Attention-Deficit/Hyperactivity Disorder in adults. Clinical characteristics and pre- and perinatal risk factors

Attention-deficit/hyperactivity disorder (ADHD) is currently a prevalent diagnosis in child psychiatry, typically affecting 2-5 % of school-aged children world-wide. The recent and increasing awareness that ADHD may persist to adulthood for a considerable proportion of the affected children has created a need for more knowledge about ADHD as a lifespan disorder. Aims: The aims of the thesis were to: 1) assess occupational functioning among adults with ADHD; 2) explore the relationship between ADHD and mood disorders; 3) investigate the role of pregnancy- and birth related complications as possible risk factors for persistent ADHD; 4) study the effect of an impaired serotonin production in utero on the development of ADHD symptoms and related behaviour. Material and methods: The thesis is based on four separate articles (Paper I-IV). The first two papers are clinical studies based on questionnaires obtained from 414 and 510 adults with a clinical diagnosis of ADHD, respectively, and controls (n=359/417) from the general population. The third paper is an epidemiologic population-based study using data from the Medical Birth Registry of Norway (MBRN), in which we compared pre- and perinatal risk factors of a national cohort of 2123 adults with ADHD and the rest of the Norwegian adult population born in the same time period (n=1.17 million). The fourth study explores the possible causative role of reduced serotonin production in ADHD related symptoms and behaviour by studying the presence and effects of mutations in the tryptophan hydroxylase 1 gene (TPH1) in adult ADHD patients, their family members and controls. Results: In paper I we showed that only 24 % of adult ADHD patients (mean age 34.5 years) were currently in work, compared to 79 % of controls (mean age 29.9 years). Having been diagnosed and treated for ADHD in childhood was the strongest predictor for being in work as an adult, independently of symptom severity, psychiatric comorbidity, and current treatment (OR 3.2, p=0.014). In the second paper, 51 % of ADHD patients screened positive for a bipolar spectrum disorder (BSD) according to the Mood Disorder Questionnaire (MDQ), compared to 8.3 % of the controls. Patients screening positive for a BSD had lower occupational functioning and significantly more drug problems than patients with low levels of affective symptoms. In the epidemiological population-based study from the MBRN, we found that low birth weight, preterm birth, and low Apgar scores were associated with ADHD in adulthood, with the highest risk for the lowest measures. We also found that maternal epilepsy and infant oral cleft were associated with ADHD in the adult offspring. In the last study, sequencing of TPH1 in 646 adults (patients and controls) resulted in the identification of 7 different missense mutations, of which 6 resulted in reduced enzyme function in vitro compared to wild type TPH1. Family based analyses showed that offspring of mothers with TPH1 mutations had higher levels of ADHD related symptoms and behaviour, compared to offspring of fathers with such mutations or controls, independently of the individuals’ own TPH1 status. Conclusions: Adults with a clinical diagnosis of ADHD had an impaired occupational functioning and a high prevalence of comorbid psychiatric problems. Symptoms of affective disorders were frequent among adults with ADHD, and were associated with lower occupational functioning and more substance abuse. Patients who were diagnosed and treated for ADHD in childhood had a more favourable outcome in adult life compared to patients who were first diagnosed in adulthood. Factors indicating a suboptimal foetal development, such as being born extremely preterm or with very low birth weight, were associated with development of ADHD. Impaired maternal serotonin production in early embryonic life may be a causative pathway in the putative altered brain development, resulting in subsequent ADHD related symptoms and behaviours

Attention Network Test in adults with ADHD - the impact of affective fluctuations

Background: The Attention Network Test (ANT) generates measures of different aspects of attention/executive function. In the present study we investigated whether adults with ADHD performed different from controls on measures of accuracy, variability and vigilance as well as the control network. Secondly, we studied subgroups of adults with ADHD, expecting impairment on measures of the alerting and control networks in a subgroup with additional symptoms of affective fluctuations. Methods: A group of 114 adults (ADHD n = 58; controls n = 56) performed the ANT and completed the Adult ADHD Rating Scale (ASRS) and the Mood Disorder Questionnaire (MDQ). The latter was used to define affective fluctuations. Results: The sex distribution was similar in the two groups, but the ADHD group was significantly older (p = .005) and their score on a test of intellectual function (WASI) significantly lower than in the control group (p = .007). The two groups were not significantly different on measures of the three attention networks, but the ADHD group was generally less accurate (p = .001) and showed a higher variability through the task (p = .033). The significance was only retained for the accuracy measure when age and IQ scores were controlled for. Within the ADHD group, individuals reporting affective fluctuations (n = 22) were slower (p = .015) and obtained a lower score on the alerting network (p = .018) and a higher score on the conflict network (p = .023) than those without these symptoms. The significance was retained for the alerting network (p = .011), but not the conflict network (p = .061) when we controlled for the total ASRS and IQ scores. Discussion: Adults with ADHD were characterized by impairment on accuracy and variability measures calculated from the ANT. Within the ADHD group, adults reporting affective fluctuations seemed to be more alert (i.e., less impacted by alerting cues), but slower and more distracted by conflicting stimuli than the subgroup without such fluctuations. The results suggest that the two ADHD subgroups are characterized by distinct patterns of attentional problems, and that the symptoms assessed by MDQ contribute to the cognitive heterogeneity characterizing groups of individuals with ADHD

Attention-Deficit/Hyperactivity Disorder in Offspring of Mothers With Inflammatory and Immune System Diseases

AbstractBackgroundPrenatal inflammatory mechanisms may play a role in the pathogenesis of psychiatric disorders and could be relevant for attention-deficit/hyperactivity disorder (ADHD). We investigated maternal chronic somatic diseases with immune components as possible risk factors for ADHD in offspring.MethodsWe performed a population-based nested case-control study by linking data from longitudinal Norwegian registers. We included all individuals born during the period 1967–2008 and alive at record linkage (2012). Individuals receiving ADHD medication during the years 2004–2012 were defined as patients with ADHD (N = 47,944), and all remaining individuals (N = 2,274,713) were defined as control subjects. The associations between maternal diseases and ADHD in offspring were analyzed using logistic regression models.ResultsThe following chronic diseases with immune components were related to ADHD in offspring: multiple sclerosis (adjusted odds ratio [OR] = 1.8; 95% confidence interval [CI] = 1.2–2.5), rheumatoid arthritis (adjusted OR = 1.7; 95% CI = 1.5–1.9), type 1 diabetes (adjusted OR = 1.6; 95% CI = 1.3–2.0), asthma (adjusted OR = 1.5; 95% CI = 1.4–1.6), and hypothyroidism (adjusted OR = 1.2; 95% CI = 1.1–1.4). In contrast, chronic hypertension and type 2 diabetes showed no significant associations. Estimates were almost unchanged with additional adjustment for parental ADHD, infant birth weight, and gestational age. Although point estimates for male and female offspring were different for some diseases (e.g., maternal asthma [adjusted OR = 1.7; 95% CI = 1.5–1.8 for female offspring and adjusted OR = 1.5; 95% CI = 1.4–1.6 for male offspring]), none of the associations differed significantly by offspring sex.ConclusionsSeveral maternal somatic diseases with immune components were found to increase the risk of ADHD in offspring. The associations could involve several causal pathways, including common genetic predisposition and environmental factors, and increased insight into the mechanisms behind these relationships could enhance our understanding of the etiology of ADHD

A systematic meta-review of systematic reviews on attention deficit hyperactivity disorder

Background. There are now hundreds of systematic reviews on attention deficit hyperactivity disorder (ADHD) of variable quality. To help navigate this literature, we have reviewed systematic reviews on any topic on ADHD. Methods. We searched MEDLINE, PubMed, PsycINFO, Cochrane Library, and Web of Science and performed quality assessment according to the Joanna Briggs Institute Manual for Evidence Synthesis. A total of 231 systematic reviews and meta-analyses met the eligibility criteria. Results. The prevalence of ADHD was 7.2% for children and adolescents and 2.5% for adults, though with major uncertainty due to methodological variation in the existing literature. There is evidence for both biological and social risk factors for ADHD, but this evidence is mostly correlational rather than causal due to confounding and reverse causality. There is strong evidence for the efficacy of pharmacological treatment on symptom reduction in the shortterm, particularly for stimulants. However, there is limited evidence for the efficacy of pharmacotherapy in mitigating adverse life trajectories such as educational attainment, employment, substance abuse, injuries, suicides, crime, and comorbid mental and somatic conditions. Pharmacotherapy is linked with side effects like disturbed sleep, reduced appetite, and increased blood pressure, but less is known about potential adverse effects after long-term use. Evidence of the efficacy of nonpharmacological treatments is mixed. Conclusions. Despite hundreds of systematic reviews on ADHD, key questions are still unanswered. Evidence gaps remain as to a more accurate prevalence of ADHD, whether documented risk factors are causal, the efficacy of nonpharmacological treatments on any outcomes, and pharmacotherapy in mitigating the adverse outcomes associated with ADHD

Goal management training improves executive control in adults with ADHD: an open trial employing attention network theory to examine effects on attention

Background Adults with Attention-Deficit/Hyperactivity Disorder (ADHD) typically experience poorer attentional control. According to the attention network theory, attentional control relies on three interacting networks of alerting, orienting, and executive control. In ADHD, it is mainly the alerting and executive control networks that are suggested and found to be compromised. Methods In the current study, we investigated if a group-based metacognitive remediation program (Goal Management Training [GMT]) in adults with ADHD would enhance attentional control using an experimental measure of the attention network theory. We expected that GMT would specifically enhance the executive control and alerting networks. Results Data from post- and follow up-assessments of 21 adults (age: 39.05 [11.93]) with ADHD who had completed GMT were included. Linear mixed-effects modeling revealed significant improvements in the functioning of the executive control network for the majority of the participants, although a small subset of participants showed a negative development following the intervention. Results also showed an improvement in the orienting network at follow up, but no change in the alerting network. Conclusion The results may indicate that improvements in the functioning of the executive control network are central to the positive effects of GMT reported in disorders characterized by impaired attentional control.publishedVersio

Variation in attitudes toward diagnosis and medication of ADHD: a survey among clinicians in the Norwegian child and adolescent mental health services

Prevalence and medication rates of ADHD vary geographically, both between and within countries. No absolute cutof exists between ADHD and normal behavior, making clinician attitudes (leading to local practice cultures) a potential explanation for the observed variation in diagnosis and medication rates. The objective of this study was to describe variation in attitudes toward diagnosis and medication of ADHD among clinicians working in child and adolescent mental health services (CAMHS). We hypothesized that attitudes would vary along a spectrum from “restrictive” to “liberal”. We also explored whether diferences in attitudes between clinicians were related to professional background and workplace (clinic). A survey in the form of a web-based questionnaire was developed. All CAMHS outpatient clinics in Norway were invited. Potential respondents were all clinicians involved in diagnosing and treating children and adolescents with ADHD. To investigate the existence of attitudes toward diagnosis and medication as latent constructs, we applied confrmatory factor analysis (CFA). We further examined how much of variance in attitudes could be ascribed to profession and clinics by estimating intraclass correlation coefcients. In total, 674 respondents representing 77 (88%) of the clinics participated. We confrmed variation in attitudes with average responses leaning toward the “restrictive” end of the spectrum. CFA supported “attitude toward diagnosis” and “attitude toward medication” as separate, and moderately correlated (r=0.4) latent variables, representing a scale from restrictive to liberal. Professional background and workplace explained only a small part of variance in these attitudes

Sex differences in parent–offspring recurrence of attention-deficit/hyperactivity disorder

Background Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder sharing genetic risk factors with other common psychiatric disorders. However, intergenerational recurrence patterns of ADHD from parents to sons and daughters are not known. We aimed to examine the risk of ADHD in offspring of parents with ADHD and parents with other psychiatric disorders by parental and offspring sex, using parents without the specific disorders as comparison. Methods In a generation study linking data from several population-based registries, all Norwegians born 1967–2011 (n = 2,486,088; Medical Birth Registry of Norway) and their parents were followed to 2015. To estimate intergenerational recurrence risk, we calculated prevalence differences (PD) and the relative risk (RR) of ADHD in offspring by parental ADHD, bipolar disorder (BD), schizophrenia spectrum disorder (SCZ), major depression (MDD), all by parental and offspring sex. Results The absolute prevalence of ADHD in offspring of parents with ADHD was very high, especially in sons of two affected parents (41.5% and 25.1% in sons and daughters, respectively), and far higher than in offspring of parents with BD, SCZ or MDD. Intergenerational recurrence risks were higher for maternal than paternal ADHD (RRmaternal 8.4, 95% confidence interval (CI) 8.2–8.6 vs. RRpaternal 6.2, 6.0–6.4) and this was also true on the absolute scale (PDmaternal 21.1% (20.5–21.7) vs. PDpaternal 14.8% (14.3–15.4)). RRs were higher in daughters, while PDs higher in sons. Parental SCZ, BD and MDD were associated with an approximately doubled risk of offspring ADHD compared to parents without the respective disorders, and estimates did not differ significantly between daughters and sons. Conclusions The intergenerational recurrence risks of ADHD were high and higher from mothers with ADHD than fathers with ADHD. Other parental psychiatric disorders also conferred increased risk of offspring ADHD, but far lower, indicating a sex- and diagnosis-specific intergenerational recurrence risk in parents with ADHD.publishedVersio

Cyclothymic temperament: Associations with ADHD, other psychopathology, and medical morbidity in the general population

Under embargo until: 2020-08-19Background: Cyclothymic temperament (CT) is an affective disposition often preceding bipolar disorder (BD), and is the most common affective temperament in patients with BD. In depressed patients, CT is a predictor for developing a bipolar course. In a clinical sample of adults with BD and attention deficit hyperactivity disorder (ADHD), CT was associated with higher loads of psychiatric symptoms, somatic comorbidity, impairment, and higher morbidity among first-degree relatives. We aimed to investigate the morbidity and occupational functioning of persons with CT in the general population. Methods: Randomly recruited Norwegian adults (n = 721) were assessed with a 21-item cyclothymic subscale from the TEMPS Autoquestionnaire. Self-reported data were collected on psychiatric symptoms, comorbidity, educational and occupational level, and known family morbidity. Results: Thirteen percent had CT associated with an increased prevalence of ADHD, BD, high scores on the Mood Disorder Questionnaire (MDQ), and childhood and adulthood ADHD symptoms. CT was found in 75% (p < .001) of the bipolar participants, and in 68% (p < .001) of those with a positive MDQ score. CT was associated with more anxiety/depression, substance and alcohol problems, lower educational and occupational levels, and having a first-degree relative with anxiety/depression, alcohol problems, ADHD, and BD. Limitations: The CT subscale alone might include overlapping features with cyclothymic, anxious, irritable, and depressed temperaments, thus increasing the prevalence estimate of CT. Conclusions: CT is a strong predictor of occupational failure and associated with more psychiatric impairment in the participants and their families. CT should be assessed in both mood disorder and ADHD patients.acceptedVersio

Physical exercise augmented cognitive behaviour therapy for older adults with generalised anxiety disorder (PEXACOG): a feasibility study for a randomized controlled trial

Background Generalised anxiety disorder (GAD) is a frequent and severe disorder among older adults. For older adults with GAD the effect of the recommended treatment, cognitive behaviour therapy (CBT), is reduced. Physical exercise (PE) may enhance the effect of CBT by improving cognitive function and increasing levels of brain-derived neurotrophic factor (BDNF), a predictor of the effect of CBT in patients with anxiety. The aim of the study was to assess the feasibility of a randomized controlled trial (RCT) investigating treatment effect of the combination of CBT and PE for GAD in a sample of older adults, including procedures for assessment and treatment. Methods Four participants aged 62–70 years (M = 65.5, SD = 3.2) with a primary diagnosis of GAD were included. Participants received 15 weeks of PE in combination with 10 weeks of CBT. Participants completed self-report measures, and clinical, biological, physiological and neuropsychological tests at pre-, interim- and post-treatment. Results Procedures, protocols, and results are presented. One participant dropped out during treatment. For the three participants completing, the total adherence to PE and CBT was 80% and 100%, respectively. An independent assessor concluded that the completers no longer fulfilled the criteria for GAD after treatment. Changes in self-report measures suggest symptom reduction related to anxiety and worry. The sample is considered representative for the target population. Conclusions The results indicate that combining CBT and PE for older adults with GAD is feasible, and that the procedures and tests are suitable and manageable for the current sample.publishedVersio

On the role of NOS1 ex1f-VNTR in ADHD – allelic, subgroup, and meta-analysis

Attention deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder featuring complex genetics with common and rare variants contributing to disease risk. In a high proportion of cases, ADHD does not remit during adolescence but persists into adulthood. Several studies suggest that NOS1, encoding nitric oxide synthase I, producing the gaseous neurotransmitter NO, is a candidate gene for (adult) ADHD. We here extended our analysis by increasing the original sample, adding two further samples from Norway and Spain, and conducted subgroup and co-morbidity analysis. Our previous finding held true in the extended sample, and also meta-analysis demonstrated an association of NOS1 ex1fVNTR short alleles with adult ADHD (aADHD). Association was restricted to females, as was the case in the discovery sample. Subgroup analysis on the single allele level suggested that the repeat allele caused the association. Regarding subgroups, we found that NOS1 was associated with the hyperactive/impulsive ADHD subtype, but not to pure inattention. In terms of comorbidity, major depression, anxiety disorders, cluster C personality disorders and migraine were associated with short repeats, in particular the repeat allele. Also, short allele carriers had significantly lower IQ. Finally, we again demonstrated an influence of the repeat on gene expression in human post-mortem brain samples. These data validate the role of NOS-I in hyperactive/impulsive phenotypes and call for further studies into the neurobiological underpinnings of this association.PostprintPeer reviewe