Pharmacotherapy of ADHD in Adults With Autism Spectrum Disorder: Effectiveness and Side Effects.

Objective: Symptoms of ADHD are expected to be more difficult to treat in patients with a combination of ADHD and autism spectrum disorder (ASD) as opposed to only ADHD. Little evidence is available on the influence of ASD on the effects of pharmacotherapy in adults with ADHD. This study addresses this gap. Method: 60 adults with ADHD and comorbid ASD were selected from an outpatient clinic and compared with 226 adults from the same clinic with only ADHD. Similar treatment regimens were received. Results: Significant decreases in symptoms of ADHD were found in both groups. A diagnosis of ASD did not affect the reduction in symptoms of ADHD. No significant group differences in side effects or vital signs were found. Conclusion: Results show that medication for ADHD can effectively and safely be prescribed to patients with ADHD and comorbid ASD. Suggestions for future research are discussed.

Burden of illness and health care resource utilization in adult psychiatric outpatients with attention-deficit/hyperactivity disorder in Europe.

OBJECTIVE: To assess the burden of illness and health care resource utilization of adult nonpsychotic psychiatric outpatients with attention-deficit/hyperactivity disorder (ADHD) in Europe. METHODS: This was a multicountry, cross-sectional, observational study where unselected routine patients from clinical psychiatric outpatient settings were screened and assessed for ADHD. Patients were evaluated using the Clinical Global Impressions of Severity (CGI-S) scale, the Sheehan Disability Scale (SDS), and the EuroQol-5 Dimensions questionnaire. Data on comorbidities, functional impairment, and health care resource utilization were captured. RESULTS: The study enrolled 2284 patients, of whom 1986 completed the study. The prevalence of ADHD was 17.4%, of whom 46.0% had a previous ADHD diagnosis. Patients with ADHD had a high clinical burden with psychiatric comorbidities, especially depression (43.0%) and anxiety disorders (36.4%). Substance abuse (9.2% vs. 3.4%) and alcohol abuse (10.3% vs. 5.2%) were more common in the ADHD cohort vs. the non-ADHD cohort. Only 11.5% of the patients with ADHD had no other psychiatric disorder. Various measures indicated a significantly poorer level of functioning for patients with ADHD than without ADHD, as indicated by higher scores for CGI-S (3.8 vs. 3.3) and SDS (18.9 vs. 11.6) and higher percentages of debt (35.5% vs. 24.3%) and criminality (13.8% vs. 6.1%). Lastly, the health care resource utilization was considerable and similar between adult psychiatric outpatients diagnosed and not diagnosed with ADHD. CONCLUSIONS: Although care was taken when choosing the sites for this study, to make it representative of the general outpatient adult psychiatric population, caution should be advised in generalizing the findings of our study to the general ADHD or psychiatric outpatient population. This was an observational study, thus no inference on causality can be drawn. Having ADHD imposes a considerable health and social burden on patient and health care resource utilization comparable to other chronic psychiatric disorders.

Predictive validity of self-report questionnaires in the assessment of autism spectrum disorders in adults.

While various screening instruments for autism spectrum disorders are widely used in diagnostic assessments, their psychometric properties have not been simultaneously evaluated in the outpatient setting where these instruments are used most. In this study, we tested the Ritvo Autism Asperger Diagnostic Scale-Revised and two short versions of the Autism-Spectrum Quotient, the AQ-28 and AQ-10, in 210 patients referred for autism spectrum disorder assessment and in 63 controls. Of the 210 patients, 139 received an autism spectrum disorder diagnosis and 71 received another psychiatric diagnosis. The positive predictive values indicate that these tests correctly identified autism spectrum disorder patients in almost 80% of the referred cases. However, the negative predictive values suggest that only half of the referred patients without autism spectrum disorder were correctly identified. The sensitivity and specificity of each of these instruments were much lower than the values reported in the literature. In this study, the sensitivity of the Ritvo Autism Asperger Diagnostic Scale-Revised was the highest (73%), and the Autism-Spectrum Quotient short forms had the highest specificity (70% and 72%). Based on the similar area under the curve values, there is no clear preference for any of the three instruments. None of these instruments have sufficient validity to reliably predict a diagnosis of autism spectrum disorder in outpatient settings.

[Feasibility and effectiveness of mindfulness training in adults with ADHD: a pilot study]. / Toepasbaarheid en effectiviteit van mindfulnesstraining bij volwassenen met AD(H)D; een open pilotonderzoek.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a developmental disorder that often continues into adulthood. Stimulant medication is the common treatment for ADHD. However, there is a need for psychosocial interventions in addition to medication. AIM: To conduct a pilot study which examines the feasibility and effectiveness of mindfulness training for adults with ADHD. METHOD: Eleven adults with ADHD participated in a mindfulness training scheme lasting 10 weeks. ADHD symptoms, anxiety and depressive symptoms, quality of life, mindfulness skills and attentional tasks were measured before and after the period of mindfulness training. RESULTS: Nine participants completed the mindfulness training and were satisfied with the training. Eight of these reported improvement in their ADHD symptoms. For all participants, their quality of life, awareness of their actions and executive control had also improved. CONCLUSION: Mindfulness is a feasible treatment strategy for adults with ADHD and seems to have a positive effect on ADHD symptoms and executive control.

Suppression of coenzyme Q10 levels and the induction of multiple PDSS and COQ genes in human cells following oligomycin treatment.

Endogenous coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant and essential for the electron transport chain. We previously demonstrated that hydrogen peroxide enhanced CoQ10 levels, whereas disruption of mitochondrial membrane potential by a chemical uncoupler suppressed CoQ10 levels, in human 143B cells. In this study, we investigated how CoQ10 levels and expression of two PDSS and eight COQ genes were affected by oligomycin, which inhibited ATP synthesis at Complex V without uncoupling the mitochondria. We confirmed that oligomycin increased the production of reactive oxygen species (ROS) and decreased mitochondria-dependent ATP production in 143B cells. We also demonstrated that CoQ10 levels were decreased by oligomycin after 42 or 48 h of treatment, but not at earlier time points. Expression of PDSS2 and COQ2-COQ9 were up-regulated after 18-hour oligomycin treatment, and the expression of PPARGC1A (PGC1-1α) elevated concurrently. Knockdown of PPARGC1A down-regulated the basal mRNA levels of PDSS2 and five COQ genes and suppressed the induction of COQ8 and COQ9 genes by oligomycin, but did not affect CoQ10 levels under these conditions. N-acetylcysteine suppressed the augmentation of ROS levels and the enhanced expression of COQ2, COQ4, COQ7, and COQ9 induced by oligomycin, but did not modulate the changes in CoQ10 levels. These results suggested that the condition of mitochondrial dysfunction induced by oligomycin decreased CoQ10 levels independent of oxidative stress. Up-regulation of PDSS2 and several COQ genes by oligomycin might be regulated by multiple mechanisms, including the signaling pathways mediated by PGC-1α and ROS, but it would not restore CoQ10 levels.

Cognitive flexibility depends on white matter microstructure of the basal ganglia.

Ample evidence shows that the basal ganglia play an important role in cognitive flexibility. However, traditionally, cognitive processes have most commonly been associated with the prefrontal cortex. Indeed, current theoretical models of basal ganglia function suggest the basal ganglia interact with the prefrontal cortex and thalamus, via anatomical fronto-striato-thalamic circuits, to implement cognitive flexibility. Here we aimed to assess this hypothesis in humans by associating individual differences in cognitive flexibility with white matter microstructure of the basal ganglia. To this end we employed an attention switching paradigm in adults with ADHD and controls, leading to a broad range in task performance. Attention switching performance could be predicted based on individual differences in white matter microstructure in/around the basal ganglia. Crucially, local white matter showing this association projected to regions in the prefrontal cortex and thalamus. Our findings highlight the crucial role of the basal ganglia and the fronto-striato-thalamic circuit for cognitive flexibility.

Shared and unique genetic contributions to attention deficit/hyperactivity disorder and substance use disorders: a pilot study of six candidate genes.

The shared genetic basis of attention deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders. One hundred seven methadone maintenance treatment patients, 36 having an ADHD diagnosis, 176 adult patients with ADHD without SUDs, and 500 healthy controls were genotyped for variants in the DRD4 (exon 3 VNTR), DRD5 (upstream VNTR), HTR1B (rs6296), DBH (rs2519152), COMT (rs4680; Val158Met), and OPRM1 (rs1799971; 118A>G) genes. Association with disease was tested using logistic regression models. This pilot study was adequately powered to detect larger genetic effects (OR≥2) of risk alleles with a low frequency. Compared to controls, ADHD patients (with and without SUDs) showed significantly increased frequency of the DBH (rs2519152: OR 1.73; CI 1.15-2.59; P=0.008) and the OPRM1 risk genotypes (rs1799971: OR 1.71; CI 1.17-2.50; P=0.006). The DBH risk genotype was associated with ADHD diagnosis, with the association strongest in the pure ADHD group. The OPRM1 risk genotype increased the risk for the combined ADHD and SUD phenotype. The present study strengthens the evidence for a shared genetic basis for ADHD and addiction. The association of OPRM1 with the ADHD and SUD combination could help to explain the contradictory results of previous studies. The power limitations of the study restrict the significance of these findings: replication in larger samples is warranted.

Removal of manganese ions from synthetic groundwater by oxidation using KMnO(4) and the characterization of produced MnO(2) particles.

The aim of this study is to investigate the conditions for the removal of manganese ions from synthetic groundwater by oxidation using KMnO(4) to keep the concentration below the allowed level (0.05 mg/L). The process includes low-level aeration and addition of KMnO(4) in a Jar test system with Mn(2 + ) concentration of 0.50 mg/L, similar to that of natural groundwater in Taiwan. Different parameters such us aeration-pH, oxidant dose, and stirring speed were studied. Aeration alone was not sufficient to remove Mn(2 + ) ions completely even when the pH was increased. When a stoichiometric amount of KMnO(4) (0.96 mg/L) was used, a complete Mn(2 + ) removal was achieved within 15 min at an optimum pH of 8.0. As the amount of KMnO(4) was doubled, lower removal efficiency was obtained because the oxidant also generated manganese ions. The removal of Mn(2 + ) ions could be completed at pH 9.0 using an oxidant dose of 0.48 mg/L because Mn(2 + ) could be sorbed onto the MnO(2) particles. Finally, The MnO(2) particles were characterized using scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDX).

Rainwater harvesting in schools in Taiwan: system characteristics and water quality.

In order to understand the current status of rainwater harvesting (RWH) practices in Taiwan's schools, a study was carried out to examine the RWH system performance, water usage, and water quality in these sites. A total of 29 schools in various regions were selected for this investigation, including 7 in the northern, 7 in the central, 8 in the southern, and 7 in the eastern regions of Taiwan. Water quality indicators tested were: pH, temperature, conductivity, oxidation-reduction potential, suspended solid, total organic carbon, fecal coliform, and total coliform. From this study, it was found that RWH systems in these sites generally had two different designs: one that collected rainwater only, and one that collected both rainwater and grey water. From statistical analysis, it was found that water quality indicators such as suspended solids, total organic carbon, and fecal coliform were significantly affected by the water source and site location. Fecal coliforms in most of the sites we studied were high and not qualified for toilet flushing. The average water retention time of 2.4 months was long and considered to be the main reason to cause high fecal coliform counts. Finally, the benefit analysis was conducted to evaluate economic feasibility of rainwater harvesting for these schools. It turned out that 20% of them were able to gain economic benefits from using rainwater.

Neural correlates of pragmatic language comprehension in autism spectrum disorders.

Difficulties with pragmatic aspects of communication are universal across individuals with autism spectrum disorders (ASDs). Here we focused on an aspect of pragmatic language comprehension that is relevant to social interaction in daily life: the integration of speaker characteristics inferred from the voice with the content of a message. Using functional magnetic resonance imaging (fMRI), we examined the neural correlates of the integration of voice-based inferences about the speaker's age, gender or social background, and sentence content in adults with ASD and matched control participants. Relative to the control group, the ASD group showed increased activation in right inferior frontal gyrus (RIFG; Brodmann area 47) for speaker-incongruent sentences compared to speaker-congruent sentences. Given that both groups performed behaviourally at a similar level on a debriefing interview outside the scanner, the increased activation in RIFG for the ASD group was interpreted as being compensatory in nature. It presumably reflects spill-over processing from the language dominant left hemisphere due to higher task demands faced by the participants with ASD when integrating speaker characteristics and the content of a spoken sentence. Furthermore, only the control group showed decreased activation for speaker-incongruent relative to speaker-congruent sentences in right ventral medial prefrontal cortex (vMPFC; Brodmann area 10), including right anterior cingulate cortex (ACC; Brodmann area 24/32). Since vMPFC is involved in self-referential processing related to judgments and inferences about self and others, the absence of such a modulation in vMPFC activation in the ASD group possibly points to atypical default self-referential mental activity in ASD. Our results show that in ASD compensatory mechanisms are necessary in implicit, low-level inferential processes in spoken language understanding. This indicates that pragmatic language problems in ASD are not restricted to high-level inferential processes, but encompass the most basic aspects of pragmatic language processing.

Association of the dopamine transporter (SLC6A3/DAT1) gene 9-6 haplotype with adult ADHD.

ADHD is a neuropsychiatric disorder characterized by chronic hyperactivity, inattention and impulsivity, which affects about 5% of school-age children. ADHD persists into adulthood in at least 15% of cases. It is highly heritable and familial influences seem strongest for ADHD persisting into adulthood. However, most of the genetic research in ADHD has been carried out in children with the disorder. The gene that has received most attention in ADHD genetics is SLC6A3/DAT1 encoding the dopamine transporter. In the current study we attempted to replicate in adults with ADHD the reported association of a 10-6 SLC6A3-haplotype, formed by the 10-repeat allele of the variable number of tandem repeat (VNTR) polymorphism in the 3' untranslated region of the gene and the 6-repeat allele of the VNTR in intron 8 of the gene, with childhood ADHD. In addition, we wished to explore the role of a recently described VNTR in intron 3 of the gene. Two hundred sixteen patients and 528 controls were included in the study. We found a 9-6 SLC6A3-haplotype, rather than the 10-6 haplotype, to be associated with ADHD in adults. The intron 3 VNTR showed no association with adult ADHD. Our findings converge with earlier reports and suggest that age is an important factor to be taken into account when assessing the association of SLC6A3 with ADHD. If confirmed in other studies, the differential association of the gene with ADHD in children and in adults might imply that SLC6A3 plays a role in modulating the ADHD phenotype, rather than causing it.

[Autism spectrum disorders in adults]. / Autismespectrumstoornissen bij volwassenen.

Early infantile autism' as defined by Kanner has grown into a spectrum of autistic disorders. The recognition of Asperger's disorder and of pervasive developmental disorder not otherwise specified (PDD-NOS), has led to increased demand for appropriate diagnostic assessment of autism in adults. The expression ofimpairments in social interaction, communication, imagination and mental flexibility changes during development into adulthood. The diagnostic procedure in adult psychiatry should comprise a collateral developmental interview. Autism spectrum disorders in adults may mimic, or be overshadowed by, other psychiatric disorders. For effective diagnosis, the application of structured interviews, such as the 'Autism diagnostic observation schedule' (ADOS), 'Autism diagnostic interview-revised' (ADI-R) or 'Diagnostic interview for social and communication disorders' (DISCO) is recommended.

[Short- and long-term results of a systematic benzodiazepine discontinuation programme for psychiatric patients]. / Korte- en langetermijnresultaten na geprotocolleerde benzodiazepineafbouw bij psychiatrische patiënten.

BACKGROUND: Although guidelines for the use of benzodiazepines emphasise that these drugs should only be prescribedfor short periods of time, in practice long-term usage persists and can be a serious problem. There is afear among patients and among doctors prescribing the drugs that symptoms will become more acute if attempts are made to terminate the regimen. AIM: To determine the short- and long-term results of a standardized method for discontinuing the use of benzodiazepines (BZD) and to test whether these results were related to the age and gender of the patients, the BZD dosage level and the treatment modality. METHOD: A retrospective cohort study was performed at the Department of Psychiatry of the Radboud University Nijmegen Medical Centre. A systematic BZD discontinuation programme was offered by the Department of Psychiatry to patients who had been using BZD for at least three months. By studying the medical records, by conducting telephone interviews and by examining the prescription data of the GP or the pharmacy it was ascertained how many patients managed to become abstinent in the short- and long-term. RESULTS: Upon termination of the discontinuation programme 65% of the patients had managed to stop taking BZD and at follow-up approximately 2 years later 37% of the patients interviewed had not used BZD for the last 3 months. Neither age, nor gender, nor treatment modality predicted BZD usage immediately after the end of the discontinuation programme or at the 2-year follow-up. A high dose of BZD was the only significant predictor of post-programme usage 2 years later. CONCLUSION: A systematic discontinuation programme seems to be just as effective for psychiatric patients as it isfor general practice patients and deserves to be included in the regular treatment programmes provided by psychiatric practices.

[Predicting the success of a benzodiazepine discontinuation programme: myths or clinical wisdom?]. / Het voorspellen van het succes van benzodiazepineafbouw: mythes of klinische wijsheden?

BACKGROUND: After successful completion of a benzodiazepine withdrawal programme it nevertheless is hard to remain abstinent in the long term. AIM: To determine to what extent the success of a benzodiazepine discontinuation programme for psychiatric patients with chronic benzodiazepine use (> or = 3 months) can be predicted from the severity of the anxiety, sleep disorders and depressive symptoms, and from the level of benzodiazepine dependence. The predictive values of coping style and personality characteristics were also studied. METHOD: A prognostic cohort study with patients of the Radboud University Nijmegen Medical Centre was conducted. Before entering the programme 92 patients were given a psychological assessment. Anxiety level, benzodiazepine dependence, coping style and personality traits were measured by means of psychological questionnaires. The DSM-IV axis I classification for each patient was known. Patients who had stopped their medication immediately after the discontinuation programme ended (n = 6o) were compared with patients who had not been successful in completing the programme (n = 32). Thereafter, patients who were still abstinent at the follow-up about 2 years later (n = 25) were compared with patients who at that time /used benzodiazepine (n = 43). RESULTS: Of all the variables examined, it was only a specific coping style whereby patients expressed their (negative) emotions which was associated with the short- and long-term success of the discontinuation programme. The more patients expressed their negative emotions, the greater the chance of a successful outcome and permanent abstinence. Coping style, however, predicted for only a small proportion of the variance in the success of the discontinuation programme. CONCLUSION: The psychological characteristics and the DSM-IV axis I classifications should not exert undue influence on the clinician's decision to advise the patient to stop or continue taking benzodiazepines.

The absence of benzodiazepine craving in a general practice benzodiazepine discontinuation trial.

This study aimed to assess benzodiazepine craving longitudinally and to describe its time course by means of the Benzodiazepine Craving Questionnaire (BCQ). Subjects were long-term benzodiazepine users participating in a two-part treatment intervention aimed to reduce long-term benzodiazepine use in general practice in The Netherlands. Four repeated measurements of benzodiazepine craving were taken over a 21-month follow-up period. Results indicated that (1) benzodiazepine craving severity decreased over time, (2) patients still using benzodiazepines experienced significantly more severe craving than patients who had quit their use after one of the two interventions, and (3) the way in which patients had attempted to quit did not influence the experienced craving severity over time, however, (4) patients who had received additional tapering off, on average, reported significantly more severe craving than patients who had only received a letter as an incentive to quit. Although benzodiazepine craving is prevalent among (former) long-term benzodiazepine users during and after discontinuation, craving severity decreases over time to negligible proportions. Self-reported craving can be longitudinally monitored and quantified by means of the BCQ.

Latent trait standardization of the benzodiazepine dependence self-report questionnaire using the Rasch scaling model.

The aim of the present study was to obtain standardized scores that correspond with the raw scores on the four Rasch scales of the Benzodiazepine Dependence-Self Report Questionnaire (Bendep-SRQ). The eligible normative group for standardization of the Bendep-SRQ scales consisted of 217 general practice (GP) patients, all using benzodiazepines. Two standardization methods were used and compared: "classical standardization," which transforms raw scores into standard scores on the unit normal distribution, and "latent trait standardization," which transforms raw scores into latent trait scores. The latter requires the Rasch model with the additional assumption of a normally distributed latent trait, which held true for the scales "problematic use," "lack of compliance," and "withdrawal," but not for "preoccupation." The observed unequal item spacing on the "preoccupation" scale was hypothesized to induce a response tendency of nondeviation, causing a local violation of the assumption of a normally distributed latent trait. Nevertheless, comparison of the results of the two standardization methods revealed such a high degree of resemblance, that latent trait standardization could be used for "preoccupation" just as well as classical standardization. The presented standard scores and corresponding percentile ranks make raw Bendep-SRQ scores clinically interpretable in relation to the normative GP sample. Incorporation of the Rasch scaling methodology into the development of the Bendep-SRQ marks the adoption of the item response theory in the field of applied test methodology. In this process, it appears that equal item spacing has to be taken into account to prevent local violations of the Rasch model with the additional assumption of a normally distributed latent trait.

Cross-validation of the benzodiazepine dependence self-report questionnaire in outpatient benzodiazepine users.

The aim of this study was to cross-validate the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ), which reflects the severity of benzodiazepine (BZD) dependence. The Bendep-SRQ, Symptom Checklist-90 (SCL-90) Schedules for Clinical Assessments in Neuropsychiatry (SCAN), and Addiction Severity Index-Revised (ASI-R) were administered to 102 general practice (GP) patients and 126 psychiatric outpatients who were using BZDs. The scalability and reliability of the Bendep-SRQ scales were reassessed in terms of Rasch homogeneity, subject discriminability, item discriminability, and test-retest stability. Present and original Rasch item orders were compared to evaluate construct validity. A matrix of all measures was factor-analyzed to assess concurrent and discriminant validity. The scalability of the Bendep-SRQ scales was confirmed. The reliability results were fairly good. Present and original Rasch item orders corresponded. The Bendep-SRQ scales and concurrent measures had high loadings on one factor, the discriminant measures on two other factors. In spite of some differences with respect to sociodemographic characteristics and pattern of BZD use, the cross-validation results agreed well with the results of the original study on the Bendep-SRQ. The Bendep-SRQ has presently acquired enough support of favorable and consistent results for clinical and scientific use.

Assessment of benzodiazepine dependence in alcohol and drug dependent outpatients: a research report.

In this study on 99 outpatients who were being treated for alcohol and/or drug dependence and also using benzodiazepines (BZDs), prevalence rates of DSM-III-R and ICD-10 substance dependence diagnoses were ascertained and scalability, reliability and validity of the scales of the Benzodiaepine Dependence Self-Report Questionnaire (Bendep-SRQ) were assessed. The latter properties were investigated by Rasch analyses, discriminability coefficients, test-retest coefficients and factor analyses. BZD dependence was found to be a prevalent additional diagnosis. The psychometric findings appear to support the use of the Bendep-SRQ at outpatient addiction centers, which could contribute to a more differentiated treatment for poly-substance dependence.

The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation.

The checkpoint kinase Chk1 is an important mediator of cell cycle arrest following DNA damage. The 1.7 A resolution crystal structures of the human Chk1 kinase domain and its binary complex with an ATP analog has revealed an identical open kinase conformation. The secondary structure and side chain interactions stabilize the activation loop of Chk1 and enable kinase activity without phosphorylation of the catalytic domain. Molecular modeling of the interaction of a Cdc25C peptide with Chk1 has uncovered several conserved residues that are important for substrate selectivity. In addition, we found that the less conserved C-terminal region negatively impacts Chk1 kinase activity.