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Highlights
• Suicides which occurred in a biologics trial targeting the IL-17R are revisited.
• High IL-17 levels are found in depression by the majority of reports.
• Results from studies regarding IL-17 and psychosis are mixed.
• Very few psychiatric studies investigated IL-17 signalling in suicidality.
• Potential mechanisms how IL-17 influences neuro-inflammation are described.
Abstract:
Interleukin 17 (IL-17) is a potent pro-inflammatory cytokine which plays a role in autoimmune disorders, such as psoriasis and multiple sclerosis, and is important for the defense against pathogens, particularly in the gut. However, IL-17 has recently also gained attention in association with suicidal behavior. In this review, we review the literature regarding IL-17 in psychiatric disorders and suicidality. We also take a closer look at the suicides which occurred in the clinical trial for psoriasis with brodalumab, a monoclonal antibody targeting the IL-17 receptor. Lastly, we discuss potential working mechanisms relevant to neuroinflammation and the possible involvement of IL-17.
Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues.
Background: Understanding which factors influence dietary intake, particularly in daily life, is crucial given the impact diet has on physical as well as mental health. However, a factor might influence whether but not how much an individual eats and vice versa or a factor’s importance may differ across these two facets. Distinguishing between these two facets, hence, studying dietary intake as a dual process is conceptually promising and not only allows further insights, but also solves a statistical issue. When assessing the association between a predictor (e.g. momentary affect) and subsequent dietary intake in daily life through ecological momentary assessment (EMA), the outcome variable (e.g. energy intake within a predefined time-interval) is semicontinuous. That is, one part is equal to zero (i.e. no dietary intake occurred) and the other contains right-skewed positive values (i.e. dietary intake occurred, but often only small amounts are consumed). However, linear multilevel modelling which is commonly used for EMA data to account for repeated measures within individuals cannot be applied to semicontinuous outcomes. A highly informative statistical approach for semicontinuous outcomes is multilevel two-part modelling which treats the outcome as generated by a dual process, combining a multilevel logistic/probit regression for zeros and a multilevel (generalized) linear regression for nonzero values. Methods: A multilevel two-part model combining a multilevel logistic regression to predict whether an individual eats and a multilevel gamma regression to predict how much is eaten, if an individual eats, is proposed. Its general implementation in R, a widely used and freely available statistical software, using the R-package brms is described. To illustrate its practical application, the analytical approach is applied exemplary to data from the Eat2beNICE-APPetite-study. Results: Results highlight that the proposed multilevel two-part model reveals process-specific associations which cannot be detected through traditional multilevel modelling. Conclusions: This paper is the first to introduce multilevel two-part modelling as a novel analytical approach to study dietary intake in daily life. Studying dietary intake through multilevel two-part modelling is conceptually as well as methodologically promising. Findings can be translated to tailored nutritional interventions targeting either the occurrence or the amount of dietary intake.
Background: Diet and physical activity (PA) have a major impact on physical and mental health. However, there is a lack of effective strategies for sustaining these health-protective behaviors. A shift to a microtemporal, within-person approach is needed to capture dynamic processes underlying eating behavior and PA, as they change rapidly across minutes or hours and differ among individuals. However, a tool that captures these microtemporal, within-person processes in daily life is currently not present.
Objective: The APPetite-mobile-app is developed for the ecological momentary assessment of microtemporal, within-person processes of complex dietary intake, objectively recorded PA, and related factors. This study aims to evaluate the feasibility and usability of the APPetite-mobile-app and the validity of the incorporated APPetite-food record.
Methods: The APPetite-mobile-app captures dietary intake event-contingently through a food record, captures PA continuously through accelerometers, and captures related factors (eg, stress) signal-contingently through 8 prompts per day. Empirical data on feasibility (n=157), usability (n=84), and validity (n=44) were collected within the Eat2beNICE-APPetite-study. Feasibility and usability were examined in healthy participants and psychiatric patients. The relative validity of the APPetite-food record was assessed with a subgroup of healthy participants by using a counterbalanced crossover design. The reference method was a 24-hour recall. In addition, the energy intake was compared with the total energy expenditure estimated from accelerometry.
Results: Good feasibility, with compliance rates above 80% for prompts and the accelerometer, as well as reasonable average response and recording durations (prompt: 2.04 min; food record per day: 17.66 min) and latencies (prompts: 3.16 min; food record: 58.35 min) were found. Usability was rated as moderate, with a score of 61.9 of 100 on the System Usability Scale. The evaluation of validity identified large differences in energy and macronutrient intake between the two methods at the group and individual levels. The APPetite-food record captured higher dietary intakes, indicating a lower level of underreporting, compared with the 24-hour recall. Energy intake was assessed fairly accurately by the APPetite-food record at the group level on 2 of 3 days when compared with total energy expenditure. The comparison with mean total energy expenditure (2417.8 kcal, SD 410) showed that the 24-hour recall (1909.2 kcal, SD 478.8) underestimated habitual energy intake to a larger degree than the APPetite-food record (2146.4 kcal, SD 574.5).
Conclusions: The APPetite-mobile-app is a promising tool for capturing microtemporal, within-person processes of diet, PA, and related factors in real time or near real time and is, to the best of our knowledge, the first of its kind. First evidence supports the good feasibility and moderate usability of the APPetite-mobile-app and the validity of the APPetite-food record. Future findings in this context will build the foundation for the development of personalized lifestyle modification interventions, such as just-in-time adaptive interventions.
Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects.
Einführung: Seit 20 Jahren ist die Vagusnervstimulation (VNS) eine europaweit zugelassene invasive Therapieoption für therapieresistente Depressionen (TRD). Im Gegensatz zu geläufigeren Behandlungen wie EKT sind Kenntnisse über VNS sowohl in der Allgemeinbevölkerung als auch in Fachkreisen gering.
Methoden: In diesem narrativen Review geben wir eine klinisch und wissenschaftlich fundierte Übersicht über die VNS. Hypothesen zum Wirkmechanismus sowie die aktuelle Evidenzlage zur Wirksamkeit werden dargestellt. Das perioperative Management, das Nebenwirkungsprofil und die Nachbetreuung einschließlich Dosistitration werden beschrieben. Ein Vergleich über internationale Leitlinienempfehlungen zur VNS findet sich ebenfalls. Ferner formulieren wir Kriterien, die bei der Auswahl geeigneter Patienten hilfreich sind.
Ergebnisse: Die elektrischen Impulse werden über den N. vagus afferent weitergeleitet und stimulieren über verschiedene Wege ein neuromodulatorisches zerebrales Netzwerk. Viele Studien und Fallserien zeigten die Wirksamkeit von VNS als adjuvantes Verfahren bei TRD. Der Effekt tritt mit einer Latenz von 3 bis 12 Monaten ein und steigt möglicherweise mit der Dauer der VNS. Unter der Beachtung der Stimulationsempfehlungen sind die Nebenwirkungen für die meisten Patienten tolerabel.
Fazit: Die VNS ist eine zugelassene, wirksame und gut verträgliche Langzeittherapie für chronische und therapieresistente Depressionen. Weitere Sham-kontrollierte Studien über einen längeren Beobachtungszeitraum sind zur Verbesserung der Evidenz wünschenswert.
The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March–December 2019 and March–December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.
Der Eintrag starker anorganischer Säuren in Wälder führte zu tiefen pH-Werten und hohen Al3+-Konzentrationen im Boden. Dem versuchte man in Deutschland seit den 1980er Jahren durch Kalkung unter Verwendung dolomitischer Kalke zu begegnen. In den ersten Jahren nach Kalkung werden organische Auflagen abgebaut und die darin enthaltenen Nährstoffe, v. a. Stickstoff (N), mobilisiert und teils im humosen Oberboden gespeichert, teils aufgenommen, teils ins Grundwasser ausgewaschen. Die Bodenvegetation reagiert auf Kalkungmit einer Zunahme an nährstoff- und stickstoffliebenden Arten, Azidophyten gehen zurück. Die Artenzusammensetzung von Mykorrhizapilzen und Bodenfauna verändern sich vollständig. Die Baumwurzeln ziehen sich in den mineralischen Oberboden zurück. Bis die basischen Kationen eine Tiefe von 30 cm erreichen, vergehen viele Jahre. Seit 1990 gingen die Depositionen an Schwefel (S) stark zurück, doch der N-Eintrag blieb bis heute auf hohem Niveau. In Nadelbaumbeständen ist der N-Eintrag wesentlich höher als in Laubwäldern oder im Freiland. Hohe N-Einträge tragen zur fortdauernden Bodenversauerung bei, zugleich eutrophieren sie Waldökosysteme, welche von Natur aus N-limitiert sind. Das verstärkte Wachstum der Waldbestände zieht einen erhöhten Bedarf an anderen Nährstoffen nach sich. In vielen Wäldern wird die kritische Belastungsgrenze („critical load“) des Eintrags von ca. 10 bis 20 kg N ha-1 a-1 überschritten. Solche Wälder werden mit N übersättigt und geben überschüssiges Nitrat, das nicht im Humus eingebaut oder von der Waldvegetation aufgenommen wird, ans Grundwasser ab. Bis heute werden in Baden-Württemberg, Rheinland-Pfalz, Hessen, Niedersachsen, Sachsen, Nordrhein-Westfalen, Thüringen und neuerdings Sachsen-Anhalt große Waldflächen mit drei bis vier Tonnen dolomitischem Kalk pro Hektar und Jahrzehnt gekalkt. Ziel ist es, eine weitere säurebedingte Verwitterung von Tonmineralen zu verhindern und die Vitalität der Waldbestände zu erhöhen. Oftmals werden dem Kalk auch Phosphor- (P) und/oder Kaliumverbindungen (K) beigemengt. Bayern, Brandenburg und Mecklenburg-Vorpommern verzichten auf Waldkalkungen oder wenden sie nur in sehr spezifischen Fällen an. Die mitteleuropäischen Hauptbaumarten Buche, Fichte, Wald-Kiefer, Tanne und Eichen sind dort ähnlich vital, da diese edaphisch eine weite ökologische Amplitude besitzen. Analysen von Blatt- und Nadelspiegeln belegen eine geringe, doch ausreichende Nährelementversorgung selbst auf den sauersten Waldböden. Heute stellt nicht Bodenversauerung, sondern N-Eutrophierung (und Klimawandel) die Hauptgefährdung der Waldökosysteme dar. Eutrophierung gefährdet die Lebensgemeinschaften auf schwach gepufferten Böden in besonderem Maße, insbesondere oligotrophe Kiefern- und Eichenwälder. Kalkung in eutrophierten Wäldern wirkt der Versauerung entgegen und führt langfristig zu tieferer Durchwurzelung. Zugleich jedoch verbessert sie angesichts hohen N-Eintrags die Verfügbarkeit limitierender Nährstoffe und verstärkt dadurch die Auswirkungen der Eutrophierung. Daher fällt die Bewertung der Kalkung ambivalent aus. Nur eine Reduzierung des N-Eintrags stellt eine wirklich gute Lösung dar. Aus Naturschutzsicht besonders bedenklich ist Waldkalkung auf natürlich basenarmen Substraten und ihren oligotraphenten Lebensgemeinschaften. Deren Habitate müssen durch Pufferzonen und angepasste Verabreichungstechniken gegen Kalkeinträge geschützt werden. Auf bestimmten mesotrophen, aber versauerungsanfälligen Lehmböden kann Kalkung fallweise toleriert werden. Die Anreicherung mit P und K entspricht einer Düngung und ist daher nicht akzeptabel. Um die Auswirkungen von Waldkalkung abwägen zu können, sollten ausreichend große ungekalkte Kontrollflächen ausgewiesen werden. Angesichts eines heute relativ hohen Waldwachstums sollte eine weitere Förderung von Waldkalkung überdacht werden.
Studying the visual system with fMRI often requires using localizer paradigms to define regions of interest (ROIs). However, the considerable interindividual variability of the cerebral cortex represents a crucial confound for group-level analyses. Cortex-based alignment (CBA) techniques reliably reduce interindividual macroanatomical variability. Yet, their utility has not been assessed for visual field localizer paradigms, which map specific parts of the visual field within retinotopically organized visual areas. We evaluated CBA for an attention-enhanced visual field localizer, mapping homologous parts of each visual quadrant in 50 participants. We compared CBA with volume-based alignment and a surface-based analysis, which did not include macroanatomical alignment. CBA led to the strongest increase in the probability of activation overlap (up to 86%). At the group level, CBA led to the most consistent increase in ROI size while preserving vertical ROI symmetry. Overall, our results indicate that in addition to the increased signal-to-noise ratio of a surface-based analysis, macroanatomical alignment considerably improves statistical power. These findings confirm and extend the utility of CBA for the study of the visual system in the context of group analyses. CBA should be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.
Background: Predicted increases in suicide were not generally observed in the early months of the COVID-19 pandemic. However, the picture may be changing and patterns might vary across demographic groups. We aimed to provide a timely, granular picture of the pandemic's impact on suicides globally.
Methods: We identified suicide data from official public-sector sources for countries/areas-within-countries, searching websites and academic literature and contacting data custodians and authors as necessary. We sent our first data request on 22nd June 2021 and stopped collecting data on 31st October 2021. We used interrupted time series (ITS) analyses to model the association between the pandemic's emergence and total suicides and suicides by sex-, age- and sex-by-age in each country/area-within-country. We compared the observed and expected numbers of suicides in the pandemic's first nine and first 10-15 months and used meta-regression to explore sources of variation.
Findings: We sourced data from 33 countries (24 high-income, six upper-middle-income, three lower-middle-income; 25 with whole-country data, 12 with data for area(s)-within-the-country, four with both). There was no evidence of greater-than-expected numbers of suicides in the majority of countries/areas-within-countries in any analysis; more commonly, there was evidence of lower-than-expected numbers. Certain sex, age and sex-by-age groups stood out as potentially concerning, but these were not consistent across countries/areas-within-countries. In the meta-regression, different patterns were not explained by countries’ COVID-19 mortality rate, stringency of public health response, economic support level, or presence of a national suicide prevention strategy. Nor were they explained by countries’ income level, although the meta-regression only included data from high-income and upper-middle-income countries, and there were suggestions from the ITS analyses that lower-middle-income countries fared less well.
Interpretation: Although there are some countries/areas-within-countries where overall suicide numbers and numbers for certain sex- and age-based groups are greater-than-expected, these countries/areas-within-countries are in the minority. Any upward movement in suicide numbers in any place or group is concerning, and we need to remain alert to and respond to changes as the pandemic and its mental health and economic consequences continue.
Purpose: Collaborative care is effective in improving symptoms of patients with depression. The aims of this study were to characterize symptom trajectories in patients with major depression during one year of collaborative care and to explore associations between baseline characteristics and symptom trajectories.
Methods: We conducted a cluster-randomized controlled trial in primary care. The collaborative care intervention comprised case management and behavioral activation. We used the Patient Health Questionnaire-9 (PHQ-9) to assess symptom severity as the primary outcome. Statistical analyses comprised latent growth mixture modeling and a hierarchical binary logistic regression model.
Results: We included 74 practices and 626 patients (310 intervention and 316 control recipients) at baseline. Based on a minimum of 12 measurement points for each intervention recipient, we identified two latent trajectories, which we labeled "fast improvers" (60.5%) and "slow improvers" (39.5%). At all measurements after baseline, "fast improvers" presented higher PHQ mean values than "slow improvers". At baseline, "fast improvers" presented fewer physical conditions, higher health-related quality of life, and had made fewer suicide attempts in their history.
Conclusions: A notable proportion of 39.5% of patients improved only "slowly" and probably needed more intense treatment. The third follow-up in month two could well be a sensible time to adjust treatment to support "slow improvers".
Beyond well-established difficulties with working memory in individuals with attention deficit hyperactivity disorder (ADHD), evidence is emerging that other memory processes may also be affected. We investigated, first, which memory processes show differences in adults and adolescents with ADHD in comparison to control participants, focusing on working and short-term memory, initial learning, interference, delayed and recognition memory. Second, we investigated whether ADHD severity, co-occurring depressive symptoms, IQ and physical fitness are associated with the memory performance in the individuals with ADHD.
We assessed 205 participants with ADHD (mean age 25.8 years, SD 7.99) and 50 control participants (mean age 21.1 years, SD 5.07) on cognitive tasks including the digit span forward (DSF) and backward (DSB), the Rey Auditory Verbal Learning Test (RAVLT), and the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence. Participants with ADHD were additionally assessed on ADHD severity, depression symptoms and cardiorespiratory fitness. A series of regressions were run, with sensitivity analyses performed when variables were skewed.
ADHD-control comparisons were significant for DSF, DSB, delayed and recognition memory, with people with ADHD performing less well than the control participants. The result for recognition memory was no longer significant in sensitivity analysis. Memory performance was not associated with greater ADHD or depression symptoms severity. IQ was positively associated with all memory variables except DSF. Cardiorespiratory fitness was negatively associated with the majority of RAVLT variables.
Individuals with ADHD showed difficulties with working memory, short-term memory and delayed memory, as well as a potential difficulty with recognition memory, despite preserved initial learning.
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the ‘missing heritability’ of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene–environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene–environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.
The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.
Fibroblasts were isolated from skin biopsies from two patients with bipolar I disorder. One patient was a 26 year old female carrying a risk haplotype in the DGKH (diacylglycerol kinase eta) gene and the other was a non-carrier 27 year old male. Patient fibroblasts were reprogrammed into human induced pluripotent stem cells (hiPSCs) by using a Sendai virus vector. DGKH-risk haplotype and non-risk haplotype hiPSCs showed expression of pluripotency markers and were able to differentiate into cells of the three germ layers. These cell models are useful to investigate the role of risk gene variants in bipolar disorder.
Background: The Catechol-O-methyltransferase (COMT) represents the key enzyme in catecholamine degradation. Recent studies suggest that the COMT rs4680 polymorphism is associated with the response to endogenous and exogenous catecholamines. There are, however, conflicting data regarding the COMT Met/Met phenotype being associated with an increased risk of acute kidney injury (AKI) after cardiac surgery. The aim of the current study is to prospectively investigate the impact of the COMT rs4680 polymorphism on the incidence of AKI in patients undergoing cardiac surgery.
Methods: In this prospective single center cohort study consecutive patients hospitalized for elective cardiac surgery including cardiopulmonary-bypass (CPB) were screened for participation. Demographic clinical data, blood, urine and tissue samples were collected at predefined time points throughout the clinical stay. AKI was defined according to recent recommendations of the Kidney Disease Improving Global Outcome (KDIGO) group. Genetic analysis was performed after patient enrolment was completed.
Results: Between April and December 2014, 150 patients were recruited. The COMT genotypes were distributed as follows: Val/Met 48.7%, Met/Met 29.3%, Val/Val 21.3%. No significant differences were found for demography, comorbidities, or operative strategy according to the underlying COMT genotype. AKI occurred in 35 patients (23.5%) of the total cohort, and no differences were evident between the COMT genotypes (20.5% Met/Met, 24.7% Val/Met, 25.0% Val/Val, p = 0.66). There were also no differences in the post-operative period, including ICU or in-hospital stay.
Conclusions: We did not find statistically significant variations in the risk for postoperative AKI, length of ICU or in-hospital stay according to the underlying COMT genotype.
Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.
Substantial evidence shows that physical activity and fitness play a protective role in the development of stress related disorders. However, the beneficial effects of fitness for resilience to modern life stress are not fully understood. Potentially protective effects may be attributed to enhanced resilience via underlying psychosocial mechanisms such as self-efficacy expectations. This study investigated whether physical activity and fitness contribute to prospectively measured resilience and examined the mediating effect of general self-efficacy. 431 initially healthy adults participated in fitness assessments as part of a longitudinal-prospective study, designed to identify mechanisms of resilience. Self-efficacy and habitual activity were assessed in parallel to cardiorespiratory and muscular fitness, which were determined by a submaximal step-test, hand strength and standing long jump test. Resilience was indexed by stressor reactivity: mental health problems in relation to reported life events and daily hassles, monitored quarterly for nine months. Hierarchical linear regression models and bootstrapped mediation analyses were applied. We could show that muscular and self-perceived fitness were positively associated with stress resilience. Extending this finding, the muscular fitness–resilience relationship was partly mediated by self-efficacy expectations. In this context, self-efficacy expectations may act as one underlying psychological mechanism, with complementary benefits for the promotion of mental health. While physical activity and cardiorespiratory fitness did not predict resilience prospectively, we found muscular and self-perceived fitness to be significant prognostic parameters for stress resilience. Although there is still more need to identify specific fitness parameters in light of stress resilience, our study underscores the general relevance of fitness for stress-related disorders prevention.
Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD–BMI and ADHD–obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD–BMI overlapping genes with brain volumes (primary GWAS data N = 10,720–10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10−3) and BMI (P = 1.63 × 10−5); the circadian rhythm was associated with BMI (P = 1.28 × 10−3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD–BMI and ADHD–obesity results. The ADHD–BMI overlapping genes were associated with putamen volume (P = 7.7 × 10−3; replication data P = 3.9 × 10−2)—a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD–obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.
Highligths
• Immune-inflammatory alterations might appear in subjects with ADHD.
• Blood levels of tumor necrosis factor-α might be reduced in individuals with ADHD.
• Individuals with ADHD might show elevated blood levels of interleukin-6.
Abstract
It has been observed that subclinical inflammation might be involved in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, studies investigating peripheral blood levels of immune-inflammatory markers have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing unstimulated serum or plasma levels of C-reactive protein (CRP) and cytokines in subjects with ADHD and healthy controls (the PROSPERO registration number: CRD 42021276869). Online searches covered the publication period until 30th Sep 2021 and random-effects meta-analyses were carried out. Out of 1844 publication records identified, 10 studies were included. The levels of interleukin (IL)-6 were significantly higher in studies of participants up to the age of 18 years (k = 10, g = 0.70, 95%CI: 0.10–1.30, p = 0.023) and after including those above the age of 18 years (k = 10, g = 0.71, 95%CI: 0.12–1.31, p = 0.019). In turn, the levels of tumor necrosis factor-α (TNF-α) were significantly lower in subjects with ADHD compared to healthy controls (k = 7, g = −0.16, 95%CI: −0.30 - -0.03, p = 0.020). Individual studies had a high contribution to the overall effect, since the overall effect was no longer significant after removing single studies. No significant differences were found with respect to the levels of CRP, IL-1β, IL-10 and interferon-γ. The present findings indicate that individuals with ADHD tend to show elevated levels of IL-6 and reduced levels of TNF-α. Larger and longitudinal studies recording potential confounding factors and comorbid psychopathology are needed to confirm our findings.
In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen’s d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.
the benefits of physical activity (PA) and sleep for health, accurate and objective population-based surveillance is important. Monitor-based surveillance has potential, but the main challenge is the need for replicable outcomes from different monitors. This study investigated the agreement of movement behavior outcomes assessed with four research-grade activity monitors (i.e., Movisens Move4, ActiGraph GT3X+, GENEActiv, and Axivity AX3) in adults. Twenty-three participants wore four monitors on the non-dominant wrist simultaneously for seven days. Open-source software (GGIR) was used to estimate the daily time in sedentary, light, moderate-to-vigorous PA (MVPA), and sleep (movement behaviors). The prevalence of participants meeting the PA and sleep recommendations were calculated from each monitor’s data. Outcomes were deemed equivalent between monitors if the absolute standardized difference and its 95% confidence intervals (CI95%) fell within ± 0.2 standard deviations (SD) of the mean of the differences. The participants were mostly men (n = 14, 61%) and aged 36 (SD = 14) years. Pairwise confusion matrices showed that 83–87% of the daily time was equally classified into the movement categories by the different pairs of monitors. The between-monitor difference in MVPA ranged from 1 (CI95%: − 6, 7) to 8 (CI95%: 1, 15) min/day. Most of the PA and sleep metrics could be considered equivalent. The prevalence of participants meeting the PA and the sleep guidelines was 100% consistent across monitors (22 and 5 participants out of the 23, respectively). Our findings indicate that the various research-grade activity monitors investigated show high inter-instrument reliability with respect to sedentary, PA and sleep-related estimates when their raw data are processed in an identical manner. These findings may have important implications for advancement towards monitor-based PA and sleep surveillance systems.
Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day–night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD.
Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up.
Discussion: This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.
Trial registration: German Clinical Trials Register, DRKS00011666. Registered on 9 February 2017. ClinicalTrials.gov, NCT03371810. Registered on 13 December 2017.
Depressive symptoms in youth with ADHD: the role of impairments in cognitive emotion regulation
(2022)
Youth with attention-deficit/hyperactivity disorder (ADHD) are at increased risk to develop co-morbid depression. Identifying factors that contribute to depression risk may allow early intervention and prevention. Poor emotion regulation, which is common in adolescents, is a candidate risk factor. Impaired cognitive emotion regulation is a fundamental characteristic of depression and depression risk in the general population. However, little is known about cognitive emotion regulation in youth with ADHD and its link to depression and depression risk. Using explicit and implicit measures, this study assessed cognitive emotion regulation in youth with ADHD (N = 40) compared to demographically matched healthy controls (N = 40) and determined the association with depressive symptomatology. As explicit measure, we assessed the use of cognitive emotion regulation strategies via self-report. As implicit measure, performance in an ambiguous cue-conditioning task was assessed as indicator of affective bias in the processing of information. Compared to controls, patients reported more frequent use of maladaptive (i.e., self-blame, catastrophizing, and rumination) and less frequent use of adaptive (i.e., positive reappraisal) emotion regulation strategies. This pattern was associated with the severity of current depressive symptoms in patients. In the implicit measure of cognitive bias, there was no significant difference in response of patients and controls and no association with depression. Our findings point to depression-related alterations in the use of cognitive emotion regulation strategies in youth with ADHD. The study suggests those alterations as a candidate risk factor for ADHD-depression comorbidity that may be used for risk assessment and prevention strategies.
Prenatal and postnatal experiences associated with epigenetic changes in the adult mouse brain
(2018)
To analyze the influences of early-life history on the brain epigenome, the offspring of mouse dams kept in an enriched or standard environment were exposed postnatally to enriched, standard, or adverse conditions. The methylation patterns of 7 candidate genes (9 loci) involved in developmental programming of stress vulnerability/resilience and psychiatric disease were analyzed in 6 brain regions of adult male and female mice. Exposure to an enriched prenatal environment was associated with widespread epigenetic changes (all of small effect size), affecting 29 of 324 (9%) gene/region-specific methylation patterns. The effects of either adverse or enriched postnatal conditions were tested separately in the two prenatal cohorts. Significant changes were observed in 2 of 324 (0.6%) loci in offspring of dams in a standard environment and 6 of 324 (1.9%) loci in animals that were exposed prenatally to an enriched environment. Prenatal life experiences appear to have a bigger effect on the adult brain epigenome than postnatal experiences. Positive prenatal life experiences may increase epigenetic plasticity of the brain later in life. All observed between-group differences were sex-specific, consistent with largely different developmental trajectories of the male and female brain. Multiple changes of small effect size are consistent with a multifactorial model of developmental programming of adult behavior and disease susceptibility.
Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability (p = 0.025), cognitive impairment (p < 0.001), febrile seizures in first-degree relatives (p = 0.023) and prominent dialeptic seizures (p = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.
Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain’s evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.
Background: Lithium has proven suicide preventing effects in the long-term treatment of patients with affective disorders. Clinical evidence from case reports indicate that this effect may occur early on at the beginning of lithium treatment. The impact of lithium treatment on acute suicidal thoughts and/or behavior has not been systematically studied in a controlled trial. The primary objective of this confirmatory study is to determine the association between lithium therapy and acute suicidal ideation and/or suicidal behavior in inpatients with a major depressive episode (MDE, unipolar and bipolar disorder according to DSM IV criteria). The specific aim is to test the hypothesis that lithium plus treatment as usual (TAU), compared to placebo plus TAU, results in a significantly greater decrease in suicidal ideation and/or behavior over 5 weeks in inpatients with MDE.
Methods/Design: We initiated a randomized, placebo-controlled multicenter trial. Patients with the diagnosis of a moderate to severe depressive episode and suicidal thoughts and/or suicidal behavior measured with the Sheehan-Suicidality-Tracking Scale (S-STS) will be randomly allocated to add lithium or placebo to their treatment as usual. Change in the clinician administered S-STS from the initial to the final visit will be the primary outcome.
Discussion: There is an urgent need to identify treatments that will acutely decrease suicidal ideation and/or suicidal behavior. The results of this study will demonstrate whether lithium reduces suicidal ideation and behavior within the first 5 weeks of treatment.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
Exercise interventions in mental disorders have evidenced a mood-enhancing effect. However, the association between physical activity and affect in everyday life has not been investigated in adult individuals with ADHD, despite being important features of this disorder. As physical activity and affect are dynamic processes in nature, assessing those in everyday life with e-diaries and wearables, has become the gold standard. Thus, we used an mHealth approach to prospectively assess physical activity and affect processes in individuals with ADHD and controls aged 14–45 years. Participants wore accelerometers across a four-day period and reported their affect via e-diaries twelve times daily. We used multilevel models to identify the within-subject effects of physical activity on positive and negative affect. We split our sample into three groups: 1. individuals with ADHD who were predominantly inattentive (n = 48), 2. individuals with ADHD having a combined presentation (i.e., being inattentive and hyperactive; n = 95), and 3. controls (n = 42). Our analyses revealed a significant cross-level interaction (F(2, 135.072)=5.733, p = 0.004) of physical activity and group on positive affect. In details, all groups showed a positive association between physical activity and positive affect. Individuals with a combined presentation significantly showed the steepest slope of physical activity on positive affect (slope_inattentive=0.005, p<0.001; slope_combined=0.009, p<0.001; slope_controls=0.004, p = 0.008). Our analyses on negative affect revealed a negative association only in the individuals with a combined presentation (slope=-0.003; p = 0.001). Whether this specifically pronounced association in individuals being more hyperactive might be a mechanism reinforcing hyperactivity needs to be empirically clarified in future studies.
TOR1A is the most common inherited form of dystonia with still unclear pathophysiology and reduced penetrance of 30–40%. ∆ETorA rats mimic the TOR1A disease by expression of the human TOR1A mutation without presenting a dystonic phenotype. We aimed to induce dystonia-like symptoms in male ∆ETorA rats by peripheral nerve injury and to identify central mechanism of dystonia development. Dystonia-like movements (DLM) were assessed using the tail suspension test and implementing a pipeline of deep learning applications. Neuron numbers of striatal parvalbumin+, nNOS+, calretinin+, ChAT+ interneurons and Nissl+ cells were estimated by unbiased stereology. Striatal dopaminergic metabolism was analyzed via in vivo microdialysis, qPCR and western blot. Local field potentials (LFP) were recorded from the central motor network. Deep brain stimulation (DBS) of the entopeduncular nucleus (EP) was performed. Nerve-injured ∆ETorA rats developed long-lasting DLM over 12 weeks. No changes in striatal structure were observed. Dystonic-like ∆ETorA rats presented a higher striatal dopaminergic turnover and stimulus-induced elevation of dopamine efflux compared to the control groups. Higher LFP theta power in the EP of dystonic-like ∆ETorA compared to wt rats was recorded. Chronic EP-DBS over 3 weeks led to improvement of DLM. Our data emphasizes the role of environmental factors in TOR1A symptomatogenesis. LFP analyses indicate that the pathologically enhanced theta power is a physiomarker of DLM. This TOR1A model replicates key features of the human TOR1A pathology on multiple biological levels and is therefore suited for further analysis of dystonia pathomechanism.
Background: Recent research has shown an increased risk of accidents and injuries in ADHD patients, which could potentially be reduced by stimulant treatment. Therefore, the first aim of our study was to evaluate the prevalence of adult ADHD in a trauma surgery population. The second aim was to investigate accident mechanisms and circumstances which could be specific to ADHD patients, in comparison to the general population.
Methods: We screened 905 accident victims for ADHD using the ASRS 18-item self-report questionnaire. The basic demographic data and circumstances of the accidents were also assessed.
Results: Prevalence of adult ADHD was found to be 6.18% in our trauma surgery patient sample. ADHD accident victims reported significantly higher rates of distraction, stress and overconfidence in comparison to non-ADHD accident victims. Overconfidence and being in thoughts as causal mechanisms for the accidents remained significantly higher in ADHD patients after correction for multiple comparison. ADHD patients additionally reported a history of multiple accidents.
Conclusion: The majority of ADHD patients in our sample had not previously been diagnosed and were therefore not receiving treatment. The results subsequently suggest that general ADHD screening in trauma surgery patients may be useful in preventing further accidents in ADHD patients. Furthermore, psychoeducation regarding specific causal accident mechanisms could be implemented in ADHD therapy to decrease accident incidence rate.
Introduction: Affective disorders are a major global burden, with approximately 15% of people worldwide suffering from some form of affective disorder. In patients experiencing their first depressive episode, in most cases it cannot be distinguished whether this is due to bipolar disorder (BD) or major depressive disorder (MDD). Valid fluid biomarkers able to discriminate between the two disorders in a clinical setting are not yet available.
Material and Methods: Seventy depressed patients suffering from BD (bipolar I and II subtypes) and 42 patients with major MDD were recruited and blood samples were taken for proteomic analyses after 8 h fasting. Proteomic profiles were analyzed using the Multiplex Immunoassay platform from Myriad Rules Based Medicine (Myriad RBM; Austin, Texas, USA). Human DiscoveryMAPTM was used to measure the concentration of various proteins, peptides, and small molecules. A multivariate predictive model was consequently constructed to differentiate between BD and MDD.
Results: Based on the various proteomic profiles, the algorithm could discriminate depressed BD patients from MDD patients with an accuracy of 67%.
Discussion: The results of this preliminary study suggest that future discrimination between bipolar and unipolar depression in a single case could be possible, using predictive biomarker models based on blood proteomic profiling.
Introduction: Bipolar disorder (BD) is characterized by recurrent episodes of depression and mania and affects up to 2% of the population worldwide. Patients suffering from bipolar disorder have a reduced life expectancy of up to 10 years. The increased mortality might be due to a higher rate of somatic diseases, especially cardiovascular diseases. There is however also evidence for an increased rate of diabetes mellitus in BD, but the reported prevalence rates vary by large.
Material and Methods: 85 bipolar disorder patients were recruited in the framework of the BiDi study (Prevalence and clinical features of patients with Bipolar Disorder at High Risk for Type 2 Diabetes (T2D), at prediabetic state and with manifest T2D) in Dresden and Würzburg. T2D and prediabetes were diagnosed measuring HBA1c and an oral glucose tolerance test (oGTT), which at present is the gold standard in diagnosing T2D. The BD sample was compared to an age-, sex- and BMI-matched control population (n = 850) from the Study of Health in Pomerania cohort (SHIP Trend Cohort).
Results: Patients suffering from BD had a T2D prevalence of 7%, which was not significantly different from the control group (6%). Fasting glucose and impaired glucose tolerance were, contrary to our hypothesis, more often pathological in controls than in BD patients. Nondiabetic and diabetic bipolar patients significantly differed in age, BMI, number of depressive episodes, and disease duration.
Discussion: When controlled for BMI, in our study there was no significantly increased rate of T2D in BD. We thus suggest that overweight and obesity might be mediating the association between BD and diabetes. Underlying causes could be shared risk genes, medication effects, and lifestyle factors associated with depressive episodes. As the latter two can be modified, attention should be paid to weight changes in BD by monitoring and taking adequate measures to prevent the alarming loss of life years in BD patients.
Background: Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4–6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen.
Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual.
Methods/design: The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient’s antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50% or greater decrease in baseline scores of depression measured using the Quick Inventory of Depressive Symptoms – Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed.
Discussion: This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients.
Trial registration: ClinicalTrials.gov, ID: NCT02790970. Registered on 30 March 2016.
Resilience has been defined as the maintenance or quick recovery of mental health during and after times of adversity. How to operationalize resilience and to determine the factors and processes that lead to good long-term mental health outcomes in stressor-exposed individuals is a matter of ongoing debate and of critical importance for the advancement of the field. One of the biggest challenges for implementing an outcome-based definition of resilience in longitudinal observational study designs lies in the fact that real-life adversity is usually unpredictable and that its substantial qualitative as well as temporal variability between subjects often precludes defining circumscribed time windows of inter-individually comparable stressor exposure relative to which the maintenance or recovery of mental health can be determined. To address this pertinent issue, we propose to frequently and regularly monitor stressor exposure (E) and mental health problems (P) throughout a study's observation period [Frequent Stressor and Mental Health Monitoring (FRESHMO)-paradigm]. On this basis, a subject's deviation at any single monitoring time point from the study sample's normative E–P relationship (the regression residual) can be used to calculate that subject's current mental health reactivity to stressor exposure (“stressor reactivity,” SR). The SR score takes into account the individual extent of experienced adversity and is comparable between and within subjects. Individual SR time courses across monitoring time points reflect intra-individual temporal variability in SR, where periods of under-reactivity (negative SR score) are associated with accumulation of fewer mental health problems than is normal for the sample. If FRESHMO is accompanied by regular measurement of potential resilience factors, temporal changes in resilience factors can be used to predict SR time courses. An increase in a resilience factor measurement explaining a lagged decrease in SR can then be considered to index a process of adaptation to stressor exposure that promotes a resilient outcome (an allostatic resilience process). This design principle allows resilience research to move beyond merely determining baseline predictors of resilience outcomes, which cannot inform about how individuals successfully adjust and adapt when confronted with adversity. Hence, FRESHMO plus regular resilience factor monitoring incorporates a dynamic-systems perspective into resilience research.
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.
Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
Pattern recognition approaches to the analysis of neuroimaging data have brought new applications such as the classification of patients and healthy controls within reach. In our view, the reliance on expensive neuroimaging techniques which are not well tolerated by many patient groups and the inability of most current biomarker algorithms to accommodate information about prior class frequencies (such as a disorder's prevalence in the general population) are key factors limiting practical application. To overcome both limitations, we propose a probabilistic pattern recognition approach based on cheap and easy-to-use multi-channel near-infrared spectroscopy (fNIRS) measurements. We show the validity of our method by applying it to data from healthy controls (n = 14) enabling differentiation between the conditions of a visual checkerboard task. Second, we show that high-accuracy single subject classification of patients with schizophrenia (n = 40) and healthy controls (n = 40) is possible based on temporal patterns of fNIRS data measured during a working memory task. For classification, we integrate spatial and temporal information at each channel to estimate overall classification accuracy. This yields an overall accuracy of 76% which is comparable to the highest ever achieved in biomarker-based classification of patients with schizophrenia. In summary, the proposed algorithm in combination with fNIRS measurements enables the analysis of sub-second, multivariate temporal patterns of BOLD responses and high-accuracy predictions based on low-cost, easy-to-use fNIRS patterns. In addition, our approach can easily compensate for variable class priors, which is highly advantageous in making predictions in a wide range of clinical neuroimaging applications. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.
Highlights
• A panel of 20 biomarkers was identified capable of differentiating BD patients from controls.
• Excellent discrimination between established BD patients and controls.
• Good to excellent discrimination between misdiagnosed BD patients and first onset MDD patients.
• Fair to good discrimination between pre-diagnostic BD patients and controls.
• Study demonstrates the potential utility of a protein biomarker panel as a diagnostic test for BD.
Abstract
Background: Bipolar disorder (BD) is a costly, devastating and life shortening mental disorder that is often misdiagnosed, especially on initial presentation. Misdiagnosis frequently results in ineffective treatment. We investigated the utility of a biomarker panel as a diagnostic test for BD.
Methods and findings: We performed a meta-analysis of eight case-control studies to define a diagnostic biomarker panel for BD. After validating the panel on established BD patients, we applied it to undiagnosed BD patients. We analysed 249 BD, 122 pre-diagnostic BD, 75 pre-diagnostic schizophrenia and 90 first onset major depression disorder (MDD) patients and 371 controls. The biomarker panel was identified using ten-fold cross-validation with lasso regression applied to the 87 analytes available across the meta-analysis studies.
We identified 20 protein analytes with excellent predictive performance [area under the curve (AUC) ⩾ 0.90]. Importantly, the panel had a good predictive performance (AUC 0.84) to differentiate 12 misdiagnosed BD patients from 90 first onset MDD patients, and a fair to good predictive performance (AUC 0.79) to differentiate between 110 pre-diagnostic BD patients and 184 controls. We also demonstrated the disease specificity of the panel.
Conclusions: An early and accurate diagnosis has the potential to delay or even prevent the onset of BD. This study demonstrates the potential utility of a biomarker panel as a diagnostic test for BD.
Physical inactivity is discussed as one of the most detrimental influences for lifestyle-related medical complications such as obesity, heart disease, hypertension, diabetes and premature mortality in in- and outpatients with major depressive disorder (MDD). In contrast, intervention studies indicate that moderate-to-vigorous-intensity physical activity (MVPA) might reduce complications and depression symptoms itself. Self-reported data on depression [Beck-Depression-Inventory-II (BDI-II)], general habitual well-being (FAHW), self-esteem and physical self-perception (FAHW, MSWS) were administrated in a cross-sectional study with 76 in- and outpatients with MDD. MVPA was documented using ActiGraph wGT3X + ® accelerometers and fitness was measured using cardiopulmonary exercise testing (CPET). Subgroups were built according to activity level (low PA defined as MVPA < 30 min/day, moderate PA defined as MVPA 30–45 min/day, high PA defined as MVPA > 45 min/day). Statistical analysis was performed using a Mann–Whitney U and Kruskal–Wallis test, Spearman correlation and mediation analysis. BDI-II scores and MVPA values of in- and outpatients were comparable, but fitness differed between the two groups. Analysis of the outpatient group showed a negative correlation between BDI-II and MVPA. No association of inpatient MVPA and psychopathology was found. General habitual well-being and self-esteem mediated the relationship between outpatient MVPA and BDI-II. The level of depression determined by the BDI-II score was significantly higher in the outpatient low- and moderate PA subgroups compared to outpatients with high PA. Fitness showed no association to depression symptoms or well-being. To ameliorate depressive symptoms of MDD outpatients, intervention strategies should promote habitual MVPA and exercise exceeding the duration recommended for general health (≥ 30 min/day). Further studies need to investigate sufficient MVPA strategies to impact MDD symptoms in inpatient settings. Exercise effects seem to be driven by changes of well-being rather than increased physical fitness.
Based on accumulating evidence of a role of lipid signaling in many physiological and pathophysiological processes including psychiatric diseases, the present data driven analysis was designed to gather information needed to develop a prospective biomarker, using a targeted lipidomics approach covering different lipid mediators. Using unsupervised methods of data structure detection, implemented as hierarchal clustering, emergent self-organizing maps of neuronal networks, and principal component analysis, a cluster structure was found in the input data space comprising plasma concentrations of d = 35 different lipid-markers of various classes acquired in n = 94 subjects with the clinical diagnoses depression, bipolar disorder, ADHD, dementia, or in healthy controls. The structure separated patients with dementia from the other clinical groups, indicating that dementia is associated with a distinct lipid mediator plasma concentrations pattern possibly providing a basis for a future biomarker. This hypothesis was subsequently assessed using supervised machine-learning methods, implemented as random forests or principal component analysis followed by computed ABC analysis used for feature selection, and as random forests, k-nearest neighbors, support vector machines, multilayer perceptron, and naïve Bayesian classifiers to estimate whether the selected lipid mediators provide sufficient information that the diagnosis of dementia can be established at a higher accuracy than by guessing. This succeeded using a set of d = 7 markers comprising GluCerC16:0, Cer24:0, Cer20:0, Cer16:0, Cer24:1, C16 sphinganine, and LacCerC16:0, at an accuracy of 77%. By contrast, using random lipid markers reduced the diagnostic accuracy to values of 65% or less, whereas training the algorithms with randomly permuted data was followed by complete failure to diagnose dementia, emphasizing that the selected lipid mediators were display a particular pattern in this disease possibly qualifying as biomarkers.
Objective: The DIRAS2 gene is associated with ADHD, but its function is largely unknown. Thus, we aimed to explore the genes and molecular pathways affected by DIRAS2. Method: Using short hairpin RNAs, we downregulated Diras2 in murine hippocampal primary cells. Gene expression was analyzed by microarray and affected pathways were identified. We used quantitative real-time polymerase chain reaction (qPCR) to confirm expression changes and analyzed enrichment of differentially expressed genes in an ADHD GWAS (genome-wide association studies) sample. Results: Diras2 knockdown altered expression of 1,612 genes, which were enriched for biological processes involved in neurodevelopment. Expression changes were confirmed for 33 out of 88 selected genes. These 33 genes showed significant enrichment in ADHD patients in a gene-set-based analysis. Conclusion: Our findings show that Diras2 affects numerous genes and thus molecular pathways that are relevant for neurodevelopmental processes. These findings may further support the hypothesis that DIRAS2 is linked to etiological processes underlying ADHD. (J. of Att. Dis. 2021; 25(4) 572-583).
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Δex1-6) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
While impulsivity is a basic feature of attention-deficit / hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.
ADHD is a neurodevelopmental disorder with a long trajectory into adulthood where it is often comorbid with depression, substance use disorder (SUD) or obesity. Previous studies described a dysregulated dopaminergic system, reflected by abnormal reward processing, both in ADHD as well as in depression, SUD or obesity. No study so far however tested systematically whether pathologies in the brain’s reward system explain the frequent comorbidity in adult ADHD. To test this, we acquired MRI scans from 137 participants probing the reward system by a monetary incentive delay task (MIDT) as well as assessing resting-state connectivity with ventral striatum as a seed mask. No differences were found between comorbid disorders, but a significant linear effect pointed toward less left intrastriatal connectivity in patients depending on the number of comorbidities. This points towards a neurobiologically impaired reward- and decision-making ability in patients with more comorbid disorders. This suggests that less intrastriatal connectivity parallels disorder severity but not disorder specificity, while MIDT abnormalities seem mainly to be driven by ADHD.
Rationale: Dysregulation of dopaminergic neurotransmission, specifically altered reward processing assessed via the reward anticipation in the MID task, plays a central role in the etiopathogenesis of neuropsychiatric disorders. Objectives: We hypothesized to find a difference in the activity level of the reward system (measured by the proxy reward anticipation) under drug administration versus placebo, in that amisulpride reduces, and L-DOPA enhances, its activity. Methods: We studied the influence of dopamine agonist L-DOPA and the antagonist amisulpride on the reward system using functional magnetic resonance imaging (fMRI) during a monetary incentive delay (MID) task in n = 45 healthy volunteers in a randomized, blinded, cross-over study. Results: The MID paradigm elicits strong activation in reward-dependent structures (such as ventral striatum, putamen, caudate, anterior insula) during reward anticipation. The placebo effect demonstrated the expected significant blood oxygen level–dependent activity in reward-dependent brain regions. Neither amisulpride nor L-DOPA led to significant changes in comparison with the placebo condition. This was true for whole-brain analysis as well as analysis of a pre-defined nucleus accumbens region-of-interest mask. Conclusion: The present results cast doubt on the sensitivity of reward anticipation contrast in the MID task for assessing dopamine-specific changes in healthy volunteers by pharmaco-fMRI. While our task was not well-suited for detailed analysis of the outcome phase, we provide reasonable arguments that the lack of effect in the anticipation phase is not due to an inefficient task but points to unexpected behavior of the reward system during pharmacological challenge. Group differences of reward anticipation should therefore not be seen as simple representatives of dopaminergic states.
Purpose of Review: Attention deficit hyperactivity disorder (ADHD) shows high heritability in formal genetic studies. In our review article, we provide an overview on common and rare genetic risk variants for ADHD and their link to clinical practice.
Recent findings: The formal heritability of ADHD is about 80% and therefore higher than most other psychiatric diseases. However, recent studies estimate the proportion of heritability based on singlenucleotide variants (SNPs) at 22%. It is a matter of debate which genetic mechanisms explain this huge difference. While frequent variants in first mega-analyses of genome-wideassociation study data containing several thousand patients give the first genome-wide results, explaining only little variance, the methodologically more difficult analyses of rare variants are still in their infancy. Some rare genetic syndromes show higher prevalence for ADHD indicating a potential role for a small number of patients. In contrast, polygenic risk scores (PRS) could potentially be applied to every patient. We give an overview how PRS explain different behavioral phenotypes in ADHD and how they could be used for diagnosis and therapy prediction.
Summary: Knowledge about a patient’s genetic makeup is not yet mandatory for ADHD therapy or diagnosis. PRS however have been introduced successfully in other areas of clinical medicine, and their application in psychiatry will begin within the next years. In order to ensure competent advice for patients, knowledge of the current state of research is useful forpsychiatrists.