Beyond the “at risk mental state” concept: transitioning to transdiagnostic psychiatry

The “at risk mental state” for psychosis approach has been a catalytic, highly productive research paradigm over the last 25 years. In this paper we review that paradigm and summarize its key lessons, which include the valence of this phenotype for future psychosis outcomes, but also for comorbid, persistent or incident non‐psychotic disorders; and the evidence that onset of psychotic disorder can at least be delayed in ultra high risk (UHR) patients, and that some full‐threshold psychotic disorder may emerge from risk states not captured by UHR criteria. The paradigm has also illuminated risk factors and mechanisms involved in psychosis onset. However, findings from this and related paradigms indicate the need to develop new identification and diagnostic strategies. These findings include the high prevalence and impact of mental disorders in young people, the limitations of current diagnostic systems and risk identification approaches, the diffuse and unstable symptom patterns in early stages, and their pluripotent, transdiagnostic trajectories. The approach we have recently adopted has been guided by the clinical staging model and adapts the original “at risk mental state” approach to encompass a broader range of inputs and output target syndromes. This approach is supported by a number of novel modelling and prediction strategies that acknowledge and reflect the dynamic nature of psychopathology, such as dynamical systems theory, network theory, and joint modelling. Importantly, a broader transdiagnostic approach and enhancing specific prediction (profiling or increasing precision) can be achieved concurrently. A holistic strategy can be developed that applies these new prediction approaches, as well as machine learning and iterative probabilistic multimodal models, to a blend of subjective psychological data, physical disturbances (e.g., EEG measures) and biomarkers (e.g., neuroinflammation, neural network abnormalities) acquired through fine‐grained sequential or longitudinal assessments. This strategy could ultimately enhance our understanding and ability to predict the onset, early course and evolution of mental ill health, further opening pathways for preventive interventions.     

Clinical,socio‐demographic and psychological characteristics in individuals with persistent psychotic experiences with and without a “need for care”

Individuals reporting persistent psychotic experiences (PEs) in the general population, but without a “need for care”, are a unique group of particular importance in identifying risk and protective factors for psychosis. We compared people with persistent PEs and no “need for care” (non‐clinical, N=92) with patients diagnosed with a psychotic disorder (clinical, N=84) and controls without PEs (N=83), in terms of their phenomenological, socio‐demographic and psychological features. The 259 participants were recruited from one urban and one rural area in the UK, as part of the UNIQUE (Unusual Experiences Enquiry) study. Results showed that the non‐clinical group experienced hallucinations in all modalities as well as first‐rank symptoms, with an earlier age of onset than in the clinical group. Somatic/tactile hallucinations were more frequent than in the clinical group, while commenting and conversing voices were rare. Participants in the non‐clinical group were differentiated from their clinical counterparts by being less paranoid and deluded, apart from ideas of reference, and having fewer cognitive difficulties and negative symptoms. Unlike the clinical group, they were characterized neither by low psychosocial functioning nor by social adversity. However, childhood trauma featured in both groups. They were similar to the controls in psychological characteristics: they did not report current emotional problems, had intact self‐esteem, displayed healthy schemas about the self and others, showed high life satisfaction and well‐being, and high mindfulness. These findings support biopsychosocial models postulating that environmental and psychological factors interact with biological processes in the aetiology of psychosis. While some PEs may be more malign than others, lower levels of social and environmental adversity, combined with protective factors such as intact IQ, spirituality, and psychological and emotional well‐being, may reduce the likelihood of persistent PEs leading to pathological outcomes. Future research should focus on protective factors and determinants of well‐being in the context of PEs, rather than exclusively on risk factors and biomarkers of disease states.     

Self‐stigma and the “why try” effect: impact on life goals and evidence‐based practices

Many individuals with mental illnesses are troubled by self-stigma and the subsequent processes that accompany this stigma: low self-esteem and self-efficacy. “Why try” is the overarching phenomenon of interest here, encompassing self-stigma, mediating processes, and their effect on goal-related behavior. In this paper, the literature that explains “why try” is reviewed, with special focus on social psychological models. Self-stigma comprises three steps: awareness of the stereotype, agreement with it, and applying it to one’s self. As a result of these processes, people suffer reduced self-esteem and self-efficacy. People are dissuaded from pursuing the kind of opportunities that are fundamental to achieving life goals because of diminished self-esteem and self-efficacy. People may also avoid accessing and using evidence-based practices that help achieve these goals. The effects of self-stigma and the “why try” effect can be diminished by services that promote consumer empowerment.     

Age matters in the prevalence and clinical significance of ultra‐high‐risk for psychosis symptoms and criteria in the general population: Findings from the BEAR and BEARS‐kid studies

Early detection of psychosis is an important topic in psychiatry. Yet, there is limited information on the prevalence and clinical significance of high‐risk symptoms in children and adolescents as compared to adults. We examined ultra‐high‐risk (UHR) symptoms and criteria in a sample of individuals aged 8‐40 years from the general population of Canton Bern, Switzerland, enrolled from June 2011 to May 2014. The current presence of attenuated psychotic symptoms (APS) and brief intermittent psychotic symptoms (BLIPS) and the fulfillment of onset/worsening and frequency requirements for these symptoms in UHR criteria were assessed using the Structured Interview for Psychosis Risk Syndromes. Additionally, perceptive and non‐perceptive APS were differentiated. Psychosocial functioning and current non‐psychotic DSM‐IV axis I disorders were also surveyed. Well‐trained psychologists performed assessments. Altogether, 9.9% of subjects reported APS and none BLIPS, and 1.3% met all the UHR requirements for APS. APS were related to more current axis I disorders and impaired psychosocial functioning, indicating some clinical significance. A strong age effect was detected around age 16: compared to older individuals, 8‐15‐year olds reported more perceptive APS, that is, unusual perceptual experiences and attenuated hallucinations. Perceptive APS were generally less related to functional impairment, regardless of age. Conversely, non‐perceptive APS were related to low functioning, although this relationship was weaker in those below age 16. Future studies should address the differential effects of perceptive and non‐perceptive APS, and their interaction with age, also in terms of conversion to psychosis.     

A meta‐review of “lifestyle psychiatry”: the role of exercise,smoking, diet and sleep in the prevention and treatment of mental disorders

There is increasing academic and clinical interest in how “lifestyle factors” traditionally associated with physical health may also relate to mental health and psychological well‐being. In response, international and national health bodies are producing guidelines to address health behaviors in the prevention and treatment of mental illness. However, the current evidence for the causal role of lifestyle factors in the onset and prognosis of mental disorders is unclear. We performed a systematic meta‐review of the top‐tier evidence examining how physical activity, sleep, dietary patterns and tobacco smoking impact on the risk and treatment outcomes across a range of mental disorders. Results from 29 meta‐analyses of prospective/cohort studies, 12 Mendelian randomization studies, two meta‐reviews, and two meta‐analyses of randomized controlled trials were synthesized to generate overviews of the evidence for targeting each of the specific lifestyle factors in the prevention and treatment of depression, anxiety and stress‐related disorders, schizophrenia, bipolar disorder, and attention‐deficit/hyperactivity disorder. Standout findings include: a) convergent evidence indicating the use of physical activity in primary prevention and clinical treatment across a spectrum of mental disorders; b) emerging evidence implicating tobacco smoking as a causal factor in onset of both common and severe mental illness; c) the need to clearly establish causal relations between dietary patterns and risk of mental illness, and how diet should be best addressed within mental health care; and d) poor sleep as a risk factor for mental illness, although with further research required to understand the complex, bidirectional relations and the benefits of non‐pharmacological sleep‐focused interventions. The potentially shared neurobiological pathways between multiple lifestyle factors and mental health are discussed, along with directions for future research, and recommendations for the implementation of these findings at public health and clinical service levels.     

Psychopathology in 7‐year‐old children with familial high risk of developing schizophrenia spectrum psychosis or bipolar disorder – The Danish High Risk and Resilience Study ‐ VIA 7, a population‐based cohort study

This study aimed to compare the psychopathological profiles of children at familial high risk of schizophrenia spectrum psychosis (FHR‐SZ) or bipolar disorder (FHR‐BP) with population‐based controls. We used Danish nationwide registers to retrieve a cohort of 522 seven‐year‐old children of parents with schizophrenia spectrum psychosis (N=202), bipolar disorder (N=120) or none of these disorders (N=200). Psychopathology was assessed by reports from multiple informants, including children, parents and teachers. Lifetime DSM‐IV diagnoses were ascertained by blinded raters through the Schedule for Affective Disorders and Schizophrenia for School‐Age Children. The dimensional assessment of psychopathology was performed by the Child Behavior Checklist, the Teacher's Report Form, a modified version of the ADHD‐Rating Scale, the Test Observation Form, and the State‐Trait Anxiety Inventory for Children. Current level of functioning was evaluated using the Children's Global Assessment Scale (CGAS). The prevalence of lifetime psychiatric diagnoses was significantly higher in both FHR‐SZ children (38.7%, odds ratio, OR=3.5, 95% confidence interval, CI: 2.2‐5.7, p < 0.001) and FHR‐BP children (35.6%, OR=3.1, 95% CI: 1.8‐5.3, p < 0.001) compared with controls (15.2%). FHR‐SZ children displayed significantly more dimensional psychopathology on all scales and subscales compared with controls except for the Anxious subscale of the Test Observation Form. FHR‐BP children showed higher levels of dimensional psychopathology on several scales and subscales compared with controls, but lower levels compared with FHR‐SZ children. Level of functioning was lower in both FHR‐SZ children (CGAS mean score = 68.2; 95% CI: 66.3‐70.2, p < 0.0001) and FHR‐BP children (73.7; 95% CI: 71.2‐76.3, p < 0.05) compared with controls (77.9; 95% CI: 75.9‐79.9). In conclusion, already at the age of seven, FHR‐SZ and FHR‐BP children show a higher prevalence of a broad spectrum of categorical and dimensional psychopathology compared with controls. These results emphasize the need for developing early intervention strategies towards this vulnerable group of children.     

Direct crystallographic observation of an acyl-enzyme intermediate in the elastase-catalyzed hydrolysis of a peptidyl ester substrate: Exploiting the “glass transition” in protein dynamics

The crystal structure of the acyl complex of porcine pancreatic elastase with its peptidyl ester substrate N-acetyl-ala-ala-ala-methyl ester (Ac(Ala)₃OMe) has been determined at 2.5 Å resolution. The complex was stabilized by exploiting the “glass transition” in protein dynamics that occurs at around −53 °C (220 K). Substrate was flowed into the crystal in a cryoprotective solvent above this temperature, and then the crystal was rapidly cooled to a temperature below the transition to trap the species that formed. The use of a flow cell makes the experiment a kinetic one and means that the species prior to the rate determining transition state has a chance to accumulate. The resulting crystal structure shows an acyl-enzyme intermediate in which the leaving group is absent and the carbonyl carbon of the C-terminal alanine residue is covalently bound to the gamma oxygen of the active site serine. The ester carbonyl shows no significant distortion from planarity, with the carbonyl oxygen forming one hydrogen bond with the oxyanion hole. The tripeptide is bound in an extended antiparallel β-sheet with main chain residues of the enzyme. The geometry and interactions of this acyl-enzyme suggest that it represents a productive intermediate. To test this hypothesis, the same crystal was then warmed above the glass transition temperature and a second data set was collected. The resulting electron density map shows no sign of the substrate, indicating hydrolysis of the intermediate followed by product release. This experiment provides direct evidence for the importance of dynamic properties in catalysis and also provides a blueprint for the stabilization of other short-lived species for direct crystallographic observation.     

Differentiation of lineages within “Colletotrichum gloeosporioides s.l.” associated with cassava anthracnose disease by BOX‐ and ERIC‐PCRs

Several molecular techniques have been used to differentiate species or genetic lineages of microorganisms prior to sequencing. Among them, BOX‐ and ERIC‐PCRs may provide specific banding patterns for different species, allowing its differentiation. Therefore, the objective of this study was to evaluate these techniques as a tool for differentiation of phylogenetic lineages belonging to the Colletotrichum gloeosporioides species complex associated with cassava anthracnose disease. Sets of BOX‐ and ERIC‐PCR primers were used to assess the differentiation of lineages belonging to the complex with 81 C. gloeosporioides sensu lato (s.l.) isolates from different cassava producing regions. Some were identified by sequencing, such as Colletotrichum fructicola, Colletotrichum tropicale, C. gloeosporioides s.s, Colletotrichum theobromicola, Colletotrichum siamense, Colletotrichum brevisporum and Colletotrichum sichuanensis. The primers were able to amplify DNA fragments from all isolates. The ERIC‐PCR presented a wider range of banding patterns in comparison to BOX‐PCR, providing better differentiation of the individuals, as well as a higher correlation with the phylogenetic data was obtained by ERIC‐PCR and the combined data set for “BOX‐/ERIC‐PCRs,” inferred by Mantel test. However, the use of concatenated data (BOX‐/ERIC‐PCRs) reduced the discriminatory capacity presented by ERIC‐PCR alone, probably due to the lowest resolution of BOX‐PCR. Therefore, ERIC‐PCR technique enabled efficient differentiation of isolates belonging to the C. gloeosporioides complex and can be used to analyse multiple isolates in a collection and also being an important tool as a guide in the decision‐making process prior to sequencing. Based on this methodology, it was possible to identify two new species associated with cassava anthracnose disease, C. brevisporum and C. sichuanensis, being the first report of these two species associated with cassava anthracnose disease in Brazil.     

Chromatography process development in the quality by design paradigm I: Establishing a high‐throughput process development platform as a tool for estimating “characterization space” for an ion exchange chromatography step

This article describes the development of a high‐throughput process development (HTPD) platform for developing chromatography steps. An assessment of the platform as a tool for establishing the “characterization space” for an ion exchange chromatography step has been performed by using design of experiments. Case studies involving use of a biotech therapeutic, granulocyte colony‐stimulating factor have been used to demonstrate the performance of the platform. We discuss the various challenges that arise when working at such small volumes along with the solutions that we propose to alleviate these challenges to make the HTPD data suitable for empirical modeling. Further, we have also validated the scalability of this platform by comparing the results from the HTPD platform (2 and 6 μL resin volumes) against those obtained at the traditional laboratory scale (resin volume, 0.5 mL). We find that after integration of the proposed correction factors, the HTPD platform is capable of performing the process optimization studies at 170‐fold higher productivity. The platform is capable of providing semi‐quantitative assessment of the effects of the various input parameters under consideration. We think that platform such as the one presented is an excellent tool for examining the “characterization space” and reducing the extensive experimentation at the traditional lab scale that is otherwise required for establishing the “design space.” Thus, this platform will specifically aid in successful implementation of quality by design in biotech process development. This is especially significant in view of the constraints with respect to time and resources that the biopharma industry faces today. © 2013 American Institute of Chemical Engineers Biotechnol. Prog., 29: 403–414, 2013     

Facial symmetry and judgements of apparent health: Support for a “good genes” explanation of the attractiveness–symmetry relationship

The “good genes” explanation of attractiveness posits that mate preferences favour healthy individuals due to direct and indirect benefits associated with the selection of a healthy mate. Consequently, attractiveness judgements are likely to reflect judgements of apparent health. One physical characteristic that may inform health judgements is fluctuating asymmetry as it may act as a visual marker for genetic quality and developmental stability. Consistent with these suggestions, a number of studies have found relationships between facial symmetry and facial attractiveness. In Study 1, the interplay between facial symmetry, attractiveness, and judgements of apparent health was explored within a partial correlation design. Findings suggest that the attractiveness–symmetry relationship is mediated by a link between judgements of apparent health and facial symmetry. In Study 2, an opposite-sex bias in sensitivity to facial symmetry was observed when judging health. Thus, perceptual analysis of symmetry may be an adaptation facilitating discrimination between potential mates on the basis of apparent health. The findings of both studies are consistent with a “good genes” explanation of the attractiveness–symmetry relationship and problematic for the claim that symmetry is attractive as a by-product of the ease with which the visual recognition system processes symmetric stimuli.     

“Partial Isometric” Solutions: A Special Ambiguity of the Optimal Configuration in MDS with Minkowski Metrics

This article deals with a special kind of ambiguity of the optimal configuration calculated with the MDSCAL procedure. These configurations – the so-called partial isometric solutions – are not restricted to the use of the MDSCAL procedure; they may always occur when using Minkowski metrics. For the City Block metric and the Supremum metric examples are demonstrated.     

Base Compositional Bias and Phylogenetic Analyses: A Test of the “Flying DNA” Hypothesis

Phylogenetic methods can produce biased estimates of phylogeny when base composition varies along different lineages. Pettigrew (1994,Curr. Biol.4:277–280) has suggested that base composition bias is responsible for the apparent support for the monophyly of bats (Chiroptera: megabats and microbats) from several different nuclear and mitochondrial genes. Pettigrew's “flying DNA” hypothesis makes several predictions: (1) that metabolic constraints associated with flying result in elevated levels of adenine and thymine throughout the genome of both megabats and microbats, (2) that the resulting base compositional bias in bats is sufficient to mislead phylogenetic methods and account for the support for bat monophyly from several nuclear and mitochondrial genes, and (3) that phylogenetic analysis using pairwise distances corrected for compositional bias should eliminate the support for bat monophyly. We tested these predictions by analyzing DNA sequences from two nuclear and three mitochondrial genes. The predicted base compositional bias does not appear to exist in some of the genes, and in other genes the differences in AT content are very small. Analyses under a wide diversity of criteria and models of evolution, including analyses that take base composition into account (using log-determinant distances), all strongly support bat monophyly. Moreover, simulation analyses indicate that even extreme bias toward AT-base composition in bats would be insufficient to explain the observed levels of support for bat monophyly. These analyses provide no support for the “flying DNA” hypothesis, whereas the monophyly of bats appears to be well supported by the DNA sequence data.     

Association of preceding psychosis risk states and non‐psychotic mental disorders with incidence of clinical psychosis in the general population: a prospective study in the NEMESIS‐2 cohort

The validity and clinical utility of the concept of “clinical high risk” (CHR) for psychosis have so far been investigated only in risk‐enriched samples in clinical settings. In this population‐based prospective study, we aimed – for the first time – to assess the incidence rate of clinical psychosis and es­timate the population attributable fraction (PAF) of that incidence for preceding psychosis risk states and DSM‐IV diagnoses of non‐psychotic mental disorders (mood disorders, anxiety disorders, alcohol use disorders, and drug use disorders). All analyses were adjusted for age, gender and education. The incidence rate of clinical psychosis was 63.0 per 100,000 person‐years. The mutually‐adjusted Cox proportional hazards model indicated that preceding diagnoses of mood disorders (hazard ratio, HR=10.67, 95% CI: 3.12‐36.49), psychosis high‐risk state (HR=7.86, 95% CI: 2.76‐22.42) and drug use disorders (HR=5.33, 95% CI: 1.61‐17.64) were associated with an increased risk for clinical psychosis incidence. Of the clinical psychosis incidence in the population, 85.5% (95% CI: 64.6‐94.1) was attributable to prior psychopathology, with mood disorders (PAF=66.2, 95% CI: 33.4‐82.9), psychosis high‐risk state (PAF=36.9, 95% CI: 11.3‐55.1), and drug use disorders (PAF=18.7, 95% CI: –0.9 to 34.6) as the most important factors. Although the psychosis high‐risk state displayed a high relative risk for clinical psychosis outcome even after adjusting for other psychopathology, the PAF was comparatively low, given the low prevalence of psychosis high‐risk states in the population. These findings provide empirical evidence for the “prevention paradox” of targeted CHR early intervention. A comprehensive prevention strategy with a focus on broader psychopathology may be more effective than the current psychosis‐focused approach for achieving population‐based improvements in prevention of psychotic disorders.     

Manganese and copper promote the binding of dopamine to “serotonin binding proteins” in bovine frontal cortex

The authors previously reported that Fe²⁺ is capable of increasing the binding of dopamine and of serotonin to “serotonin binding proteins” which are present in soluble extracts from calf brain. In this study, it is shown that Mn²⁺ and Cu²⁺ are also capable of increasing the binding, but for dopamine only. As for Fe²⁺, Mn²⁺ and Cu²⁺ are likely to promote the binding by virtue of their ability to enhance the oxidation of dopamine into dopamine-O-quinone, a derivative which is known to undergo covalent association with sulfhydryl groups of proteins. Data such as the irreversible nature of the majority of the binding, the inhibitory action of reducing agents (sodium ascorbate) and of reagents which contain, or modify sulfhydryl groups (reduced glutathione) are compatible with such a mechanism. The three metal ions are also capable of inactivating part of the binding sites on SBP directly; this effect is more pronounced for Cu²⁺ than for Fe²⁺ and it is only weak for Mn²⁺. The Fe²⁺-mediated binding of dopamine is inhibited by the superoxide dismutase enzyme, and it was therefore suggested that Fe²⁺ enhances the oxidation of dopamine by virtue of its ability to produce superoxide radicals out of dissolved molecular oxygen. Such a mechanism does not appear to take place in the case of Mn²⁺ and Cu²⁺. Instead, it is likely that Cu²⁺ and dopamine form a complex which is highly susceptible towards oxidation by dissolved molecular oxygen. Mn²⁺, on the other hand, can easily be oxidized into Mn³⁺, which is capable to oxidize dopamine by itself. Chronic manganese intoxication (from exposure to manganese) and Wilson's disease (related to inadequate elimination of copper) go along with neurological symptoms which are very similar to those encountered in Parkinson's disease. Our data indicate that manganese and copper ions accelerate the oxidation of catecholamines to produce toxic quinones. These quinones could, at least in part, account for the degeneration of dopamininergic neurons in such pathologies.     

Etiology in psychiatry: embracing the reality of poly‐gene‐environmental causation of mental illness

Intriguing findings on genetic and environmental causation suggest a need to reframe the etiology of mental disorders. Molecular genetics shows that thousands of common and rare genetic variants contribute to mental illness. Epidemiological studies have identified dozens of environmental exposures that are associated with psychopathology. The effect of environment is likely conditional on genetic factors, resulting in gene‐environment interactions. The impact of environmental factors also depends on previous exposures, resulting in environment‐environment interactions. Most known genetic and environmental factors are shared across multiple mental disorders. Schizophrenia, bipolar disorder and major depressive disorder, in particular, are closely causally linked. Synthesis of findings from twin studies, molecular genetics and epidemiological research suggests that joint consideration of multiple genetic and environmental factors has much greater explanatory power than separate studies of genetic or environmental causation. Multi‐factorial gene‐environment interactions are likely to be a generic mechanism involved in the majority of cases of mental illness, which is only partially tapped by existing gene‐environment studies. Future research may cut across psychiatric disorders and address poly‐causation by considering multiple genetic and environmental measures across the life course with a specific focus on the first two decades of life. Integrative analyses of poly‐causation including gene‐environment and environment‐environment interactions can realize the potential for discovering causal types and mechanisms that are likely to generate new preventive and therapeutic tools.     

A newly identified group of adolescents at “invisible” risk for psychopathology and suicidal behavior: findings from the SEYLE study

This study explored the prevalence of risk behaviors (excessive alcohol use, illegal drug use, heavy smoking, reduced sleep, overweight, underweight, sedentary behavior, high use of Internet/TV/videogames for reasons not related to school or work, and truancy), and their association with psychopathology and self‐destructive behaviors, in a sample of 12,395 adolescents recruited in randomly selected schools across 11 European countries. Latent class analysis identified three groups of adolescents: a low‐risk group (57.8%) including pupils with low or very low frequency of risk behaviors; a high‐risk group (13.2%) including pupils who scored high on all risk behaviors, and a third group (“invisible” risk, 29%) including pupils who were positive for high use of Internet/TV/videogames for reasons not related to school or work, sedentary behavior and reduced sleep. Pupils in the “invisible” risk group, compared with the high‐risk group, had a similar prevalence of suicidal thoughts (42.2% vs. 44%), anxiety (8% vs. 9.2%), subthreshold depression (33.2% vs. 34%) and depression (13.4% vs. 14.7%). The prevalence of suicide attempts was 5.9% in the “invisible” group, 10.1% in the high‐risk group and 1.7% in the low‐risk group. The prevalence of all risk behaviors increased with age and most of them were significantly more frequent among boys. Girls were significantly more likely to experience internalizing (emotional) psychiatric symptoms. The “invisible” group may represent an important new intervention target group for potentially reducing psychopathology and other untoward outcomes in adolescence, including suicidal behavior.