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OBJECTIVE: Sleep disturbances are highly frequent features in a range of child and adolescent psychiatric conditions. However, it is commonly not clear if such sleep problems represent symptomatic features, co-morbidities or risk factors for these conditions. It is believed that underlying dysfunction in the daily biological (circadian) clock may play important roles in the etiology of many sleep disorders, and circadian rhythm changes are also reported in a number of neuropsychiatric conditions. Here we explore the key identifying features of circadian rhythm disorders in child and adolescent psychiatry, and address how such disorders may be managed in the clinic. METHOD: A narrative review of the extant literature of circadian rhythm disorders in children and adolescents with psychiatric conditions. RESULTS: We identify key biological and social factors that contribute to circadian rhythm disorders in children and adolescents, as well as outlining the cognitive and neurobehavioral consequences resulting from insufficient sleep. We outline the roles of melatonin and other chronotherapeutic and behavioral interventions for the management of circadian rhythm disorders. Further, we highlight the importance of careful investigation of circadian rhythm abnormalities in shaping the most effective treatment plan according to chronobiological principles. CONCLUSION: Circadian rhythm disorders are common in children and adolescents with psychiatric conditions, and arise out of complex interactions between biological and social factors. Careful clinical attention to, and management of, circadian rhythm disorders in child and adolescent psychiatry has the potential for significant benefit not only in the domain of sleep but also in a range of cognitive, affective and behavioral outcomes.

This is the first study to assess the prevalence of symptoms of premenstrual dysphoric disorder (PMDD), episodes of postpartum depression symptoms (PPD) after first childbirth, and climacteric mood symptoms in Attention-Deficit/Hyperactivity Disorder (ADHD). 209 consecutive women (18–71 years) with ADHD completed the PMDD chapter of the Neuropsychiatric Interview Plus version 5.0.0 to assess PMDD, the Edinburgh Postnatal Depression Scale to assess PPD, and the Greene Climacteric Scale to assess climacteric symptoms. Comorbid psychiatric disorders, medication use, and chronobiological sleep characteristics were also assessed. The prevalence of PMDD and PPD were high in ADHD, compared to the general population. PMDD symptoms were associated with less use of contraceptives. Antidepressants were associated with more PMDD symptoms. The following GCS scores were significant increased: anxiety, depression, and sexual dysfunction, vasomotor and somatic complaints. No significant differences were found in sleep characteristics or current comorbidity between the groups with and without PPD or PMDD, or increased climacteric scores. The prevalences of PMDD, PPD and climacteric scores were high in women with ADHD. This is the first study in women with ADHD that suggests that female ADHD patients suffer from significant PMDD symptoms, experience PPD during the first child birth, and experience more severe climacteric symptoms.

Background This study was to assess the validity of the Korean version of the semi-structured Diagnostic Interview for Adult ADHD, third edition (DIVA-5). The secondary aim was to compare sociodemographic and psychiatric comorbidities in adult patients with and without a diagnosis of ADHD. Methods A total of 279 participants were recruited from nine psychiatric outpatient clinics in Korea. All participants were administered the Mini-International Neuropsychiatric Interview (MINI) Plus v.5.0.0, the Adult ADHD Self-Report Scale v1.1 (ASRS-v1.1) Symptom Checklist, and DIVA-5. Diagnosis concordance between two board-certified psychiatrists and DIVA-5 were analysed. Results The DIVA-5 showed a diagnostic accuracy of 92%, a sensitivity of 91.30%, and a specificity of 93.62%. Significant clinical and demographic differences between ADHD and control groups were found. Conclusion The Korean version of DIVA-5 is a reliable tool for assessing and diagnosing ADHD in adult Korean populations.

BackgroundMisconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base.MethodsWe reviewed studies with more than 2,000 participants or meta-analyses from five or more studies or 2,000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder.ResultsWe generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 79 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 362 people who have read this document and agree with its contents.ConclusionsMany findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

The majority of adults with Attention-Deficit/Hyperactivity Disorder (ADHD) have a delayed circadian rhythm that is a characteristic of Delayed Sleep Phase Syndrome (DSPS). Treatment of DSPS may improve both the circadian rhythm and ADHD symptoms. In this three-armed randomized clinical trial, 51 adults (18–55 y) with ADHD and DSPS received sleep education and 3 weeks of (1) 0.5 mg/d placebo, (2) 0.5 mg/d melatonin, or (3) 0.5 mg/d melatonin plus 30 minutes of 10,000 lux bright light therapy (BLT) between 07:00 and 08:00 h. Placebo/melatonin conditions were double-blind. Treatment took place in the participants’ naturalistic home settings. Dim-light melatonin onset (DLMO) was measured in saliva as marker of internal circadian rhythm. Melatonin or placebo administration followed individual schedules, starting 3 hours before the individual DLMO and weekly advancing by 1 h. DLMO and ADHD Rating Scale score were assessed at baseline, directly after 3-week treatment, and two weeks after the end of treatment. Results show that at baseline 77% had a DLMO after 21:00 h with an average DLMO at 23:43 h ± 1h46. Directly after treatment, melatonin had advanced DLMO by 1h28 (p = .001), and melatonin plus BLT by 1h58 (p

Insomnia and short or long sleep duration are important comorbid conditions in adults with attention-deficit hyperactivity disorder (ADHD), but reports of the association vary. In a general population study, we evaluated the relationship between ADHD symptom severity, insomnia symptoms, and sleep duration in adults.Data were from the third wave of the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2; n = 4,618). ADHD symptom severity and symptom dimensions (hyperactivity and inattention) were assessed using the Adult ADHD Self-Report Scale screener. Self-reported insomnia symptoms (Insomnia Rating Scale; IRS) were defined as clinically relevant if IRS ≥ 9. Self-reported short sleep duration was defined as ≤ 6 hours, and long sleep duration as ≥ 10 hours.Within the group with clinically relevant ADHD symptoms, 43% reported significant insomnia symptoms (odds ratio [OR] = 2.66, 95% confidence interval [CI] 1.74-4.07); 41% short sleep duration (relative risk ratio [RRR] = 1.94, 95% CI 1.31-2.85) and 6% long sleep (RRR = 5.87, 95% CI 1.97-17.45). Increased inattention symptoms were associated with IRS ≥ 9, short and long sleep duration in fully adjusted models (OR = 1.10, 95% CI 1.06-1.14; RRR = 1.06, 95% CI 1.02-1.09; RRR = 1.16, 95% CI 1.05-1.28, respectively). Increased hyperactivity symptoms were associated with IRS ≥ 9 (OR = 1.17, 95% CI 1.11-1.23) and short sleep duration (RRR = 1.12, 95% CI 1.05-1.19).Both clinically significant ADHD symptoms and inattention and hyperactivity symptom dimensions were consistently associated with insomnia symptoms and altered sleep duration. These associations confirm that sleep disturbances should be assessed and given appropriate clinical attention in adults with ADHD.

Insomnia and short or long sleep duration are important comorbid conditions in adults with attention-deficit hyperactivity disorder (ADHD), but reports of the association vary. In a general population study, we evaluated the relationship between ADHD symptom severity, insomnia symptoms, and sleep duration in adults. Methods: Data were from the third wave of the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2; n = 4,618). ADHD symptom severity and symptom dimensions (hyperactivity and inattention) were assessed using the Adult ADHD Self-Report Scale screener. Self-reported insomnia symptoms (Insomnia Rating Scale; IRS) were defined as clinically relevant if IRS ≥9. Self-reported short sleep duration was defined as ≤6 hours, and long sleep duration as ≥10 hours. Results: Within the group with clinically relevant ADHD symptoms, 43% reported significant insomnia symptoms (odds ratio [OR] = 2.66, 95% confidence interval [CI] 1.74-4.07); 41% short sleep duration (relative risk ratio [RRR] = 1.94, 95% CI 1.31-2.85) and 6% long sleep (RRR = 5.87, 95% CI 1.97-17.45). Increased inattention symptoms were associated with IRS ≥9, short and long sleep duration in fully adjusted models (OR = 1.10, 95% CI 1.06-1.14; RRR = 1.06, 95% CI 1.02-1.09; RRR = 1.16, 95% CI 1.05-1.28, respectively). Increased hyperactivity symptoms were associated with IRS ≥9 (OR = 1.17, 95% CI 1.11-1.23) and short sleep duration (RRR = 1.12, 95% CI 1.05-1.19). Conclusions: Both clinically significant ADHD symptoms and inattention and hyperactivity symptom dimensions were consistently associated with insomnia symptoms and altered sleep duration. These associations confirm that sleep disturbances should be assessed and given appropriate clinical attention in adults with ADHD.

Study Objectives We evaluated the relationship between leukocyte telomere length (LTL) and sleep duration, insomnia symptoms, and circadian rhythm, to test whether sleep and chronobiological dysregulations are associated with cellular aging. Methods Data from the Netherlands Study of Depression and Anxiety (N = 2,936) were used at two waves 6 years apart, to measure LTL. Telomeres shorten during the life span and are important biomarkers for cellular aging. LTL was assessed by qualitative polymerase chain reaction and converted into base pair number. Sleep parameters were: sleep duration and insomnia symptoms from the Insomnia Rating Scale. Circadian rhythm variables were: indication of Delayed Sleep Phase Syndrome (DSPS), mid-sleep corrected for sleep debt on free days (MSFsc), sleep-onset time, and self-reported chronotype, from the Munich Chronotype Questionnaire. Generalized estimating equations analyzed the associations between LTL, sleep, and chronobiological factors, adjusted for baseline age, sex, North European ancestry, and additionally for current smoking, depression severity, obesity, and childhood trauma. Results Indicators of delayed circadian rhythm showed a strong and consistent effect on LTL, after adjustment for sociodemographic and health indicators. Late MSFsc (B = −49.9, p = .004), late sleep-onset time (B = −32.4, p = .001), indication of DSPS (B = −73.8, p = .036), and moderately late chronotype in adulthood (B = −71.6, p = .003) were associated with significantly shorter LTL across both waves; whereas sleep duration and insomnia symptoms were not. Extremely early chronotype showed significantly less LTL shortening than intermediate chronotype (B = 161.40, p = .037). No predictors showed accelerated LTL attrition over 6 years. Conclusions Individuals with delayed circadian rhythm have significantly shorter LTL, but not faster LTL attrition rates.

Background Diagnostic guidelines recommend using a variety of methods to assess and diagnose ADHD. Applying subjective measures always incorporates risks such as informant biases or large differences between ratings obtained from diverse sources. Furthermore, it has been demonstrated that ratings and tests seem to assess somewhat different constructs. The use of objective measures might thus yield valuable information for diagnosing ADHD. This study aims at evaluating the role of objective measures when trying to distinguish between individuals with ADHD and controls. Our sample consisted of children (n = 60) and adults (n = 76) diagnosed with ADHD and matched controls who completed self- and observer ratings as well as objective tasks. Diagnosis was primarily based on clinical interviews. A popular pattern recognition approach, support vector machines, was used to predict the diagnosis. Results We observed relatively high accuracy of 79% (adults) and 78% (children) applying solely objective measures. Predicting an ADHD diagnosis using both subjective and objective measures exceeded the accuracy of objective measures for both adults (89.5%) and children (86.7%), with the subjective variables proving to be the most relevant. Conclusions We argue that objective measures are more robust against rater bias and errors inherent in subjective measures and may be more replicable. Considering the high accuracy of objective measures only, we found in our study, we think that they should be incorporated in diagnostic procedures for assessing ADHD.

Adults with ADHD often have sleep problems that are caused by a delay of their internal circadian rhythm system. Such individuals are often typified as 'evening' or 'night' persons. This review focuses on the link between ADHD symptoms and the evening typology through multiple pathways. Etiology of the internal circadian rhythm system, the genetic basis for evening typology, overlap between ADHD symptoms and evening preference and risk factors for various chronic health conditions, including metabolic syndrome and cancer, are discussed. The treatment perspectives to reset the delayed rhythm in adults with ADHD involve psychoeducation on sleep hygiene, melatonin in the afternoon or evening and bright light therapy in the morning.

SUMMARY Irregular sleep–wake patterns and delayed sleep times are common in adults with attention-deficit/hyperactivity disorder, but mechanisms underlying these problems are unknown. The present case–control study examined whether circadian abnormalities underlie these sleep problems in a naturalistic home setting. We included 12 medication-naive patients with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome, and 12 matched healthy controls. We examined associations between sleep/wake rhythm in attention-deficit/hyperactivity disorder and circadian parameters (i.e. salivary melatonin concentrations, core and skin temperatures, and activity patterns) of the patients and controls during five consecutive days and nights. Daily bedtimes were more variable within patients compared with controls (F = 8.19, P < 0.001), but melatonin profiles were equally stable within individuals. Dim-light melatonin onset was about 1.5 h later in the patient group (U = 771, Z = 4.63, P < 0.001). Patients slept about 1 h less on nights before work days compared with controls (F = 11.21, P = 0.002). The interval between dim-light melatonin onset and sleep onset was on average 1 h longer in patients compared with controls (U = 1117, Z = 2.62, P = 0.009). This interval was even longer in patients with extremely late chronotype. Melatonin, activity and body temperatures were delayed to comparable degrees in patients. Overall temperatures were lower in patients than controls. Sleep-onset difficulties correlated with greater distal–proximal temperature gradient (DPG; i.e. colder hands, r 2 = 0.32, P = 0.028) in patients. Observed day-to-day bedtime variability of individuals with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome were not reflected in their melatonin profiles. Irregular sleep–wake patterns and delayed sleep in individuals with attention-deficit/hyperactivity disorder and delayed sleep phase syndrome are associated with delays and dysregulations of the core and skin temperatures.

ADHD is an often heritable, neurodevelopmental disorder with a prevalence of 4-5% in children and adults and about 3% in older adults. The disorder in older adults (55 years) is accompanied by similar comorbidities such as anxiety and depression, and social impairment as in younger age groups. Areas covered: An overview of the literature on diagnostic assessment, differential diagnosis, and treatment of older adults with ADHD is described. Case studies show that stimulant treatment is beneficial for ADHD in old age, but randomized controlled trials are lacking. Stimulant treatment has been studied in depression and even dementia in older adults, and seems safe with active cardiovascular risk management. In this paper, a proposal for diagnostic assessment and treatment is described for ADHD in older adults, including differential diagnosis with other psychiatric and neurocognitive disorders. Expert commentary: Regarding the organization of mental health, professionals in geriatric psychiatry need to be trained in assessment and treatment of ADHD in older age. Lifespan ADHD clinics may help patients of all ages to receive better specialized care.

Melanopsin-containing retinal ganglion cells play an important role in the non-image forming effects of light, through their direct projections on brain circuits involved in circadian rhythms, mood and alertness. Individual differences in the functionality of the melanopsin-signaling circuitry can be reliably quantified using the maximum post-illumination pupil response (PIPR) after blue light. Previous protocols for acquiring PIPR relied on the use of mydriatics to dilate the light-exposed eye. However, pharmacological pupil dilation is uncomfortable for the participants and requires ophthalmological expertise. Hence, we here investigated whether an individual’s maximum PIPR can be validly obtained in a protocol that does not use mydriatics but rather increases the intensity of the light stimulus. In 18 participants (5 males, mean age ± SD: 34.6 ± 13.6 years) we evaluated the PIPR after exposure to intensified blue light (550 µW/cm 2 ) provided to an undilated dynamic pupil. The test-retest reliability of the primary PIPR outcome parameter was very high, both between day-to-day assessments (Intraclass Correlation Coefficient (ICC) = 0.85), as well as between winter and summer assessments (ICC = 0.83). Compared to the PIPR obtained with the use of mydriatics and 160 µW/cm 2 blue light exposure, the method with intensified light without mydriatics showed almost zero bias according to Bland-Altman plots and had moderate to strong reliability (ICC = 0.67). In conclusion, for PIPR assessments, increasing the light intensity is a feasible and reliable alternative to pupil dilation to relieve the participant’s burden and to allow for performance outside the ophthalmological clinic.

Contains fulltext : 97904.pdf (Publisher’s version ) (Closed access) Attention-deficit hyperactivity disorder (ADHD) is a common behavioral disorder affecting about 4-8% of children. ADHD persists into adulthood in around 65% of cases, either as the full condition or in partial remission with persistence of symptoms. Pharmacological, animal and molecular genetic studies support a role for genes of the dopaminergic system in ADHD due to its essential role in motor control, cognition, emotion, and reward. Based on these data, we analyzed two functional polymorphisms within the DRD4 gene (120 bp duplication in the promoter and 48 bp VNTR in exon 3) in a clinical sample of 1,608 adult ADHD patients and 2,352 controls of Caucasian origin from four European countries that had been recruited in the context of the International Multicentre persistent ADHD CollaboraTion (IMpACT). Single-marker analysis of the two polymorphisms did not reveal association with ADHD. In contrast, multiple-marker meta-analysis showed a nominal association (P = 0.02) of the L-4R haplotype (dup120bp-48bpVNTR) with adulthood ADHD, especially with the combined clinical subtype. Since we previously described association between adulthood ADHD and the dopamine transporter SLC6A3 9R-6R haplotype (3'UTR VNTR-intron 8 VNTR) in the same dataset, we further tested for gene x gene interaction between DRD4 and SLC6A3. However, we detected no epistatic effects but our results rather suggest additive effects of the DRD4 risk haplotype and the SLC6A3 gene.

Contains fulltext : 89288.pdf (Publisher’s version ) (Closed access) 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. 01 februari 2010

Contains fulltext : 87790.pdf (Publisher’s version ) (Closed access) BACKGROUND: Declarative memory deficits are common in untreated adults with attention-deficit hyperactivity disorder (ADHD), but limited evidence exists to support improvement after treatment with methylphenidate. The objective of this study was to examine the effects of methylphenidate on memory functioning of adults with ADHD. METHODS: Eighteen adults with ADHD who were clinical responders to methylphenidate participated in this randomized crossover trial. After 3 days of no treatment, patients received in random order either their usual methylphenidate dose (mean: 14.7 mg; range: 10-30 mg) or placebo, separated by a 6-7-day washout period. Patients performed an immediate word recall test 1 h after treatment administration. Three hours after intake, patients performed the second part of the memory test (delayed word recall and a recognition test). RESULTS: Delayed recognition and immediate recall was similar on treatment and on placebo. Delayed word recall was significantly better in the methylphenidate than in the placebo condition (F (1, 17) = 7.0, p < 0.017). A significant correlation was found between prestudy CES-D depression scores and difference scores on delayed recall (r = 0.602, p < 0.008). CONCLUSION: Methylphenidate improves declarative memory functioning in patients with ADHD. New studies should further examine whether subclinical depressive symptoms mediate the effect of methylphenidate on declarative memory. 01 oktober 2010

Jan K Buitelaar1, J Antoni Ramos-Quiroga2, Miguel Casas2, J J Sandra Kooij3, Asko Niemelä4, Eric Konofal5, Joachim Dejonckheere6, Bradford H Challis7, Rossella Medori81Department of Psychiatry, University Medical Center, St. Radboud and Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands; 2Department of Psychiatry, Hospital Universitari Vall d’Hebron and Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 3PsyQ, Psycho-Medical Programs, Program Adult ADHD, Den Haag, The Netherlands; 4Oulu University Hospital, Department of Psychiatry, Oulu, Finland; 5Groupe Hospitalier Pitie-Salpetriere, Paris, France; 6SGS Life Sciences, Mechelen, Belgium; 7Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ, USA; 8Janssen-Cilag EMEA, Neuss, GermanyAbstract: The osmotic release oral system (OROS) methylphenidate formulation is a prolonged-release medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. We conducted a seven-week open-label extension of a double-blind study to assess the safety and tolerability of OROS methylphenidate in a flexible dose regimen (18–90 mg daily) for the treatment of adults diagnosed with ADHD (N = 370). Medication was adjusted to optimize efficacy and tolerability for each patient. Adverse events, vital signs, and laboratory parameters were assessed. Most patients (337; 91%) completed the seven-week treatment and the final dispensed dose was 18 mg (8%), 36 mg (29%), 54 mg (34%), 72 mg (20%), or 90 mg (9%). Adverse events were reported in 253 (68%) patients and most were mild or moderate in severity; most frequently reported included headache (17%), decreased appetite (13%), and insomnia (11%). Adverse events were rarely serious (

Contains fulltext : 71149.pdf (Publisher’s version ) (Closed access) In this pharmacogenetic study in adults with ADHD (n = 42), a stratified analysis was performed of the association between response to methylphenidate (MPH), assessed under double-blind conditions, and polymorphisms in the genes encoding the dopamine transporter, SLC6A3 (DAT1), the norepinephrine transporter, SLC6A2 (NET), and the dopamine receptor D4, DRD4. The VNTR polymorphism in the 3' untranslated region of SLC6A3 was significantly associated with an increased likelihood of a response to MPH treatment (OR 3.8; 95% CI 1.0-15.2, and OR 5.4; 95% CI 1.4-21.9, depending on the definition of response) in carriers of a single 10-repeat allele compared to patients with the 10/10 genotype. The polymorphisms in DRD4 and the SLC6A2 were not associated with treatment response. This study supports a role of the SLC6A3 genotype in determining the response to MPH in the treatment of adults with ADHD.

Contains fulltext : 69754.pdf (Publisher’s version ) (Closed access) Since neurocognitive performance is a possible endophenotype for Attention Deficit Hyperactivity Disorder (ADHD) we explored the relationship between four genetic polymorphisms and neurocognitive performance in adults with ADHD. We genotyped a sample of 45 adults with ADHD at four candidate polymorphisms for the disorder (DRD4 48 base pair (bp) repeat, DRD4 120 bp duplicated repeat, SLC6A3 (DAT1) 40 bp variable number of tandem repeats (VNTR), and COMT Val158Met). We then sub-grouped the sample for each polymorphism by genotype or by the presence of the (putative) ADHD risk allele and compared the performance of the subgroups on a large battery of neurocognitive tests. The COMT Val158Met polymorphism was related to differences in IQ and reaction time, both of the DRD4 polymorphisms (48 bp repeat and 120 bp duplication) showed an association with verbal memory skills, and the SLC6A3 40 bp VNTR polymorphism could be linked to differences in inhibition. Interestingly, the presence of the risk alleles in DRD4 and SLC6A3 was related to better cognitive performance. Our findings contribute to an improved understanding of the functional implications of risk genes for ADHD.

Contains fulltext : 48908.pdf (Publisher’s version ) (Closed access) We examined the effect of methylphenidate (Mph) on inhibition and several other cognitive abilities in 43 adults with Attention Deficit Hyperactivity Disorder (ADHD) by use of Conners' Continuous Performance Test (CPT) and the Change Task (ChT), an extension of the Stop Signal Test (SST). In a double blind, cross-over, placebo controlled study with Mph, tests were administered during the third week of individually titrated treatment with Mph (maximum dose 1 mg / kg / day) and during the third week of treatment with placebo. We established large medication effects for commission errors, standard error of mean reaction time, and attentiveness on the CPT, as well as moderate medication effects for mean reaction time on the CPT and response re-engagement speed on the ChT. For Stop Signal Reaction Time (SSRT) on the ChT, we also established large effects of Mph, but only in a group of participants who showed slow SSRTs on placebo. Mph indeed ameliorates inhibition, which is the core problem of ADHD, and certain other cognitive abilities in adults with ADHD.

Many adult outpatients with attention-deficit/hyperactivity disorder (ADHD) report an oversensitivity to light. We explored the link between ADHD and photophobia in an online survey (N = 494). Self-reported photophobia was prevalent in 69% of respondents with, and in 28% of respondents without, ADHD (symptoms). The ADHD (symptoms) group wore sunglasses longer during daytime in all seasons. Photophobia may be related to the functioning of the eyes, which mediate dopamine and melatonin production systems in the eye. In the brain, dopamine and melatonin are involved in both ADHD and circadian rhythm disturbances. Possibly, the regulation of the dopamine and melatonin systems in the eyes and in the brain are related. Despite the study’s limitations, the results are encouraging for further study on the pathophysiology of ADHD, eye functioning, and circadian rhythm disturbances.

Purpose:To evaluate the QbTest as an objective measure versus self-reported ADHD Rating Scale (ADHD-RS) before and during stimulant treatment in adults with ADHD.Patients and methods:We used the subjective ADHD Rating Scale (ADHD-RS), and the objective computerized QbTest, which is a 20-minute unconditional identical pairs test that measures attention, impulsivity, and also hyperactivity using a motion-tracking system. Patients were assessed before (baseline) and during medical treatment with stimulants (follow-up) in an observational study design.Results:Data of n = 145 patients at baseline and n = 82 patients at follow-up were analyzed. There were significant symptom reductions on all symptom domains, but correlations between the tests were weak. Improvement on the QbTest was independent of the patient's age, gender, educational level, ADHD subtype, co-morbid disorders, and use of other medications. Patients with worst QbTest results at baseline showed most improvement at follow-up. The QbTest was more sensitive to medication effects than the ADHD-RS. QbTest objectified clinical significant medication effect in 54% of patients who subjectively did not report any clinical effects.Discussion:Symptoms dimensions of objective and subjective tests refer to different psychological constructs.Conclusion:The QbTest is a valuable addition to existing subjective measures to assess medication effects in ADHD patients who have difficulties reporting treatment effects.

The systematic review and meta-analysis by Cortese and colleagues, published in this issue of the Journal (1), shows a clear association between attention deficit hyperactivity disorder (ADHD) and obesity inmore than 700,000 children and adults, ofwhom48,161 hadADHD. Strengths of the study are that the finding was validated in both children and adults separately. The findings were also similar in both epidemiological and clinical populations. The association between ADHD and obesity remained significant after controlling for confounding factors such as gender, study setting, study country, and study quality. The association between ADHD andobesity also remained significantwhen investigating only studies that had adjusted for possible confounding factors such as depression,when restricted to diagnoses of ADHDby direct interview (instead of rating scales), and when using directlymeasuredheight andweight (insteadof self-reported height and weight). The risk of obesity was higher in adult ADHD compared with childhood ADHD, pointing to an obesity risk that increases over time. Interestingly, individuals medicated for ADHDwere not at higher risk for obesity. Many unpublished studies were included, but a limitation of the study is that data fromsomeunpublished studieswerenot available or otherwise included.

IntroductionAttention Deficit Hyperactivity Disorder (ADHD) prevalence in the general adult population is estimated to be between 2–4%. Despite the high prevalence, until recently there was only one validated semi-structured interview available for the accurate diagnostic assessment of ADHD within the adult population: the Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID).ObjectivesTo examine the concurrent validity of the DIVA 2.0 interview comparing the diagnostic rate with the CAADID interview. To analyse the criterion validity of the DIVA 2.0 in the Spanish language in an adult sample.AimsThe aim of this is to study was to evaluate criterion validity of the DIVA 2.0 in an adult sample comparing with the CAADID and other ADHD severity scales.MethodsA transversal study was performed to check the criteria and concurrent validity of the DIVA 2.0 compared to the CAADID.ResultsForty patients were recruited in an adult ADHD program at a university hospital. The DIVA 2.0 interview showed a diagnostic accuracy of 100% when compared with the diagnoses obtained with the CAADID interview and goods correlations with three self-reported rating scales: the WURS, the ADHD Rating Scale and Sheehan's’ Dysfunction Inventory.ConclusionsThe DIVA 2.0 has good psychometric properties and is a reliable tool for the assessment of ADHD in adults.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Background: Little is known about the prevalence of attention-deficit hyperactivity disorder (ADHD) among older adults. Aims: To estimate the prevalence of the syndromatic and symptomatic DSM-IV ADHD diagnosis in older adults in The Netherlands. Method: Data were used from the Longitudinal Aging Study Amsterdam (LASA). At baseline, 1494 participants were screened with an ADHD questionnaire and in 231 respondents a structured diagnostic interview was administered. The weighted prevalence of ADHD was calculated. Results: The estimated prevalence rate of syndromatic ADHD in older adults was 2.8%; for symptomatic ADHD the rate was 4.2%. Younger elderly adults (60-70 years) reported significantly more ADHD symptoms than older elderly adults (71-94 years). Conclusions: This is the first epidemiological study on ADHD in older persons. With a prevalence of 2.8% the study demonstrates that ADHD does not fade or disappear in adulthood and that it is a topic very much worthy of further study. Declaration of interest A.T.F.B. has received an unrestricted research grant from Eli Lilly and AstraZeneca and has been a speaker for Lundbeck and Eli Lilly. J.J.S.K. is a speaker for Eli Lilly, Janssen and Shire and has received unrestricted research grants for this study from Shire, as well as for another study from Janssen.

Contains fulltext : 95784.pdf (Publisher’s version ) (Closed access) Several linkage analyses implicated the chromosome 9q22 region in attention deficit/hyperactivity disorder (ADHD), a neurodevelopmental disease with remarkable persistence into adulthood. This locus contains the brain-expressed GTP-binding RAS-like 2 gene (DIRAS2) thought to regulate neurogenesis. As DIRAS2 is a positional and functional ADHD candidate gene, we conducted an association study in 600 patients suffering from adult ADHD (aADHD) and 420 controls. Replication samples consisted of 1035 aADHD patients and 1381 controls, as well as 166 families with a child affected from childhood ADHD. Given the high degree of co-morbidity with ADHD, we also investigated patients suffering from bipolar disorder (BD) (n=336) or personality disorders (PDs) (n=622). Twelve single-nucleotide polymorphisms (SNPs) covering the structural gene and the transcriptional control region of DIRAS2 were analyzed. Four SNPs and two haplotype blocks showed evidence of association with ADHD, with nominal p-values ranging from p=0.006 to p=0.05. In the adult replication samples, we obtained a consistent effect of rs1412005 and of a risk haplotype containing the promoter region (p=0.026). Meta-analysis resulted in a significant common OR of 1.12 (p=0.04) for rs1412005 and confirmed association with the promoter risk haplotype (OR=1.45, p=0.0003). Subsequent analysis in nuclear families with childhood ADHD again showed an association of the promoter haplotype block (p=0.02). rs1412005 also increased risk toward BD (p=0.026) and cluster B PD (p=0.031). Additional SNPs showed association with personality scores (p=0.008-0.048). Converging lines of evidence implicate genetic variance in the promoter region of DIRAS2 in the etiology of ADHD and co-morbid impulsive disorders.

Contains fulltext : 87687.pdf (Publisher’s version ) (Closed access) Attention-deficit hyperactivity disorder (ADHD) is a multifactorial, neurodevelopmental disorder that often persists into adolescence and adulthood and is characterized by inattention, hyperactivity and impulsiveness. Before the advent of the first genome-wide association studies in ADHD, genetic research had mainly focused on candidate genes related to the dopaminergic and serotoninergic systems, although several other genes had also been assessed. Pharmacological data, analysis of animal models and association studies suggest that Brain-Derived Neurotrophic Factor (BDNF) is also a strong candidate gene for ADHD. Several polymorphisms in BDNF have been reported and studied in psychiatric disorders but the most frequent is the p.Val66Met (rs6265G > A) single nucleotide polymorphism (SNP), with functional effects on the intracellular trafficking and secretion of the protein. To deal with the inconsistency raised among different case-control and family-based association studies regarding the p.Val66Met contribution to ADHD, we performed a meta-analysis of published as well as unpublished data from four different centers that are part of the International Multicentre Persistent ADHD CollaboraTion (IMpACT). A total of 1,445 adulthood ADHD patients and 2,247 sex-matched controls were available for the study. No association between the p.Val66Met polymorphism and ADHD was found in any of the four populations or in the pooled sample. The meta-analysis also showed that the overall gene effect for ADHD was not statistically significant when gender or comorbidity with mood disorders were considered. Despite the potential role of BDNF in ADHD, our data do not support the involvement of p.Val66Met in the pathogenesis of this neuropsychiatric disorder.

Contains fulltext : 70740.pdf (Publisher’s version ) (Closed access) Several studies have evaluated the association between individual polymorphisms and response to methylphenidate (MPH) in subjects with attention-deficit/hyperactivity disorder (ADHD). There are few replication studies for each polymorphism of interest and results are sometimes inconsistent in this field. Although data collection from multiple international sites would allow large sample sizes, this approach has been criticized for introducing sampling variability due to differences in ethnicity and methodology between studies. To examine these issues, we aggregated nine pharmacogenetic studies from four different continents and conducted a two stage analysis: (a) we evaluated the role of methodological aspects in the variability of ADHD symptom improvement between studies using meta-regression analysis; (b) we assessed the role of individual characteristics of the subjects in the variability of ADHD symptoms improvement using multivariate regression analysis in the same data sets. At the study level, from five evaluated factors, only the design of the study (open studies vs. randomized controlled trials) was significantly associated with heterogeneity of results (P = 0.001). At the individual level, age (P < 0.001), comorbid oppositional defiant disorder (P < 0.001), and pre-treatment scores (P < 0.001) were associated with change of ADHD scores with treatment in the final multivariate model. Our results suggest that joint analyses of pharmacogenetic studies are feasible and promising, since fixed variables, such as the site where the study was conducted, were not related to results. Nevertheless, stratified analyses according to the design of the study must be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders should be assessed.

Contains fulltext : 69295.pdf (Publisher’s version ) (Closed access) Although patients with attention-deficit hyperactivity disorder (ADHD) have reported improved driving performance on methylphenidate, limited evidence exists to support an effect of treatment on driving performance and some regions prohibit driving on methylphenidate. A randomized, crossover trial examining the effects of methylphenidate versus placebo on highway driving in 18 adults with ADHD was carried out. After three days of no treatment, patients received either their usual methylphenidate dose (mean: 14.7 mg; range: 10-30 mg) or placebo and then the opposite treatment after a six to seven days washout period. Patients performed a 100 km driving test during normal traffic, 1.5 h after treatment administration. Standard deviation of lateral position (SDLP), the weaving of the car, was the primary outcome measure. Secondary outcome measurements included the standard deviation of speed and patient reports of driving performance. Driving performance was significantly better in the methylphenidate than in the placebo condition, as reflected by the SDLP difference (2.3 cm, 95% CI = 0.8-3.8, P = 0.004). Variation in speed was similar on treatment and on placebo (-0.05 km/h, 95% CI = -0.4 to 0.2, P = 0.70). Among adults with ADHD, with a history of a positive clinical response to methylphenidate, methylphenidate significantly improves driving performance.

Contains fulltext : 52254.pdf (Publisher’s version ) (Open Access) STUDY OBJECTIVES: To investigate parameters of sleep, activity, and circadian rhythm, as well as the effects of methylphenidate on these variables, in adults with ADHD. DESIGN: 1) Baseline group comparison; 2) Double blind, placebo-controlled, cross-over medication trial. SETTING: Data collection took place during daily lives of participants. PARTICIPANTS: 39 normal controls and 33 adults with ADHD for baseline comparisons; 31 adults with ADHD in medication trial. INTERVENTIONS: Treatment with placebo and methylphenidate during medication trial. MEASUREMENTS AND RESULTS: Actigraphy and sleep log data were collected for 7 consecutive nights and days to obtain baseline values for ADHD and normal controls. Repeated measurements during placebo and methylphenidate treatment were conducted for the ADHD group. Actigraphic sleep estimates showed that ADHD subjects took longer to fall asleep, had lower sleep efficiency, and had shorter within-night periods of uninterrupted sleep. These findings were consistent with subjective complaints. Actigraphic measures of ADHD subjects showed continuously elevated daytime activity levels, resulting in a 24-hour pattern that was more stable and less variable than in controls. Methylphenidate led to a later bedtime, later sleep onset, and reduction in sleep duration. However, number and total duration of nocturnal awakenings decreased, while mean duration of within-night periods of uninterrupted sleep increased, indicating more consolidated sleep. CONCLUSIONS: Our data suggest that sleep problems are inherent in adults with ADHD and that methylphenidate reduced total sleep time but improved sleep quality by consolidating sleep.

The comorbidity of attention deficit hyperactivity disorder (ADHD) is frequently not well recognized in substance abuse treatment institutions in The Netherlands. As a consequence, patients with substance use disorder (SUD) and ADHD often receive suboptimal treatment. To prevent every treatment center from having to invent its own diagnostic procedure and intervention for ADHD, a national working group was established. This group developed an intervention program for the screening, diagnosis, and treatment of ADHD in patients with SUD. This article describes the development and content of this intervention program. An important part of this development was testing the intervention program in two addiction treatment centers in The Netherlands. Systematic screening of ADHD was part of the test. A self-report questionnaire was used. Subjects with positive screening results were referred for the diagnostic procedure. Nine hundred twenty-eight screenings were performed: 207 screened positive, 115 came for further diagnostics, and 65 were ultimately diagnosed with ADHD.

Background. Follow-up studies of childhood ADHD have shown persistence of the disorder into adulthood, but no epidemiological data are yet available.Method. ADHD DSM-IV symptoms were obtained by self-report in an adult population-based sample of 1813 adults (aged 18–75 years), that was drawn from an automated general practitioner system used in Nijmegen, The Netherlands. The structure of ADHD symptoms was analysed by means of confirmatory factor analyses. Other data used in this report are the General Health Questionnaire (GHQ-28), information about the presence of three core symptoms of ADHD in childhood, and about current psychosocial impairment.Results. The three-factor model that allowed for cross-loadings provided the best fit in the entire sample. This result was replicated across gender and age subsamples. Inattentive and hyperactivity symptom scores were significantly associated with measures of impairment, even after controlling for the GHQ-28. Subjects with four or more inattentive or hyperactive–impulsive symptoms were significantly more impaired than subjects with two, one and no symptoms. The prevalence of ADHD in adults was 1·0% (95% CI 0·6–1·6) and 2·5% (1·9–3·4) using a cutoff of six and four current symptoms respectively, and requiring the presence of all three core symptoms in childhood.Conclusions. These results support the internal and external validity of ADHD in adults between 18 and 75 years. ADHD is not merely a child psychiatric disorder that persists into young adulthood, but an important and unique manifestation of psychopathology across the lifespan.

Background Medication non-adherence has an important impact on treatment efficacy and healthcare burden across a range of conditions and therapeutic areas. The aim of this analysis was to determine predictors of non-adherence and impact of non-adherence on treatment response in adults with attention-deficit/hyperactivity disorder (ADHD). Methods Post-hoc analysis of a 13-week randomized, double-blind placebo-controlled study of OROS methylphenidate (MPH) 54 and 72 mg/day. Primary efficacy variable was the Conners’ Adult ADHD Rating Scale – Screening Version (CAARS:O-SV). Daily adherence was calculated as average daily adherence (100 × capsules taken/2), with overall adherence calculated as the average daily adherence. Predictors of adherence were assessed using mixed-effects logistic regression. Descriptive statistics were generated for change in CAARS:O-SV score for adherent (> 95% adherence) and non-adherent subjects. Predictors of change were analyzed using a mixed model. Results Subjects were allocated to OROS MPH (54 mg, n = 87; 72 mg, n = 92) or placebo (n = 97). Mean adherence was 92.6% and 93.3% (OROS MPH 54 and 72 mg/day, respectively), versus 97.5% (placebo). Adherence was higher and less variable in completers. Factors significantly associated with non-adherence included female sex, shorter time since ADHD diagnosis, higher education level (completion of university) and score on the Drug Use Screening Inventory psychiatric disorders subscale. Improvements from baseline in CAARS:O-SV score were numerically greater in subjects defined as adherent than in those who were non-adherent. Significant predictors of CAARS:O-SV change in patients who completed the study included percentage adherence up to the point of assessment (p < 0.0001), baseline score (p < 0.0001) and family history of ADHD (p = 0.0003). Conclusion The results of this analysis suggest that newly diagnosed patients, those with a high score on the DUSI-R psychiatric disorder scale, women, and subjects with high educational degrees may be at increased risk of non-adherence. Clinicians and policymakers should therefore pay special attention to these individuals, as non-adherence is a significant predictor of reduced response to treatment. Trial registration EudraCT #: 2007-002111-82