most common form is Alzheimer’s disease, accounting for roughly 60–70% of cases, followed by vascular dementia at around 20%. Other types include dementia with Lewy bodies, Parkinson’s disease dementia, and frontotemporal dementia. While no cure exists, managing modifiable risk factors (such as high blood pressure, smoking, physical inactivity, and poorly controlled diabetes) can delay or slow both the onset and progression of the condition. 

Several studies have reported an elevated dementia risk among people with ADHD, and a number of mechanisms may explain this association. These include shared genetic or neurobiological vulnerabilities, reduced cognitive reserve (leaving the brain less resilient to age-related damage), and greater lifetime exposure to other established dementia risk factors. 

Earlier reviews explored the possible link between ADHD and dementia, but tended toward a broader scope (incorporating other neurodegenerative disorders or mixing study designs), which introduced substantial variability and precluded quantitative synthesis. The relevant research literature has also expanded considerably since those reviews appeared. 

The Study:

This meta-analysis restricted inclusion to case-control and cohort studies, yielding five that met the criteria. One was a case-control study with 400 participants; the other four were cohort studies collectively covering 3.7 million individuals, two retrospective and two prospective. 

The Results:

Pooling the four cohort studies, individuals with ADHD showed approximately two-and-a-half times the dementia risk of those without the diagnosis. There was no indication of publication bias. 

The Take-Away:

The authors concluded that ADHD is associated with a significantly increased risk of all-cause dementia in later life, while noting that its relationship to specific dementia subtypes remains less clear and warrants attention in future research. 

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October 8, 2026

Meta-analysis Finds Association Between Maternal Polycystic Ovary Syndrome (PCOS) and ADHD in Offspring

The Background:

Women with polycystic ovary syndrome (PCOS) themselves show higher rates of ADHD. Because ADHD is partly heritable (meaning genes contribute to the condition), some of the increased ADHD seen in children of mothers with PCOS could come from shared genetic factors. In other words, a mother’s and her child’s increased risk might sometimes reflect common genes rather than an effect of the pregnancy itself. 

Beyond genetics, growing evidence points to maternal metabolic problems during pregnancy as another important risk factor for neurodevelopmental outcomes. PCOS is one of these conditions and is considered both potentially modifiable (treatable or manageable) and biologically plausible as a contributor to risk. PCOS affects an estimated 5–10% of women of reproductive age worldwide and is characterized by signs such as hyperandrogenism (higher-than-normal levels of “male” hormones), insulin resistance (poorer ability to use the hormone insulin, which can affect blood sugar and metabolism), and chronic low-grade inflammation. 

However, studies to date have not all reached the same conclusions. Some research suggests the association between maternal PCOS and offspring ADHD is stronger for girls, while other studies did not analyze results by child sex. Methodological differences make it harder to draw clear conclusions. 

The Study:

It’s important to note that the studies included in this meta-analysis were observational (cohort studies and case-control studies). Observational studies can identify associations (that two things occur together) but cannot prove that one causes the other. A cohort study follows people over time, and a case-control study compares people with a condition to similar people without it. 

The pooled results came from six studies that together included almost 1.4 million mother–child pairs and that adjusted for confounders (other factors that might influence the result, such as maternal age or socioeconomic status). After statistical adjustment, children of mothers with PCOS had about 40% greater odds of ADHD than children of mothers without PCOS. The analysis reported no evidence of publication bias (no clear sign that only positive studies were published) and zero heterogeneity (the results were consistent across the studies). 

There was no meaningful difference in results between cohort and case-control studies, and the meta-analysis did not find a significant difference in the association when comparing male and female offspring. 

The Take-Away:

The research team concluded that this large-scale synthesis found an association between maternal PCOS and higher odds of ADHD and other neuropsychiatric conditions in children. They suggested that children born to mothers with PCOS may benefit from developmental monitoring to identify and address problems early, while emphasizing that causal relationships have not been established. They called for further studies to confirm these findings and to investigate the biological and environmental mechanisms that might explain the association. Indeed, because women with PCOS show higher rates of ADHD than other women, we need genetically informed research designs to see if the reported association is confounded.

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October 1, 2026

Large Cohort Study Finds Dose-Response Association Between Food Insecurity and ADHD

The Background:

Food insecurity is a widespread public‑health problem. Food insecurity refers to limited or uncertain access to enough safe, nutritious food. This term is used to describe households that sometimes or often can’t afford enough food or can only buy cheaper, less‑healthy options. 

In the United States, almost eleven million children and teens (14%) lived in food‑insecure households in 2019. By 2023, the share of households with food‑insecure children and adolescents was estimated to have risen to about 18%. 

Food insecurity is linked to worse physical health in children, including conditions like anemia (low red‑blood‑cell count), asthma, and delays in physical or mental development. It is also associated with problems in thinking and conduct (for example, aggressive behavior, anxiety, depression, and trouble concentrating or sitting still). 

Those thinking and behavior problems can look a lot like ADHD (persistent patterns of inattention, hyperactivity, and impulsivity. This can make it hard for clinicians to tell whether symptoms come from ADHD itself, from the stress of poverty and food insecurity, or a mix of both. That overlap can complicate diagnosis and sometimes lead to misdiagnosis. 

Smaller recent studies have looked at mental‑health links and found higher odds of ADHD and other mental‑health conditions among food‑insecure children aged 5–11 years. In one set of findings, moderate food insecurity was associated with 50% greater odds of an ADHD diagnosis and severe food insecurity with about 67% greater odds relative to food‑secure children. 

The Study:

Because many past studies looked at single risk factors or only measured symptom severity, fewer investigations have focused specifically on household food insecurity as it relates to actual ADHD diagnoses and how that might matter for care. To address that gap, researchers used multiple years (2016–2022) of data from the U.S. National Survey of Children’s Health (NSCH). This survey is designed to be nationally representative and asks parents about their child’s health, including whether a doctor or other clinician has diagnosed ADHD. 

The study included 232,571 children and adolescents (ages 3–17) and used statistical methods to adjust for other factors that could affect ADHD risk. Those factors included the child’s sex and race/ethnicity; the mother’s age; family income expressed as a percentage of the federal poverty level (a government measure used to classify income groups); the highest level of parent education; adverse childhood experiences (such as exposure to abuse, household substance use, or parental separation); birthweight (for example, low birthweight); and not getting enough sleep. Adjusting for these variables helps isolate the association between food insecurity and ADHD, though it cannot prove cause and effect. 

The Results:

In this large, nationally representative sample, the researchers found a clear dose–response relationship: as the level of household food insecurity increased, so did the odds of a child having a clinician‑diagnosed ADHD (as reported by parents). In other words, greater food insecurity was linked to a higher likelihood of ADHD. 

Compared with children in households that “could always afford to eat good, nutritious meals” (the reference group), the study found the following increases in odds of ADHD: children in households that “could always afford enough to eat but not always the kinds of food we should eat” had about 30% greater odds; children in households that sometimes “could not afford enough to eat” had about 55% greater odds; and children in households that often “could not afford enough to eat” had about 80% greater odds. (Saying “30% greater odds,” etc., means the odds were 1.30, 1.55, and 1.80 times those of the reference group, respectively — this describes a relative increase, not the absolute percentage of children with ADHD.) 

The Take-Away:

The authors conclude that household food insecurity was associated with higher odds of parent‑reported clinician‑diagnosed ADHD in a dose‑response pattern. They suggest that reducing food insecurity (for example, ,by improving access to nutritious food and combining nutritional supports with mental‑health care) may help lower ADHD risk or reduce symptoms in some children. Reducing food insecurity should be a priority for society, but it is premature to conclude it will reduce the risk for ADHD. We know that parents with ADHD are more likely to lose their jobs and have lower incomes compared to parents with ADHD.  That might create food insecurity for their children who we know are at high risk for ADHD from genetic studies.  

 

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