Bipolar disorder is a severe mental illness that afflicts over one in fifty persons worldwide. About a quarter of those with bipolar disorder also has alcohol use disorder (AUD). This in turn complicates the treatment of their bipolar disorder. It exacerbates their symptoms, makes them more likely to be suicidal, and increases the risk of hospitalization.
More than one in five persons with bipolar disorder also have ADHD, which is likewise known to be correlated with AUD. To what extent does ADHD contribute to AUD in persons with comorbid bipolar disorder?
A European study team recently conducted a systematic search of the peer-reviewed medical literature to address that question. The team identified eleven studies with a combined total of 2,734 participants that could be aggregated to perform a meta-analysis.
They found that persons with comorbid ADHD and bipolar disorder were two and a half times more likely to be diagnosed with alcohol use disorder than persons with bipolar disorder but no ADHD.
Between-study heterogeneity was negligible, and there was no sign of publication bias.
The authors concluded, "At least a portion of the high rates of AUD in BD may, thereby, be related to comorbid ADHD. Longitudinal studies are needed to clarify the nature of this relationship."
Childhood antibiotic use is not found to be associated with development of ADHD
A Chinese research team recently conducted a systematic search of the peer-reviewed medical journal literature for studies exploring the association between childhood antibiotic exposure and subsequent diagnosis of ADHD in youths 18 years and younger.
A meta-analysis of six studies with a combined total of over 1.5 million participants found that children exposed to antibiotics were 18% more likely to later be diagnosed with ADHD.
There was absolutely no indication of publication bias. Between-study heterogeneity, on the other hand, was extremely high.
With such large cohorts, one can often tease out whether an association is causal, or due to genetic and familial confounding, by looking at matched close relatives.
Three of the studies, with a combined total of well over half a million participants, also compared matched siblings.
Significantly, the meta-analysis among matched siblings found no association whatsoever between childhood exposure to antibiotics and subsequent ADHD. Between-study heterogeneity was virtually nonexistent.
The team concluded, "Our meta-analysis indicated that early-life antibiotic exposure was associated with a subsequent increased risk of ASD or ADHD. However, such association was not found in the sibling-matched analysis, indicating that genetic and familial confounding factors may largely explain the observed association."
Population study finds that early enterovirus infection can put those individuals at a 25% higher risk for later ADHD diagnosis.
Enteroviruses (EV) are a class of RNA viruses. This group of viruses includes some no-longer endemic forms such as polio and some serious but rare forms that cause encephalitis and meningitis. The most common virus in this population and period (1999-2003) was EV71, which can have complications, sometimes fatal, especially for children under five years old. It has also been linked to various chronic diseases, many of them neurological.
Is it associated with the subsequent diagnosis of ADHD and, if so, to what extent?
Taiwan offers an excellent opportunity to study this in an entire population. This is because of its single-payer health care system. Its database "the National Health Insurance research database" covers 99.5 percent of the population.
The Taiwanese study team used a sub-database, the Longitudinal Health Insurance Database 2000, containing claims data from a million persons randomly sampled from the parent database.
From this database, the researchers identified over 49,000 EV patients. They excluded all who were 18 and older, were missing essential data or had been diagnosed with ADHD, epilepsy, topic diseases, coronary artery disease, stroke, rheumatoid arthritis, or systemic lupus erythematosus before being diagnosed with enterovirus. That left an EV cohort of 14,168, who were matched with an equal number of non-EV individuals matched by age and sex.
After adjusting for age, sex, paternal occupation, and urbanization level of the residence, the EV cohort group was found to have a 25 percent greater risk for ADHD than the control group.
Oxytocin is a hormone released by the pituitary gland that stimulates the contraction of the uterus during labor. Synthetic oxytocin is widely administered during labor to supplement a birthing parent's supply and facilitate childbirth.
Previous studies have found an association between synthetic oxytocin and increased odds of ADHD in offspring.
A joint Danish and Finnish team used their countries' national registers to obtain countrywide cohorts encompassing over 577,000 Danes and over 945,000 Finns. Oxytocin had been administered in 31% of the Danish deliveries and 46% of the Finnish ones. Any children either diagnosed with ADHD or who received prescriptions for ADHD drugs were categorized as having ADHD.
As in previous studies, unadjusted results found a significant association with ADHD. Combining the two populations, children whose mothers had received oxytocin during labor were 16% more likely to later develop ADHD.
After adjusting for a series of confounders such as birth year, maternal age, education, marital status, parity, smoking in pregnancy, labor induction, gestational age, and intrauterine growth, the association dropped markedly, to an increased likelihood of barely 3%.
Looking at Denmark alone, the unadjusted risk was 9% greater, vanishing altogether after adjusting for confounders. In Finland, the unadjusted risk was 20% greater, declining to 4% after adjusting for confounders.
The authors noted that "Exposure to obstetric oxytocin is not a random process, and it is likely that other factors than the ones included here vary systematically between women treated vs not treated with oxytocin. ... Therefore, we find it most likely that the minor elevations in risk are due to uncontrolled and residual confounding, and thereby our results underscore the lack of a causal association between obstetric oxytocin exposure and ADHD."
There was no association found between ADHD and ASD diagnoses and early antibiotic use when environmental and genetic family factors were taken into account.
Proper development of the gut biota is important for the health of the brain and nervous system. It has been hypothesized that disturbances of gut bacteria by antibiotics could contribute to the development of neurodevelopmental disorders, including ADHD.
In the case of ADHD, studies to date have produced conflicting results. To tease out any familial confounding reflecting shared environment and genetics, a joint Dutch-Swedish team of researchers further tested the hypothesis through 7- to 12-year-old twins in the Netherlands Twin Register (25,781 twins) and 9-year-old twins in the Swedish Twin Registry (7,946 twins).
ADHD symptoms in the Netherlands cohort were derived from mothers' answers to the short Conners' Parental Rating Scale-Revised. For the Swedish cohort, ADHD was determined through the International Classification of Diseases codes for ADHD in the cross-linked National Patient Register.
Exposure to antibiotics during the first two years of childhood was determined by parent reports for the Netherlands twin cohort, and by prescription claims for antibiotics in the Swedish twin cohort.
Covariates were explored in both twin cohorts including educational attainment of parents, gender of the infant, birth weight, delivery mode, and asthma. Breastfeeding was also explored in the Dutch cohort.
In the unmatched analysis, comparing children with ADHD with non-related children without ADHD, early-life antibiotic use was associated with a significant 8% greater odds of ADHD in the Netherlands cohort and a significant 14% greater odds of ADHD in the Swedish cohort.
However, when limiting the analysis to matched monozygotic twins, the association disappeared altogether in both the Dutch and Swedish cohorts. Pooling both cohorts resulted in the same outcome. In all three cases, the odds flipped into a mildly negative association, but with no statistical significance.
Using higher cutoff values for ADHD symptoms made no difference.
The authors concluded, "In this large co-twin study performed in two countries, early-life antibiotic use was associated with increased risk of ADHD and ASD, but the results suggest that the association disappeared when controlled for shared familial environment and genetics, indicating that this association may be susceptible to confounding. Our results indicate that there is no association between ADHD and ASD diagnoses and early antibiotic use when environmental and genetic family factors are taken into account."
After noting that the association between ADHD and obesity has been called into question because of small sample sizes, wide age ranges, self-reported assessments, and inadequate attention to potential confounders, an Israeli study team set out "to assess the association between board-certified psychiatrist diagnoses of ADHD and measured adolescent BMI [body mass index] in a nationally represented sample of over one million adolescents who were medically evaluated before mandatory military service."
The team distinguished between severe and mild ADHD. It also focused on a single age group.
All Israelis are subject to compulsory military service. In preparation for that service, military physicians perform a thorough medical evaluation. Trained paramedics recorded every conscript's height and weight.
The study cohort was divided into five BMI percentile groups according to the U.S. Centers for Disease Control and Prevention's BMI percentiles for 17-year-olds, and further divided by sex: <5th percentile (underweight), 5th-49th percentile (low-normal), 50th-84th percentile (high normal), 85th-94th percentile (overweight) and ≥95th (obese). Low-normal was used as the reference group.
Adjustments were made for sex, birth year, age at examination, height, country of birth (Israeli or other), socioeconomic status, and education level.
In the fully adjusted results, those with severe ADHD were 32% more likely to be overweight and 84% more likely to be obese than their typically developing peers. Limiting results to Israeli-born conscripts made a no difference.
Male adolescents with mild ADHD were 24% more likely to be overweight, and 42% more likely to be obese. Females with mild ADHD are 33% more likely to be overweight, and 42% more likely to be obese. Again, the country of birth made no difference.
The authors concluded, that both severe and mild ADHD was associated with an increased risk for obesity in adolescents at the age of 17 years. The increasing recognition of the persistence of ADHD into adulthood suggests that this dual morbidity may have a significant impact on the long-term health of individuals with ADHD, thus early preventive measures should be taken.
To gauge the extent of stigma towards persons with ADHD, a European research team hired a company specialized in market and social research to conduct a poll of some five thousand randomly selected Germans. Just over a thousand completed the interview, representing a response rate of only one in five. The team acknowledged, “Although non-responder bias has to be considered to be important, ethical considerations prohibited the collection of any detailed information on non-respondents.” The sample had slightly more women and elderly persons, and a higher average level of educational attainment relative to the German population as a whole. Sampling weights were used to compensate for these discrepancies.
The poll relied on computer-assisted telephone interviews. Interviews began with prerecorded vignettes of either a 12-year-old child or 35-year-oldadult exhibiting core symptoms of ADHD (such as “careless mistakes in schoolwork,” “does not follow through on instructions,” “easily distracted by extraneous stimuli”, “loses things”, “leaves his place in the classroom or when sitting at the dining table”). Half of those interviewed were presented with child vignettes, and half with adult vignettes. The gender of the person described varied randomly.
On a scale of one to five, respondents were asked to indicate levels of agreement with two statements: 1. ‘‘Basically, we are all sometimes like this person. It’s just a question of how pronounced this state is.’’ 2. “All in all, the problems of Robert / Anne are abnormal.” For both child and adult vignettes, two out of three respondents agreed that “we are all sometimes like this person.” One in three respondents considered the problems depicted in the child vignettes as abnormal. That dropped to one in four in the adult vignettes.
Next, respondents were asked whether they ever had a problem like this, and whether someone among their family or close friends ever had to deal with such a problem. For both vignettes, one in four acknowledged having had a problem like this, and half said a close friend or family member had such a problem.
On the assumption that “negative emotional reactions are an important consequence of negative stereotypes, leading to separation, discrimination and status loss,” respondents were probed for their specific emotional reactions. “I feel annoyed,” “I react angrily,” and “provokes my incomprehension” were interpreted as indicating varying levels of anger.“Provokes fear” and “Makes me feel insecure” were seen as indicating fear. “I feel uncomfortable” was viewed as indicating somewhere between fear and anger. On the other hand, “I feel the need to help,” “I feel pity,” and “I feel sympathy” were interpreted as “pro-social” responses.
Pro-social reactions were by far the most common. Over two-thirds felt a need to help a child, and over half to help an adult, in such a situation. In both instances, almost half felt sympathy, and a half or more felt pity. On the other hand, a quarter of respondents in each case felt annoyed, and just under one in five felt uncomfortable. Almost one in seven reacted angrily to the child vignette, and almost one in six to the adult vignette. Fear was the least frequent emotional reaction.
In the case of adults, respondents were also asked about their willingness to accept the person described in the vignette in seven social situations:
· Working together
· As a neighbor
· Marrying into the family
· Introducing to a friend
· Renting a room
· Recommending for a job
old adult· Taking care of chi
While three out of four respondents were willing to accept such persons as co-workers, only one in three would recommend them for a job. Two out of three would accept such persons as neighbors, and almost as many to marry into the family. Three out of five would very willingly introduce such persons to friends. Slightly over half would rent a room to them. But less than one in three would be willing to have such individuals take care of their own children.
Older respondents were more likely to see the problems as“abnormal” and to seek greater social distance. Women, and respondents with higher levels of education, were less likely to see the problems as abnormal and more likely to respond in pro-social ways.
Though showing most Germans to be accepting of persons with ADHD, these findings still indicate a significant degree of stigma, though less than for other psychiatric conditions such as depression, schizophrenia, or alcohol dependence.
A team of U.S. endocrinologists recently published the results of a meta-analysis examining a possible association between bisphenol A(BPA) and childhood ADHD. BPA is used in a variety of consumer products, including plastic bottles for food and drink, epoxy resins used to line cans of food, dental sealants, and the thermal receipts issued by stores.
A review of the literature found 29 rodent studies, but only three with humans. The human studies were too different from each other to be suitable for meta-analysis. One found no association between prenatal exposure and ADHD. A second found prenatal BPA exposure to be associated with teacher-reported hyperactivity in 4-year-old boys, but not girls. The third found is to be associated with hyperactivity scores in 3-year-old girls.
As the authors note, "Often, there is little human data available, particularly in the environmental toxicology/health fields, due to the time and expense of conducting epidemiological studies and the ethical barriers for human-controlled trials that involve human exposure to potentially hazardous chemicals. Thus, it is important to have methods for using animal data to inform human health hazard conclusions; indeed, animal models are traditionally used to study human health."
Twelve of the mice and rat studies, with a total of 709 rodents, were suitable for meta-analysis.
Overall these pointed to a tiny SMD effect size of 0.09, but it was not significant, with the odds of such a result being obtained by chance being almost one in four (p = 0.237). But when results from the 356 males and353 females were looked at separately, a significant sex difference emerged. There was essentially no effect on female rodents, with an effect size of -0.07and a 95% confidence interval of -0.27 to 0.14, widely spanning the zero mark, rendering the result statistically non-significant. Among male rodents, however, there was a small but statistically significant effect size (0.24), with a 95%confidence interval from 0.04 to 0.45. The odds of obtaining this outcome by chance were only one in 50 (p = .02).
This result must be viewed with caution, as rodent physiology often differs substantially from that of humans. The authors, therefore, conclude, "early BPA exposure is associated with a presumed hazard of hyperactivity in humans. Our conclusion is based on 'moderate' levels of evidence for the human and 'high' levels of evidence for animal literature."
A working group of the International League Against Epilepsy(ILAE), consisting of twenty experts spanning the globe (U.S., U.K., France, Germany, Japan, India, South Africa, Kenya, Brazil), recently published "consensus paper" summarizing and evaluating what is currently known about comorbid epilepsy with ADHD, and best practices.
ADHD is two to five times more prevalent among children with epilepsy. The authors suggest that ADHD is underdiagnosed in children with epilepsy because its symptoms are often attributed either to epilepsy itself or to the effects of antiepileptic drugs (AEDs).
The working group did a systematic search of the English-language research literature. It then reached a consensus on practice recommendations, graded on the strength of the evidence.
Three recommendations were graded A, indicating they are well-established by evidence:
· Children with epilepsy with comorbid intellectual and developmental disabilities are at increased risk of ADHD.
· There is no increased risk of ADHD in boys with epilepsy compared to girls with epilepsy.
· The anticonvulsant valproate can exacerbate attentional issues in children with childhood absence epilepsy (absence seizures look like staring spells during which the child is not aware or responsive). Moreover, a single high-quality population-based study indicates that valproate use during pregnancy is associated with inattentiveness and hyperactivity in offspring.
Four more were graded B, meaning they are probably useful/predictive:
· Poor seizure control is associated with an increased risk of ADHD.
· Data support the ability of the Strengths and difficulties questionnaire (SDQ) to predict ADHD diagnosis in children with epilepsy: "Borderline or abnormal SDQ total scores are highly correlated with the presence of a validated psychiatric diagnosis (93.6%), of which ADHD is the most common (31.7%)." The SDQ can therefore be useful as a screening tool.
· Evidence supports the efficacy of methylphenidate in children with epilepsy and comorbid ADHD.
· Methylphenidate is tolerated in children with epilepsy.
At the C level of being possibly useful, there is limited evidence that supports that atomoxetine is tolerated in children with ADHD and epilepsy and that the combined use of drugs for ADHD and epilepsy (polytherapy) is more likely to be associated with behavioral problems than monotherapy. In the latter instance, "Studies are needed to elucidate whether the polytherapy itself has resulted in the behavioral problems, or the combination of polytherapy and the underlying brain problem reflects difficult-to-control epilepsy, which, in turn, has resulted in the prescription of polytherapy."
All other recommendations were graded U (for Unproven), "Data inadequate or conflicting; treatment, test or predictor unproven." These included three where the evidence is ambiguous or insufficient:
· Evidence is conflicted on the impact of early seizure onset on the development of ADHD in children with epilepsy.
· Tolerability for amphetamine in children with epilepsy is not defined.
· Limited evidence exists for the efficacy of atomoxetine and amphetamines in children with epilepsy and ADHD.
There were also nine U-graded recommendations based solely on expert opinion. Most notable among these:
· Screening of children with epilepsy for ADHD beginning at age 6.
· Reevaluation of attention function after any change in antiepileptic drug.
· Screening should not be done within 48 hours following a seizure.
· ADHD should be distinguished from childhood absence epilepsy based on history and an EEG with hyperventilation.
· Multidisciplinary involvement in transition and adult ADHD clinics is essential as many patients experience challenges with housing, employment, relationships, and psychosocial wellbeing.
To gauge the extent of stigma towards persons with ADHD, a European research team hired a company specialized in market and social research to conduct a poll of some five thousand randomly selected Germans. Just over a thousand completed the interview, representing a response rate of only one in five. The team acknowledged, "Although non-responder bias has to be considered to be important, ethical considerations prohibited the collection of any detailed information on non-respondents." The sample had slightly more women and elderly persons, and a higher average level of educational attainment relative to the German population as a whole. Sampling weights we reused to compensate for these discrepancies.
The poll relied on computer-assisted telephone interviews. Interviews began with prerecorded vignettes of either an a12-year-old child or a 35-year-old adult exhibiting core symptoms of ADHD (such as "careless mistakes in schoolwork," "does not follow through on instructions," easily distracted by extraneous stimuli, "loses things", "leaves his place in the classroom or when sitting at the dining table"). Half of those interviewed were presented with child vignettes and half with adult vignettes. The gender of the person described varied randomly.
On a scale of one to five, respondents were asked to indicate levels of agreement with two statements: 1. "Basically, we are all sometimes like this person. It's just a question of how pronounced this state is." 2. "All in all, the problems of Robert / Anne are abnormal." For both child and adult vignettes, two out of three respondents agreed that "we are all sometimes like this person." One in three respondents considered the problems depicted in the child vignettes as abnormal. That dropped to one in four in the adult vignettes.
Next, respondents were asked whether they ever had a problem like this and whether someone among their family or close friends ever had to deal with such a problem. For both vignettes, one in four acknowledged having had a problem like this, and half said a close friend or family member had such a problem.
On the assumption that "negative emotional reactions are an important consequence of negative stereotypes, leading to separation, discrimination and status loss," respondents were probed for their specific emotional reactions. "I feel annoyed," " react angrily," and" provokes my incomprehension" were interpreted as indicating varying levels of anger. "Provokes fear" and "Makes me feel insecure" were seen as indicating fear. "I feel uncomfortable" was viewed as indicating somewhere between fear and anger. On the other hand, "I feel the need to help," "I feel pity," and "I feel sympathy" were interpreted as "pro-social" responses.
Pro-social reactions were by far the most common. Over two-thirds felt a need to help a child, and over half to help an adult, in such a situation. In both instances, almost half felt sympathy, and a half or more felt pity. On the other hand, a quarter of respondents in each case felt annoyed, and just under one in five felt uncomfortable. Almost one in seven reacted angrily to the child vignette, and almost one in six to the adult vignette. Fear was the least frequent emotional reaction.
In the case of adults, respondents were also asked about their willingness to accept the person described in the vignette in seven social situations:
· Working together
· As a neighbor
· Marrying into the family
· Introducing to a friend
· Renting a room
· Recommending for a job
· Taking care of children
While three out of four respondents were willing to accept such persons as co-workers, only one in three would recommend them for a job. Two out of three would accept such persons as neighbors, and almost as many to marry into the family. Three out of five would very willingly introduce such persons to friends. Slightly over half would rent a room to them. But less than one in three would be willing to have such individuals take care of their children.
Older respondents were more likely to see the problems as "abnormal" and to seek greater social distance. Women, and respondents with higher levels of education, were less likely to see the problems as abnormal and more likely to respond in pro-social ways.
Though showing most Germans to be accepting of persons with ADHD, these findings still indicate a significant degree of stigma, though less than for other psychiatric conditions such as depression, schizophrenia, or alcohol dependence.
