An exploratory metabolomic comparison of participants with fast or absent functional progression from 2CARE, a randomized, double-blind clinical trial in Huntington's disease.

Huntington's disease (HD) is increasingly recognized for diverse pathology outside of the nervous system. To describe the biology of HD in relation to functional progression, we previously analyzed the plasma and CSF metabolome in a cross-sectional study of participants who had various degrees of functional impairment. Here, we carried out an exploratory study in plasma from HD individuals over a 3-year time frame to assess whether differences exist between those with fast or absent clinical progression. There were more differences in circulating metabolite levels for fast progressors compared to absent progressors (111 vs 20, nominal p < 0.05). All metabolite changes in faster progressors were decreases, whereas some metabolite concentrations increased in absent progressors. Many of the metabolite levels that decreased in the fast progressors were higher at Screening compared to absent progressors but ended up lower by Year 3. Changes in faster progression suggest greater oxidative stress and inflammation (kynurenine, diacylglycerides, cysteine), disturbances in nitric oxide and urea metabolism (arginine, citrulline, ornithine, GABR), lower polyamines (putrescine and spermine), elevated glucose, and deficient AMPK signaling. Metabolomic differences between fast and absent progressors suggest the possibility of predicting functional decline in HD, and possibly delaying it with interventions to augment arginine, polyamines, and glucose regulation.

Postmortem toxicology findings from the Camden Opioid Research Initiative.

The United States continues to be impacted by decades of an opioid misuse epidemic, worsened by the COVID-19 pandemic and by the growing prevalence of highly potent synthetic opioids (HPSO) such as fentanyl. In instances of a toxicity event, first-response administration of reversal medications such as naloxone can be insufficient to fully counteract the effects of HPSO, particularly when there is co-occurring substance use. In an effort to characterize and study this multi-faceted problem, the Camden Opioid Research Initiative (CORI) has been formed. The CORI study has collected and analyzed post-mortem toxicology data from 42 cases of decedents who expired from opioid-related toxicity in the South New Jersey region to characterize substance use profiles. Co-occurring substance use, whether by intent or through possible contamination of the illicit opioid supply, is pervasive among deaths due to opioid toxicity, and evidence of medication-assisted treatment is scarce. Nearly all (98%) of the toxicology cases show the presence of the HPSO, fentanyl, and very few (7%) results detected evidence of medication-assisted treatment for opioid use disorder, such as buprenorphine or methadone, at the time of death. The opioid toxicity reversal drug, naloxone, was detected in 19% of cases, but 100% of cases expressed one or more stimulants, and sedatives including xylazine were detected in 48% of cases. These results showing complex substance use profiles indicate that efforts at mitigating the opioid misuse epidemic must address the complications presented by co-occurring stimulant and other substance use, and reduce barriers to and stigmas of seeking effective medication-assisted treatments.

Single Nucleus Transcriptome Data from Alzheimer's Disease Mouse Models Yield New Insight into Pathophysiology.

BACKGROUND: 5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer's disease (AD)-related pathology. OBJECTIVE: To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice. METHODS: Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA). RESULTS: We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr, Fth1, Pcsk1n, Malat1, Rpl37, Rtn1, Sepw1, Uba52, Mbp, Arl6ip5, Gm26917, Vwa1, and Pgrmc1. We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp, Rbm4b, Pnisr, Opcml, Cpne7, Adgrb1, Gabarapl2, Ubb, Ndfip1, Car11, and Stmn4. IPA identified three statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including 'FXR/RXR Activation', 'LXR/RXR Activation', and 'Acute Phase Response Signaling'. CONCLUSION: DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings.

Single nucleus transcriptomic analysis of rat nucleus accumbens reveals cell type-specific patterns of gene expression associated with volitional morphine intake.

Opioid exposure is known to cause transcriptomic changes in the nucleus accumbens (NAc). However, no studies to date have investigated cell type-specific transcriptomic changes associated with volitional opioid taking. Here, we use single nucleus RNA sequencing (snRNAseq) to comprehensively characterize cell type-specific alterations of the NAc transcriptome in rats self-administering morphine. One cohort of male Brown Norway rats was injected with acute morphine (10 mg/kg, i.p.) or saline. A second cohort of rats was allowed to self-administer intravenous morphine (1.0 mg/kg/infusion) for 10 consecutive days. Each morphine-experienced rat was paired with a yoked saline control rat. snRNAseq libraries were generated from NAc punches and used to identify cell type-specific gene expression changes associated with volitional morphine taking. We identified 1106 differentially expressed genes (DEGs) in the acute morphine group, compared to 2453 DEGs in the morphine self-administration group, across 27 distinct cell clusters. Importantly, we identified 1329 DEGs that were specific to morphine self-administration. DEGs were identified in novel clusters of astrocytes, oligodendrocytes, and D1R- and D2R-expressing medium spiny neurons in the NAc. Cell type-specific DEGs included Rgs9, Celf5, Oprm1, and Pde10a. Upregulation of Rgs9 and Celf5 in D2R-expressing neurons was validated by RNAscope. Approximately 85% of all oligodendrocyte DEGs, nearly all of which were associated with morphine taking, were identified in two subtypes. Bioinformatic analyses identified cell type-specific upstream regulatory mechanisms of the observed transcriptome alterations and downstream signaling pathways, including both novel and previously identified molecular pathways. These findings show that volitional morphine taking is associated with distinct cell type-specific transcriptomic changes in the rat NAc and highlight specific striatal cell populations and novel molecular substrates that could be targeted to reduce compulsive opioid taking.

Decoding brain memory formation by single-cell RNA sequencing.

To understand how distinct memories are formed and stored in the brain is an important and fundamental question in neuroscience and computational biology. A population of neurons, termed engram cells, represents the physiological manifestation of a specific memory trace and is characterized by dynamic changes in gene expression, which in turn alters the synaptic connectivity and excitability of these cells. Recent applications of single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) are promising approaches for delineating the dynamic expression profiles in these subsets of neurons, and thus understanding memory-specific genes, their combinatorial patterns and regulatory networks. The aim of this article is to review and discuss the experimental and computational procedures of sc/snRNA-seq, new studies of molecular mechanisms of memory aided by sc/snRNA-seq in human brain diseases and related mouse models, and computational challenges in understanding the regulatory mechanisms underlying long-term memory formation.

Patient Perceptions and Potential Utility of Pharmacogenetic Testing in Chronic Pain Management and Opioid Use Disorder in the Camden Opioid Research Initiative.

Pharmacogenetics (PGx) has the potential to improve opioid medication management. Here, we present patient perception data, pharmacogenetic data and medication management trends in patients with chronic pain (arm 1) and opioid use disorder (arm 2) treated at Cooper University Health Care in Camden City, NJ. Our results demonstrate that the majority of patients in both arms of the study (55% and 65%, respectively) are open to pharmacogenetic testing, and most (66% and 69%, respectively) believe that genetic testing has the potential to improve their medical care. Our results further support the potential for CYP2D6 PGx testing to inform chronic pain medication management for poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Future efforts to implement PGx testing in chronic pain management, however, must address patient concerns about genetic test result access and genetic discrimination.

Genetics and prescription opioid use (GaPO): study design for consenting a cohort from an existing biobank to identify clinical and genetic factors influencing prescription opioid use and abuse.

BACKGROUND: Prescription opioids (POs) are commonly used to treat moderate to severe chronic pain in the health system setting. Although they improve quality of life for many patients, more work is needed to identify both the clinical and genetic factors that put certain individuals at high risk for developing opioid use disorder (OUD) following use of POs for pain relief. With a greater understanding of important risk factors, physicians will be better able to identify patients at highest risk for developing OUD for whom non-opioid alternative therapies and treatments should be considered. METHODS: We are conducting a prospective observational study that aims to identify the clinical and genetic factors most stongly associated with OUD. The study design leverages an existing biobank that includes whole exome sequencing and array genotyping. The biobank is maintained within an integrated health system, allowing for the large-scale capture and integration of genetic and non-genetic data. Participants are enrolled into the health system biobank via informed consent and then into a second study that focuses on opioid medication use. Data capture includes validated self-report surveys measuring addiction severity, depression, anxiety, and nicotine use, as well as additional clinical, prescription, and brain imaging data extracted from electronic health records. DISCUSSION: We will harness this multimodal data capture to establish meaningful patient phenotypes in order to understand the genetic and non-genetic contributions to OUD.

Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy.

We performed a genome-wide association study (GWAS) to identify genetic variation associated with common forms of idiopathic generalized epilepsy (GE) and focal epilepsy (FE). Using a cohort of 2220 patients and 14,448 controls, we searched for single nucleotide polymorphisms (SNPs) associated with GE, FE and both forms combined. We did not find any SNPs that reached genome-wide statistical significance (p ≤ 5 × 10-8) when comparing all cases to all controls, and few SNPs of interest comparing FE cases to controls. However, we document multiple linked SNPs in the PADI6-PADI4 genes that reach genome-wide significance and are associated with disease when comparing GE cases alone to controls. PADI genes encode enzymes that deiminate arginine to citrulline in molecular pathways related to epigenetic regulation of histones and autoantibody formation. Although epilepsy genetics and treatment are focused strongly on ion channel and neurotransmitter mechanisms, these results suggest that epigenetic control of gene expression and the formation of autoantibodies may also play roles in epileptogenesis.

Effectiveness of a Team-Based Learning exercise in the learning outcomes of a medical pharmacology course: insight from struggling students.

We have previously reported that multiple Team-Based Learning (TBL™) exercises in a 4-week pre-clinical medical school course improved final exam performance and significantly reduced the number of course failures. Here, we conducted a long-term study, with eight cohorts of first-year medical students, to determine whether the implementation of a single TBL individual readiness assessment test (iRAT) exercise in a 4-week medical school pharmacology course produces similar effects in overall course performance. We implemented a single TBL iRAT exercise that covered the subjects addressed during one week of the medical pharmacology course, with the four most recent cohorts of students matriculating at Cooper Medical School of Rowan University (n = 403). The first four cohorts matriculating at CMSRU did not participate in the TBL exercises (n = 266). Correlation of individual student TBL iRAT and final examination scores in the medical pharmacology course was compared to a second, unrelated first-year course (physiology) to control for variation in student performance between cohorts. We found that there was a significant moderate correlation between final examination and TBL iRAT scores (r = 0.49, p < 0.01, n = 403). Interestingly this moderate correlation was seen in students performing in the lower 25th percentile on the course final examination (r = 0.41, p < 0.01, n = 101) and negligible in students performing in the upper 25th percentile (r = 0.11, n = 101, p > 0.05). Implementation of the single TBL exercise also significantly reduced variance or range of student final examination performance compared to the group of the first four cohorts. These results suggest that implementation of a single TBL exercise, which covers only one week of content delivered in a 1-month medical pharmacology course, benefits first-year medical students by reducing the disparity in knowledge acquisition among them and providing a means to identify students who may struggle with course content.

Consensus clustering of single-cell RNA-seq data by enhancing network affinity.

Elucidation of cell subpopulations at high resolution is a key and challenging goal of single-cell ribonucleic acid (RNA) sequencing (scRNA-seq) data analysis. Although unsupervised clustering methods have been proposed for de novo identification of cell populations, their performance and robustness suffer from the high variability, low capture efficiency and high dropout rates which are characteristic of scRNA-seq experiments. Here, we present a novel unsupervised method for Single-cell Clustering by Enhancing Network Affinity (SCENA), which mainly employed three strategies: selecting multiple gene sets, enhancing local affinity among cells and clustering of consensus matrices. Large-scale validations on 13 real scRNA-seq datasets show that SCENA has high accuracy in detecting cell populations and is robust against dropout noise. When we applied SCENA to large-scale scRNA-seq data of mouse brain cells, known cell types were successfully detected, and novel cell types of interneurons were identified with differential expression of gamma-aminobutyric acid receptor subunits and transporters. SCENA is equipped with CPU + GPU (Central Processing Units + Graphics Processing Units) heterogeneous parallel computing to achieve high running speed. The high performance and running speed of SCENA combine into a new and efficient platform for biological discoveries in clustering analysis of large and diverse scRNA-seq datasets.

Investigation of long interspersed element-1 retrotransposons as potential risk factors for idiopathic temporal lobe epilepsy.

OBJECTIVE: To determine if long interspersed element-1 (L1) retrotransposons convey risk for idiopathic temporal lobe epilepsy (TLE). METHODS: Surgically resected temporal cortex from individuals with TLE (N = 33) and postmortem temporal cortex from individuals with no known neurological disease (N = 33) were analyzed for L1 content by Restriction Enzyme Based Enriched L1Hs sequencing (REBELseq). Expression of three KCNIP4 splice variants was assessed by droplet digital PCR (ddPCR). Protein ANalysis THrough Evolutionary Relationships (PANTHER) was used to determine ontologies and pathways for lists of genes harboring L1 insertions. RESULTS: We identified novel L1 insertions specific to individuals with TLE, and others specific to controls. Although there were no statistically significant differences between cases and controls in the numbers of known and novel L1 insertions, PANTHER analyses of intragenic L1 insertions showed statistically significant enrichments for epilepsy-relevant gene ontologies in both cases and controls. Gene ontologies "neuron projection development" and "calcium ion transmembrane transport" were among those found only in individuals with TLE. We confirmed novel L1 insertions in several genes associated with seizures/epilepsy, including a de novo somatic L1 retrotransposition in KCNIP4 that occurred after neural crest formation in one patient. However, ddPCR results suggest this de novo L1 did not alter KCNIP4 mRNA expression. SIGNIFICANCE: Given current data from this small cohort, we conclude that L1 elements, either rare heritable germline insertions or de novo somatic retrotranspositions, may contribute only minimally to overall genetic risk for idiopathic TLE. We suggest that further studies in additional patients and additional brain regions are warranted.

The Genomics of Opioid Addiction Longitudinal Study (GOALS): study design for a prospective evaluation of genetic and non-genetic factors for development of and recovery from opioid use disorder.

BACKGROUND: The opioid use disorder and overdose crisis in the United States affects public health as well as social and economic welfare. While several genetic and non-genetic risk factors for opioid use disorder have been identified, many of the genetic associations have not been independently replicated, and it is not well understood how these factors interact. This study is designed to evaluate relationships among these factors prospectively to develop future interventions to help prevent or treat opioid use disorder. METHODS: The Genomics of Opioid Addiction Longitudinal Study (GOALS) is a prospective observational study assessing the interplay of genetic and non-genetic by collecting comprehensive genetic and non-genetic information on 400 participants receiving medication for opioid use disorder. Participants will be assessed at four time points over 1 year. A saliva sample will be collected for large-scale genetic data analyses. Non-genetic assessments include validated surveys measuring addiction severity, depression, anxiety, and adverse childhood experiences, as well as treatment outcomes such as urine toxicology results, visit frequency, and number of pre and post-treatment overdoses extracted from electronic medical records. DISCUSSION: We will use these complex data to investigate the relative contributions of genetic and non-genetic risk factors to opioid use disorder and related treatment outcomes.

Cross-sectional analysis of plasma and CSF metabolomic markers in Huntington's disease for participants of varying functional disability: a pilot study.

Huntington's Disease (HD) is a progressive, fatal neurodegenerative condition. While generally considered for its devastating neurological phenotype, disturbances in other organ systems and metabolic pathways outside the brain have attracted attention for possible relevance to HD pathology, potential as therapeutic targets, or use as biomarkers of progression. In addition, it is not established how metabolic changes in the HD brain correlate to progression across the full spectrum of early to late-stage disease. In this pilot study, we sought to explore the metabolic profile across manifest HD from early to advanced clinical staging through metabolomic analysis by mass spectrometry in plasma and cerebrospinal fluid (CSF). With disease progression, we observed nominally significant increases in plasma arginine, citrulline, and glycine, with decreases in total and D-serine, cholesterol esters, diacylglycerides, triacylglycerides, phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins. In CSF, worsening disease was associated with nominally significant increases in NAD+, arginine, saturated long chain free fatty acids, diacylglycerides, triacylglycerides, and sphingomyelins. Notably, diacylglycerides and triacylglyceride species associated with clinical progression were different between plasma and CSF, suggesting different metabolic preferences for these compartments. Increasing NAD+ levels strongly correlating with disease progression was an unexpected finding. Our data suggest that defects in the urea cycle, glycine, and serine metabolism may be underrecognized in the progression HD pathology, and merit further study for possible therapeutic relevance.

Assessment of Probable Opioid Use Disorder Using Electronic Health Record Documentation.

Importance: Electronic health records are a potentially valuable source of information for identifying patients with opioid use disorder (OUD). Objective: To evaluate whether proxy measures from electronic health record data can be used reliably to identify patients with probable OUD based on Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) criteria. Design, Setting, and Participants: This retrospective cross-sectional study analyzed individuals within the Geisinger health system who were prescribed opioids between December 31, 2000, and May 31, 2017, using a mixed-methods approach. The cohort was identified from 16 253 patients enrolled in a contract-based, Geisinger-specific medication monitoring program (GMMP) for opioid use, including patients who maintained or violated contract terms, as well as a demographically matched control group of 16 253 patients who were prescribed opioids but not enrolled in the GMMP. Substance use diagnoses and psychiatric comorbidities were assessed using automated electronic health record summaries. A manual medical record review procedure using DSM-5 criteria for OUD was completed for a subset of patients. The analysis was conducted beginning from June 5, 2017, until May 29, 2020. Main Outcomes and Measures: The primary outcome was the prevalence of OUD as defined by proxy measures for DSM-5 criteria for OUD as well as the prevalence of comorbidities among patients prescribed opioids within an integrated health system. Results: Among the 16 253 patients enrolled in the GMMP (9309 women [57%]; mean [SD] age, 52 [14] years), OUD diagnoses as defined by diagnostic codes were present at a much lower rate than expected (291 [2%]), indicating the necessity for alternative diagnostic strategies. The DSM-5 criteria for OUD can be assessed using manual medical record review; a manual review of 200 patients in the GMMP and 200 control patients identifed a larger percentage of patients with probable moderate to severe OUD (GMMP, 145 of 200 [73%]; and control, 27 of 200 [14%]) compared with the prevalence of OUD assessed using diagnostic codes. Conclusions and Relevance: These results suggest that patients with OUD may be identified using information available in the electronic health record, even when diagnostic codes do not reflect this diagnosis. Furthermore, the study demonstrates the utility of coding for DSM-5 criteria from medical records to generate a quantitative DSM-5 score that is associated with OUD severity.

Epidemiological study of Trichosporon asahii infections over the past 23 years.

Trichosporon is a yeast-like basidiomycete, a conditional pathogenic fungus that is rare in the clinic but often causes fatal infections in immunocompromised individuals. Trichosporon asahii is the most common pathogenic fungus in this genus and the occurrence of infections has dramatically increased in recent years. Here, we report a systematic literature review detailing 140 cases of T. asahii infection reported during the past 23 years. Statistical analysis shows that T. asahii infections were most frequently reported within immunodeficient or immunocompromised patients commonly with blood diseases. Antibiotic use, invasive medical equipment and chemotherapy were the leading risk factors for acquiring infection. In vitro susceptibility, clinical information and prognosis analysis showed that voriconazole is the primary drug of choice in the treatment of T. asahii infection. Combination treatment with voriconazole and amphotericin B did not show superiority over either drug alone. Finally, we found that the types of infections prevalent in China are significantly different from those in other countries. These results provide detailed information and relevant clinical treatment strategies for the diagnosis and treatment of T. asahii infection.

The Molecular Genetic Interaction Between Circadian Rhythms and Susceptibility to Seizures and Epilepsy.

Seizure patterns observed in patients with epilepsy suggest that circadian rhythms and sleep/wake mechanisms play some role in the disease. This review addresses key topics in the relationship between circadian rhythms and seizures in epilepsy. We present basic information on circadian biology, but focus on research studying the influence of both the time of day and the sleep/wake cycle as independent but related factors on the expression of seizures in epilepsy. We review studies investigating how seizures and epilepsy disrupt expression of core clock genes, and how disruption of clock mechanisms impacts seizures and the development of epilepsy. We focus on the overlap between mechanisms of circadian-associated changes in SCN neuronal excitability and mechanisms of epileptogenesis as a means of identifying key pathways and molecules that could represent new targets or strategies for epilepsy therapy. Finally, we review the concept of chronotherapy and provide a perspective regarding its application to patients with epilepsy based on their individual characteristics (i.e., being a "morning person" or a "night owl"). We conclude that better understanding of the relationship between circadian rhythms, neuronal excitability, and seizures will allow both the identification of new therapeutic targets for treating epilepsy as well as more effective treatment regimens using currently available pharmacological and non-pharmacological strategies.

Cognitive and behavioral effects of brief seizures in mice.

Comorbidities associated with epilepsy greatly reduce patients' quality of life. Since antiepilepsy drugs show limited success in ameliorating cognitive and behavioral symptoms, there is a need to better understand the mechanisms underlying epilepsy-related cognitive and behavioral impairments. Most prior research addressing this problem has focused on chronic epilepsy, wherein many factors can simultaneously impact cognition and behavior. The purpose of the present study was to develop a testing paradigm using mice that can provide new insight into how short-term biological changes underlying acute seizures impact cognition and behavior. In Experiment 1, naïve C57BL/6J mice were subjected to either three brief, generalized electroconvulsive seizure (ECS) or three sham treatments equally spaced over the course of 30 min. Over the next 2 h, mice were tested in a novel object recognition paradigm. Follow-up studies examined locomotor activity immediately before and after (Experiment 2), immediately after (Experiment 3), and 45 min after (Experiment 4) a set of three ECS or sham treatments. Whereas results demonstrated that there was no statistically significant difference in recognition memory acquisition between ECS and sham-treated mice, measures of anxiety-like behavior were increased and novel object interest was decreased in ECS-treated mice compared with that in sham. Interestingly, ECS also produced a delayed inhibitory effect on locomotion, decreasing open-field activity 45-min posttreatment compared to sham. We conclude that a small cluster of brief seizures can have acute, behaviorally relevant effects in mice, and that greater emphasis should be placed on events that take place before chronic epilepsy is established in order to better understand epilepsy-related cognitive and behavioral impairments. Future research would benefit from using the paradigms defined above to study the effects of individual seizures on mouse cognition and behavior.

Deletion of the vesicular monoamine transporter 1 (vmat1/slc18a1) gene affects dopamine signaling.

The vesicular monoamine transporter is involved in presynaptic catecholamine storage and neurotransmission. Two isoforms of the transporter exist, VMAT1 and VMAT2, and both are expressed in the brain, though VMAT2 expression is more robust and has been more widely studied. In this study we investigated the role of VMAT1 KO on markers of dopaminergic function and neurotransmission, and dopamine-related behaviors. Null-mutant VMAT1 mice were studied behaviorally using the tail suspension test, elevated zero maze and locomotor activity assessments. Tissue monoamines were measured both ex vivo and by using in vivo microdialysis. Protein expression of tyrosine hydroxylase and D2 dopamine receptors was measured using western blot analysis. Results show that VMAT1 KO mice have decreased dopamine levels in the frontal cortex, increased postsynaptic D2 expression, and lower frontal cortex tyrosine hydroxylase expression compared to WT mice. VMAT1 KO mice also show an exaggerated behavioral locomotor response to acute amphetamine treatment. We conclude that dopaminergic signaling is robustly altered in the frontal cortex of VMAT1 null-mutant mice and suggest that VMAT1 may be relevant to the pathogenesis and/or treatment of psychiatric illnesses including schizophrenia and bipolar disease.