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The general understanding of the ‘vulnerability–stress model’ of mental disorders neglects the modifying impact of resilience-increasing factors such as coping ability.
Probing a conceptual framework integrating both adverse events and coping factors in an extended ‘vulnerability–stress–coping model’ of mental disorders, the effects of functional neuropeptide S receptor gene (NPSR1) variation (G), early adversity (E) and coping factors (C) on anxiety were addressed in a three-dimensional G × E × C model.
In two independent samples of healthy probands (discovery: n = 1403; replication: n = 630), the interaction of NPSR1 rs324981, childhood trauma (Childhood Trauma Questionnaire, CTQ) and general self-efficacy as a measure of coping ability (General Self-Efficacy Scale, GSE) on trait anxiety (State-Trait Anxiety Inventory) was investigated via hierarchical multiple regression analyses.
In both samples, trait anxiety differed as a function of NPSR1 genotype, CTQ and GSE score (discovery: β = 0.129, P = 3.938 × 10−8; replication: β = 0.102, P = 0.020). In A allele carriers, the relationship between childhood trauma and anxiety was moderated by general self-efficacy: higher self-efficacy and childhood trauma resulted in low anxiety scores, and lower self-efficacy and childhood trauma in higher anxiety levels. In turn, TT homozygotes displayed increased anxiety as a function of childhood adversity unaffected by general self-efficacy.
Functional NPSR1 variation and childhood trauma are suggested as prime moderators in the vulnerability–stress model of anxiety, further modified by the protective effect of self-efficacy. This G × E × C approach – introducing coping as an additional dimension further shaping a G × E risk constellation, thus suggesting a three-dimensional ‘vulnerability–stress–coping model’ of mental disorders – might inform targeted preventive or therapeutic interventions strengthening coping ability to promote resilient functioning.
We investigated the contribution of polymorphisms shown to moderate transcription of serotonin transporter (5HTT) and monoamine oxidase A (MAOA) to the development of violence, and furthermore to test for gene x environment interactions. To do so, a cohort of 184 adult male volunteers referred for forensic assessment were assigned to a violent or non-violent group. 45% of violent, but only 30% of non-violent individuals carried the low-activity, short MAOA allele. In the violent group, carriers of low-function variants of 5HTT were found in 77%, as compared to 59%. Logistic regression was performed and the best fitting model revealed a significant, independent effect of childhood environment and MAOA genotype. A significant influence of an interaction between childhood environment and 5HTT genotype was found (Fig. 1). MAOA thus appears to be independently associated with violent crime, while there is a relevant 5HTT x environment interaction.
We have followed up a patient with 8q24.2 → qter and 15q14 → pter duplication due to a maternal reciprocal translocation, a condition related to Prader-Willi Syndrome. Apart from dysmorphic features, the patient suffered from recurring episodes of bipolar psychosis. Interestingly, PET scanning revealed revealed prominent bilateral hypometabolism in the frontal, temporal, and parietal lobes as well as in the cerebellum. Possible implications of this rare chromosomal abnormality with regards to psychiatric disorders are discussed, with emphasis on recent evidence suggesting chromosome 15q13-15 as a susceptiblity locus for psychosis.
Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.
The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.
There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.
These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.
The glutamate decarboxylase (GAD67/65; GAD1/GAD2) as the rate-limiting enzyme in gamma-aminobutyric acid (GABA) synthesis has been suggested as a prime candidate in the pathogenesis of anxiety disorders. In the present study, DNA methylation of GAD1/2 gene regulatory regions was investigated for association with panic disorder with particular attention to possible effects of environmental factors.
Sixty-five patients with panic disorder (f=44, m=21) and 65 matched healthy controls were analyzed for DNA methylation status at 40 GAD1 and 10 GAD2 CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. The occurrence of recent positive and negative life events was ascertained. Patients and controls were genotyped for GAD1 genetic variation.
Patients with panic disorder exhibited significantly lower average GAD1 methylation than healthy controls. The occurrence of negative life events was correlated with relatively decreased average methylation mainly in the female subsample. GAD1 SNPs rs3749034 and rs3762555 conferred a significantly lower methylation at three GAD1 CpG sites. No differential methylation was observed in the GAD2 gene.
The present pilot data suggest a - potentially compensatory - role of GAD1 gene hypomethylation in panic disorder possibly mediating the influence of negative life events and dependent on genetic variation. Future studies are warranted to replicate the present finding in independent samples, preferably applying a longitudinal design.
Second-generation antipsychotics (SGAs) are a frequently and effectively used treatment in schizophrenia and psychotic disorders. Other than First-generation antipsychotics (FGAs), which mainly exert their pharmacologic effect in subcortical dopaminergic systems, SGAs additionally affect partly serotonergically innervated structures within prefrontal areas, such as the Anterior Cingulate Cortex (ACC). However, only few controlled, randomized studies have so far investigated direct and indirect effects of SGAs on the ACC.
The present study investigated differential effects of one SGA (quetiapine) and one FGA (flupentixol) on the human action monitoring system.
ACC function in 18 quetiapine-medicated patients and 13 flupentixol-treated patients suffering from schizophrenia was assessed by means of the error-related negativity (ERN), a neurophysiological marker of ACC function, in a pre-post design. Results Between-group comparisons revealed different effects of quetiapine and flupentixol on ACC function despite similar improvement in psychopathology, cognitive performance and quality of life. Whereas SGA treatment was associated with an increase in amplitudes over time, there were prolonged ERN peak latencies in patients treated with the FGA. Moreover, treatment effects depended on baseline PFC function in both groups.
We conclude that both flupentixol and quetiapine improve prefrontal function especially in patients with weak initial ACC function which might be due to their shared affinity for 5HT-receptors in frontal brain regions. However, since this affinity is more pronounced for SGAs, patients treated with quetiapine seemed to profit more evidently concerning PFC function compared to patients of the flupentixol group, who exhibited a compensatory prolongation of processes.
The monoamine oxidase A (MAO-A) gene has been suggested as a vulnerability gene in the pathogenesis of panic disorder.
Epigenetic processes such as methylation critically influencing gene regulation and mediating adaptation to environmental factors have so far not been investigated in panic disorder.
Thus, in the present study DNA methylation patterns in the MAO-A regulatory and exon1/intron1 region were investigated for association with panic disorder.
Sixty-five patients with panic disorder (m = 21, f = 44) and 65 healthy controls were analyzed for DNA methylation status at 42 MAO-A CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. The occurrence of positive and negative life events was ascertained. All subjects were genotyped for the MAO-A VNTR.
Male subjects showed no or only very minor methylation. In female patients, significantly lower methylation was observed at ten MAO-A CpG sites in the promoter and exon/intron 1 in comparison to healthy controls. Additionally, in female subjects the occurrence of negative life events was associated with a decreased methylation status, while positive life events were associated with relatively increased methylation. Age, smoking status or medication did not influence methylation status, the more active MAO-A VNTR alleles were associated with increased methylation in controls.
The present study suggests a potentially female-specific role of epigenetic alterations, i.e. MAO-A gene hypomethylation, in interaction with environmental factors in the pathogenesis of panic disorder. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design.
Recent research in bipolar disorder points at the relevance and persistence of cognitive deficits in bipolar patients (BPD) even beyond acute episodes of depression or mania. Impairments were found in attention, processing speed, memory and executive functioning. Up to now, the mechanisms, why some BPD do not reach their former level of cognitive performance and psychosocial functioning, while others are remitted completely, is not understood. In this study we aimed to identify a’deficit vs. nondeficit subgroup’ within BPD. For this purpose, we investigated the association between demographic and disease specific variables and the cognitive performance of BPD. The test performance of 70 remitted outpatients (Bipolar-Type I and II) was compared to 70 healthy controls (HC). Participants performed an extensive neuropsychological test battery.
As expected our sample of euthymic BPD performed significantly worse than HCs in three of eight cognitive domains, namely Planning, Cognitive Flexibility and Divided Attention. In line with previous findings, more than a half of the euthymic BPD did not have any neuropsychological deficits. We found no significant correlations between test performance and clinical variables. But interestingly, we revealed significant associations between subthreshold depressive symptomatology and psychomotor slowing, impaired long term and working memory.
In sum, these results suggest the presence of cognitive subgroups in bipolar disorder. However, we found no evidence of underlying etiologies: Clinical characteristics seem to have no influence. However, our results indicate that cognitive deficits found in euthymic BPD could result from a subdepressive syndrome and not per se by disease characteristics.
Mild cognitive impairment (MCI) often precedes Alzheimer’s Dementia (AD), and in a high proportion of individuals affected by MCI, there are already neuropathological processes ongoing that become more evident when patients progress to AD. Accordingly, there is a need for reliable biomarkers to distinguish between normal aging and incipient AD. Recent research suggests that, in addition to established biomarkers such as CSF Aß42, total tau and hyperphosphorylated tau, resting state connectivity established by functional magnetic resonance imaging might also be a feasible biomarker for prodromal stages of AD. In order to explore this possibility, we investigated resting state functional connectivity as well as cerebrospinal fluid (CSF) biomarker profiles in patients with MCI (n = 30; age 66.43 ± 7.06 years) and cognitively healthy controls (n = 38; age 66.89 ± 7.12 years). CSF Aß42, total tau and hyperphosphorylated tau concentrations were correlated with measures of cognitive performance (immediate and delayed recall, global cognition, processing speed). Moreover, MCI-related alterations in intrinsic functional connectivity within the default mode network were investigated using functional resting state MRI. As expected, MCI patients showed decreased CSF Aß42 and increased total tau concentrations. These alterations were associated with cognitive performance. However, there were no differences between MCI patients and cognitively healthy controls regarding intrinsic functional connectivity. In conclusion, our results indicate that CSF protein profiles seem to be more closely related to cognitive decline than alterations in resting state activity. Thus, resting state connectivity might not be a reliable biomarker for early stages of AD.
Despite its numerous side effects, clozapine is still the most effective antipsychotics making it an ideal reference substance to validate the efficacy of novel compounds for the treatment of schizophrenia. However, blood–brain barrier permeability for most new molecular entities is unknown, requiring central delivery. Thus, we performed a dose-finding study for chronic intracerebroventricular (icv) delivery of clozapine in mice.
Specifically, we implanted wild-type C57BL/6J mice with osmotic minipumps (Alzet) delivering clozapine at a rate of 0.15 µl/h at different concentrations (0, 3.5, 7 and 14 mg/ml, i.e. 0, 12.5, 25 and 50 µg/day). Mice were tested weekly in a modified SHIRPA paradigm, for locomotor activity in the open field and for prepulse inhibition (PPI) of the acoustic startle response (ASR) for a period of 3 weeks.
None of the clozapine concentrations caused neurological deficits or evident gross behavioural alterations in the SHIRPA paradigm. In male mice, clozapine had no significant effect on locomotor activity or PPI of the ASR. In female mice, the 7 and 14 mg/ml dose of clozapine significantly affected both open field activity and PPI, while 3.5 mg/ml of clozapine increased PPI but had no effects on locomotor activity.
Our findings indicate that 7 mg/ml may be the optimal dose for chronic icv delivery of clozapine in mice, allowing comparison to screen for novel antipsychotic compounds.
ADHD is a highly prevalent disease in childhood which often persists into adulthood, then co-occurring with common adult conditions. Especially for adult ADHD, little is known about the costs of ADHD and the additional costs of comorbid conditions.
To determine medical costs of ADHD and costs of comorbidities (mood, anxiety and substance use disorders, obesity), including their co-occurrence rates, stratified by age and gender.
Claims data from a German Statutory Health Insurance database with approximately four million member-records per year were analysed. A total of 25,300 prevalent ADHD patients were identified by means of an ICD-10 GM diagnosis of ADHD. A 1:1 age and gender adjusted reference group without ADHD diagnosis was randomly selected. Total health claims and health care costs related to ADHD were analysed, in addition to more targeted analyses of the occurrence and costs of pre-defined common comorbidities of, in particular, adult ADHD (SUD, mood and anxiety disorders, obesity). Outcomes were mean costs per patient and occurrence rates of comorbid conditions. Surplus costs of a comorbid condition in persons with ADHD relative to costs of this condition in persons without ADHD were calculated. Subgroup analyses were conducted based on age (0–12 years, 13–17 years, 18–30years, 30+ years) and gender.
Patients with ADHD were €1500 more expensive annually than individuals without ADHD (p < 0.001). Main cost drivers were inpatient care, psychiatrists and psychotherapists. Mood, anxiety, substance use disorders and obesity were significantly more frequent in ADHD patients and additional costs resulting from the comorbid conditions amounted up to €2800. Costs were slightly higher in women than men and increased with age for both genders. In young adults (18–30 years) health care costs dropped notably, especially costs for the medical treatment of ADHD with stimulants and costs for psychiatrists, before rising again in the group of patients over 30 years who had higher comorbidity rates.
Medical costs for ADHD are substantial, in part through frequently occurring comorbid conditions, and particularly in adulthood, and are likely to further accelerate in the coming years. A gap of care was found, starting with the transition age group of patients over 17 years, as indicated by reduced costs per person during young adulthood, as well as an overall strong drop in administrative prevalence. In the future, approaches to improve the situation of care and reduce costs at the same time, i.e. through managed care programmes, should be implemented and benefit from detailed knowledge on age and gender-specific cost-drivers.
There is accumulating evidence that the error-related negativity (ERN), an event-related potential elicited after erroneous actions, is altered in different psychiatric disorders and may help to guide treatment options. Thus, the ERN is a promising candidate as a psychiatric biomarker. Basic methodological requirements for a biomarker are that their measurements are standardised and reliable. The aim of the present study was to establish ERN acquisition in a reliable, time-efficient and patient-friendly way for use in clinical practice.
Healthy subjects performed a speeded Eriksen Flanker Task that increases the number of errors. In a test–retest design (N = 14) with two sessions separated by 28 days we assessed the reliability of the ERN. To ensure external validity, we aimed to replicate previously reported correlation patterns of ERN amplitude with (A) number of errors and (B) negative affect. In order to optimise the clinical use of the task, we determined to which extent the task can be shortened while keeping reliability >0.80.
We found excellent reliability of the ERN (intraclass correlation coefficients = 0.806–0.947) and replicated ERN correlation patterns. The task can be halved to a patient-friendly length of 200 trials (recorded in 8 min) keeping reliability >0.80.
The modified task provides reliable and efficient recording of the ERN, facilitating its use as a psychiatric biomarker.
Individual biological predispositions should play a role in risky driving behaviour. Platelet monoamine oxidase (MAO) activity, dopamine transporter gene (DAT1) and neuropeptide S receptor 1 (NPSR1) gene polymorphisms have been identified as markers of impulsivity, alcohol use and excessive risk-taking. We aimed to find out how this knowledge on neurobiology of impulsivity applies to drunk driving and traffic behaviour in general.
We have longitudinally examined the behaviour of drunk drivers (n = 203) and controls (n = 211) in traffic, in association with their alcohol-related problems, personality measures and the three biomarkers. We analysed differences between the subjects based on whether they had committed driving while impaired by alcohol (DWI) violation in a 10-year time period after recruitment or not and investigated further, what kind of predictive value do the different biomarkers have in committing DWI and other traffic violations and accidents.
The original drunk drivers group had lower platelet MAO activity but further DWI was not significantly associated with this measure. Being a NPSR1 T-allele carrier contributed to the risk of repeatedly committing DWI. DAT1 9R carriers in contrast were involved in more traffic accidents by their own fault (active accidents), compared to 10R homozygotes in the whole sample. All groups with DWI also had significantly more alcohol-related problems and higher scores in maladaptive impulsivity compared to controls without DWI.
Established biological markers of alcohol use and impulsivity can be reliably associated with everyday traffic behaviour and help in contributing to the understanding of the need for more personalized prevention activities.
Need for Cognition (NFC) and Openness to Ideas are intellectual investment traits that are characterized by a tendency to seek out, engage in and enjoy effortful cognitive activity. Little, however, is known about the extent to which they are influenced by genetic and environmental factors. With the present contribution, we aim at furthering our knowledge on the mechanisms underlying intellectual investment traits by following-up on a recent investigation of the role of dopaminergic gene variation in intellectual investment. Employing a standard approach that relied on null-hypothesis significance testing, we found that, first, two dopaminergic genetic variants interacted in modulating individual differences in NFC, but not in Openness to Ideas; that, second, negative life events played a role in the modulation of Openness to Ideas, but not of NFC; and that, third, negative life events as assessed using another measure were only marginally related to Openness to Ideas while positive life events were associated with both Openness to Ideas and NFC, with the latter effect being also dependent on DRD4 exon III genotype. However, employing a Bayesian approach, the assumption of a genetic effect on investment traits was overall not supported, while the assumption of a role of positive life events in the modulation of investment traits could be confirmed, with a tentative increment in the prediction of NFC by adding an interaction of positive life events and DRD4 variation to the main effect of positive life events. Our findings underscore the importance to use different approaches in the field of personality neuroscience. To gain deeper insight into the basis of personality traits does not only require to consider genetic as well as environmental influences and their interplay, but also requires more differentiated statistical analyses that can at least in part tackle the often inconsistent findings in this field.
Working memory (WM) deficits in schizophrenia (SCZ) have been linked to impairments in the encoding phase that are associated with aberrant neuronal functioning. Similar abnormalities have been observed in unaffected first-degree relatives (REL) and are thus discussed as candidate endophenotypes. The process of WM consolidation – i.e. the formation of durable WM representations – is assumed to be impaired in SCZ, but no study has investigated WM consolidation and neuronal correlates of visual WM encoding in REL before.
We examined whole-brain activation during the encoding phase with an event-related functional magnetic resonance imaging study design in 25 SCZ subjects, 22 REL subjects, and 25 healthy controls. Subjects performed a visual masked change detection task that assessed WM performance and consolidation.
SCZ showed deficient WM performance indicating an impairment consolidation process, accompanied by broad neuronal hypoactivation, most prominently in frontal brain regions, as well as increased activity of the anterior cingulate during the encoding phase. REL showed decreased neuronal activity in the middle and medial frontal gyrus and increased activity in the precentral gyrus and insula during encoding, but no significant behavioral deficits were observed. In respect of given consolidation times, REL showed a shift from decreased frontal activity at short time intervals to increased frontal activity at longer time intervals.
Findings suggest WM consolidation may be slowed in REL so that the deployment of compensatory neuronal resources during encoding is needed to assure proper WM performance. This supports the view of WM-related neuronal dysfunctions as a potential endophenotypic marker.
We discuss the importance of digitised sky-limited Schmidt B- and R-band, and Hα images of extended translucent (AB ≃ 1–5 mag) and dark (AB > 5 mag) clouds. In translucent clouds (e.g. high-latitude cirrus) photons can penetrate through the whole cloud and control the physical and chemical processes. Comparison of the B images with far-infrared/submillimetre CO, CI, and CII emission provides important information on the non-homogeneous cloud structure, carbon chemistry and energy balance. In dark clouds the interior is completely shielded from the interstellar radiation field. L1204 is a dark cloud with at its edge the well-known HII rim S140. The R-band image shows S140 as well as the diffuse extended HII region around the exciting B-type star. However, the sensitivity for Hα in the R-band is rather low and there is contamination with diffusely scattered red light from dust. Deep Hα and R-band imaging of an ∼20′×20′ field has recently been done with the 1 m Hoher List telescope of Bonn University. A wealth of small-scale structures can been seen on continuum-subtracted images which provide new insight on the geometry of this cloud.