Improving the prospective prediction of a near-term suicide attempt in veterans at risk for suicide, using a go/no-go task.

BACKGROUND: Neurocognitive testing may advance the goal of predicting near-term suicide risk. The current study examined whether performance on a Go/No-go (GNG) task, and computational modeling to extract latent cognitive variables, could enhance prediction of suicide attempts within next 90 days, among individuals at high-risk for suicide. METHOD: 136 Veterans at high-risk for suicide previously completed a computer-based GNG task requiring rapid responding (Go) to target stimuli, while withholding responses (No-go) to infrequent foil stimuli; behavioral variables included false alarms to foils (failure to inhibit) and missed responses to targets. We conducted a secondary analysis of these data, with outcomes defined as actual suicide attempt (ASA), other suicide-related event (OtherSE) such as interrupted/aborted attempt or preparatory behavior, or neither (noSE), within 90-days after GNG testing, to examine whether GNG variables could improve ASA prediction over standard clinical variables. A computational model (linear ballistic accumulator, LBA) was also applied, to elucidate cognitive mechanisms underlying group differences. RESULTS: On GNG, increased miss rate selectively predicted ASA, while increased false alarm rate predicted OtherSE (without ASA) within the 90-day follow-up window. In LBA modeling, ASA (but not OtherSE) was associated with decreases in decisional efficiency to targets, suggesting differences in the evidence accumulation process were specifically associated with upcoming ASA. CONCLUSIONS: These findings suggest that GNG may improve prediction of near-term suicide risk, with distinct behavioral patterns in those who will attempt suicide within the next 90 days. Computational modeling suggests qualitative differences in cognition in individuals at near-term risk of suicide attempt.

Assessing Risk of Future Suicidality in Emergency Department Patients.

BACKGROUND: Emergency departments (ED) are the first line of evaluation for patients at risk and in crisis, with or without overt suicidality (ideation, attempts). Currently employed triage and assessments methods miss some of the individuals who subsequently become suicidal. The Convergent Functional Information for Suicidality (CFI-S) 22-item checklist of risk factors, which does not ask directly about suicidal ideation, has demonstrated good predictive ability for suicidality in previous studies in psychiatrict patients but has not been tested in the real-world setting of EDs. METHODS: We administered CFI-S prospectively to a convenience sample of consecutive ED patients. Patients were also asked at triage about suicidal thoughts or intentions per standard ED suicide clinical screening (SCS), and the treating ED physician was asked to fill a physician gestalt visual analog scale (VAS) for likelihood of future suicidality spectrum events (SSE; ideation, preparatory acts, attempts, completed suicide). We performed structured chart review and telephone follow-up at 6 months post-index visit. RESULTS: The median time to complete the CFI-S was 3 minutes (first to third quartile = 3-6 minutes). Of the 338 patients enrolled, 45 (13.3%) were positive on the initial SCS, and 32 (9.5%) experienced a SSE in the 6 months of follow-up. Overall, SCS had modest diagnostic accuracy sensitivity 14/32 = 44%, (95% CI: 26-62%) and specificity 275/306 = 90%, (86-93%). The physician VAS also had moderate overall diagnostic accuracy (AUC 0.75, confidence interval [CI] = 0.66-0.85), and the CFI-S was best (AUC = 0.81, CI = 0.76-0.87). The top CFI-S differentiating items were psychiatric illness, perceived uselessness, and social isolation. CONCLUSIONS: Using CFI-S, or some of its items, in busy EDs may help improve the detection of patients at high risk for future suicidality.

Suppression of transcriptional drift extends C. elegans lifespan by postponing the onset of mortality.

Longevity mechanisms increase lifespan by counteracting the effects of aging. However, whether longevity mechanisms counteract the effects of aging continually throughout life, or whether they act during specific periods of life, preventing changes that precede mortality is unclear. Here, we uncover transcriptional drift, a phenomenon that describes how aging causes genes within functional groups to change expression in opposing directions. These changes cause a transcriptome-wide loss in mRNA stoichiometry and loss of co-expression patterns in aging animals, as compared to young adults. Using Caenorhabditis elegans as a model, we show that extending lifespan by inhibiting serotonergic signals by the antidepressant mianserin attenuates transcriptional drift, allowing the preservation of a younger transcriptome into an older age. Our data are consistent with a model in which inhibition of serotonergic signals slows age-dependent physiological decline and the associated rise in mortality levels exclusively in young adults, thereby postponing the onset of major mortality.

Atypical antidepressants extend lifespan of Caenorhabditis elegans by activation of a non-cell-autonomous stress response.

Oxidative stress has long been associated with aging and has recently been linked to psychiatric disorders, including psychosis and depression. We identified multiple antipsychotics and antidepressants that extend Caenorhabditis elegans lifespan and protect the animal from oxidative stress. Here, we report that atypical antidepressants activate a neuronal mechanism that regulates the response to oxidative stress throughout the animal. While the activation of the oxidative stress response by atypical antidepressants depends on synaptic transmission, the activation by reactive oxygen species does not. Lifespan extension by atypical antidepressants depends on the neuronal oxidative stress response activation mechanism. Neuronal regulation of the oxidative stress response is likely to have evolved as a survival mechanism to protect the organism from oxidative stress, upon detection of adverse or dangerous conditions by the nervous system.

Characteristics of Bipolar I patients grouped by externalizing disorders.

BACKGROUND: Bipolar disorder co-occurs with a number of disorders with externalizing features. The aim of this study is to determine whether Bipolar I (BPI) subjects with comorbid externalizing disorders and a subgroup with externalizing symptoms prior to age 15 have different clinical features than those without externalizing disorders and whether these could be attributed to specific genetic variations. METHODS: A large cohort (N=2505) of Bipolar I subjects was analyzed. Course of illness parameters were compared between an Externalizing Group, an Early-Onset Subgroup and a Non-Externalizing Group in the Discovery sample (N=1268). Findings were validated using an independent set of 1237 BPI subjects (Validation sample). Genetic analyses were carried out. RESULTS: Subjects in the Externalizing Group (and Early-Onset Subgroup) tended to have a more severe clinical course, even in areas specifically related to mood disorder such as cycling frequency and rapid mood switching. Regression analysis showed that the differences are not completely explainable by substance use. Genetic analyses identified nominally associated SNPs; calcium channel genes were not enriched in the gene variants identified. LIMITATIONS: Validation in independent samples is needed to confirm the genetic findings in the present study. CONCLUSIONS: Our findings support the presence of an externalizing disorder subphenotype within BPI with greater severity of mood disorder and possible specific genetic features.

Comprehensive gene- and pathway-based analysis of depressive symptoms in older adults.

Depressive symptoms are common in older adults and are particularly prevalent in those with or at elevated risk for dementia. Although the heritability of depression is estimated to be substantial, single nucleotide polymorphism-based genome-wide association studies of depressive symptoms have had limited success. In this study, we performed genome-wide gene- and pathway-based analyses of depressive symptom burden. Study participants included non-Hispanic Caucasian subjects (n = 6,884) from three independent cohorts, the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Health and Retirement Study (HRS), and the Indiana Memory and Aging Study (IMAS). Gene-based meta-analysis identified genome-wide significant associations (ANGPT4 and FAM110A, q-value = 0.026; GRM7-AS3 and LRFN5, q-value = 0.042). Pathway analysis revealed enrichment of association in 105 pathways, including multiple pathways related to ERK/MAPK signaling, GSK3 signaling in bipolar disorder, cell development, and immune activation and inflammation. GRM7, ANGPT4, and LRFN5 have been previously implicated in psychiatric disorders, including the GRM7 region displaying association with major depressive disorder. The ERK/MAPK signaling pathway is a known target of antidepressant drugs and has important roles in neuronal plasticity, and GSK3 signaling has been previously implicated in Alzheimer's disease and as a promising therapeutic target for depression. Our results warrant further investigation in independent and larger cohorts and add to the growing understanding of the genetics and pathobiology of depressive symptoms in aging and neurodegenerative disorders. In particular, the genes and pathways demonstrating association with depressive symptoms may be potential therapeutic targets for these symptoms in older adults.

Schizophrenia: from genetics to biology to predictive medicine.

Identifying genes for psychiatric disorders using traditional genetic approaches has thus far proven quite difficult. Reasons for this include the complexity of these disorders and the poor definition of the clinical phenotype. However, recent studies have demonstrated the power of an approach called convergent functional genomics (CFG). CFG is a methodology that integrates different types of data to increase the ability to identify genes involved in various psychiatric and nonpsychiatric disorders. The work exemplified in this article integrated human brain and blood gene expression data, relevant animal model brain and blood gene expression data, and human genetic data to identify candidate genes and blood biomarkers for schizophrenia.

Convergent functional genomics of psychiatric disorders.

Genetic and gene expression studies, in humans and animal models of psychiatric and other medical disorders, are becoming increasingly integrated. Particularly for genomics, the convergence and integration of data across species, experimental modalities and technical platforms is providing a fit-to-disease way of extracting reproducible and biologically important signal, in contrast to the fit-to-cohort effect and limited reproducibility of human genetic analyses alone. With the advent of whole-genome sequencing and the realization that a major portion of the non-coding genome may contain regulatory variants, Convergent Functional Genomics (CFG) approaches are going to be essential to identify disease-relevant signal from the tremendous polymorphic variation present in the general population. Such work in psychiatry can provide an example of how to address other genetically complex disorders, and in turn will benefit by incorporating concepts from other areas, such as cancer, cardiovascular diseases, and diabetes.

Convergent integration of animal model and human studies of bipolar disorder (manic-depressive illness).

Animal models and human studies of bipolar disorder and other psychiatric disorders are becoming increasingly integrated, prompted by recent successes. Particularly for genomics, the convergence and integration of data across species, experimental modalities and technical platforms is providing a fit-to-disease way of extracting reproducible and biologically important signal, in sharp contrast to the fit-to-cohort effect, disappointing findings to date, and limited reproducibility of human genetic analyses alone. Such work in psychiatry can provide an example of how to address other genetically complex disorders, and in turn will benefit by incorporating concepts from other areas, such as cancer biology and diabetes.

Handwriting movement kinematics for quantifying extrapyramidal side effects in patients treated with atypical antipsychotics.

Ongoing monitoring of neuroleptic-induced extrapyramidal side effects (EPS) is important to maximize treatment outcome, improve medication adherence and reduce re-hospitalization. Traditional approaches for assessing EPS such as Parkinsonism, tardive akathisia, or dyskinesia rely upon clinical ratings. However, these observer-based EPS severity ratings can be unreliable and are subject to examiner bias. In contrast, quantitative instrumental methods are less subject to bias. Most instrumental methods have only limited clinical utility because of their complexity and costs. This paper describes an easy-to-use instrumental approach based on handwriting movements for quantifying EPS. Here, we present findings from psychiatric patients treated with atypical (second generation) antipsychotics. The handwriting task consisted of a sentence written several times within a 2 cm vertical boundary at a comfortable speed using an inkless pen and digitizing tablet. Kinematic variables including movement duration, peak vertical velocity and the number of acceleration peaks, and average normalized jerk (a measure of smoothness) for each up or down stroke and their submovements were analyzed. Results from 59 psychosis patients and 46 healthy comparison subjects revealed significant slowing and dysfluency in patients compared to controls. We observed differences across medications and daily dose. These findings support the ecological validity of handwriting movement analysis as an objective behavioral biomarker for quantifying the effects of antipsychotic medication and dose on the motor system.

The P-value illusion: how to improve (psychiatric) genetic studies.

There is an emerging appreciation that genome-wide association studies (GWAS) have failed to live up to expectations and deliver major advances to date. A "surge" strategy, of pooling resources and increasing number of subjects tested, is underway. We argue that, while useful, it will not be enough by itself. Complementary approaches are needed to mine these large datasets. We describe a series of problems, opportunities, and offer a potential comprehensive solution.

Mindscape: a convergent perspective on life, mind, consciousness and happiness.

What are mind, consciousness and happiness, in the fundamental context of life? We propose a convergent perspective (coupling evolutionary biology, genomics, neurobiology and clinical medicine) that could help us better understand what life, mind, consciousness and happiness are, as well as provides empirically testable practical implications.

Evidence for genetic association of RORB with bipolar disorder.

BACKGROUND: Bipolar disorder, particularly in children, is characterized by rapid cycling and switching, making circadian clock genes plausible molecular underpinnings for bipolar disorder. We previously reported work establishing mice lacking the clock gene D-box binding protein (DBP) as a stress-reactive genetic animal model of bipolar disorder. Microarray studies revealed that expression of two closely related clock genes, RAR-related orphan receptors alpha (RORA) and beta (RORB), was altered in these mice. These retinoid-related receptors are involved in a number of pathways including neurogenesis, stress response, and modulation of circadian rhythms. Here we report association studies between bipolar disorder and single-nucleotide polymorphisms (SNPs) in RORA and RORB. METHODS: We genotyped 355 RORA and RORB SNPs in a pediatric cohort consisting of a family-based sample of 153 trios and an independent, non-overlapping case-control sample of 152 cases and 140 controls. Bipolar disorder in children and adolescents is characterized by increased stress reactivity and frequent episodes of shorter duration; thus our cohort provides a potentially enriched sample for identifying genes involved in cycling and switching. RESULTS: We report that four intronic RORB SNPs showed positive associations with the pediatric bipolar phenotype that survived Bonferroni correction for multiple comparisons in the case-control sample. Three RORB haplotype blocks implicating an additional 11 SNPs were also associated with the disease in the case-control sample. However, these significant associations were not replicated in the sample of trios. There was no evidence for association between pediatric bipolar disorder and any RORA SNPs or haplotype blocks after multiple-test correction. In addition, we found no strong evidence for association between the age-at-onset of bipolar disorder with any RORA or RORB SNPs. CONCLUSION: Our findings suggest that clock genes in general and RORB in particular may be important candidates for further investigation in the search for the molecular basis of bipolar disorder.

Handwriting movement analyses for monitoring drug-induced motor side effects in schizophrenia patients treated with risperidone.

Epidemiologic studies indicate that nearly 60% of schizophrenia (SZ) patients treated with conventional antipsychotic drugs develop extrapyramidal side effects (EPS) such as parkinsonism and tardive dyskinesia. Although the prevalence of EPS has decreased due to the newer antipsychotics, EPS continue to limit the effectiveness of these medicines. Ongoing monitoring of EPS is likely to improve treatment outcome or compliance and reduce the frequency of re-hospitalization. A quantitative analysis of handwriting kinematics was used to evaluate effects of antipsychotic medication type and dose in schizophrenia patients. Twenty-seven schizophrenia patients treated with risperidone, six schizophrenia patients who received no antipsychotic medication and 47 healthy comparison participants were enrolled. Participants performed a 20-min handwriting task consisting of loops of various sizes and a sentence. Data were captured and analyzed using MovAlyzeR software. Results indicated that risperidone-treated participants exhibited significantly more dysfluent handwriting movements than either healthy or untreated SZ participants. Risperidone-treated participants exhibited lower movement velocities during production of simple loops compared to unmedicated patients. Handwriting dysfluency during sentence writing increased with dose. A 3-factor model consisting of kinematic variables derived from sentence writing accounted for 83% (r=.91) of the variability in medication dose. In contrast, we found no association between observer-based EPS severity ratings and medication dose. These findings support the importance of handwriting-based measures to monitor EPS in medicated schizophrenia patients.

Evidence of association between brain-derived neurotrophic factor gene and bipolar disorder.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) plays an important role in the survival, differentiation, and outgrowth of select peripheral and central neurons throughout adulthood. Growing evidence suggests that BDNF is involved in the pathophysiology of mood disorders. METHODS: Ten single nucleotide polymorphisms (SNPs) across the BDNF gene were genotyped in a sample of 1749 Caucasian Americans from 250 multiplex bipolar families. Family-based association analysis was used with three hierarchical bipolar disorder models to test for an association between SNPs in BDNF and the risk of bipolar disorder. In addition, an exploratory analysis was performed to test for an association of the SNPs in BDNF and the phenotypes of rapid cycling and episode frequency. RESULTS: Evidence of association (P<0.05) was found with several of the SNPs using multiple models of bipolar disorder; one of these SNPs also showed evidence of association (P<0.05) with rapid cycling. CONCLUSION: These results provide further evidence that variation in BDNF affects the risk for bipolar disorder.

Polypharmacy in oligopopulations: what psychiatric genetics can teach biological psychiatry.

Psychiatric genetics and genomics have made major strides in recent years. Some of that knowledge has yet to permeate in the clinical practice of biological psychiatry. The example of cancer-genetics, biology and clinical treatments may be profitable in terms of accelerating translational integration in psychiatry. We propose that current developments in genetics and genomics point to an Early Low-Dose Rational Polypharmacy in Oligopopulations model for psychiatric pharmacotherapy.