August 15, 2024
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.”
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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Background:
An international research team used the nationally representative 2020–2021 U.S. Survey of Children’s Health to explore associations between ADHD, weeknight sleep insufficiency, and bedtime irregularity.
"Sleep sufficiency" refers to the recommended amount of sleep for an individual. Sleep recommendations vary by age and other factors, such as health and lifestyle. For example, 7-9 hours is typically considered sufficient sleep for most adults, but an active teen may require closer to 10 hours of sleep per day.
Previous studies have shown that issues with both falling and staying asleep are common in individuals with ADHD.
The Study:
The team matched 7,671 children and adolescents with ADHD aged 3-17 to 51,572 controls.
Noting that “The few available population-based studies examining sleep in children with ADHD have focused on circumscribed age ranges, limiting generalizability across childhood, and have seldom included controls,” and “bedtime irregularity has received limited empirical attention in children with ADHD,” this study focused on these aspects of sleep impairment.
The study group excluded children and adolescents with ADHD with Down syndrome, current or lifetime cerebral palsy, and current or lifetime intellectual disability. In the control group, it excluded individuals with Down syndrome, cerebral palsy, intellectual disability, speech and language disorder, autism spectrum disorder, ADHD, anxiety, depression, behavioral or conduct problems, Tourette syndrome, and use of mental health services in the preceding 12 months. These groups were excluded to limit potential confounding factors.
After adjustment for covariates, parents of children and adolescents with ADHD reported weekday sleep insufficiency 65% more frequently than parents of controls.
However, when comparing matched controls with children and adolescents with ADHD who were being treated with ADHD medication, there was no significant difference.
Similarly, there was a small but significant effect size increase in bedtime irregularity among children and adolescents with ADHD relative to their matched controls.
Yet there was also a small but significant effect size decrease in bedtime irregularity among those taking medication for ADHD relative to those who were unmedicated.
The team noted, “Interestingly, here, ADHD medication use was linked to less bedtime irregularity across full and age-stratified samples, and not related to sleep insufficiency. However, research indicates the association between stimulant use and sleep problems is attenuated with longer duration of use, and also suggests the potential for stimulants to produce positive effects on sleep through reduced bedtime resistance. Further, ADHD medication type, not specified, may have influenced outcomes.”
The Take-Away:
The study concluded that ADHD in children was linked to insufficient sleep and irregular bedtimes in a nationally representative sample, reinforcing and expanding previous research. The findings emphasize the influence of various factors on sleep insufficiency and bedtime irregularity, including race, screen time, poverty, ADHD severity, and depression.
Noting that “the association between adult ADHD and dementia risk remains a topic of interest because of inconsistent results,” an Israeli study team tracked 109,218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020.
Israeli law forbids nonprofit HMOs from turning anyone away based on demographic factors, health conditions, or medication needs, thereby limiting sample selection bias.
The estimated prevalence of dementia in this HMO, as diagnosed by geriatricians, neurologists, or psychiatrists, is 6.6%. This closely matches estimates in Western Europe (6.9%) and the United States (6.5%).
The team considered, and adjusted for, numerous covariates: age, sex, socioeconomic status, smoking, depression, obesity, chronic obstructive pulmonary disease, hypertension, atrial fibrillation, heart failure, ischemic heart disease, cerebrovascular disease, diabetes, Parkinson’s disease, traumatic brain injury, migraine, mild cognitive impairment, psychostimulants.
With these adjustments, individuals diagnosed with ADHD were almost three times as likely to be subsequently diagnosed with dementia as those without ADHD. Men with ADHD were two and a half times more likely to be diagnosed with dementia, whereas women with ADHD were over three times more likely, than non-ADHD peers.
More concerning still, persons with ADHD were 5.5 times more likely to be subsequently diagnosed with early onset dementia, as opposed to 2.4 times more likely to be diagnosed with late onset dementia.
On the other hand, the team found no significant difference in rates of dementia between individuals with ADHD who were being treated with stimulant medications and individuals without ADHD. Those with untreated ADHD had three times the rate of dementia. The team nevertheless cautioned, “Due to the underdiagnosis of dementia as well as bidirectional misdiagnosis, this association requires further study before causal inference is plausible.”
Conclusions and Relevance:
This study reinforces existing evidence that adult ADHD is associated with an increased risk of dementia. Notably, the increased risk was not observed in individuals receiving psychostimulant medication, however the mechanism behind this association is not clear.
These findings underscore the importance of reliable ADHD assessment and management in adulthood. They also highlight the need for further study into the link between stimulant medications and the decreased risk of dementia.
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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.”
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