Genome Guided Personalized Drug Therapy in Attention Deficit Hyperactivity Disorder

ADHD is a common behavioral syndrome with a heritability of 70–80%. Genome wide sequencing and association studies indicate that ADHD risk variants are distributed across a wide range of allele frequencies and relative risks. Several common single nucleotide variants (SNPs) have been identified that increase the risk of ADHD with a few percent. Many of the reported risk genes and copy number variants are shared with other neuropsychiatric disorders. Moreover, ADHD often coexists with common or rare somatic diseases, including rare Mendelian neurometabolic diseases that can affect normal brain development and function. Some genetic/metabolic syndromes masquerading as common ADHD may lead to irreversible brain damage if not properly identified and treated during early childhood. As ADHD is such a heterogeneous condition in terms of severity, clinical features and most probably also underlying biology, it is crucial to offer individualized treatments. Recent progress in ADHD genetics is reviewed, prospects of using this information for targeted pharmacotherapy are discussed and critical knowledge gaps are identified. It is suggested that genome guided therapies could be introduced gradually, starting with rare ADHD syndromes with highly penetrant risk genes. Routine diagnostic application of whole exome or whole genome sequencing combined with metabolomic screening, and brain imaging may be needed in cases with suspected neurometabolic disorders. Identification and treatment of ADHD patients with defined neurometabolic aberrations could be a first step toward genome guided personalized treatment of ADHD. Possibly, screening for relevant biomarkers may gradually be implemented to guide treatment choices in larger patient groups.publishedVersio

Insomnia, Alcohol Consumption and ADHD Symptoms in Adults

Introduction Substance use disorders and insomnia are common in the general population, and particularly among adults with attention-deficit/hyperactivity disorder (ADHD). Here we investigated the relationship between insomnia, alcohol consumption and ADHD symptoms. Methods: Adults with an ADHD diagnosis (n = 235, 41.3% males) and controls (n = 184, 38% males) completed a questionnaire assessing insomnia (Bergen Insomnia Scale), alcohol consumption (Alcohol Use Disorders Identification Test), and current ADHD symptoms (Adult ADHD Self-report Scale). The majority of the sample (95%) gave additional information about childhood ADHD symptoms (Wender Utah Rating Scale), and information about lifetime occurrence of an internalizing disorder was included as part of background information. Results: Compared to controls, the ADHD group reported a higher frequency of insomnia, a higher quantity of consumed alcohol and a higher frequency of internalizing disorders. Current and childhood ADHD symptoms were more severe in those with than without insomnia. Scores on ADHD symptom scales were explained by the presence of insomnia and internalizing disorders, while the contribution from alcohol consumption was restricted to the control group. Discussion: The high functional impact of insomnia, alcohol misuse and internalizing disorders is well known. The present study contributed by focusing on their relations to ADHD symptoms, and by showing that strong relations were not restricted to adults with a clinical ADHD diagnosis. By this, the results put a critical light on a categorical delineation between adults with an ADHD diagnosis and population selected controls, and call for further studies including dimensional metrics of ADHD symptoms and co-occurring problems.publishedVersio

The 14-3-3 proteins in regulation of cellular metabolism

AbstractThirty years ago, it was discovered that 14-3-3 proteins could activate enzymes involved in amino acid metabolism. In the following decades, 14-3-3s have been shown to be involved in many different signaling pathways that modulate cellular and whole body energy and nutrient homeostasis. Large scale screening for cellular binding partners of 14-3-3 has identified numerous proteins that participate in regulation of metabolic pathways, although only a minority of these targets have yet been subject to detailed studies. Because of the wide distribution of potential 14-3-3 targets and the resurging interest in metabolic pathway control in diseases like cancer, diabetes, obesity and cardiovascular disease, we review the role of 14-3-3 proteins in the regulation of core and specialized cellular metabolic functions. We cite illustrative examples of 14-3-3 action through their direct modulation of individual enzymes and through regulation of master switches in cellular pathways, such as insulin signaling, mTOR- and AMP dependent kinase signaling pathways, as well as regulation of autophagy. We further illustrate the quantitative impact of 14-3-3 association on signal response at the target protein level and we discuss implications of recent findings showing 14-3-3 protein membrane binding of target proteins

Functional studies of tyrosine hydroxylase missense variants reveal distinct patterns of molecular defects in dopa-responsive dystonia

Congenital tyrosine hydroxylase deficiency (THD) is found in autosomal-recessive Dopa-responsive dystonia and related neurological syndromes. The clinical manifestations of THD are variable, ranging from early-onset lethal disease to mild Parkinson disease-like symptoms appearing in adolescence. Until 2014, approximately 70 THD patients with a total of 40 different disease-related missense mutations, five nonsense mutations, and three mutations in the promoter region of the tyrosine hydroxylase (TH) gene have been reported. We collected clinical and biochemical data in the literature for all variants, and also generated mutant forms of TH variants previously not studied (N = 23). We compared the in vitro solubility, thermal stability, and kinetic properties of the TH variants to determine the cause(s) of their impaired enzyme activity, and found great heterogeneity in all these properties among the mutated forms. Some TH variants had specific kinetic anomalies and phenylalanine hydroxylase, and Dopa oxidase activities were measured for variants that showed signs of altered substrate binding. p.Arg233His, p.Gly247Ser, and p.Phe375Leu had shifted substrate specificity from tyrosine to phenylalanine and Dopa, whereas p.Cys359Phe had an impaired activity toward these substrates. The new data about pathogenic mechanisms presented are expected to contribute to develop individualized therapy for THD patients.publishedVersio

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

Male to female ratios in autism spectrum disorders by age, intellectual disability and attention-deficit/hyperactivity disorder

Objective To examine the gender distribution in ASD in adults compared with children and the impact of comorbid intellectual disability (ID) and attention-deficit/hyperactivity disorder (ADHD) on the male to female ratio (MFR). Methods We estimated the MFR and the male prevalence ratio (PR) for ASD in adults and children using the Medical Birth Registry of Norway, including all individuals born during 1967–2011. We examined variation with age, comorbid ID and ADHD as defined by diagnoses in the Norwegian Patient Registry during 2008–2015 and/or a dispensed prescription for ADHD medication. Results The sample included 1,701,206 adults and 804,146 children, including 8,995 (0.5%) adults and 8,056 (1.0%) children with ASD, 53,822 (3.2%) adults and 26,967 (3.4%) children with ADHD and 9,178 (0.5%) adults and 5,038 (0.6%) children with ID. The MFR for ASD was 3.67 in children and 2.57 in adults, corresponding to a male PR in ASD of 1.54 (95% CI 1.53–1.56) and 1.41 (1.39–1.24), respectively. Comorbid ID decreased the MFR and the male PR in both adults and children, whereas comorbid ADHD significantly increased the male PR in children. The MFR and the population prevalence of ASD, ADHD and ID decreased from children to younger adults and yet further to older adults. Conclusion We found a lower MFR and male PR in adults than in children. Findings suggest the strong male predominance seen in childhood/clinical studies of ASD diminishes in adult samples, possibly reflecting the influence of non-aetiological factors such as later diagnosis in females, diagnostic biases and diagnostic trends.publishedVersio

Validity and accuracy of the Adult Attention-Deficit/Hyperactivity Disorder (ADHD) Self-Report Scale (ASRS) and the Wender Utah Rating Scale (WURS) symptom checklists in discriminating between adults with and without ADHD

Objective To validate the Adult ADHD Self‐Report Scale (ASRS) and the Wender Utah Rating Scale (WURS) in a well‐characterized sample of adult attention‐deficit/hyperactivity disorder (ADHD) patients and population controls. Methods Both the ASRS and the WURS were administered to clinically diagnosed adult ADHD patients (n = 646) and to population controls (n = 908). We performed principal component analyses (PCA) and calculated receiver operating curves (ROC) including area under the curve (AUC) for the full WURS and ASRS, as well as for the PCA generated factors and the ASRS short screener. Results We found an AUC of 0.956 (95% CI: 0.946–0.965) for the WURS, and 0.904 (95% CI: 0.888–0.921) for the ASRS. The ASRS short screener had an AUC of 0.903 (95%CI: 0.886–0.920). Combining the two full scales gave an AUC of 0.964 (95% CI: 0.955–0.973). We replicated the two‐factor structure of the ASRS and found a three‐factor model for the WURS. Conclusion The WURS and the ASRS both have high diagnostic accuracy. The short ASRS screener performed equally well as the full ASRS, whereas the WURS had the best discriminatory properties. The increased diagnostic accuracy may be due to the wider symptom range of the WURS and/or the retrospective childhood frame of symptoms.publishedVersio

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

ADHD symptoms in neurometabolic diseases: Underlying mechanisms and clinical implications

Neurometabolic diseases (NMDs) are typically caused by genetic abnormalities affecting enzyme functions, which in turn interfere with normal development and activity of the nervous system. Although the individual disorders are rare, NMDs are collectively relatively common and often lead to lifelong difficulties and high societal costs. Neuropsychiatric manifestations, including ADHD symptoms, are prominent in many NMDs, also when the primary biochemical defect originates in cells and tissues outside the nervous system. ADHD symptoms have been described in phenylketonuria, tyrosinemias, alkaptonuria, succinic semialdehyde dehydrogenase deficiency, X-linked ichthyosis, maple syrup urine disease, and several mitochondrial disorders, but are probably present in many other NMDs and may pose diagnostic and therapeutic challenges. Here we review current literature linking NMDs with ADHD symptoms. We cite emerging evidence that many NMDs converge on common neurochemical mechanisms that interfere with monoamine neurotransmitter synthesis, transport, metabolism, or receptor functions, mechanisms that are also considered central in ADHD pathophysiology and treatment. Finally, we discuss the therapeutic implications of these findings and propose a path forward to increase our understanding of these relationships.publishedVersio

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