Linda Halldner

Structure and function of adenosine receptors and their genes

Four adenosine receptors have been cloned from many mammalian and some non-mammalian species. In each case the translated part of the receptor is encoded by two separate exons. Two separate promoters regulate the A1 receptor expression, and a similar situation may pertain also for the other receptors. The receptors are expressed in a cell and tissue specific manner, even though A1 and A2B receptors are found in many different cell types. Emerging data indicate that the receptor protein is targeted to specific parts of the cell. A1 and A3 receptors activate the Gi family of G proteins, whereas A2A and A2B receptors activate the Gs family. However, other G proteins can also be activated even though the physiological significance of this is unknown. Following the activation of G proteins several cellular effector pathways can be affected. Signaling via adenosine receptors is also known to interact in functionally important ways with signaling initiated via other receptors.

Medication for Attention Deficit–Hyperactivity Disorder and Criminality

BACKGROUNDnAttention deficit-hyperactivity disorder (ADHD) is a common disorder that has been associated with criminal behavior in some studies. Pharmacologic treatment is available for ADHD and may reduce the risk of criminality.nnnMETHODSnUsing Swedish national registers, we gathered information on 25,656 patients with a diagnosis of ADHD, their pharmacologic treatment, and subsequent criminal convictions in Sweden from 2006 through 2009. We used stratified Cox regression analyses to compare the rate of criminality while the patients were receiving ADHD medication, as compared with the rate for the same patients while not receiving medication.nnnRESULTSnAs compared with nonmedication periods, among patients receiving ADHD medication, there was a significant reduction of 32% in the criminality rate for men (adjusted hazard ratio, 0.68; 95% confidence interval [CI], 0.63 to 0.73) and 41% for women (hazard ratio, 0.59; 95% CI, 0.50 to 0.70). The rate reduction remained between 17% and 46% in sensitivity analyses among men, with factors that included different types of drugs (e.g., stimulant vs. nonstimulant) and outcomes (e.g., type of crime).nnnCONCLUSIONSnAmong patients with ADHD, rates of criminality were lower during periods when they were receiving ADHD medication. These findings raise the possibility that the use of medication reduces the risk of criminality among patients with ADHD. (Funded by the Swedish Research Council and others.).

The Swedish Twin Registry: Establishment of a Biobank and Other Recent Developments

The Swedish Twin Registry (STR) today contains more than 194,000 twins and more than 75,000 pairs have zygosity determined by an intra-pair similarity algorithm, DNA, or by being of opposite sex. Of these, approximately 20,000, 25,000, and 30,000 pairs are monozygotic, same-sex dizygotic, and opposite-sex dizygotic pairs, respectively. Since its establishment in the late 1950s, the STR has been an important epidemiological resource for the study of genetic and environmental influences on a multitude of traits, behaviors, and diseases. Following large investments in the collection of biological specimens in the past 10 years we have now established a Swedish twin biobank with DNA from 45,000 twins and blood serum from 15,000 twins, which effectively has also transformed the registry into a powerful resource for molecular studies. We here describe the main projects within which the new collections of both biological samples as well as phenotypic measures have been collected. Coverage by year of birth, zygosity determination, ethnic heterogeneity, and influences of in vitro fertilization are also described.

Stimulant and non-stimulant attention deficit/hyperactivity disorder drug use : total population study of trends and discontinuation patterns 2006-2009

Zetterqvist J, Asherson P, Halldner L, Långström N, Larsson H. Stimulant and non‐stimulant attention deficit/hyperactivity disorder drug use: total population study of trends and discontinuation patterns 2006–2009.

Stimulant ADHD medication and risk for substance abuse.

BACKGROUNDnThere are persistent concerns of long-term effects of stimulant ADHD medication on the development of substance abuse.nnnMETHODSnUsing Swedish national registers, we studied all individuals born between 1960 and 1998 and diagnosed with ADHD (26,249 men and 12,504 women). We investigated the association between stimulant ADHD medication in 2006 and substance abuse during 2009. Substance abuse was indexed by substance-related death, crime, or hospital visits.nnnRESULTSnADHD medication was not associated with increased rate of substance abuse. Actually, the rate during 2009 was 31% lower among those prescribed ADHD medication in 2006, even after controlling for medication in 2009 and other covariates (hazard ratio: 0.69; 95% confidence interval: 0.57-0.84). Also, the longer the duration of medication, the lower the rate of substance abuse. Similar risk reductions were suggested among children and when investigating the association between stimulant ADHD medication and concomitant short-term abuse.nnnCONCLUSIONSnWe found no indication of increased risks of substance abuse among individuals prescribed stimulant ADHD medication; if anything, the data suggested a long-term protective effect on substance abuse. Although stimulant ADHD medication does not seem to increase the risk for substance abuse, clinicians should remain alert to the potential problem of stimulant misuse and diversion in ADHD patients.

Relative immaturity and ADHD: findings from nationwide registers, parent- and self-reports

BACKGROUNDnWe addressed if immaturity relative to peers reflected in birth month increases the likelihood of ADHD diagnosis and treatment.nnnMETHODSnWe linked nationwide Patient and Prescribed Drug Registers and used prospective cohort and nested case-control designs to study 6-69xa0year-old individuals in Sweden from July 2005 to December 2009 (Cohort 1). Cohort 1 included 56,263 individuals diagnosed with ADHD or ever used prescribed ADHD-specific medication. Complementary population-representative cohorts provided DSM-IV ADHD symptom ratings; parent-reported for 10,760 9-year-old twins born 1995-2000 from the CATSS study (Cohort 2) and self-reported for 6,970 adult twins age 20-47xa0years born 1959-1970 from the STAGE study (Cohort 3). We calculated odds ratios (OR:s) for ADHD across age for individuals born in November/December compared to January/February (Cohort 1). ADHD symptoms in Cohorts 2 and 3 were studied as a function of calendar birth month.nnnRESULTSnADHD diagnoses and medication treatment were both significantly more common in individuals born in November/December versus January/February; peaking at ages 6 (OR: 1.8; 95% CI: 1.5-2.2) and 7xa0years (OR: 1.6; 95% CI: 1.3-1.8) in the Patient and Prescribed Drug Registers, respectively. We found no corresponding differences in parent- or self-reported ADHD symptoms by calendar birth month.nnnCONCLUSIONnRelative immaturity compared to class mates might contribute to ADHD diagnosis and pharmacotherapy despite absence of parallel findings in reported ADHD symptom loads by relative immaturity. Increased clinical awareness of this phenomenon may be warranted to decrease risk for imprecise diagnostics and treatment. We speculate that flexibility regarding age at school start according to individual maturity could reduce developmentally inappropriate demands on children and improve the precision of ADHD diagnostic practice and pharmacological treatment.

A study of the possible association between adenosine A2A receptor gene polymorphisms and attention-deficit hyperactivity disorder traits

The adenosine A2A receptor (ADORA2A) is linked to the dopamine neurotransmitter system and is also implicated in the regulation of alertness, suggesting a potential association with attention‐deficit hyperactivity disorder (ADHD) traits. Furthermore, animal studies suggest that the ADORA2A may influence ADHD‐like behavior. For that reason, the ADORA2A gene emerges as a promising candidate for studying the etiology of ADHD traits. The aim of this study was to examine the relationship between ADORA2A gene polymorphisms and ADHD traits in a large population‐based sample. This study was based on the Child and Adolescent Twin Study in Sweden (CATSS), and included 1747 twins. Attention‐deficit hyperactivity disorder traits were assessed through parental reports, and samples of DNA were collected. Associations between six single nucleotide polymorphisms (SNPs) and ADHD traits were examined, and results suggested a nominal association between ADHD traits and three of these SNPs: rs3761422, rs5751876 and rs35320474. For one of the SNPs, rs35320474, results remained significant after correction for multiple comparisons. These results indicate the possibility that the ADORA2A gene may be involved in ADHD traits. However, more studies replicating the present results are warranted before this association can be confirmed.

Stimulant and non-stimulant attention deficit/hyperactivity disorder drug use

Zetterqvist J, Asherson P, Halldner L, Långström N, Larsson H. Stimulant and non‐stimulant attention deficit/hyperactivity disorder drug use: total population study of trends and discontinuation patterns 2006–2009.

Stimulant and non-stimulant attention deficit/hyperactivity disorder drug use: total population study of trends and discontinuation patterns 2006-2009: ADHD drug use: total population study

Zetterqvist J, Asherson P, Halldner L, Långström N, Larsson H. Stimulant and non‐stimulant attention deficit/hyperactivity disorder drug use: total population study of trends and discontinuation patterns 2006–2009.