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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
People with eating disorders (ED) are at high risk for suicidal behavior. Among different ED, anorexia nervosa (AN) has the highest rates of completed suicide whereas suicide attempt rates are similar or lower than in bulimia nervosa (BN). Attempted suicide is a key predictor of completed suicide, thus this mismatch is intriguing. We sought to explore whether the clinical characteristics of suicidal acts differ between suicide attempters with AN, BN or without an ED.
Case-control study in cohort of suicide attempters (n = 1563). Forty-four patients with AN and 71 with BN were compared with 235 non-ED attempters matched for sex, age and education, using interview measures of suicidal intent and severity.
AN patients were more likely to have made a serious attempt (OR = 3.4, 95% CI 1.4–7.9), with a higher expectation of dying (OR = 3.7, 95% CI 1.1–13.5), and an increased risk of lethality (OR = 3.4, 95% CI 1.2–9.6). BN patients did not differ from the control group.
There are distinct features of suicide attempts in AN. This may explain the higher suicide rates in AN. Deaths from suicide in AN may not be the result simply of their greater physical frailty.
This guidance paper from the European Psychiatric Association (EPA) aims to provide evidence-based recommendations on early intervention in clinical high risk (CHR) states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra-high risk and/or basic symptom criteria. Besides analyses on treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n = 1394), early intervention generally produced significantly reduced conversion rates at 6- to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional improvements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates, but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples could have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk status.
The aim of this guidance paper of the European Psychiatric Association is to provide evidence-based recommendations on the early detection of a clinical high risk (CHR) for psychosis in patients with mental problems. To this aim, we conducted a meta-analysis of studies reporting on conversion rates to psychosis in non-overlapping samples meeting any at least any one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria. Further, effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates were examined. Conversion rates in the identified 42 samples with altogether more than 4000 CHR patients who had mainly been identified by UHR criteria and/or the basic symptom criterion ‘cognitive disturbances’ (COGDIS) showed considerable heterogeneity. While UHR criteria and COGDIS were related to similar conversion rates until 2-year follow-up, conversion rates of COGDIS were significantly higher thereafter. Differences in onset and frequency requirements of symptomatic UHR criteria or in their different consideration of functional decline, substance use and co-morbidity did not seem to impact on conversion rates. The ‘genetic risk and functional decline’ UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for an early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states.
Psychotic and psychotic-like experiences (PLEs) are frequently found in the general population when assessed with self-report questionnaires. It is not clear how these assessments can help to predict the future development of mental disorders. The degree of certainty in appraisal or the experience-related distress may add prognostic power of clinical PLE assessments. This study was designed to provide baseline data of PLEs in a representative sample, which will be monitored for the future development.
We studied the frequency of PLEs in a representative sample of 4483 participants of the German population recruited through the Mental Health Module of the German Health Interview and Examination Survey for Adults (DEGS1-MH). Participants were asked if they had had psychotic or psychosis-like experiences over their lifetime. We used the psychosis section of the Composite International Diagnostic Interview (CIDI), the Launay-Slade Hallucination Scale (LSHS) and the Peter's Delusion Inventory (PDI).
33.3% of the participants endorsed at least one item of the CIDI psychosis scale, 68.8% of the PDI and 49.0% of the LSHS. In the PDI assessments, conspiracy-related delusional experiences were most often experienced as distressing, while religious beliefs were experienced less distressing, but with high levels of conviction.
Our findings show frequent endorsement of lifetime psychotic or psychotic-like experiences in the general population in self-report questionnaires with varying degrees of distress and conviction. This provides the needed baseline assessment for follow-up studies observing the development of mental disorders with a view to determine the predictive values of these tests.
After two decades of research, prevention of psychosis becomes increasingly accepted in clinical psychiatry. However, there are still unmet scientific and clinical needs. Therefore, guidance for prediction as well as prevention is required, reflecting their current capabilities, but also their requirements and limitations.
Evaluating the current state of risk estimation and prevention.
Developing clinical recommendations for the prediction and prevention of psychosis.
42 samples, mainly defined by ultra-high risk criteria and/or the basic symptoms criterion ‘COGDIS‘, were included into meta-analyses of prevention, 15 studies into meta-analyses of prevention.
The pooled conversion rate at >4-year follow-up was 37.0% in UHR and 61.3% in COGDIS samples. The 12-month pooled risk ratio was 0.44, the NNT 10. Psychosocial functioning seemed not to improve, however results were inconclusive due to methodological issues of the trials. Both meta-analyses indicated age related differences.
Several recommendations were developed to guide prediction and prevention, emphasizing age-adapted strategies; details will be presented and discussed during the symposium.
Regarding future steps to further improve prediction and thus prevention, neurocognitive and neurobiological parameters of information processing, i.e. mismatch negativity, P300 and processing speed, as well as support vector machine based analysis of structural MRI seem to be most promising. Furthermore, with regard to current developmental models of psychotic disorders, risk should be conceptualized as dynamically modulated over time and thus presumably non-linearly related to future outcome. Therefore, studies need to consider the fluid interplay of risk and resilience factors to advance prediction significantly.
The basic symptom criterion 'cognitive disturbances” (COGDIS) and ultra-high risk (UHR) criteria are commonly used for the prediction of psychosis.
However, their predictive value has been assessed so far only by survival analyses using one-time baseline ratings and time-to-conversion. Thereby, potentially risk status-informative fluctuations in risk criteria ratings over time remained unaccounted for.
Therefore we studied if and how the predictive value of COGDIS and the main UHR criterion attenuated psychotic symptoms (APS) and their combination might be influenced by their presence across different assessment times.
In a naturalistic 24-month study, 146 patients at risk for 'cognitive-perceptive basic symptoms” were repeatedly examined (monthly assessments until month 6, thereafter 3-monthly) for COGDIS and APS with the Schizophrenia Proneness Instrument, Adult version, and the Structured Interview of Prodromal Syndromes. Joint latent class analysis was applied to identify different patterns of risk criteria over time and to detect the degree of their association with risk for conversion to psychosis.
The final model included 4 classes: no risk criteria, exclusively BS, exclusively APS and the combination of COGDIS and APS. Class-specific trajectories and survival functions were associated with an increased risk for the conversion to psychosis from a mild to an intense degree, demonstrating a superior performance of the combination of BS and APS.
This result reinforces earlier results of a clearly superior psychosis-predictive value of this combination at baseline and shows that its stability over time. Thus, APS and COGDIS should be repeatedly monitored.
Schizotypy is regarded as a subthreshold expression or precursor of schizophrenia spectrum psychosis.
Schizotypal personality disorder is a risk factor of the ‘genetic risk and functional decline’ criterion of the ultra-high risk (UHR) criteria for psychosis; and its positive features are part of attenuated psychotic symptoms (APS) of the UHR criteria. Furthermore, schizotypy as assessed with the Wisconsin Scales of Schizophrenia Proneness (WSSP) 'Perceptual Aberration”, 'Magical Ideation”, and 'Social Anhedonia” but not 'Physical Anhedonia” was predictive of psychosis in the community.
Thus, we examined the psychosis-predictive value of the for WSSP in 128 patients seeking help at an early detection service (23+/-7 yrs; 56% male; 81% at-risk for UHR and/or basic symptom criteria) with a median follow-up of 24 (1-101) months by Cox regression.
Within 48 months; 36 patients converted to psychosis. Unexpectedly, none of the four WSSP was a significant predictor of conversion. This negative finding was replicated when the positive (Perceptual Aberration and Magical Ideation) and negative (both Anhedonia scales) dimension were examined. Thus, although schizotypy scales might be able to identify a more extreme range of the psychotic continuum in the community, they lack the ability to further separate ‘true’ from ‘false’ risk cases in a clinical sample already representing this more extreme range of the psychotic continuum.
This indicates that WSSP might be useful rather as an initial screening for persons potentially at-risk for current criteria in the community than as additional predictors in already identified risk patients.
Frowning expresses negative emotions like anger, fear, and sadness. According to the facial feedback hypothesis, suppression of frowning will also diminish the corresponding negative emotions. Hence, mood improvement has been observed in patients who underwent treatment of glabellar frown lines with botulinum neurotoxin. This observation suggests the possibility that the intervention may be employed for the management of psychiatric disorders associated with negative emotions. Preliminary data from an open case series indicate that the intervention might improve the symptoms of depression.
Aims & objectives
To test whether an onabotulinumtoxinA injection into the glabellar region is benefical as an adjunctive treatment of major depression within a clinical trial.
We used a randomized, double-blinded, placebo-controlled study design (n = 30; ClinicalTrials.gov, number, NCT00934687).
We show that a single onabotulinumtoxinA treatment shortly leads to a strong and sustained improvement in partly chronic major depression that did not respond sufficiently to previous treatment. As for the primary end-point, Hamilton Depression Rating Scale (HAM-D17) six weeks after treatment compared to baseline, scores of onabotulinumtoxinA recipients showed 37.9% (8.34 points) more improvement than those of placebo-treated participants (F = 12.30, p = 0.002, η2 = 0.31, d = 1.28).
Our findings support the concept that the facial musculature not only expresses, but also regulates, mood states. As it stands, treatment of glabellar frown lines with botulinum neurotoxin can be considered for depressed patients with the objective of inducing mood-lifting effects.
Childhood adversity (CA) is associated with poor mental health outcomes including psychotic symptoms.
However, the mechanisms linking CA to the development of psychosis are still poorly understood – in both their nature and the specificity of links for psychosis development. Possible links (mediators) are an excessive use of external attributions, dysfunctional coping patterns, and depressive symptoms that were associated with CA in healthy subjects but have not been studied in patients at-risk for psychosis.
Therefore, pathways models from CA to depressiveness were generated based on literature and examined separately in two samples by structural equation modeling: 137 patients at-risk for psychosis and 228 help-seeking controls.
Mediators between CA (Trauma and Distress Scale) and depressiveness (BDI II) were attribution style, self-efficacy (Competence and Control Beliefs Questionnaire) and coping strategies (Stress-Coping-Questionnaire).
Both final models showed 3 pathways running from CA to external attributions and low-self-efficacy, from these beliefs to maladaptive coping strategies and from there to depressiveness (CFI>0.9, RMSEA<0.1). In addition, the at-risk group displayed an alternative effect of CA on maladaptive coping.
Our findings suggest that CA generally increases the risk for mental health problems by the development of dysfunctional attributions and low self-efficacy that lead to maladaptive coping strategies and heightened levels of depressiveness with an additional effect of CA on maladaptive coping in at-risk patients. Thus, integrated interventions targeting these factors may enhance resilience and, thereby, prevent both the persistence of distressing symptoms and their progression to mental disorders, including psychosis.
Thromboxane (TX) A2 and the activation of its receptor have been shown to modulate vasoconstriction, platelet aggregation, but also dopaminergic and serotonergic signaling.
As dopaminergic and serotonergic systems play a crucial role in the pathophysiology of schizophrenia and as these systems are main targets of antipsychotics, we hypothesized that antipsychotics might also influence TXA2 production.
We measured levels of TXB2, the metabolite of the very unstable molecule TXA2, in the stimulated blood of 10 healthy female subjects in a whole blood assay using the toxic shock syndrome toxin-1 (TSST-1) and the monoclonal antibody against the surface antigen CD3 combined with the protein CD40 (OKT3/CD40) as stimulants. Blood was either supplemented with antipsychotics (chlorpromazine, clozapine, and its metabolite N-desmethylclozapine with four different concentrations each) or not.
Under TSST-1 as well as OKT3/CD40 stimulation, mean TXB2 concentrations were significantly (p < 0.05) decreased by clozapine over all of the applied concentrations. N-desmethylclozapine led to a decrease in TXB2 levels under TSST-1 stimulation only. Chlorpromazine did not show any significant influence on TXB2 production.
Clozapine might, complementary to serotonin and dopamine receptor binding, act on the dopaminergic and serotonergic system via a modulation of TXA2 production. Additionally, side effects of clozapine such as orthostatic hypotension may be a result of the reported TXA2 changes.
Aim was to examine depressive symptoms in acutely ill schizophrenia patients on a single symptom basis and to evaluate their relationship with positive, negative and general psychopathological symptoms.
Two hundred and seventy-eight patients suffering from a schizophrenia spectrum disorder were analysed within a naturalistic study by the German Research Network on Schizophrenia. Using the Calgary Depression Scale for Schizophrenia (CDSS) depressive symptoms were examined and the Positive and Negative Syndrome Scale (PANSS) was applied to assess positive, negative and general symptoms. Correlation and factor analyses were calculated to detect the underlying structure and relationship of the patient’s symptoms.
The most prevalent depressive symptoms identified were depressed mood (80%), observed depression (62%) and hopelessness (54%). Thirty-nine percent of the patients suffered from depressive symptoms when applying the recommended cut-off of a CDSS total score of > 6 points at admission. Negligible correlations were found between depressive and positive symptoms as well as most PANSS negative and global symptoms despite items on depression, guilt and social withdrawal. The factor analysis revealed that the factor loading with the PANSS negative items accounted for most of the data variance followed by a factor with positive symptoms and three depression-associated factors.
The naturalistic study design does not allow a sufficient control of study results for the effect of different pharmacological treatments possibly influencing the appearance of depressive symptoms.
Results suggest that depressive symptoms measured with the CDSS are a discrete symptom domain with only partial overlap with positive or negative symptoms.
Limited clinical relevance of attenuated psychotic symptoms before the turn from early to late adolescence, i.e., age 15/16, was reported.
This emphasizes the potentially important role of neurodevelopmental aspects in the early detection of psychoses.
We examined the age effect on prevalence and clinical relevance of 14 cognitive and perceptive basic symptoms (BS) included in risk criteria of psychosis in a random representative 8–40-year-old community sample (n = 689).
Participants underwent clinical interviews for BS, psychosocial functioning and current mental disorder on the telephone.
BS were reported by 18% of participants, mainly cognitive BS (15%). Age seemed to affect perceptive and cognitive BS differently, indicating an age threshold for perceptive BS in late adolescence (around age 18) and for cognitive BS in young adulthood (early twenties) – with higher prevalence, but a lesser association with functional deficits and the presence of mental disorder in the below-threshold groups. Thereby, effects of the interaction between age and BS on functioning and mental disorder were commonly stronger than individual effects of age and BS.
Differential age effects of perceptual and cognitive BS seem to follow normal brain maturation processes, in which they might occur as infrequent and temporary nonpathological disturbances. Their persistence or occurrence after the conclusion of main brain maturation processes, however, might signify aberrant maturation processes. Thus, BS might provide important insight into the pathogenesis of psychosis and into potential neuroprotective targets.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Hepatitis B vaccination is recommended for men who have sex with men (MSM) in many countries, but information on vaccine coverage is scarce. We studied hepatitis B vaccination programmes and coverage among MSM in Europe to guide prevention. From a large (N = 174 209) pan-European MSM survey (EMIS-2010), we used data on self-reported hepatitis B vaccination, age, education, settlement size and disclosure of the same-sex sexual orientation (‘outness’). We excluded participants with a history of hepatitis B. In multilevel (participants, countries) logistic regression models, we calculated adjusted odds ratios (aOR) with 95% confidence intervals (95% CI). We analysed data of 163 987 MSM in 38 European countries: 38.3% were ‘out’ to all or almost all, 56.4% reported vaccination against hepatitis B and 65.5% lived in countries with free recommended hepatitis B vaccination for MSM. In the final model the odds for being vaccinated increased with outness (‘out to all or almost all’: aOR 1.76, 95% CI 1.70–1.83 vs. ‘out to no one’) and with living in countries, where hepatitis B vaccination was recommended and free-of-charge for MSM (aOR 2.21, 95% CI 1.47–3.32 vs. ‘no or unclear recommendation’). To increase hepatitis B vaccination coverage among MSM, implementation of MSM-specific recommendations and improvement of the societal climate for MSM is needed.
Positive symptoms are a useful predictor of aggression in schizophrenia. Although a similar pattern of abnormal brain structures related to both positive symptoms and aggression has been reported, this observation has not yet been confirmed in a single sample.
To study the association between positive symptoms and aggression in schizophrenia on a neurobiological level, a prospective meta-analytic approach was employed to analyze harmonized structural neuroimaging data from 10 research centers worldwide. We analyzed brain MRI scans from 902 individuals with a primary diagnosis of schizophrenia and 952 healthy controls.
The result identified a widespread cortical thickness reduction in schizophrenia compared to their controls. Two separate meta-regression analyses revealed that a common pattern of reduced cortical gray matter thickness within the left lateral temporal lobe and right midcingulate cortex was significantly associated with both positive symptoms and aggression.
These findings suggested that positive symptoms such as formal thought disorder and auditory misperception, combined with cognitive impairments reflecting difficulties in deploying an adaptive control toward perceived threats, could escalate the likelihood of aggression in schizophrenia.
Music performance anxiety (MPA) is one of the most common disorders among professional musicians, nevertheless, little is known about the disease. With this systematic review, prevalence, risk factors and treatment procedures for MPA were assessed, and for the first time, quality assessments were carried out for all studies using standardized assessment tools. A systematic literature search was conducted via search algorithms in the databases MEDLINE, EMBASE, CINAHL, PsycArticles, PsycInfo and ERIC. Included were case reports, case–control, cohort, cross-sectional and intervention studies examining professional musicians with MPA. For quality assessment, adapted tools of the National Heart, Lung, and Blood Institute were used. A total of 43 studies were included (10 case reports, 21 intervention, 11 cross-sectional, one cohort study). Quality ratings ranged from −11 to 6 out of a maximum of 15/16 points for cross-sectional/cohort studies and −4 to 11 out of 18 points for intervention studies. The prevalence of MPA was between 16.5% and 60%. More women than men were affected and musicians older than 45–50 years reported less MPA than younger musicians. Regarding treatment cognitive behavioural therapy (CBT) and β-blockers were most often researched with beneficial results for CBT. However, studies with adequate control groups for CBT interventions are needed to clarify its efficacy. Studies showed methodological weaknesses, especially in the selection of participants, recording of influencing factors, blinding of interventions, randomization of participants and analysis of comorbidity. Recommendations for further research are made.
In Central America, population and food demands are rising rapidly, while yields of staple crops, maize and beans, remain low. To identify the main factors limiting production, field trials were established in six maize- and bean-producing regions in Guatemala, Honduras and El Salvador, representing about three-quarters of the maize-producing area. Potential yield-limiting factors were evaluated in 2017 and included: water stress, nutrient deficiency, pest and disease pressure, and/or inter-plant competition. When considering all sites, improved fertilization and pest and disease control significantly improved yields in maize by 11 and 16%, respectively but did not have a significant effect in beans. Irrigation had no effect due to good rainfall distribution over the growing season. Optimized planting arrangement resulted in an average 18% increase in maize yield, making it the most promising factor evaluated. The treatment and site combinations that increased both crop productivity and net profit included management changes that improved resource use efficiency. However, the contribution of each limiting factor to yield gaps varied across sites and no treatment was effective at increasing yield consistently across sites. Production constraints are highly dependent on local management practices and agroecological location. Therefore, public and private development efforts that seek to increase production should conduct multi-year, participatory experiments to identify limitations pertinent to the area in question. The next step is then to evaluate sustainable and profitable practices, to address those limitations and provide sound recommendations to farmers while decreasing the environmental and economic costs.
Laser-based compact MeV X-ray sources are useful for a variety of applications such as radiography and active interrogation of nuclear materials. MeV X rays are typically generated by impinging the intense laser onto ~mm-thick high-Z foil. Here, we have characterized such a MeV X-ray source from 120 TW (80 J, 650 fs) laser interaction with a 1 mm-thick tantalum foil. Our measurements show X-ray temperature of 2.5 MeV, flux of 3 × 1012 photons/sr/shot, beam divergence of ~0.1 sr, conversion efficiency of ~1%, that is, ~1 J of MeV X rays out of 80 J incident laser, and source size of 80 m. Our measurement also shows that MeV X-ray yield and temperature is largely insensitive to nanosecond laser contrasts up to 10−5. Also, preliminary measurements of similar MeV X-ray source using a double-foil scheme, where the laser-driven hot electrons from a thin foil undergoing relativistic transparency impinging onto a second high-Z converter foil separated by 50–400 m, show MeV X-ray yield more than an order of magnitude lower compared with the single-foil results.