Anne Halmøy

Occupational Outcome in Adult ADHD: Impact of Symptom Profile, Comorbid Psychiatric Problems, and Treatment A Cross-Sectional Study of 414 Clinically Diagnosed Adult ADHD Patients

Objective: To determine the effects of symptom profile, comorbid psychiatric problems, and treatment on occupational outcome in adult ADHD patients. Method: Adult ADHD patients (N = 414) responded to questionnaires rating past and present symptoms of ADHD, comorbid conditions, treatment history, and work status. Results: Of the patients, 24% reported being in work, compared to 79% in a population-based control group (N = 359). Combined subtype of ADHD, substance abuse, and a reported history of depression or anxiety were correlated with being out of work. Current and past medical treatment of ADHD was correlated with being in work. Logistic regression analyses showed that stimulant therapy during childhood was the strongest predictor for being in work as adults (odds ratio = 3.2, p = .014). Conclusion: Early recognition and treatment of ADHD is a strong predictor of being in work as an adult, independently of comorbidity, substance abuse, and current treatment. (J. of Att. Dis. 2009; 13(2) 175-187)

Multicenter Analysis of the SLC6A3/DAT1 VNTR Haplotype in Persistent ADHD Suggests Differential Involvement of the Gene in Childhood and Persistent ADHD

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4–5% in children and 1–4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3′-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3′-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.

Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies.

Attention-deficit/hyperactivity disorder (ADHD) is a common disorder of childhood that often persists into adulthood. Although stimulant medications are recommended as the first-line treatment for ADHD because of their documented short-term effects in children and adults, less is known about their effects on long-term outcome in adults. Here we review the long-term efficacy and safety of the stimulant drugs methylphenidate and amphetamine, as well as the related compound atomoxetine. We performed a systematic review to identify direct and indirect effects of stimulant therapy on long-term outcome in adults. Five randomized controlled trials (RCTs), and 10 open-label extension studies of initial short-term RCTs, with total follow-up of at least 24weeks, were identified. All these RCTs found that medication was significantly more efficacious than placebo in treating ADHD in adults, and the extension studies showed that this favorable effect of medication was maintained during the open-label follow-up period. However, since the maximum duration of these pharmacological trials was 4years, we also reviewed 18 defined naturalistic longitudinal and cross-sectional studies, to provide more information about longer term functional outcomes, side effects and complications. These observational studies also showed positive correlations between early recognition of the disorder, stimulant treatment during childhood and favorable long-term outcome in adult ADHD patients. In conclusion, stimulant therapy of ADHD has long-term beneficial effects and is well tolerated. However, more longitudinal studies of long duration should be performed. In addition, the ethical issues involved in performing double blind RCTs of many years duration should be further explored.

Pre- and Perinatal Risk Factors in Adults with Attention-Deficit/Hyperactivity Disorder

BACKGROUND Attention-deficit/hyperactivity disorder (ADHD) is a prevalent and disabling lifespan disorder, but little is yet known about risk factors for ADHD persisting beyond adolescence. The present study investigates the association between pregnancy and birth complications and ADHD in adulthood. METHODS We used data from the Medical Birth Registry of Norway to compare pre-and perinatal risk factors among 2323 adults approved for medical treatment for ADHD, with the remaining population born during the same years, 1967-1987, and surviving into adulthood (n = 1,170,073). Relative risks (RR) adjusted for potential confounders were calculated. RESULTS Preterm (< 37 weeks of gestation) and extremely preterm birth (< 28 weeks of gestation) were associated with 1.3- and 5-fold increased risks of ADHD, respectively. Birth weights <2500 g and <1500 g also increased the risk of ADHD (RR: 1.5, 95% confidence interval [CI]: 1.2-1.8, and RR: 2.1, 95% CI: 1.3-3.6, respectively). Five-minute Apgar scores <4 and <7 were associated with 2.8- and 1.5-fold increased risks of persisting ADHD, respectively. Maternal epilepsy (RR: 1.7, 95% CI: 1.1-2.7) and offspring oral cleft (RR: 2.8, 95% CI: 1.6-4.9) occurred more frequently among adult ADHD patients. CONCLUSIONS This is the first population-based study of pre-and perinatal risk factors in adults with ADHD. We show that low birth weight, preterm birth, and low Apgar scores increase the risk of ADHD, persisting up to 40 years after birth. The increased risk of ADHD related to oral cleft and to maternal epilepsy warrants further investigation to explore possible causal mechanisms.

Clinical assessment and diagnosis of adults with attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a prevalent disorder in adult psychiatry, particularly in out-patient settings. There are no objective, laboratory-based tests that can establish this diagnosis. Present diagnostic criteria for ADHD are formulated primarily according to behavior in childhood, based on age inappropriate and impairing levels of hyperactivity, impulsivity and inattention. Other symptoms, such as mood instability and frustration intolerance, are not included in current criteria for ADHD, but are very prevalent in this patient group. ADHD is often comorbid with alcohol and substance abuse and other psychiatric disorders, in particular anxiety and personality disorders. Thus, the diagnostic assessment should both include a comprehensive clinical interview, rating scales for past and present symptoms and collateral information from multiple informants, as well as assessment of a broader spectrum of psychiatric and somatic conditions. As ADHD is associated with changes in brain function mediating different aspects of neuropsychological functions, assessment of those functions is important to understand the symptom patterns and to develop targeted treatment programs. Some topics for further research and for future developments of diagnostic criteria and tools are highlighted.

Genetic Analyses of Dopamine Related Genes in Adult ADHD Patients Suggest an Association With the DRD5-Microsatellite Repeat, But Not With DRD4 or SLC6A3 VNTRs

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable psychiatric disorder in children and adults. Recent meta‐analyses have indicated an association between genes involved in dopaminergic signaling and childhood ADHD, but little is known about their possible role in adult ADHD. In this study of adults with ADHD, we evaluated the three most commonly studied ADHD candidate genetic polymorphisms; the dopamine receptor D4 (DRD4) exon 3 VNTR repeat, a microsatellite repeat 18.5 kb upstream of the DRD5 locus and the 3′UTR dopamine transporter SLC6A3 (DAT 1) VNTR. We examined 358 clinically diagnosed adult Norwegian ADHD patients (51% males) and 340 ethnically matched controls. We found a nominally significant overall association with adult ADHD for the DRD5 microsatellite marker (P = 0.04), and a trend toward increased risk associated with the 148‐bp allele consistent with recent meta‐analyses. The strongest overall association (P = 0.02) and increased risk for the 148‐bp allele [odds ratio (OR) = 1.27 (95% CI: 1.00–1.61)] were seen in the inattentive and combined inattentive/hyperactive group as previously reported for childhood ADHD. No association was found for the DRD4 or SLC6A3 polymorphisms in this patient sample. In conclusion, our results among adults with a clinical diagnosis of ADHD support an association between ADHD and the DRD5 locus, but not the DRD4 or SLC6A3 loci. It is possible that the latter polymorphisms are associated with a transient form of ADHD with better long‐term clinical outcome.

Association between catechol O-methyltransferase (COMT) haplotypes and severity of hyperactivity symptoms in adults.

It has been suggested that symptoms of attention‐deficit/hyperactivity disorder (ADHD) is related to low dopamine levels in the prefrontal cortex. The enzyme catechol O‐methyltransferase (COMT), which degrades dopamine and other catecholamines, is important for monoamine signaling in this brain‐region, but genetic studies of the functional Val158Met (rs4680) polymorphism in ADHD have been inconsistent. However, recently it was shown that also common synonymous COMT variants modulate total COMT enzymatic activity by affecting the expression of the gene [Nackley et al. (2006); Science 314(5807):1930–1933]. We therefore hypothesized that analysis of haplotypes could reveal more about the association between COMT and ADHD symptoms than the Val158Met polymorphism alone. SNPs rs6269, rs4633, rs4818, and rs4680, tagging the common putative functional COMT haplotypes, were genotyped in 435 adult subjects with a clinical diagnosis of ADHD and 383 controls and analyzed for association with ADHD and the hyperactivity/impulsivity and inattention dimensions from the Adult ADHD Self‐Report Scale (ASRS). All markers showed a trend for association with the hyperactivity/impulsivity scale, peaking at marker rs6269 (P = 0.007). Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT‐activity haplotype, which is associated with the highest hyperactivity/impulsivity score in our sample (P = 0.01). Our results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, we suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies.

Bipolar Symptoms in Adult Attention-Deficit/Hyperactivity Disorder: A Cross-Sectional Study of 510 Clinically Diagnosed Patients and 417 Population-Based Controls

OBJECTIVE Bipolar spectrum disorders (BSD) have several symptoms and features in common with attention-deficit/hyperactivity disorder (ADHD). Here we explored the prevalence of BSD and the relationship between symptoms of BSD and ADHD in adult ADHD patients. METHOD Norwegian adults diagnosed with DSM-IV ADHD during 1997 through 2007 (n = 510) and a random sample of 417 controls from the general population (aged 18-40 years) were recruited and responded to 85 questions rating symptoms of ADHD, lifetime symptoms of mood disorders, other comorbid conditions, and sociodemographic data. RESULTS According to the Mood Disorder Questionnaire (MDQ), 50.6% of the ADHD patients screened positive for BSD, compared to 8.3% of the controls. In comparison, the prevalence of BSD according to DSM-IV in a subsample of interviewed patients (n = 50) was 32%. In the whole study sample (N = 927), an ADHD diagnosis was the strongest predictor for screening positive on the MDQ (OR = 5.0, P < .001), but the correlation between dimensional symptom levels of ADHD and of BSD was strongest in the control group (Pearson correlation r = 0.7, P < .001 vs r = 0.3, P < .001). Patients screening positive on the MDQ had significantly more drug problems, higher ADHD symptom scores, and lower educational and occupational levels. CONCLUSIONS Our findings illustrate the close relationship between some symptoms of BSD and ADHD in adults. In clinical and research settings, patients screening positive for BSD should be assessed for a possible underlying or coexisting ADHD condition and vice versa.

An international multicenter association study of the serotonin transporter gene in persistent ADHD.

Attention deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting children and adults. It has been suggested that gene variants related to serotonin neurotransmission are associated with ADHD. We tested the functional promoter polymorphism 5‐HTTLPR and seven single nucleotide polymorphisms in SLC6A4 for association with ADHD in 448 adult ADHD patients and 580 controls from Norway. Replication attempts were performed in a sample of 1454 Caucasian adult ADHD patients and 1302 controls from Germany, Spain, the Netherlands and USA, and a meta‐analysis was performed also including a previously published adult ADHD study. We found an association between ADHD and rs140700 [odds ratio (OR ) = 0.67; P = 0.01] and the short (S) allele of the 5‐HTTLPR (OR = 1.19; P = 0.06) in the Norwegian sample. Analysis of a possible gender effect suggested that the association might be restricted to females (rs140700: OR = 0.45; P = 0.00084). However, the meta‐analysis of 1894 cases and 1878 controls could not confirm the association for rs140700 [OR = 0.85, 95% confidence interval (CI) = 0.67–1.09; P = 0.20]. For 5‐HTTLPR, five of six samples showed a slight overrepresentation of the S allele in patients, but meta‐analysis refuted a strong effect (OR = 1.10, 95% CI = 1.00–1.21; P = 0.06). Neither marker showed any evidence of differential effects for ADHD subtype, gender or symptoms of depression/anxiety. In conclusion, our results do not support a major role for SLC6A4 common variants in persistent ADHD, although a modest effect of the 5‐HTTLPR and a role for rare variants cannot be excluded.

A genome-wide association study of bipolar disorder and comorbid migraine.

Both migraine and bipolar affective disorder (BPAD) are complex phenotypes with significant genetic and nongenetic components. Epidemiological and clinical studies have showed a high degree of comorbidity between migraine and BPAD, and overlapping regions of linkage have been shown in numerous genome‐wide linkage studies. To identify susceptibility factors for the BPAD/migraine phenotype, we conducted a genome‐wide association study (GWAS) in 1001 cases with bipolar disorder collected through the NIMH Genetics Initiative for Bipolar Disorder and genotyped at 1 m single‐nucleotide polymorphisms (SNPs) as part of the Genetic Association Information Network (GAIN). We compared BPAD patients without any headache (n = 699) with BPAD patients with doctor diagnosed migraine (n = 56). The strongest evidence for association was found for several SNPs in a 317‐kb region encompassing the uncharacterized geneKIAA0564 {e.g. rs9566845 [OR = 4.98 (95% CI: 2.6–9.48), P = 7.7 × 10−8] and rs9566867 (P = 8.2 × 10−8)}. Although the level of signficance was significantly reduced when using the Fishers exact test (as a result of the low count of cases with migraine), rs9566845 P = 1.4 × 10−5 and rs9566867 P = 1.5 × 10−5, this region remained the most prominent finding. Furthermore, marker rs9566845 was genotyped and found associated with migraine in an independent Norwegian sample of adult attention deficit hyperactivity disorder (ADHD) patients with and without comorbid migraine (n = 131 and n = 324, respectively), OR = 2.42 (1.18–4.97), P = 0.013. This is the first GWAS examining patients with bipolar disorder and comorbid migraine. These data suggest that genetic variants in the KIAA0564 gene region may predispose to migraine headaches in subgroups of patients with both BPAD and ADHD.