Posts Tagged ‘mood disorders’

Failed pain relief drug candidate clinical trial

Larry H. Bernstein, MD, FCAP, Curator




What was the drug in Clinical Trial Tragedy In France Jan 2016



BIA 10-2474

3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide

BIA 10-2474 is an experimental fatty acid amide hydrolase inhibitor[1] developed by the Portuguese pharmaceutical company Bial-Portela & Ca. SA. The drug was developed to relieve pain,[2][3] to ease mood and anxiety problems, and to improve movement coordination linked to neurodegenerative illnesses.[4] It interacts with the humanendocannabinoid system.[5][6] It has been linked to severe adverse events affecting 5 patients in a drug trial in Rennes, France, and at least one death, in January 2016.[7]

French newspaper Le Figaro has obtained Bial study protocol documents listing the the chemical name of BIA-10-2474 as 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.[8] A Bial news release described BIA-10-2474 as “a long-acting inhibitor of FAAH”.[9]

Fatty acid amide hydrolase (FAAH) is an enzyme which degrades endocannabinoid neurotransmitters like anandamide,[10] which relieves pain and can affect eating and sleep patterns.[11][12] FAAH inhibitors have been proposed for a range of nervous-system disorders including anxiety, alcoholism, pain and nausea.

The Portuguese pharmaceutical company Bial holds several patents on FAAH enzyme inhibitors.[12][13][14][15]


No target organ was identified during toxicology studies and few adverse clinical findings were observed at the highest dose tested. For the single ascending dose part [of the clinical trial], a starting dose of 0.25 mg was judged to be safe for a first-in-human administration.[8]

The protocol defines no starting dose for the multi-dose treatment groups, noting that this will be based on the outcome of the single dose portion of the trial (an approach known as adaptive trial design). The authors note that nonetheless, the starting dose will not exceed 33% of the maximum tolerated dose (MTD) identified in the single dose groups (or 33% of the maximum administered dose if the MTD is not reached).[8]


In July 2015 Biotrial, a contract research organization, began testing the drug in a human phase one clinical trial for the manufacturer. The study was approved by French regulatory authority, the Agence Nationale de Sécurité du Médicament (ANSM), on June 26, 2015, and by the Brest regional ethics committee on July 3, 2015.[20] The trial commenced on July 9, 2015,[21] in the city of Rennes, and recruited 128 healthy volunteers, both men and women aged 18 to 55. According to French authorities, the study employed a three-stage design with 90 of the volunteers having received the drug during the first two stages of the trial, with no serious adverse events being reported .[17][20] Participants of the study were to receive €1,900 and, in turn, asked to stay at Biotrial’s facility for two weeks during which time they would take the drug for ten days and undergo tests.[22]

In the third stage of the trial evaluating multiple doses, six male volunteers received doses by mouth, starting on 7 January 2016. The first volunteer was hospitalized at theRennes University Hospital on January 10, became brain dead,[17][23][24][25] and died on January 17.[26] The other five men in the same dosage group were also hospitalized, in the period of January 10 through January 13[27] four of them suffering injuries including deep hemorrhagic and necrotic lesions seen on brain MRI.[7] The six men who were hospitalised were the group which received the highest dose.[26] A neurologist at the University of Rennes Hospital Center, Professor Pierre-Gilles Edan, stated in a press conference with the French Minister for Health, that 3 of the 4 men who were displaying neurological symptoms “already have a severe enough clinical picture to fear that even in the best situation there will be an irreversible handicap” and were being given corticosteroids to control the inflammation.[27] The sixth man from the group was not showing adverse effects but had been hospitalized for observation.[25][28][29] Biotrial stopped the experiment on January 11, 2016.[4]


Le Figaro posted a 96-page clinical study protocol for BIA 10-2474 that the French newspaper procured from an unnamed source.

According to the document, BIA 10-2474 is 3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide.

BIA 10-2474 “is designed to act as a long-active and reversible inhibitor of brain and peripheral FAAH,” notes the protocol. The compound “increases anandamide levels in the central nervous system and in peripheral tissues.”

The clinical trial protocol also notes that the company tested BIA 10-2474 on mice, rats, dogs, and monkeys for effects on the heart, kidneys, and gastrointestinal tract, among other pharmacological and toxicological evaluations.


The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana.

Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes.

The French health minister has stated the drug acted on natural receptors found in the body known as endocannibinoids, which regulate mood and appetite. It did not contain cannabis or anything derived from it, as was originally reported. All six trial participants were administered the doses simultaneously.


The trial was being performed at Biotrial, a French-based firm that was formed in 1989 and has conducted thousands of trials. A message on the company’s website stated that they are working with health authorities to understand the cause of the accident, while extending thoughts to the patients and their families. Bial has disclosed the drug was a FAAH (fatty acid amide hydrolase) inhibitor, which is an enzyme produced in the brain and elsewhere that breaks down neurotransmitters called endocannabinoids. Two scientists from the Nottingham Medical School who have worked with FAAH tried over the weekend to try and identify the drug by examining a list of drugs Bial currently has in its pipeline. They believe the culprit is one identified by the codename BIA 10-2474.


While safety issues like this are rare, they are not unheard of. In 2006, a clinical trial in London left six men ill. All were taking part in a study testing a drug designed to fight auto-immune disease and leukemia. Within hours of taking the drug TGN1412, all experienced a serious reaction, were admitted to intensive care, and had to be treated for organ failure.


The Duff Report, written in response to the TGN1412 trial, noted the medicine should have been tested in one person at a time. It also helped to put additional safety measures in place. The Medicines and Health Products Regulatory Agency (MHRA) now requires committees to look at pre-clinical data to determine the proper initial dose, and rules are in place to stop the trial if unintended reactions occur.


Other pharmaceutical companies, including Merck, Pfizer, Johnson & Johnson, Sanofiand Vernalis, have previously taken other FAAH inhibitors into clinical trials without experiencing such adverse events (e.g. respectively, MK-4409,[35][36] PF-04457845,JNJ-42165279,[37] SSR411298 and V158866.[38][39] Related enzyme inhibitor compounds such as URB-597 and LY-2183240 have been sold illicitly as designer drugs,[40][41] all without reports of this type of toxicity emerging, so the mechanism of the toxicity observed with BIA 10-2474 remains poorly understood.

Clinical Trial Tragedy, France, Jan 2016, PHASE 1 | Categories: Uncategorized | URL:


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Targeting Neuropathologies with GSK33 Inhibitor

Larry H. Bernstein, MD, FCAP,  Curator




New 5-​Substituted-​N-​(piperidin-​4-​ylmethyl)​-​1H-​indazole-​3-​carboxamides: Potent Glycogen Synthase Kinase-​3 (GSK-​3) Inhibitors in Model of Mood Disorders




CAS 1452582-16-9, 428.47, C23 H26 F2 N4 O2

1H-​Indazole-​3-​carboxamide, 5-​(2,​3-​difluorophenyl)​-​N-​[[1-​(2-​methoxyethyl)​-​4-​piperidinyl]​methyl]​-

Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.


1 H-indazole-3-carboxamide compounds acting as glycogen synthase kinase 3 beta (GSK-33) inhibitors and to their use in the treatment of GSK-33-related disorders such as (i) insulin-resistance disorders; (ii) neurodegenerative diseases; (iii) mood disorders; (iv) schizophrenic disorders; (v) cancerous disorders; (vi) inflammation, (vii) substance abuse disorders; (viii) epilepsies; and (ix) neuropathic pain.

Protein kinases constitute a large family of structurally related enzymes, which transfer phosphate groups from high-energy donor molecules (such as adenosine triphosphate, ATP) to specific substrates, usually proteins. After phosphorylation, the substrate undergoes to a functional change, by which kinases can modulate various biological functions.

In general, protein kinases can be divided in several groups, according to the substrate that is phosphorylated. For example, serine/threonine kinase phosphorylates the hydroxyl group on the side chain of serine or threonine aminoacid.

Glycogen synthase kinases 3 (GSK-3) are constitutively active multifunctional enzymes, quite recently discovered, belonging to the serine/threonine kinases group.

Human GSK-3 are encoded by two different and independent genes, which leads to GSK-3a and GSK-33 proteins, with molecular weights of about 51 and 47 kDa, respectively. The two isoforms share nearly identical sequences in their kinase domains, while outside of the kinase domain, their sequences differ substantially (Benedetti et al., Neuroscience Letters, 2004, 368, 123-126). GSK-3a is a multifunctional protein serine kinase and GSK-33 is a serine-threonine kinase.

It has been found that GSK-33 is widely expressed in all tissues, with widespread expression in the adult brain, suggesting a fundamental role in neuronal signaling pathways (Grimes and Jope, Progress in Neurobiology, 2001, 65, 391-426). Interest in glycogen synthase kinases 3 arises from its role in various physiological pathways, such as, for example, metabolism, cell cycle, gene expression, embryonic development oncogenesis and neuroprotection (Geetha et al., British Journal Pharmacology, 2009, 156, 885-898).

GSK-33 was originally identified for its role in the regulation of glycogen synthase for the conversion of glucose to glycogen (Embi et al., Eur J Biochem, 1980, 107, 519-527). GSK-33 showed a high degree of specificity for glycogen synthase.

Type 2 diabetes was the first disease condition implicated with GSK- 3β, due to its negative regulation of several aspects of insulin signaling pathway. In this pathway 3-phosphoinositide-dependent protein kinase 1 (PDK-1 ) activates PKB, which in turn inactivates GSK-33. This inactivation of GSK-33 leads to the dephosphorylation and activation of glycogen synthase, which helps glycogen synthesis (Cohen et al., FEBS Lett, 1997, 410, 3-10). Moreover, selective inhibitors of GSK-33 are expected to enhances insulin signaling in prediabetic insulin- resistant rat skeletal muscle, thus making GSK-33 an attractive target for the treatment of skeletal muscle insulin resistance in the pre-diabetic state (Dokken et al., Am J. Physiol. Endocrinol. Metab., 2005, 288, E1 188-E1 194).

GSK-33 was also found to be a potential drug target in others pathological conditions due to insulin-resistance disorders, such as syndrome X, obesity and polycystic ovary syndrome (Ring DB et al., Diabetes, 2003, 52: 588-595).

It has been found that GSK-33 is involved in the abnormal phosphorylation of pathological tau in Alzheimer’s disease (Hanger et al., Neurosci. Lett, 1992, 147, 58-62; Mazanetz and Fischer, Nat Rev Drug Discov., 2007, 6, 464-479; Hong and Lee, J. Biol. Chem., 1997, 272, 19547- 19553). Moreover, it was proved that early activation of GSK-33, induced by apolipoprotein ApoE4 and β-amyloid, could lead to apoptosis and tau hyperphosphorylation (Cedazo-Minguez et al., Journal of Neurochemistry, 2003, 87, 1 152- 1 164). Among other aspect of Alzheimer’s disease, it was also reported the relevance of activation of GSK-33 at molecular level (Hernandez and Avila, FEBS Letters, 2008, 582, 3848-3854).

Moreover, it was demonstrated that GSK-33 is involved in the genesis and maintenance of neurodegenerative changes associated with Parkinson’s disease (Duka T. et al., The FASEB Journal, 2009; 23, 2820- 2830).

Accordingly to these experimental observations, inhibitors of GSK-33 may find applications in the treatment of the neuropathological consequences and the cognitive and attention deficits associated with tauopathies; Alzheimer’s disease; Parkinson’s disease; Huntington’s disease (the involvement of GSK-33 in such deficits and diseases is disclosed in Meijer L. et al., TRENDS Pharm Sci, 2004; 25, 471 -480); dementia, such as, but not limited to, vascular dementia, post-traumatic dementia, dementia caused by meningitis and the like; acute stroke; traumatic injuries; cerebrovascular accidents; brain and spinal cord trauma; peripheral neuropathies; retinopathies and glaucoma (the involvement of GSK-33 in such conditions is disclosed in WO 2010/109005).

The treatment of spinal neurodegenerative disorders, like amyotrophic lateral sclerosis, multiple sclerosis, spinal muscular atrophy and neurodegeneration due to spinal cord injury has been also suggested in several studies related to GSK-33 inhibition, such as, for example in Caldero J. et al., “Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord”, Neuroscience. 2010 Feb 17;165(4):1353-69, Leger B. et al., “Atrogin-1 , MuRF1 , and FoXO, as well as phosphorylated GSK-3beta and 4E-BP1 are reduced in skeletal muscle of chronic spinal cord-injured patients”, Muscle Nerve, 2009 Jul; 40(1 ):69-78, and Galimberti D. et al., “GSK33 genetic variability in patients with Multiple Sclerosis”, Neurosci Lett. 201 1 Jun 1 5;497(1 ):46- 8. Furthermore, GSK-33 has been linked to the mood disorders, such as bipolar disorders, depression, and schizophrenia.

Inhibition of GSK-33 may be an important therapeutic target of mood stabilizers, and regulation of GSK-33 may be involved in the therapeutic effects of other drugs used in psychiatry. Dysregulated GSK-33 in mood disorder, bipolar disorder, depression and schizophrenia could have multiple effects that could impair neural plasticity, such as modulation of neuronal architecture, neurogenesis, gene expression and the ability of neurons to respond to stressful, potentially lethal conditions (Jope and Ron, Curr. Drug Targets, 2006, 7, 1421- 1434).

The role of GSK-33 in mood disorder was highlighted by the study of lithium and valproate (Chen et al., J. Neurochem., 1999, 72, 1327- 1330; Klein and Melton, Proc. Natl. Acad. Sci. USA, 1996, 93, 8455-8459), both of which are GSK-33 inhibitors and are used to treat mood disorders. There are also existing reports from the genetic perspective supporting the role of GSK-33 in the disease physiology of bipolar disorder (Gould, Expert. Opin. Ther. Targets, 2006, 10, 377-392).

It was reported a decrease in AKT1 protein levels and its phosphorylation of GSK-33 at Serine-9 in the peripheral lymphocytes and brains of individuals with schizophrenia. Accordingly, this finding supports the proposal that alterations in AKT1 -GSK-33 signaling contribute to schizophrenia pathogenesis (Emamian et al., Nat Genet, 2004, 36, 131- 137).

Additionally, the role of GSK-33 in cancer is a well-accepted phenomenon.

The potential of small molecules that inhibit GSK-33 has been evidenced for some specific cancer treatments (Jia Luo, Cancer Letters, 2009, 273, 194-200). GSK-33 expression and activation are associated with prostate cancer progression (Rinnab et al., Neoplasia, 2008, 10, 624-633) and the inhibition of GSK3b was also proposed as specific target for pancreatic cancer (Garcea et al., Current Cancer Drug Targets, 2007, 7, 209-215) and ovarian cancer (Qi Cao et al., Cell Research, 2006, 16 671 -677). Acute inhibition of GSK-33 in colon-rectal cancer cells activates p53-dependent apoptosis and antagonizes tumor growth (Ghosh et al., Clin Cancer Res 2005, 1 1 , 4580-4588).

The identification of a functional role for GSK-33 in MLL-associated leukaemia suggests that GSK-33 inhibition may be a promising therapy that is selective for transformed cells that are dependent on HOX overexpression (Birch et al., Cancer Cell, 2010, 1 7, 529-531 ).

GSK-33 is involved in numerous inflammatory signalling pathways, for example, among others GSK-33 inhibition has been shown to induce secretion of the anti-inflammatory cytokine IL-1 0. According to this finding, GSK-33 inhibitors could be useful to regulate suppression of inflammation (G. Klamer et al., Current Medicinal Chemistry, 2010, 17(26), 2873-2281, Wang et al., Cytokine, 2010, 53, 130-140).

GSK-33 inhibition has been also shown to attenuate cocaine-induced behaviors in mice. The administration of cocaine in mice pretreated with a GSK-33 inhibitor demonstrated that pharmacological inhibition of GSK3 reduced both the acute behavioral responses to cocaine and the long- term neuroadaptations produced by repeated cocaine (Cocaine-induced hyperactivity and sensitization are dependent on GSK3, Miller JS et al. Neuropharmacology. 2009 Jun; 56(8):1 1 16-23, Epub 2009 Mar 27).

The role of GSK-33 in the development of several forms of epilepsies has been demonstrated in several studies, which suggest that inhibition of GSK-33 could be a pathway for the treatment of epilepsy (Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy, Lohi H et al., Hum Mol Genet. 2005 Sep 15;14(18):2727-36 and Hyperphosphorylation and aggregation of Tau in laforin-deficient mice, an animal model for Lafora disease, Purl R et al., J Biol Chem. 2009 Aug 21 ;284(34) 22657-63). The relationship between GSK-33 inhibition and treatment of neuropathic pain has been demonstrated in Mazzardo-Martins L. et al., “Glycogen synthase kinase 3-specific inhibitor AR-A014418 decreases neuropathic pain in mice: evidence for the mechanisms of action”, Neuroscience. 2012 Dec 13;226, and Xiaoping Gu et al., “The Role of Akt/GSK33 Signaling Pathway in Neuropathic Pain in Mice”, Poster A525, Anesthesiology 2012 October 13-17, 2012 Washington.

A review on GSK-33, its function, its therapeutic potential and its possible inhibitors is given in “GSK-33: role in therapeutic landscape and development of modulators” (S. Phukan et al., British Journal of Pharmacology (2010), 160, 1- 19).

WO 2004/014864 discloses 1 H-indazole-3-carboxamide compounds as selective cyclin-dependant kinases (CDK) inhibitors. Such compounds are assumed to be useful in the treatment of cancer, through a mechanism mediated by CDK2, and neurodegenerative diseases, in particular Alzheimer’s disease, through a mechanism mediated by CDK5, and as anti-viral and anti-fungine, through a mechanism mediated by CDK7, CDK8 and CDK9.

Cyclin-dependant kinases (CDKs) are serine/threonine kinases, first discovered for their role in regulating the cell cycle. CDKs are also involved in regulating transcription, mRNA processing, and the differentiation of nerve cells. Such kinases activate only after their interaction and binding with regulatory subunits, namely cyclins.

Moreover, 1 H-indazole-3-carboxamide compounds were also described as analgesics in the treatment of chronic and neuropathic pain (see, for example, WO 2004/074275 and WO 2004/101 548) and as 5-HT4 receptor antagonists, useful in the treatment of gastrointestinal disorders, central nervous system disorders and cardiovascular disorders (see, for example, WO 1994/101 74).

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Outstanding Achievement in Schizophrenia Research

Larry H. Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Innovation

Series E. 2; 5.9

2014 Prizewinner:
David Braff, M.D.
 – University of California, San Diego School of Medicine – Watch Video

David Braff M.D. named Lieber Prize winner

David Braff MD, Distinguished Professor at UCSD’s Department of Psychiatry has been named this year’s Lieber Prize winner by the National Brain and Behavior Research Foundation (NBBRF) and the National Association for Research in Schizophrenia and Depression (NARSAD). This Prize is given to an outstanding neuropsychiatric researcher who has enhanced our fundamental understanding of schizophrenia, a devastating no fault heritable clinical brain disorder affecting 1% of the world’s population. Schizophrenia causes psychosis, cognitive dysfunction and profound disability in many patients. It also affects the families of the patients, since the disability-often strikes early in young adult life. Past Lieber Prize winners include two Nobel Laureates and many other world leading distinguished neuroscientists. The Award will be presented at a scientific meeting, ceremony and dinner in New York at the NBBRF-NARSAD Annual Gala at Lincoln Center in late October.

Dr. Braff has pursued and extended our understanding of schizophrenia via a number of major research projects. The Consortium on the Genomics of Schizophrenia (COGS) is a 30 million-dollar 10 year NIMH-funded consortium on the neurocognitive, neurophysiological, neural circuit and dysfunctional genomic architecture of schizophrenia. Dr Braff has been Principal Scientist and Director of this 7-site study: COGS 1 examined clinical features, neurocognitive and neurophysiological, and other familial endophenotypes or biomarkers in schizophrenia patients and their families as well as healthy control subjects. The follow up COGS 2 is studying 2500 schizophrenia patients and case-control subjects. Genomic and related methods include extensive behavioral, candidate gene, genome wide association, sequencing, methylation and stem cell projects from COGS and UCSD grants. This has led to an increased understanding of both the neural network and underlying genomic network bases of schizophrenia and has enhanced our understanding of risk and vulnerability markers which may provide targets for very early intervention and even, in the longer run, prevention. This neurodevelopmental psychotic process starts early in life but usually manifests itself in late teenagers and young adults. In addition, because of the underlying complex neural and genomic networks that have been identified by this work and the studies of other scientific projects, we have hope of finding novel therapeutic targets for pharmacological and sensory training- cognitive behavioral therapies for this devastating disorder.

Dr. Braff also has conducted longstanding translational (TRANS) and genomic studies over 30 years of continuously funded projects supported by NIMH, NARSAD and the Brain and Behavior Foundation. This research, conducted with many essential colleagues, including TRANS Co-PIs Mark Geyer, Ph.D. and Neal Swerdlow, M.D. Ph.D., has led to cross-species translational advances in understanding the neurobiology of schizophrenia and created powerful tools for screening candidate antipsychotic compounds to treat schizophrenia. Braff has also Directed the VA VISN 22 Mental Illness Research Center Clinical Neuroscience and Genomics Project, which provides crucial infrastructure and intellectual support for this work.

In recent years, Dr. Braff, a NARSAD Distinguished Investigator, has consistently been ranked by “ISI” in the top half of the top percent of all cited neuropsychiatric researchers based on the frequency with which his 300 publications are cited. He has also been awarded the Warren Award from the International Congress of Schizophrenia, the Inspiration Pioneer Research Award from NAMI, the Dean Award from the American College of Psychiatrists and the Marmor Award from the American Psychiatric Association, all given to honor an outstanding neuropsychiatric researcher. Dr. Braff’s colleagues at UCSD have included crucial contributions and context from TRANS Co-PIs, Mark Geyer Ph.D. and Neal Swerdlow MD Ph.D., Department Vice Chair (Also Deputy Director of COGS) as well as more recent faculty appointees Gregory Light, Ph.D (UCSD COGS Director and San Diego VA VISN 22 MIRECC Director) and Tiffany Greenwood, Ph.D. (Genetics And Statistical Genetics Lead Scientist) and many others.

Dr. Igor Grant, Chair of the Department commented, “Professor David Braff has been at the forefront of research into the neurobiology of schizophrenia. Beginning with observations on neurophysiologic biomarkers related to aberrant attentional and other cognitive mechanisms in those afflicted with schizophrenia, his work has progressed to linking such biomarkers to genetic underpinnings of this serious disorder, which affects 1% of our population, and causes great disruptions both for the person affected, and their families and loved ones. Professor Braff’s innovative work has opened better understanding of the interplay of genetic and neurodevelopmental factors in the evolution of schizophrenia, as well as promise of specific diagnostic markers that may help with early identification of people vulnerable to this disorder, at a time when preventive strategies may be most useful. As such his work will inform both improved treatment and prevention. Dr. Braff has also been a generative mentor to younger scientists, a fine educator, and helped the Department establish a modern inpatient psychiatric unit to care for people with severe mental disorders. The Department is very proud that Professor Braff was recognized with the Lieber Prize, reserved for the very finest psychiatrist scientists.”

“We are entering a new era of the neuropsychiatric and genomic revolutions, where advanced bioinformatics and other evolving technologies will help us to integrate brain, behavioral and genomic data about schizophrenia that we only imagined was possible in the past. Receiving this prize will serve to enhance all of our endeavors.”


Patrick F. Sullivan, M.D., Karolinska Institutet & University of North Carolina – Watch Video

Patrick F. Sullivan Awarded 2014 Lieber Prize for Outstanding Achievement in Schizophrenia Research

Patrick F. Sullivan, MD, FRANZCP, M. Hayworth & Family Distinguished Professor of Psychiatry and Professor of Genetics and Psychiatry at the University of North Carolina School of Medicine, is one of two researchers awarded the 2014 Lieber Prize for Outstanding Achievement in Schizophrenia Research.

The $50,000 cash award from the Brain & Behavior Research Foundation is given in recognition of a research scientist who has made distinguished contributions to the understanding of schizophrenia. It rewards past achievement and provides further incentive for an outstanding working scientist to continue to do exceptional research into the causes, prevention, and treatment of schizophrenia.

“The 2014 Outstanding Achievement Prize winners have dedicated their lives to solving some of the most intractable psychiatric problems in order to improve the lives of millions of people and their families,” said Jeffrey Borenstein, MD, CEO of the Brain & Behavior Research Foundation. “We applaud their past and future accomplishments.”

As a psychiatric geneticist, Dr. Sullivan works to decode the molecular and cellular consequences of genetic variations underlying schizophrenia. He heads large, multinational projects across a range of disorders, dividing his time between Sweden, where he is a Professor at the Karolinska Institutet, and UNC, where he is the Director of the Center for Psychiatric Genomics.

As founder and lead investigator of the Psychiatric Genomics Consortium (PGC), Dr. Sullivan directs 300 scientists from 70 institutions in 19 countries who are conducting mega-analyses, involving 90,000 participants, of genetic risk for schizophrenia, depression, autism, bipolar disorder and attention-deficit hyperactivity disorder. He is also the principal investigator for a Swedish genetic study of 10,000 patients with schizophrenia and bipolar disorder, one of the few projects looking into the impact of environmental factors in these disorders.    Feb 5, 2015

A Stockholm Psychiatry Lecture held at Karolinska Institutet Feb 3 2015 by Prof. Patrick F Sullivan, UNC and KI. 14, 2015

Baby steps may become giant steps in the next ten years for schizophrenia, an illness which impacts an estimated 2.4 million Americans 

“It is my deep hope that the work that led to my selection of this prize will continue so that we can greatly expand our knowledge of the genetic basis of schizophrenia so that these new findings will, in turn, lead to advances that improve the lives of people living with schizophrenia and other serious mental disorders.”


Gregory Light, Ph.D.
University of California, San Diego

“This award strengthens my resolve to continue to develop treatment strategies that will ameliorate, prevent, and perhaps even cure schizophrenia and related psychotic illnesses in the next stages of my career.”

Stephan Ripke, M.D.
Broad Institute

“As a result of the immense collaborative efforts of the PGC, I believe that we are now on the path towards making seminal discoveries into the biology of this devastating disease. New therapeutic targets are imminent and the support of this prize will have a great impact on realizing this goal.”


Colvin Prize for Outstanding Achievement in Mood Disorders Research:

Wayne C. Drevets, M.D.
Janssen Pharmaceutica

“This prize not only affirms the significance of our past work, it also inspires and invigorates our current and future research, which we hope will improve the lives of people affected by bipolar disorder by leading to the discovery and development of new treatments.”

Fritz A. Henn, M.D., Ph.D.
Cold Spring Harbor Laboratory

“That my peers feel our work merits recognition is the greatest reward after a lifetime of work aimed at understanding and better treating major mental illness.”

2013 Marc G. Caron, Ph.D.
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Duke University School of Medicine
2012 Michael J. Owen, M.D., Ph.D.
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Cardiff University
2012 Michael O’Donovan, M.D., Ph.D.
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Cardiff University
2011 Carol A. Tamminga, M.D.
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UT Southwestern Medical Center at Dallas
2011 Joel E. Kleinman, M.D., Ph.D.
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National Institute of Mental Health (NIMH)
2010 Ming T. Tsuang, M.D., Ph.D., D.Sc.
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Goldman-Rakic Prize for Outstanding Achievement in Cognitive Neuroscience

2014 Prizewinner:

Richard L. Huganir, Ph.D. – The Johns Hopkins University School of Medicine – Watch Video

Department Affiliation: Primary: Neuroscience; Secondary: Biological Chemistry; Howard Hughes Medical Institute
Degree: Ph.D., Cornell University
Rank: Professor/Director, Department of Neuroscience

Regulation of Neurotransmitter Receptors and Brain Function in Heath and Disease

Neurotransmitter receptors mediate signal transduction at the postsynaptic membrane of synaptic connections between neurons in the nervous system. We have been studying the molecular mechanisms in the regulation of neurotransmitter receptor function. Recently we have focused on glutamate receptors, the major excitatory receptors in the brain. Glutamate receptors can be divided into two major classes: AMPA and NMDA receptors. AMPA receptors mediate rapid excitatory synaptic transmission while NMDA receptors play important roles in neuronal plasticity and development. Studies in our laboratory have found that both AMPA and NMDA receptors are multiply phosphorylated by a variety of protein kinases. Phosphorylation regulates several functional properties of these receptors including conductance and membrane targeting. Recent studies in our lab have demonstrated that the phosphorylation of AMPA receptors is regulated during cellular models of learning and memory such as long-term potentiation (LTP) and long-term depression (LTD). Moreover, phosphorylation of the AMPA receptor GluR1 subunit is required for the expression of these forms of plasticity and for the retention of spatial memory and also regulates emotional memory formation and erasure.

We have also been examining the mechanisms of the subcellular targeting and clustering of glutamate receptors at synapses. We have recently identified a variety of proteins that directly or indirectly interact with AMPA and NMDA receptors. We have found a novel family of proteins that we call GRIPs (Glutamate Receptor Interacting Proteins) that directly bind to the C-termini of the GluR2/3 subunits of AMPA receptors. GRIPs contain seven PDZ domains, protein-protein interaction motifs, which crosslink AMPA receptors to each other or link them to other proteins. In addition, we have found that the C-termini of GluR2 also interacts with the PDZ domain of PICK1, a protein kinase C-binding protein that is found at excitatory synapses. The GluR2 subunit also interacts with the NSF protein, a protein involved in the regulation of membrane fusion events. These AMPA receptor interacting proteins are critical in the proper membrane trafficking and synaptic targeting of these receptors. We have shown that the binding of PICK1 and GRIP is required for a specific form of LTD in the cerebellum that is a cellular model for motor learning. Moreover, we have found that this receptor complex is critical for hippocampal LTP and LTD and spatial learning.

In addition to these studies on AMPA receptors, we have been characterizing a separate NMDA receptor associated protein complex that is important in synaptic targeting and downstream signaling of NMDA receptors. We have identified an excitatory synapse specific rasGAP, which we call synGAP that regulates synaptic Ras signaling and has profound effects on synaptic plasticity.

Importantly, recent evidence has implicated glutamate receptor associated complexes in several neurological and psychiatric disorders including Alzheimer’s disease, schizophrenia, autism, mental retardation as well as in chronic pain and drug addiction.

In summary, we have examined the molecular mechanisms underlying the regulation of neurotransmitter receptor function. Our studies have suggested that regulation of receptor function may be a major mechanism for the regulation of synaptic plasticity in the nervous system in health and disease and may be an important determinant of animal behavior.

Representative Publications:

  • Volk, L.J., Bachman, J.L., Johnson, R., Yu, Y., Huganir, R.L. (2013) PKM-Z is not required for hippocampal synaptic plasticity, learning and memory. Nature 493(7432): 420-3. Pub Med Reference
  • Thomas, G.M., Hayashi, T., Chiu, S.L., Chen, C.M., Huganir, R.L. (2012) Palmitoylation by DHHC5/8 targets GRIP1 to dendritic endosomes to regulate AMPA-R trafficking. Neuron73(3):482-96. Pub Med Reference
  • Makuch, L., Volk, L., Anggono, V., Johnson, R.C., Yu, Y., Duning, K., Kremerskothen, J., Xia, J., Takamiya, K., Huganir, R.L. (2011) Regulation of AMPA receptor function by the human memory-associated gene KIBRA. Neuron 71(6):1022-9. Pub Med Reference
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“This has been my life long career goal—to understand how memory is encoded in the brain and how these mechanisms are disrupted in cognitive disorders. I am honored to be associated with Dr. Goldman- Rakic’s legacy.”

2013 Karl Deisseroth, M.D., Ph.D.
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Stanford University
2012 Larry R. Squire, Ph.D.
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University of California, San Diego
2011 Michael E. Goldberg, M.D.
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Columbia University/NYSPI
2010 Robert Malenka, M.D., Ph.D.
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Stanford University

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