Whole-exome sequencing identifies rare genetic variants associated with human plasma metabolites.

Metabolite levels measured in the human population are endophenotypes for biological processes. We combined sequencing data for 3,924 (whole-exome sequencing, WES, discovery) and 2,805 (whole-genome sequencing, WGS, replication) donors from a prospective cohort of blood donors in England. We used multiple approaches to select and aggregate rare genetic variants (minor allele frequency [MAF] < 0.1%) in protein-coding regions and tested their associations with 995 metabolites measured in plasma by using ultra-high-performance liquid chromatography-tandem mass spectrometry. We identified 40 novel associations implicating rare coding variants (27 genes and 38 metabolites), of which 28 (15 genes and 28 metabolites) were replicated. We developed algorithms to prioritize putative driver variants at each locus and used mediation and Mendelian randomization analyses to test directionality at associations of metabolite and protein levels at the ACY1 locus. Overall, 66% of reported associations implicate gene targets of approved drugs or bioactive drug-like compounds, contributing to drug targets' validating efforts.

Sex-specific genetic architecture of late-life memory performance.

BACKGROUND: Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS: We conducted the largest sex-aware genetic study on late-life memory to date (Nmales  = 11,942; Nfemales  = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex-stratified and sex-interaction genome-wide association studies in 24,216 non-Hispanic White and 3367 non-Hispanic Black participants. RESULTS: We identified three sex-specific loci (rs67099044-CBLN2, rs719070-SCHIP1/IQCJ-SCHIP), including an X-chromosome locus (rs5935633-EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex-specific pathway and found sex-specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION: This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex-specific genes, pathways, and genetic correlations that related to late-life memory. HIGHLIGHTS: Demonstrated the heritable component of late-life memory is similar across sexes. Identified two genetic loci with a sex-interaction with baseline memory. Identified an X-chromosome locus associated with memory decline in females. Highlighted sex-specific candidate genes and pathways associated with memory. Revealed sex-specific shared genetic architecture between memory and complex traits.

Effects of methylphenidate on mismatch negativity and P3a amplitude of initially psychostimulant-naïve, adult ADHD patients.

BACKGROUND: Deficient information processing in ADHD theoretically results in sensory overload and may underlie the symptoms of the disorder. Mismatch negativity (MMN) and P3a amplitude reflect an individual's detection and subsequent change in attention to stimulus change in their environment. Our primary aim was to explore MMN and P3a amplitude in adult ADHD patients and to examine the effects of methylphenidate (MPH) on these measures. METHODS: Forty initially psychostimulant-naïve, adult ADHD patients without comorbid ASD and 42 matched healthy controls (HC) were assessed with an MMN paradigm at baseline. Both groups were retested after 6 weeks, in which patients were treated with MPH. RESULTS: Neither significant group differences in MMN nor P3a amplitude were found at baseline. Although 6-week MPH treatment significantly reduced symptomatology and improved daily functioning of the patients, it did not significantly affect MMN amplitude; however, it did significantly reduce P3a amplitude compared to the HC. Furthermore, more severe ADHD symptoms were significantly associated with larger MMN amplitudes in the patients, both at baseline and follow-up. CONCLUSION: We found no evidence for early information processing deficits in patients with ADHD, as measured with MMN and P3a amplitude. Six-week treatment with MPH decreased P3a but not MMN amplitude, although more severe ADHD-symptoms were associated with larger MMN amplitudes in the patients. Given that P3a amplitude represents an important attentional process and that glutamate has been linked to both ADHD and MMN amplitude, future research should investigate augmenting MPH treatment of less responsive adults with ADHD with glutamatergic antagonists.

In memory of Professor Iain Wilkinson: cognitive and neuroimaging endophenotypes in a consanguineous schizophrenia multiplex family.

BACKGROUND: Schizophrenia endophenotypes may help elucidate functional effects of genetic risk variants in multiply affected consanguineous families that segregate recessive risk alleles of large effect size. We studied the association between a schizophrenia risk locus involving a 6.1Mb homozygous region on chromosome 13q22-31 in a consanguineous multiplex family and cognitive functioning, haemodynamic response and white matter integrity using neuroimaging. METHODS: We performed CANTAB neuropsychological testing on four affected family members (all homozygous for the risk locus), ten unaffected family members (seven homozygous and three heterozygous) and ten healthy volunteers, and tested neuronal responses on fMRI during an n-back working memory task, and white matter integrity on diffusion tensor imaging (DTI) on four affected and six unaffected family members (four homozygous and two heterozygous) and three healthy volunteers. For cognitive comparisons we used a linear mixed model (Kruskal-Wallis) test, followed by posthoc Dunn's pairwise tests with a Bonferroni adjustment. For fMRI analysis, we counted voxels exceeding the p < 0.05 corrected threshold. DTI analysis was observational. RESULTS: Family members with schizophrenia and unaffected family members homozygous for the risk haplotype showed attention (p < 0.01) and working memory deficits (p < 0.01) compared with healthy controls; a neural activation laterality bias towards the right prefrontal cortex (voxels reaching p < 0.05, corrected) and observed lower fractional anisotropy in the anterior cingulate cortex and left dorsolateral prefrontal cortex. CONCLUSIONS: In this family, homozygosity at the 13q risk locus was associated with impaired cognition, white matter integrity, and altered laterality of neural activation.

Peripheral Inflammatory Markers in Subtypes and Core Features of Depression: A Systematized Review.

INTRODUCTION: The aim of this work was to summarize relationships between two subtypes of major depressive disorder (melancholic and atypical) and four core features of depression that reflect the domains identified consistently in previous studies of major depressive disorder endophenotypes (exaggerated reactivity to negative information, altered reward processing, cognitive control deficits, and somatic symptoms) on the one hand and selected peripheral inflammatory markers (C-reactive protein [CRP], cytokines, and adipokines) on the other. METHODS: A systematized review was conducted. The database used for searching articles was PubMed (MEDLINE). RESULTS: According to our search, most peripheral immunological markers associated with major depressive disorder are not specific to a single depressive symptom group. The most evident examples are CRP, IL-6, and TNF-α. The strongest evidence supports the connection of peripheral inflammatory markers with somatic symptoms; weaker evidence indicates a role of immune changes in altered reward processing. The least amount of evidence was found for the role of peripheral inflammatory markers in exaggerated reactivity to negative information and cognitive control deficits. Regarding the depression subtypes, a tendency for higher CRP and adipokines was observed in atypical depression; increased IL-6 was found in melancholic depression. CONCLUSION: Somatic symptoms of depression could be a manifestation of a specific immunological endophenotype of depressive disorder. Melancholic and atypical depression may be characterized by different profiles of immunological markers.

Whole-exome rare-variant analysis of Alzheimer's disease and related biomarker traits.

INTRODUCTION: Despite increasing evidence of a role of rare genetic variation in the risk of Alzheimer's disease (AD), limited attention has been paid to its contribution to AD-related biomarker traits indicative of AD-relevant pathophysiological processes. METHODS: We performed whole-exome gene-based rare-variant association studies (RVASs) of 17 AD-related traits on whole-exome sequencing (WES) data generated in the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study (n = 450) and whole-genome sequencing (WGS) data from ADNI (n = 808). RESULTS: Mutation screening revealed a novel probably pathogenic mutation (PSEN1 p.Leu232Phe). Gene-based RVAS revealed the exome-wide significant contribution of rare coding variation in RBKS and OR7A10 to cognitive performance and protection against left hippocampal atrophy, respectively. DISCUSSION: The identification of these novel gene-trait associations offers new perspectives into the role of rare coding variation in the distinct pathophysiological processes culminating in AD, which may lead to identification of novel therapeutic and diagnostic targets.

Neuropathology-based APOE genetic risk score better quantifies Alzheimer's risk.

INTRODUCTION: Apolipoprotein E (APOE) ε4-carrier status or ε4 allele count are included in analyses to account for the APOE genetic effect on Alzheimer's disease (AD); however, this does not account for protective effects of APOE ε2 or heterogeneous effect of ε2, ε3, and ε4 haplotypes. METHODS: We leveraged results from an autopsy-confirmed AD study to generate a weighted risk score for APOE (APOE-npscore). We regressed cerebrospinal fluid (CSF) amyloid and tau biomarkers on APOE variables from the Wisconsin Registry for Alzheimer's Prevention (WRAP), Wisconsin Alzheimer's Disease Research Center (WADRC), and Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: The APOE-npscore explained more variance and provided a better model fit for all three CSF measures than APOE ε4-carrier status and ε4 allele count. These findings were replicated in ADNI and observed in subsets of cognitively unimpaired (CU) participants. DISCUSSION: The APOE-npscore reflects the genetic effect on neuropathology and provides an improved method to account for APOE in AD-related analyses.

Peripheral Blood Mononuclear Cell-Related Biomarkers in Schizophrenia.

INTRODUCTION: Schizophrenia is a severe mental illness causing significant impairment in personal, family, social, educational, occupational, and other important areas of life. While there is no widely accepted endophenotype, peripheral blood cells may serve as an accessible model of intracellular changes in schizophrenia. METHODS: We reviewed the literature on the query "peripheral blood mononuclear cells AND schizophrenia" in Medline (Pubmed), selecting studies that searched for specific biomarkers of schizophrenia. We considered both diagnostic biomarkers and biomarkers of therapeutic response, specific schizophrenia disorders or differential diagnostic biomarkers. RESULTS: We retrieved 41 articles matching the search criteria, among which were studies that considered changes in the production of pro-inflammatory and anti-inflammatory markers, proteins, receptors, enzyme activity, and gene expression as potential biomarkers. CONCLUSION: Approaches analysing a biological axis or a group of related biomarkers may hold the greatest promise for identifying schizophrenia. In addition, pharmacological status, smoking status, inflammatory markers and glucose metabolites, the presence of comorbidities should be considered. Certain biomarkers, while not specific for the diagnosis of schizophrenia, may indicate the prognosis and effectiveness of treatment in the established diagnosis.

Evaluating brain structure traits as endophenotypes using polygenicity and discoverability.

Human brain structure traits have been hypothesized to be broad endophenotypes for neuropsychiatric disorders, implying that brain structure traits are comparatively "closer to the underlying biology." Genome-wide association studies from large sample sizes allow for the comparison of common variant genetic architectures between traits to test the evidence supporting this claim. Endophenotypes, compared to neuropsychiatric disorders, are hypothesized to have less polygenicity, with greater effect size of each susceptible SNP, requiring smaller sample sizes to discover them. Here, we compare polygenicity and discoverability of brain structure traits, neuropsychiatric disorders, and other traits (91 in total) to directly test this hypothesis. We found reduced polygenicity (FDR = 0.01) and increased discoverability (FDR = 3.68 × 10-9 ) of cortical brain structure traits, as compared to aggregated estimates of multiple neuropsychiatric disorders. We predict that ~8 M individuals will be required to explain the full heritability of cortical surface area by genome-wide significant SNPs, whereas sample sizes over 20 M will be required to explain the full heritability of depression. In conclusion, our findings are consistent with brain structure satisfying the higher power criterion of endophenotypes.

Combined electrophysiological and morphological phenotypes in patients with genetic generalized epilepsy and their healthy siblings.

OBJECTIVE: Genetic generalized epilepsy (GGE) is characterized by aberrant neuronal dynamics and subtle structural alterations. We evaluated whether a combination of magnetic and electrical neuronal signals and cortical thickness would provide complementary information about network pathology in GGE. We also investigated whether these imaging phenotypes were present in healthy siblings of the patients to test for genetic influence. METHODS: In this cross-sectional study, we analyzed 5 min of resting state data acquired using electroencephalography (EEG) and magnetoencephalography (MEG) in patients, their siblings, and controls, matched for age and sex. We computed source-reconstructed power and connectivity in six frequency bands (1-40 Hz) and cortical thickness (derived from magnetic resonance imaging). Group differences were assessed using permutation analysis of linear models for each modality separately and jointly for all modalities using a nonparametric combination. RESULTS: Patients with GGE (n = 23) had higher power than controls (n = 35) in all frequencies, with a more posterior focus in MEG than EEG. Connectivity was also increased, particularly in frontotemporal and central regions in theta (strongest in EEG) and low beta frequencies (strongest in MEG), which was eminent in the joint EEG/MEG analysis. EEG showed weaker connectivity differences in higher frequencies, possibly related to drug effects. The inclusion of cortical thickness reinforced group differences in connectivity and power. Siblings (n = 18) had functional and structural patterns intermediate between those of patients and controls. SIGNIFICANCE: EEG detected increased connectivity and power in GGE similar to MEG, but with different spectral sensitivity, highlighting the importance of theta and beta oscillations. Cortical thickness reductions in GGE corresponded to functional imaging patterns. Our multimodal approach extends the understanding of the resting state in GGE and points to genetic underpinnings of the imaging markers studied, providing new insights into the causes and consequences of epilepsy.

A family study on first episode of psychosis patients: Exploring neuropsychological performance as an endophenotype.

INTRODUCTION: Family studies provide a suitable approach to analyzing candidate endophenotypes of schizophrenia, including cognitive features. OBJECTIVE: To characterize different neurocognitive functions in a group of patients with first episode of psychosis (FEP), their first-degree relatives (parents and siblings), and healthy controls (HC), in order to identify potential endophenotypes for schizophrenia spectrum disorders (SSD). METHODS: Participants were assessed in the context of a national project in Spain called PAFIP-FAMILIAS. They completed the same neuropsychological battery, which included tests of verbal memory, visual memory, processing speed, working memory, executive functions, motor dexterity, attention, and theory of mind. Group comparisons were performed using one-way ANOVA, followed by tests of multiple comparisons when appropriate. RESULTS: One hundred thirty-three FEP patients were included, as well as 244 of their first-degree relatives (146 parents and 98 siblings) and 202 HC. In general, relatives showed an intermediate performance between the HC and the FEP patients in all neurocognitive domains. However, the domains of executive functions and attention stood out, as relatives (especially parents) showed similar performance to FEP patients. This was replicated when selecting patients subsequently diagnosed with schizophrenia and their relatives. CONCLUSION: These findings suggest that executive and attention dysfunctions might have a family aggregation and could be relevant cognitive endophenotypes for psychotic disorders. The study shows the potential of exploring intra-family neuropsychological performance supporting neurobiological and genetic research in SSD.

Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation.

Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of laryngeal dystonia in families, including 21 probands and 21 unaffected relatives, compared to 32 unrelated healthy controls. We further used a supervised machine-learning algorithm to predict the risk for dystonia development in susceptible individuals based on neural features of identified endophenotypes. We found that abnormalities in prefrontal-parietal cortex, thalamus, and caudate nucleus were commonly shared between patients and their unaffected relatives, representing an intermediate endophenotype of laryngeal dystonia. Machine learning classified 95.2% of unaffected relatives as patients rather than healthy controls, substantiating that these neural alterations represent the endophenotypic marker of dystonia penetrance, independent of its symptomatology. Additional abnormalities in premotor-parietal-temporal cortical regions, caudate nucleus, and cerebellum were present only in patients but not their unaffected relatives, likely representing a secondary endophenotype of dystonia manifestation. Based on alterations in the parietal cortex and caudate nucleus, the machine learning categorized 28.6% of unaffected relative as patients, indicating their increased lifetime risk for developing clinical manifestation of dystonia. The identified endophenotypic neural markers may be implemented for screening of at-risk individuals for dystonia development, selection of families for genetic studies of novel variants based on their risk for disease penetrance, or stratification of patients who would respond differently to a particular treatment in clinical trials.

Association of CACNA1C polymorphisms with serum BDNF levels in bipolar disorder.

Variation in the CACNA1C gene has been associated with bipolar disorder in several genome-wide association studies. This gene encodes the alpha 1C subunit of L-type voltage-gated calcium channels, which play an essential role in neurons. We analysed 39 biomarkers in either cerebrospinal fluid or serum in relation to six different CACNA1C variants in 282 patients with bipolar disorder and 90 controls. We report associations of CACNA1C risk alleles with serum levels of BDNF as well as tissue plasminogen activator, which converts pro-BDNF to mature BDNF. This sheds light on links between CACNA1C genetic variants and pathophysiological mechanisms in bipolar disorder.

Drug Desensitizations for Chemotherapy: Safety and Efficacy in Preventing Anaphylaxis.

Hypersensitivity reactions (HSRs) to antineoplastic drugs are increasing due to the expanding use of classical and new drugs in a wide variety of malignancies. PURPOSE OF REVIEW: The goal of this review is to provide current best practices in the diagnosis and management of HSRs based on data and evidence. RECENT FINDINGS: A plethora of studies have provided evidence of the safety and efficacy of rapid drug desensitizations (RDD) to allow for the reintroduction of antineoplastic drugs following an HSR, based on risk stratification. Recently described biomarkers such as basophil activation test, total IgE, BRCA genotyping, and serum IL-6 can aid in guiding improved precision desensitization protocols. Personalized premedication regimens and protocols have improved RDD safety and outcomes. RDD allows for the continued use of chemotherapeutic drugs without impaired drug efficacy. RDD represents the best approach to maintain cancer patients on their most effective treatments.

Identification of persistent and resolving subphenotypes of acute hypoxemic respiratory failure in two independent cohorts.

BACKGROUND: Acute hypoxemic respiratory failure (HRF) is associated with high morbidity and mortality, but its heterogeneity challenges the identification of effective therapies. Defining subphenotypes with distinct prognoses or biologic features can improve therapeutic trials, but prior work has focused on ARDS, which excludes many acute HRF patients. We aimed to characterize persistent and resolving subphenotypes in the broader HRF population. METHODS: In this secondary analysis of 2 independent prospective ICU cohorts, we included adults with acute HRF, defined by invasive mechanical ventilation and PaO2-to-FIO2 ratio ≤ 300 on cohort enrollment (n = 768 in the discovery cohort and n = 1715 in the validation cohort). We classified patients as persistent HRF if still requiring mechanical ventilation with PaO2-to-FIO2 ratio ≤ 300 on day 3 following ICU admission, or resolving HRF if otherwise. We estimated relative risk of 28-day hospital mortality associated with persistent HRF, compared to resolving HRF, using generalized linear models. We also estimated fold difference in circulating biomarkers of inflammation and endothelial activation on cohort enrollment among persistent HRF compared to resolving HRF. Finally, we stratified our analyses by ARDS to understand whether this was driving differences between persistent and resolving HRF. RESULTS: Over 50% developed persistent HRF in both the discovery (n = 386) and validation (n = 1032) cohorts. Persistent HRF was associated with higher risk of death relative to resolving HRF in both the discovery (1.68-fold, 95% CI 1.11, 2.54) and validation cohorts (1.93-fold, 95% CI 1.50, 2.47), after adjustment for age, sex, chronic respiratory illness, and acute illness severity on enrollment (APACHE-III in discovery, APACHE-II in validation). Patients with persistent HRF displayed higher biomarkers of inflammation (interleukin-6, interleukin-8) and endothelial dysfunction (angiopoietin-2) than resolving HRF after adjustment. Only half of persistent HRF patients had ARDS, yet exhibited higher mortality and biomarkers than resolving HRF regardless of whether they qualified for ARDS. CONCLUSION: Patients with persistent HRF are common and have higher mortality and elevated circulating markers of lung injury compared to resolving HRF, and yet only a subset are captured by ARDS definitions. Persistent HRF may represent a clinically important, inclusive target for future therapeutic trials in HRF.

Social endophenotypes in autism spectrum disorder: A scoping review.

Endophenotypes are measurable markers of genetic vulnerability to current or future disorder. Autism spectrum disorder (ASD) is well-suited to be examined within an endophenotype framework given past and current emphases on the broader autism phenotype and early detection. We conducted a scoping review to identify potential socially-related endophenotypes of ASD. We focused on paradigms related to sociality (e.g., theory of mind (TOM), social attention), which comprise most of this literature. We integrated findings from traditional behavioral paradigms with brain-based measures (e.g., electroencephalography, functional magnetic resonance imaging). Broadly, infant research regarding social attention and responsivity (Research Domain Criteria (RDoC) domain of affiliation) and attention to faces and voices (social communication) finds consistent abnormality in vulnerable infant siblings. Several additional paradigms that have shown differences in vulnerable infants and young children include animacy perception tasks (perception and understanding of others), measures of recognition and response to familiar faces (attachment), and joint attention and false-belief tasks (understanding mental states). Research areas such as alexithymia (the perception and understanding of self), empathic responding, and vocal prosody may hold interest; however, challenges in measurement across populations and age ranges is a limiting factor. Future work should address sex differences and age dependencies, specificity to ASD, and heterogeneous genetic pathways to disorder within samples individuals with ASD and relatives.

Patient outcomes in idiopathic scoliosis are associated with biological endophenotypes: 2020 SOSORT award winner.

PURPOSE: Bracing is the treatment of choice for idiopathic scoliosis (IS), unfortunately factors underlying brace response remain unknown. Clinicians are currently unable to identify patients who may benefit from bracing, and therefore, better molecular stratification is critically needed. The aim of this study is to evaluate IS patient outcomes at skeletal maturity in relation to biological endophenotypes, and determine specific endophenotypes associated to differential bracing outcomes. This is a retrospective cohort with secondary cross-sectional comparative studies. METHODS: Clinical and radiological data were collected from 563 IS patients, stratified into biological endophenotypes (FG1, FG2, FG3) based on a cell-based test. Measured outcomes were maximum Cobb angle at skeletal maturity, and if severe, spinal deformity (≥ 45°) or surgery was attained. Treatment success/failure was determined by standard progression thresholds (Cobb ≥ 45° or surgery; Cobb angle progression ≥ 6°). Multivariable analyses were performed to evaluate associations between endophenotypes and clinical outcome. RESULTS: Higher Cobb angles at maturity for FG1 and FG2 patients were observed (p = 0.056 and p = 0.05), with increased likelihood of ≥ 45° and/or surgery for FG1 (OR = 2.181 [1.002-4.749] and FG2 (OR = 2.141 [1.038-4.413]) compared to FG3. FG3 was 9.31 [2.58-33.61] and 5.63 [2.11-15.05] times more likely for bracing success at treatment termination and based on the < 6° progression criterion, respectively, compared to FG1. CONCLUSION: Associations between biological endophenotypes and outcomes suggest differences in progression and/or bracing response among IS patients. Outcomes were most favorable in FG3 patients. The results pave the way for establishing personalized treatments, distinguishing who may benefit or not from treatment.

Precision Psychiatry: Biomarker-Guided Tailored Therapy for Effective Treatment and Prevention in Major Depression.

Depression contributes greatly to global disability and is a leading cause of suicide. It has multiple etiologies and therefore response to treatment can vary significantly. By applying the concepts of personalized medicine, precision psychiatry attempts to optimize psychiatric patient care by better predicting which individuals will develop an illness, by giving a more accurate biologically based diagnosis, and by utilizing more effective treatments based on an individual's biological characteristics (biomarkers). In this chapter, we discuss the basic principles underlying the role of biomarkers in psychiatric pathology and then explore multiple biomarkers that are specific to depression. These include endophenotypes, gene variants/polymorphisms, epigenetic factors such as methylation, biochemical measures, circadian rhythm dysregulation, and neuroimaging findings. We also examine the role of early childhood trauma in the development of, and treatment response to, depression. In addition, we review how new developments in technology may play a greater role in the determination of new biomarkers for depression.

Self-perceived cognitive lapses and psychological well-being in schizotypy: Generalized and domain-specific associations.

A critical link between schizotypy and schizophrenia is impoverished cognitive functioning. In the majority of studies, though: (1) cognition is examined with standard neuropsychological tasks; and (2) high-schizotypal individuals are defined according to criteria applied in the respective study sample. Taking these considerations into account, the aims of the present study were to examine: (1) differences between four pre-defined, according to normative criteria, schizotypal (paranoid, negative, disorganized and cognitive-perceptual) and one control groups in self-perceived cognitive lapses; and (2) associations between schizotypal dimensions, self-perceived cognitive lapses and psychological well-being. Two hundred and sixty-one participants were administered the Schizotypal Personality Questionnaire, the Cognitive Failures Questionnaire (CFQ) and the Flourishing Scale, which assesses psychological well-being. Negative schizotypals reported higher scores in almost all CFQ measures compared with the control group (all p values < 0.01) along with poorer psychological well-being compared with the control and the cognitive-perceptual groups (both p values < 0.001). The disorganized group had higher scores in distractibility, blunders and total CFQ scores compared with the control group (all p values < 0.001). High psychological well-being was significantly associated with low negative schizotypy and CFQ blunders along with high cognitive-perceptual schizotypy (all p values < 0.05). To summarize, negative schizotypy is associated with a profile of "generalized" self-perceived cognitive lapses while disorganized schizotypy is characterized by self-perceived cognitive slips that have previously been shown to be mediated by a fronto-parietal network. Although psychological well-being is negatively associated with social-context specific cognitive failures and negative schizotypy, it is positively associated with cognitive-perceptual schizotypy.

Biomarkers in psychiatry: a clinician's viewpoint.

INTRODUCTION: The dearth of biomarkers limits the precision of our research into pathogenesis of psychiatric disorders and has slowed down the development of new drugs. In clinical practice, it undermines the validity of psychiatric diagnoses and hampers the delivery of personalized treatment. SOURCES OF DATA: The data quoted in this paper are gathered from a range of sources encompassing scientific and journalistic both in print and electronic. AREAS OF AGREEMENT: Availability of clinically useful biomarkers will improve the prognosis and outcome of psychiatric patients by helping in early diagnosis and delivery of individualized treatment. AREAS OF CONTROVERSY: The cross-sectional and longitudinal observation of psychopathology is the bedrock of current clinical practice. Are psychiatric biomarkers advanced enough to supplant it? GROWING POINTS: The need for biomarkers of psychiatric disorders has become more acute with the advent of new treatments which require precision and an individualized approach. AREAS TIMELY FOR DEVELOPING RESEARCH: Identification and deployment of intermediate phenotypes in classification, research and clinical practice of psychiatry.