Law Office of Michael W. Patrick West Franklin St. Box Chapel Hill, NC Orange, VA Suite 20 Batavia, NY Lee J. Hollis West 95th St. Prairie Village, KS Suite Portland, ME Levy, Angstreich, Finney Walnut St. Eric Roberson Esq. Longview, TX Hollis Law Firm W. Suite Kansas City, MO University Dr. Ste Rochester, MI Suite Philadelphia, PA Big Beaver Rd. Suite Troy, MI Dowdy and Cockerham P. Box 30 Magnolia, MS Schroeter and Goldmark 3rd Ave.
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Represented by. Casey D. Charles M. Price Fax: Joseph M. Stephen G. D'Souza Fax: Tanya S. Doe California Pharmaceutical Companies. Doe Pharmacies. Minal Mehta. Jennifer A. John Does. Kristine K. McKesson Corporation,. Wendi J. Merck and Co Inc. Eric J. Steven J. Thomas J. Anna S. Daniel K. Michael S. Dan H. Melissa A. Randy J. Richard P. Sonja S. Natasha D.
Richard L. Kellner Kabateck and Brown S. Organon Biosciences NV. Organon, Inc. Bryant T. Jonathan B. Organon International, Inc. Amelia T. Barbara R. Christopher W. Deirdre C. Fred M. Hal M. James H. Matthew P. Raymond E. Robert K. Woo , Jr. Terri L. Tracy G. Kathryn R. Rebecca A. Organon USA, Inc. David B. Schering-Plough Corporation.
Nuvaring Products Liability Litigation. Timothy Redmon. Benjamin W. Richard W. Bethany Brittan Terminated June 13, Christopher Donnelly Terminated June 13, Christopher Wirth Terminated June 13, Edward Breivik. Holly Bruce Terminated June 13, James Holmes Terminated June 13, James Holmes James Holmes S. Jimmy James Thule Terminated June 13, John Lindh Terminated June 13, Jonathan Rich Terminated June 13, Karen Wilson Terminated June 13, Mary Sihoff Terminated June 13, Ramzi Yusef Terminated June 13, Rebecca Sanderson Terminated June 13, Rebecca Turner Terminated June 13, Rhonda Bays.
Richard Reid Terminated June 13, Shirley Moore Terminated June 13, Terry Nichols Terminated June 13, John T. Gregory N McEwen. Gregory N. Aaron Cooper. Hunter J. Abby Puls. Lucia J. Michael K. Abigail Fiedler. Abigail Lardizabal. Eric H. Adalee Arias. Rebecca M. Adam Lee Jones. Todd S. Adelita Perez. Adriana Hernandez Rodriguez. Adriane Goetschius. John J. Adrianna Dougherty. Adrienne Morales. Aimee Axelrod.
Aimee Ellison. Aimee Lashlee. Aime Gomez. Aisling C. Lowell W. Alaina Gurdo. Alana Kramer. Alba Vargas. Albert Ernest. Aleshia Cuthbertson. Alexander Strong. Claude Wood Anderson , Jr. Alexandra Myers. Alexandria Ingley. Alexandria Jo Neiswender. David W. Alexandria McCormack. Alexis Byam. Alexis Johnson. Alfonso Reyes. Brian J. Alicia Gillman. Alicia Pryor. Alisha Little. Alisha Parra-Munoz. Alissa Lamb. Kathleen A. Allessandra Arguellez.
Allison Binder. Shezad Ahmed Malik Fax: Dr. Allison Brooks. Allison Hengemuhle. Allison Patterson. Allyson Wallace. Almeka Hamilton. Alyssa Ferrera. The family data indicate a partial overlap between mood and psychotic disorders. Rather than following the current diagnostic categories, the familial patterns are suggestive of genetic influences in relation to the clinical course episodic versus chronic and specific syndromes the risk of suicide. The risk of co-morbid anxiety and suicide behaviour is elevated especially in individuals with early onset; the age at onset appears to correlate in families.
Conclusions: Our data support the existence of subtypes of severe mental illness that do not necessarily follow the current diagnostic classification, but are familial and likely correlate with response to specific treatments. To understand the pathophysiology of severe mental illness, studies of subjects in early disease stages need to be complemented by investigations of individuals at genetic risk, but who are clinically unaffected.
Background: The onset of BD typically coincides with the structural maturation of the brain during the transition period between childhood and adulthood. The neuroanatomical changes predisposing for BD need to be differentiated from the typical brain maturation and from changes secondary to the presence of the illness.
Identifying the brain structural changes predisposing for BD could aid in early diagnosis. Isolating the neuronal sequellae of BD could yield biological outcome measures for prevention and treatment. We also recruited 99 healthy controls matched to the above mentioned cohorts by age and sex.
Conclusions: Certain neuroanatomical changes, such as increased rIFG volume, are unique to unaffected subjects at risk for BD or those early in the course of illness. These changes could help identify who among the offspring of bipolar parents is at a particularly high risk of developing psychiatric disorders.
Other brain structural or neurochemical alterations, such as decreased hippocampal volume or reduced prefrontal N-acetyl aspartate are found predominantly in subjects with established illness, but not among unaffected relatives of bipolar parents or participants early in the course of BD.
Thus, these abnormalities may reflect the neuroprogressive nature of BD, which may possibly be prevented by treatment. Indeed, Li treated subjects did not show these changes despite a substantial illness burden. Background: How can brain imaging carried out in community-based samples contribute to the goals of psychiatric genetics?
Results: In particular, I will focus on one of the challenges of this work, namely the trait-like stability of functional brain phenotypes, and will outline novel approaches for estimating within-subject predictability of the brain response and its heritability.
Conclusions: We believe that this imaging-based approach, applied in community-based samples ascertained in an unbiased manner, provides a window to potential patho-physiological pathways relevant to common brain disorders, such as depression, substance use, and dementia Paus Paus T. Population Neuroscience. Background: Converging evidence suggests that schizophrenia is a progressive neurodevelopmental disorder, with childhood onset schizophrenia COS cases resulting in more profound brain abnormalities.
Siblings of COS patients, which also tend to be younger in age, provide an invaluable resource for differentiating between trait andstate markers, thus highlighting possible endophenotypes for ongoing research. The false-discovery rate procedure was used to control for type I errors due to multiple comparisons. The cortical deficits in siblings disappeared by age 18 years and the process of deficit reduction correlated with overall functioning GAS scores at the last scan. Conclusions: Prefrontal and temporal GM loss in COS appears to be an age specific and subregionally specific endophenotype.
Amelioration of regional GM deficits in healthy siblings was associated with higher global functioning GAS scores , suggesting a relationship between brain plasticity and functional outcome; suggesting the role for resilience factors in non psychotic siblings. Ongoing functional imaging and magnetoencephalography data on the sibling cohort also show overlapping shared abnormalties between COS probands and non psychotic siblings. Background: Proinflammatory cytokines are thought to contribute, in part, to the onset of depressive symptoms, and possibly to the onset and incidence of major depressive disorder.
Meta-analytic results have found that depressive disorders are associated with increases in circulating levels of C-reactive protein CRP and interleukin IL-6 , as well as other cellular markers of inflammation. Additionally, elevated levels of systemic inflammation eg, CRP are prospectively associated with depression. Recent data also implicate sleep disturbance as an independent prospective risk factor depression. We have found that persistent sleep disturbance prospectively predicts the recurrence of depression in at risk populations such as older adults.
However, the mechanisms that link sleep disturbance and depression are not known. Given that even modest amounts of sleep loss activate cellular and genomic markers of inflammation, due in part to activation of cellular inflammatory signaling pathways eg, NF-kB especially in women and those with a history of depression, an activation of inflammatory signaling is hypothesized to be one pathway that links sleep disturbance and depression.
Here, we examined the effect of proinflammatory cytokine activation on the neural correlates of socially painful experience and associated depressed mood, and the contribution of sleep disturbance in moderating the induction of depressed mood. Methods: Participants were randomly assigned to receive either placebo or low-dose endotoxin, which induces increases in proinflammatorycytokine levels in a safe and physiologically relevant manner.
Cytokine levels were repeatedly assessed through hourly blood draws; self-reported and observer-rated depressed mood were assessed regularly as well. Two hours after drug administration, neural activity was recorded as participants completed a task in which they anticipated monetary rewards or underwent a task of social exclusion. Results: Endotoxin led to significant increases from baseline in IL-6 and TNF-a levels as well as feelings of depressed mood. Among females, but not males, exposed to endotoxin, increases in IL-6 were associated with increases in social pain-related neural activity dorsal anterior cingulate cortex, anterior insula that mediated the relationship between IL-6 increases and depressed mood increases.
Additional analyses focused on neural activity associated with anhedonia, another key symptom of depression. These results demonstrated that subjects exposed to endotoxin, compared with placebo, showed greater increases in self-reported and observer-rated depressed mood over time, as well as significant reductions in ventral striatum activity to monetary reward cues.
Moreover, the relationship between exposure to inflammatory challenge and increases in observer-rated depressed mood was mediated by between group differences in ventral striatum activity to anticipated rewards. Finally, reports of sleep disturbance prior to the administration of endotoxin was associated with greater increases in depressed mood.
Conclusions: These data are among the first experimental data to show that increases of proinflammatory cytokine activity are associated with increases in feelings of depressed mood, as well as related neural responding. Social pain-related neural activity, as welll as reward-related neural processes mediate the relationship between inflammation and and depressed mood.
The presence of sleep disturbance exaggerates increases of depressed mood in response to an inflammatory challenge. Together, these findings raise the possibility that activation of cellular and genomic markers of inflammation, which we have found in association with sleep disturbance, may have recursive, reciprocal effects on depressed mood, and contribute to the risk of depression or its recurrence in those with persistent sleep disturbance.
Background: Both animal and human studies suggest that behavioral traits related to hostility, anger, and aggressive tendencies are associated with elevations in inflammatory markers. For example, defensive rage in cats is associated with higher levels of IL-6, and mice deficient in cytokine receptors fail to exhibit aggressive and defensive behavior even when threatened Human studies suggest similar patterns in which elevations of C-Reactive Protein CRP and IL-6 are directly associated with hostility, anger, and aggressive tendency.
Despite this, no studies of aggression and inflammatory markers have been reported in psychiatric subjects or in subjects with recurrent, problematic impulsive aggressive behavior. These findings remained significant even after variables related to body mass index, state depression, psychosocial stress, and other relevant variables, were accounted for.
Conclusions: These data suggest a direct relationship between plasma inflammatory processes and aggression in human subjects. This finding adds to the complex picture of the central neuromodulatory role of aggression in human subjects. Background: Recent studies from our lab have addressed a number of related questions including 1 whether childhood adversities have lasting, detectable consequences for inflammation and cell aging late in life; 2 whether depressive symptoms influence the magnitude of stress-induced inflammatory responses; and 3 how stress-reducing interventions such as yoga impact inflammation and mood.
Results: Among the older adult sample whose average age was 70, childhood adversities were associated with both heightened IL-6 and shorter telomeres even after controlling for caregiving status; the telomere length difference between individuals reporting no adversities and those reporting multiple adversities could translate into a 7- to year difference in life span. Breast cancer survivors who were randomized to the yoga intervention had significantly lower inflammation compared to the wait-list controls; furthermore, more frequent yoga practice produced larger changes in both inflammation and mood.
Conclusions: Adverse childhood events are related to continued vulnerability among older adults, enhancing the impact of chronic stressors like dementia family caregiving on inflammation and telomere length. Inflammation triggers T-cell proliferation, one known cause of telomere shortening, and thus heightened stress- and depression-related inflammation may influence mortality through this pathway, among others. These data are important because even modest levels of depressive symptoms can heighten inflammatory responses to stressors.
Interventions that diminish stress or depression may also diminish inflammation. Chronic inflammation has been suggested as one key biological mechanism that may fuel declines in physical function leading to frailty, disability, and, ultimately, death.
The current study was designed to further explore genetic predictors and targets of response to infliximab. Results: One-hundred-forty-eight gene transcripts were significantly associated 1. Although there were no differences in infliximab responders and non-responders in body mass index or the presence of manifest metabolic disorders, transcripts predictive of infliximab response were associated with gluconeogenesis and cholesterol transport, and were enriched in a network regulated by hepatocyte nuclear factor HNF 4-alpha, a transcription factor involved in gluconeogenesis and cholesterol and lipid homeostasis.
Responders also demonstrated inhibition of genes related to apoptosis through TNF signaling at 6hr and 24hr after infusion. Transcripts down-regulated in responders 2 weeks after infliximab were related to innate immune signaling and nuclear factor-kappa B. Conclusions: Baseline transcriptional signatures reflective of alterations in glucose and lipid metabolism and potential incipient processes related to the metabolic syndrome predicted antidepressant response to infliximab, and infliximab response involved regulation of metabolic genes and inhibition of genes related to innate immune activation.
The stimulant drugs methylphenidate and amphetamine affect behavior and cognition. The primary medical use is to treat individuals with Attention Deficit Hyperactivity Disorder ADHD , but non-medical use intended for cognitive enhancement in non-ADHD individuals occurs in educational, workplace, athletic and other settings Smith and Farah, This is a very controversial topic often addressed in newspapers Schwarz, New York Times, and magazines Stix, Scientific American, for the general public.
A discussion of this controversial topic is proposed for a Study Group. James Swanson will review the trends of overall use of stimulant drugs tracked by prescription records, national supplies, and the Monitoring the Future survey, all of which have information across several decades Swanson et al , Kathleen Merikangas will present data from the National Comorbidity Survey, which indicates that most adolescents with ADHD are not recognized or treated with stimulants Merikangas et al , The National Survey of Children's Health has tracked the diagnosis of ADHD and its treatment with stimulant drugs for the past decade Visser et al , , and the most recent findings will be presented by Susanna Visser.
William Pelham will summarize the dose-related effects of stimulant drugs on children with ADHD on cognition as well as on symptom-severity in the context of concurrent psychosocial treatment Strand, Hawk, Bubnik, Shiels, Pelham, and Waxmonsky, James Waxmonsky will review hypotheses of placebo response and tolerance to the cognitive and behavioral effects of clinical doses of stimulant drugs Waxmonsky, Waschbusch, Glatt, and Faraone, Ruben Baler will review the complex mechanisms underlying the effects of stimulant drugs on the brain Swanson, Baler and Volker, Marc Lerner will discuss the long-term safety of medical use of stimulant drugs in children Lerner and Wigal, and the rules and monitoring of medical use in major league and minor league baseball players.
Barbara Sahakian will discuss the neuroethics of the non-medical use of cognitive enhancing drugs that has generated considerable interest and debate and was the topic of a recent book Illes and Sahakian, Tim Wigal will discuss differences in medical and non-medical use of stimulant drugs Swanson, Wigal, and Volow, , especially on college campuses that depend on non-academic factors, such as membership in fraternities, sororities, and athletic teams. The adverse effects of non-medical use of amphetamine may differ than in medical use, and James McCracken will review similarities and differences Berman, Kuczenski, McCracken and London, Raul Gonzalez will discuss the cognitive effects of marijuana Gonzalez et al , and address concurrent use of stimulant drugs.
Trevor Robbins will review new compounds that are similar and dissimilar to the stimulant drugs and preclinical studies of some of these Chamberlain and Robbins, Disclosure: J. Visser, Nothing to Disclose; R.
Baler, Nothing to Disclose; R. Gonzalez, Nothing to Disclose; J. Lerner, Nothing to Disclose; W. Compton, Nothing to Disclose. The tragic killings carried out by individuals with apparent serious mental illness has led to a national dialogue regarding the links between mental illness, violence and gun control. The ACNP Ethics Committee determined it would be timely to explore the clinical knowledge and scientific evidence base regarding violence and mental illness.
In this study group data associating mental illness to risk for violence will be briefly summarized, including neuroscientific perspectives David Pickar, Emil Coccaro, Dee Higley. Maryland State Senator Brian Frosh, Chair Judicial Proceedings Committee, will summarize his legislative efforts and experience relating to gun control and the mentally ill. Paul Appelbaum, Ken Davis and Jerrold Rosenbaum will provide practical and ethical perspective from academic, hospital and institutional medicine.
The ethical considerations drawn from privacy violation, civil liberty restriction and profiling will be central in the discussion. The core features of the discussion will then be passed back to the Ethics Committee for their consideration. Panel hopes to hear views of ACNP members on this issue of critical importance to psychiatry, psychology and the behavioral sciences.
Disclosure: D. Pickar, Nothing to Disclose; J. Rosenbaum, Nothing to Disclose; E. Davis, Part 1: My wife, Bonnie M. She receives royalty income from this license. Frosh, Nothing to Disclose; J. Higley, Nothing to Disclose. Section 1: Primary Purpose of the Study Group This study group will facilitate a unique gathering of academic, government and industry leaders to address the changing product development ecosystem with special emphasis on sharing, intellecutal property IP and the importance of translational research for CNS drug development.
A major theme that will link the participants and engage the audience is the concept of open innovation, first articulated by Henry Chesbrough at Berkeley. The panel will consider how this concept, used successfully in some industries, could be applied to rejuvenate CNS Drug Development.
Highlights from recent approaches for IP sharing will be discussed, with the goal of explicating the barriers, benefits and path to an open innovation environment in CNS Translational Research and Drug Development. Section 2: Experimental Design or Methods Used:We will begin with a brief outline of challenges to CNS translational research sharing and the current climate of drug discovery. This will be followed by discussions from a business and a law academician. The first is an expert on the management of innovation and the use of open innovation in rapid development.
The latter will deal directly with how IP sharing can be fostered within a legal framework. Section 3—Summary of Results: Speakers will consist of Husseini Manji J and J who will define the ecosystem, describe where new medicines have traditionally come from in the past, and the roles of key members in the evolving ecosystem. Steve Paul, Cornell Medical College, will discuss trends in R and D productivity and then highlight some of the successful and recently initiated public:private partnerships that seek to catalyze innovation in the form of new drugs.
Phil Phan, of Johns Hopkins Carey Business School, will discuss how open innovation, combined with real options decision models, can accelerate innovation. Dean Wong, of Johns Hopkins Medicine, will discuss the challenges for biomarker sharing in an academic setting, while Steve Grant, of the NIH, will describe the efforts by Extramural NIH staff to facilitate data sharing across multiple domains eg, genetics, brain imaging, phenotype harmonization.
Section 4—Conclusion Statement: Open innovation by leveraging a state-of-the-art biomarker exchange and other sharing processes across the biopharmaceutical ecosystem might help to manage the costs of drug discovery, provide a stimulus for start-up companies trying to exploit scientific research at NIH and academia, and link efforts across academia, government and industry around the focused mission of new CNS therapeutics.
Sung, Nothing to Disclose; L. Phan, Nothing to Disclose; S. Grant, Nothing to Disclose; H. What data would be useful beyond these instruments? If not, what else is necessary? Has the FDA Guidance Document had any effect on industry interest in new psychotropic drugs or drug classes?
Meyer, Nothing to Disclose; A. Hameed, Nothing to Disclose; J. I have never purchased or held any pharmaceutical stocks in my personal investment account, nor has my spouse. Chappell, Part 1: ; J. Payment for manuscript preparation from Quadrant HealthCom Inc. Stock in Medical Outcomes Systems. Jude Medical, Inc. Clayton, Nothing to Disclose; K. Posner, Part 1: Dr. Posner is the director of the Center for Suicide Risk Assessment.
This proposal aims to provide a forum to discuss some of the controversies around clinical trials with depots and the challenges of translating research into every day clinical practice. If improved compliance is truly the main advantage of depot over oral antipsychotics, clinical trials, in which indirect compliance enhancing factors, such as the ones inherent in rigorous RCTs see above can be controlled for are desirable. Pragmatic randomized trials, could be such an option discussed by Wolfgang Fleischhacker.
The enthusiasm with which clinicians will engage in such trials will depend on their general attitude towards depots which, as we know, differs considerably across continents, countries, regions and hospitals. The logistical issues regulatory requirements, ethics committees, and recruitment challenges will be reviewed by Ray Sanchez for the US and Sri Gopal for Europe.
In addition, Stephan Heres will review differences in depot utilization across the world and provide potential explanations for them based on the attitudes of prescribers. As recent imaging studies suggest that depot antipsychotics may differ from their oral counterparts with respect to receptor pharmacology and brain functioning, Hiroyuki Uchida will present pertinent data from PET and SPECT studies.
These will also be discussed in light of its potential clinical relevance. Disclosure: W. Background: Dopamine neurons in the ventral tegmental area VTA are implicated in adolescent behavioral and psychiatric vulnerabilities, but little is known about how adolescent VTA neurons process motivated behavior.
Methods: We recorded from VTA neurons of adolescent and adult rats during learning and maintenance of a cue-driven, reward-motivated instrumental task, and during extinction from this task. Results: During learning and maintenance of the task, VTA neurons of adolescents and adults similarly responded to cue, instrumental response, and reward. During extinction, however, despite similar behavioral responses indicating that both age groups had learned the absence of reward availability, the adolescent VTA neurons continued to respond to the cue that had been previously associated with reward.
These findings demonstrate the presence of a latent neuronal correlate of reward opportunity in the VTA of adolescents. Conclusions: Maintaining representation of events that had once predicted reward availability may impact reward seeking behavior and facilitate reinstatement of previously learned contingencies. The latent representation may facilitate renewal and reinstatement of previously associated experience.
This would present a mechanism for increased motivation of vulnerability of adolescents to reward-related problems, such as affective disorders and addiction. Background: Disrupted function in neural reward circuitry has been implicated in affective disorders. To understand the emergence of such disorders, it is critical to investigate reward circuitry during adolescence, the developmental period in which affective disorders emerge and reward circuitry continues to develop.
Control stimuli were video clips of an unfamiliar same-sex peer displaying positive and neutral affect. Results: Whole-brain analyses indicated that while viewing a friend's positive affect relative to an unfamiliar peer's positive affect, adolescents exhibited response in a set of regions implicated in reward function and social processing, including the ventral striatum, medial PFC, orbitofrontal cortex, and precuneus.
Regression analyses indicated that manic symptoms were associated with greater response in the insula and precuneus, while depressive symptoms were associated with less response in the striatum, dorsal anterior cingulate, and dorsolateral prefrontal cortex. Conclusions: This novel and innovative fMRI social reward paradigm engaged reward and social processing circuitry and was sensitive to individual differences in affective symptoms. Consistent with previous findings, depression was related to disrupted response to reward in the mPFC, which could reflect altered regulation of reward function and poor flexibility in responding to affective stimuli.
Mania was associated with increased response in regions implicated in social cognition, which suggests an enhanced engagement with social rewards. Background: Irritability is one of the most common presenting complaints in child psychiatry, yet its mediating neural mechanisms have received little research attention. Irritability can be defined as a decreased threshold for, and maladaptive responses to, frustration, where frustration is the emotion experienced when goal attainment is blocked.
The relevance of reward circuitry to mechanisms mediating frustration is further supported by longitudinal and familial associations between irritability and depression. Such associations have been demonstrated across development, from preschoolers through adolescence and adulthood. Deveney et al used a paradigm in which subjects completed a Posner attentional task with and without rewards. During scanning, youth were frustrated by rigged feedback and lost money that they have won on previous trials.
Compared to healthy subjects, chronically irritable youth ie, severe mood dysregulation, or SMD showed increased subjective responses to frustration, as well as attentional deficits and decreased amygdala-striatal-parietal activation on frustrating, compared to non-frustrating, trials. Subjects are scanned during a task which includes trials of the Posner attentional task, first in a condition where they receive rewards on all correct trials, and then in a rigged frustration condition where they are told that they are responding too slowly and lose the previously rewarded money.
Jitter is present between trials and between the response and feedback portions of each trial. Analyses will include ROIs based on prior work and a whole brain analysis. An exploratory analysis including 10 ADHD subjects will examine neural activation across groups as a function of irritability, treated as a dimensional variable measured with the Affective Reactivity Index. Results: These are pending.
Based on prior work, we anticipate that, compared to healthy subjects, SMD will report increased frustration during the frustration condition, and show increased reaction time only on invalid trials during the frustration condition. Further, we anticipate amygdala-striatal-parietal deactivation during frustration trials in SMD vs healthy subjects, and an association between irritability and amygdala-striatal-parietal deactivation across diagnoses.
Conclusions: Chronic irritability is associated with increased subjective response to a frustrating task, and decreased attentional control and amygdala-striatal-parietal deactivation during frustration. Frustrating paradigms can be challenging indeed frustrating!
Background: Childhood trauma is associated with affective processing biases in different psychiatric disorders but its effect in bipolar disorder BPD has not yet been investigated. Although BPD prevalence is almost equal in males and females, sex is believed to modulate clinical course, severity of illness and is likely to have an influence on affective processing.
The aim of this study is to investigate the effect of sex and childhood trauma on affective processing in a sample of BPD patients. Conclusions: Emotional abuse differently affects males and females suffering from BPD when engaged in affective processing tasks.
Further investigations are needed to elucidate potential pathophysiological mechanisms underlying this interaction. Background: Several lines of evidence suggest that maltreated children may be subject to aberrant brain development as a result of the maltreatment. To date, however, few studies have examined whether the changes observed in pediatric samples are still evident in the brains of healthy adults who report a history of childhood maltreatment.
Moreover, despite considerable evidence that childhood maltreatment is a risk factor for psychotic disorders, even less is known about how structural differences related to childhood maltreatment contributes to the expression of psychotic symptoms. Methods: High-resolution T1 magnetic resonance images were acquired for healthy adults characterized for a history of childhood maltreatment.
Volumetric profiles of regions previously implicated in studies of children with PTSD were assessed for their relation to a history of childhood maltreatment. Regions showing significant association were then assessed for their relationship to subclinical psychotic-like experiences.
Conclusions: These data suggest that some of the brain structural differences observed in children who have experienced maltreatment persist into adulthood and may have a significant impact on the expression of subclinical psychopathology. We investigated the neuroanatomy of pediatric maltreatment-related PTSD controlling for maltreatment. Subjects underwent a 3T anatomical MRI brain scan. Cerebrum was measured using parcellation procedures to examine specific brain regions.
We also measured amygdala and hippocampal volumes. Maltreatment groups did not differ in IQ. Posterior Grey matter findings persisted when controlling for IQ. These regions include brain areas involved in the developing default or resting state network. Left amgdala volumes were larger in maltreated youth compared with controls and maltreated youth with PTSD. Right hippocampal volumes were larger in maltreated youth compared with maltreated youth with PTSD. Conclusions: Maltreated Children and Adolescents may show Stress-Induced decreased process in leading to Grey Matter posterior loss and and suboptimal Myelination Indexes that may limit Neuroplasticity, Cognitive Flexibility, Impairs default network or resting state and result in Increased PTSD symptoms, Co-morbid psychopathology, and Cognitive Compromise in these children and Adolescents.
Intracranial self-stimulation ICSS may be a useful behavioral procedure for discriminating both DA-mediated abuse-related and 5-HT-mediated abuse-limiting drug effects in a single procedure. Methods: Male Sprague-Dawley rats with surgically-implanted electrodes targeting the medial forebrain bundle responded for multiple frequencies of brain stimulation and were tested in two phases. First, dose-effect curves for methcathinone 0. Second, time courses were determined for effects produced by the highest dose of each compound.
MDPV, methylone and mephedrone produced dose- and time-dependent increases in low ICSS rates maintained by low brain stimulation frequencies, but also produced abuse-limiting depression of high ICSS rates maintained by high brain stimulation frequencies. Methcathinone was the most potent compound, and MDPV was the longest acting.
Conclusions: All cathinone derivatives facilitated ICSS at some doses and pretreatment times, which is consistent with the abuse liability of these compounds. However, efficacies of compounds to facilitate ICSS varied, with methcathinone displaying the highest efficacy and mephedrone the lowest efficacy to facilitate ICSS. These results provide a foundation upon which to assess abuse-related effects of second-generation cathinone derivatives and build structure activity relationships regarding ring substitutions that may influence expression of DA-mediated abuse-related effects and 5-HT mediated abuse-limiting effects.
Studies with second generation compounds are in progress. Banks, Part 1: Collaborator on a grant from Perdue Pharmaceuticals related to opioid pharmacology in nonhuman primates. Common constituents of bath salts, including 3,4-methylenedioxypyrovalerone MDPV and 4-methylmethcathinone mephedrone , have been rendered illegal in the US as a means to prohibit sale and use. Unfortunately, new cathinone analogs are now being marketed as legal alternatives to MDPV and mephedrone.
The purpose of the present study was to examine the interaction of these newly-emerging cathinones with transporters for dopamine i. Methods: Specific drugs were selected for evaluation based on forensic data from the Drug Enforcement Administration. In vitro assays were carried out in rat brain synaptosomes to assess drug-induced effects on transporter-mediated uptake and release.
In vivo microdialysis was carried out in n. Microdialysis studies showed that MDPV 0. In vivo studies with other cathinones are in progress. Conclusions: Each of the cathinone derivatives examined displays a unique profile of in vitro transporter activity. Increasing the N -alkyl chain length of mephedrone creates compounds with reduced releasing activity, converting them to transporter blockers. The in vivo bioactivity of newer cathinones remains to be determined, but in vitro effects of the drugs at DAT point to significant propensity for abuse.
Background: The recent emergence of cathinone derivative stimulant drugs in recreational use markets recommends controlled laboratory studies to better delineate the risks posed for personal and public health. Although limited, the early evidence shows that some of the more common cathinones, such as 3,4-methylenedioxypyrovalerone MDPV and 4-methylmethcathinone 4-MMC; mephedrone , exhibit properties in vivo that would not be inferred from structure alone.
The purpose of the present work was to determine the extent to which these two compounds support intravenous self-administration in rats. Conclusions: The self-administration of MDPV is highly consistent with the emerging pharmacological profile which demonstrates rapid brain entry and activity dominated by dopamine transporter blockade. This compound poses significant threat for compulsive use.
Background: The Abelson helper integration site 1 AHI1 gene plays a pivotal role in brain development. AHI1 encodes Jouberin Jbn which is highly expressed in mammals throughout the developing brain and has been localized to the primary cilium, a highly conserved organelle central to the regulation of cellular signaling pathways. Studies by our group and others have demonstrated association of AHI1 with schizophrenia and autism. Serum cortisol and core body temperature were measured following behavioral and pharmacological experiments.
We examined neural circuits through the use of functional connectivity imaging during resting state rsfMRI. Using behavioral paradigms that involve exposure to environmental and social stress, significantly decreased anxiety was evident in the open field, elevated plus maze and dark light box, as well as during social interaction in pairs. However, response to centrally-acting anxiogenic compounds was intact. Using resting-state functional MRI, connectivity of the amygdala with other brain regions involved in processing of anxiogenic stimuli and inhibitory avoidance learning, such as the lateral entorhinal cortex, ventral hippocampus and ventral tegmental area, was found to be significantly reduced in the mutant mice.
Conclusions: Taken together, our data link Ahi1 under-expression with a defect in the process of threat detection; such emotional and cognitive defects have been described in schizophrenia and autism. Background: Primary cilia are evolutionary ancient structures that, in humans, have well established functions in sensory signaling and in development.
It is now clear that a number of diseases involve disruption of ciliary structure or function, and in which dysfunction of primary cilia is likely fundamental to etiology. This suggests the possibility that ciliary dysfunction may be of etiologic significance to major neuropsychiatric disorders or their treatment. Several observations made in the lab support this general hypothesis, and have motivated efforts to understand the functional significance of primary cilia to neural function.
My presentation will briefly review these observations and then will discuss recent work investigating the cellular basis of dopamine receptor localization to cilia and the functional significance of ciliary receptor localization to G protein-mediated signaling. Methods: We have used RNA interference to achieve targeted knockdown of the expression of genes implicated in major neuropsychiatric diseases. We have used fixed and live cell imaging methods to examine receptor localization and dynaicms in cultured neurons relative to cilia.
We have developed cilia-targeted signaling biosensors to investigate location of receptor signaling events and thedownstream mediators cyclic AMP relative to cilia. Results: We find that a significant fraction of genes associated with major neuropsychiatric disrupt cilia when knocked down in cell culture, and that a number of the protein products of these genes localize in or near cilia.
We have shown that D1 and D2 dopamine receptors present in cilia represent a diffusionally isolated population that is capable of G protein-linked stimulation of adenylyl cyclase. We have observed that cAMP produced by activation of ciliary D1 receptors is not constrained to cilia and can access the peripheral cytoplasm on a similar time scale as the acute signaling response. We have found a discrete signaling function of ciliary receptor localization to cilia, as well as of exclusion of receptors from cilia, which suggests a form of combinatiorial control of integrated cellular GPCR signaling.
Conclusions: Primary cilia are likely to represent a major site of signal integration in neurons, mediate signaling specificity at the level of closely related GPCRs, and have intriguing disease implications for neurology and psychiatry. Background: While neurons have elaborate dendrites and spines, they also have a newly re-appreciated organelle called the primary cilium PC. However, little is known regarding the function of PC, particularly as it relates to its role on neurons. Enriched receptor and protein expression and an isolated subcellular compartment make PC a unique organelle for receiving and transducing extracellular signals.
However, it is unclear whether GPCRs at PC and at the cell body have the same ability for efficiently initiating signaling and activating downstream events. In addition, another function for PC on neurons and glia may be in monitoring local osmolarity shifts, particularly given that brain cells are constantly undergoing fluctuations in osmolytes. Since regulation of osmolarity in the brain is critical for normal function, PC may be a focused center for osmolarity sensing that when dysregulated could lead to a variety of pathophysiological brain conditions.
Lastly, I will show evidence that PC may be serving as a critical osmolarity sensor for neurons that depends on the presence of Ahi1. Methods: Mice with targeted deletions of Ahi1 and wildtype littermate control mice were used.
Most experiments utilized neuronal cultures from embryonic day To examine osmolarity sensing of neuronal PC, neuronal cultures from embryonic day 19 rat embryos were used. Changes in neuronal osmolarity were accomplished by increasing the extracellular concentration of osmolytes in the media followed principally by immunolabeling and Western blot experiments using antibodies to Ahi1 and ciliary proteins. In addition, removal of PC from neurons using chloral hydrate was used to assess the effects of PC on the ability of neurons to sense changes in extracellular osmolarity.
Given normal expression and surface targeting of MchR1, the decreased ciliary MchR1 distribution in Ahi1 knockout neurons is likely a result of defective ciliary membrane protein trafficking. Strikingly, Ahi1 knockout neurons with normal MchR1 plasma membrane expression, but lacking MchR1 expression on PC, have reduced signaling upon ligand stimulation as indicated by an inhibition of forskolin-induced cAMP production. For osmolarity, we identified a novel and unknown hyperosmotic-induced structure that was localized with Ahi1.
Both the actin polymerization inhibitor, latrunculin, and the loss of Hap1, one of the main interactors with Ahi1, resulted in an inability to observe the Ahi1-positive structure under hyperosmotic conditions. Moreover, loss of neuronal PC using chloral hydrate eliminated the formation of these hyperosmotic-induced Ahi1-positive structures.
Conclusions: This study suggests a critical role for PC as a requisite site for GPCR localization and ligand reception in order to activate downstream signaling. In addition, our work begins to shed light on how the neuronal PC may help neurons sense and signal osmolarity fluctuations both in the normal and diseased brain.
Background: Considerable evidence indicates that hypofunction of prefrontal cortex glutamate signalling and decreased NMDA receptor activation may play an important role in schizophrenia. These receptors are located on GABAergic interneurons, suggesting that hypofunction results in a lack of downstream inhibition and disruption of cortical circuit activity. Activation of the mGluR2 receptor is proposed as a novel therapeutic strategy for schizophrenia, based on the hypothesis that this mechanism would counteract the glutamatergic disinhibition produced by NMDA receptor hypofunction.
Methods: In-vitro pharmacological studies used recombinant human mGluR receptors and rat hippocampal slice electrophysiological assays. MK 0. Administration of AZD significantly reversed the MKinduced increase in firing rate variance reflecting a normalization of cortical function.
AZD was well tolerated in human volunteers, with CNS drug exposure confirmed through csf analysis and subseuqently examined in a proof of principle study in symptomatic patients with schizophrenia Litman et al Conclusions: The current data are not consistent with positive modulation of mGluR2 receptors as a mechanism for monotherapy to treat acute schizophrenia. Whether different treatment regimens and particularly adjunct treatment would provide benefit remains to be determined.
Background: Increasing evidence is emerging that several neurological and psychiatric diseases are characterized by disturbed glutamatergic signalling. The mGlu2 receptor is a current focus of research for the treatment of schizophrenia, mood and anxiety disorders.
Modulation of the mGlu2 receptor can occur via allosteric or orthosteric ligands. Methods: Various in vitro and in vivo preclinical tools were used in the course of the program, including ex vivo and in vivo mGlu2 receptor occupancy with novel radioligands, sleep-wake EEG recording in rodents, conditioned avoidance responding and 2-deoxyglucose utilization, a lactate-induced rat challenge model and a dominant-submissive rat model. An exploratory treatment study of subtypes of patients with schizophrenia was conducted to generate hypotheses for future proof-of-concept studies.
Results: The talk will cover the discovery and early clinical development of novel mGlu2 receptor PAMs. We will discuss our efforts that have led to the identification of mGlu2 receptor-specific radioligands to measure target engagement and at the same time focus on the challenge of using occupancy studies for this target, because of discrepancies between in vitro and in vivo labeling of mGlu2 receptors. Though mGlu2 receptor-mediated effects on sleep-wake EEG recording in rodents were found to be a highly reliable, functional read-out of central activity, circadian aspects were found to be of importance for translational clinical testing.
The pharmacological properties of different PAMs in models predictive of antipsychotic-like activity will be shown, as well as the effect in animal models evaluating the potential of mGlu2 receptor PAMs in other indications such as anxiety or depression. The difficulties in determining which in vivo read outs are most indicative for allosteric modulation of changes in synaptic glutamate levels, and similarities and differences compared to orthosteric agonists will be discussed.
Conclusions: Based on the observations in various preclinical models, JNJ was selected for further clinical development. The translation from preclinical observations to human studies, along with the first data of JNJ in a patient trial in schizophrenia will be discussed. Safety of the compound was found to be good, and a signal in patients with residual negative symptoms of schizophrenia was identified. Background: Experimental medicine studies in healthy human subjects may accelerate the drug development process by providing insights that support the hypothesized mechanism of action of novel therapeutics.
In studies that date to the late 's, it was hypothesized that the ability of novel schizophrenia therapeutics to attenuate the schizophrenia-like symptoms produced by the NMDA glutamate receptor antagonist, ketamine, might provide this type of experimental medicine assay. Subsequently, as similarities between the effects of ketamine on neural systems and network dysregulation in schizophrenia became more clear, it was hypothesized that the ability of drugs developed for schizophrenia to attenuate ketamine effects on circuit activity related to cognition or symptoms might be reflective of aspects of its therapeutic potential for schizophrenia.
Methods: Two studies are reviewed. Test days involved the blinded intravenous infusion of saline and then ketamine in a fixed order while in the Siemens Tim Trio 3T magnet. A previous study from our group Driesen et al. Biol Psychiatry showed that schizophrenia patients showed impaired PFC activation while performing this task.
Results: In the initial study, LY produced a significant dose-related attenuation of ketamine-related impairments in working memory. There was also a trend to reduce positive symptoms produced by ketamine. In the second study, AZD did not attenuate the ketamine-related impariment in spatial working memory-related PFC activation or reduce psychotic symptoms produced by ketamine. However, ketamine produced asynchrony in the activation of DLPFC and BA 10 that was associated with the severity of ketamine-induced symptoms.
Preliminary analyses suggest that AZD normalized the synchrony between these regions and eliminated the statistical association between synchrony and symptoms. Conclusions: These data suggest that mGluR2 agonoists or PAMs might be able to reduce some behavioral and circuit effects of ketamine in healthy human subjects. The effects of the mGluR2 modulators are dose dependent and may additionally depend on the ketamine dose and the specific outcome evaluated. Background: Although dopamine has traditionally received attention as the key neurotransmitter mediating the symptoms of schizophrenia, accumulating evidence implicates a dysregulation of the glutamatergic system as a prominent contributant to the pathophysiology of the disease.
Understanding the role of glutamate in schizophrenia may provide a new direction for the development of innovative and hopefully more effective drug therapies for schizophrenia. Pomaglumetad methionil LY monohydrate is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a clinical development program assessing the efficacy of pomaglumetad methionil in reducing psychopathology either as a monotherapy in patients with an acute psychotic exacerbation or as an add-on therapy in patients with prominent negative symptoms.
Negative findings from these studies have dampened hope that a glutamate-based therapy for schizophrenia will be forthcoming in the near future, although a new strategic reconceptualization may be evolving. Methods: The efficacy and safety results of 5 acute monotherapy trials, 3 long-term safety trials, and a sub-acute add-on trial will be summarized. Pomaglumetad was generally well-tolerated across all trials and demonstrated a low association for weight gain and DAD2-mediated adverse events.
The incidence of seizures was found to be comparable to currently available antipsychotic drugs. Post-hoc analyses suggested that a subgroup of patients may demonstrate response to pomaglumetad. Conclusions: Pomaglumetad methionil treatment did not demonstrate efficacy in the a priori specified populations studied.
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