- Email: [email protected]
CANNABIS, COGNITION AND SCHIZOPHRENIA: STRUCTURAL BRAIN ALTERATIONS AND SYMPTOMATOLOGY
Abstracts
imaging (DTI) demonstrated an overlay of middle temporal hyperactivations found during a semantic fluency task in minor allele carriers of DTNBP1 that was accompanied by reduced fractional anisotropy in the same region, among others. The data show that single susceptibility variants for schizophrenia exert an influence on behaviour and neural systems on a structural and functional basis that can already be detected in healthy subjects. These influences were found in regions that are also implied in schizophrenia. These results shed more light on the pathogenetic mechanisms underlying the aetiology of psychiatric disorders and could result ultimately in novel insights into diagnosis, classification and therapeutic strategies of schizophrenia. doi:10.1016/j.schres.2010.02.063
IMAGING GENETICS IN PSYCHIATRY: DISEASE PATH OR GARDEN PATH? Michael Owen University of Cardiff Cardiff United Kingdom Over the past few years there has been great interest in the use of endophenotypes, especially those based upon neuroimaging, both for risk gene discovery and for studying the function of established risk genes. This approach has been embraced enthusiastically but uncritically. In particular there are concerns about the two major assumptions underlying the use of endophenotypes: that the genetic architecture will be simpler than for disease and that endophenotypes necessarily lie upon the pathway between gene and clinical phenotype. With regard to the latter there have been few if any studies addressing the question of whether imaging endophenotypes mediate the effect of risk genes rather than indexing common risk mechanisms. Given the evidence for pleiotropy in psychiatric genetics this is of particular concern. These issues will be discussed in relation to research on schizophrenia and recommendations for future studies presented. doi:10.1016/j.schres.2010.02.064
123
subclinical psychotic symptoms, all of which resemble schizophrenia, and will also examine the effects of comorbid cannabis use in people with schizophrenia. Sagnik Bhattacharyya will present data from a series of studies that examined the effects of acute cannabinoid administration to healthy volunteers and show that different cannabinoids have markedly different effects on brain function and symptoms. Markus Leweke will then discuss the role of the endogenous cannabinoid system in schizophrenia and present evidence that cannabidiol may act as an efficacious antipsychotic medication. Our discussant, Robin Murray, will synthesise the evidence presented with regard to the neural substrates underlying the association between cannabis use and schizophrenia, drawing on his wealth of experience in this important area of research to lead a discussion around how advances in the field may serve to prevent those at risk from developing the disorder, as well as benefit people with schizophrenia who may also use cannabis. doi:10.1016/j.schres.2010.02.065
CROSS-SENSITISATION BETWEEN CANNABIS AND STRESS: GENE-ENVIRONMENT INTERACTIONS UNDERLYING PSYCHOSIS
Cecile Henquet Maastricht University, Maastricht, Netherlands Gene-environment interactions are likely to underlie the association between cannabis and psychosis. Epidemiological data and observational studies in daily life will be presented to further examine these underlying mechanisms of gene-environment interaction, as well as possible self-medication effects. In addition to the use of cannabis, the urban environment and traumatic experiences during childhood have been found to increase the risk for psychotic illness. It is unknown, however, whether these environmental factors may interact with cannabis use as well in increasing psychosis risk. Prospective data from the German EDSP study, the Greek National Perinatal survey and the Dutch NEMESIS study will be presented to show that the effects of cannabis may be particularly detrimental for those who are growing up in an urban environment or for individuals who have experienced childhood trauma.
Symposium 10 NEURAL SUBSTRATES OF THE ASSOCIATION BETWEEN CANNABIS AND SCHIZOPHRENIA Co-Chairpersons: Nadia Solowij, F. Markus Leweke Monday, 12 April, 2010 - 1:30 pm - 3:30 pm
doi:10.1016/j.schres.2010.02.066
Overall Abstract: Evidence for an association between cannabis use and schizophrenia has grown from large scale epidemiological studies as well as from clinical observation and laboratory studies. Cannabis use can trigger psychotic symptoms or overt schizophrenia in vulnerable individuals and significant recent research has aimed to understand the mechanisms by which this can occur and the inherent vulnerabilities. For example, there is some evidence that individuals with a specific polymorphism of the COMT gene are at risk of developing schizophrenia if they use cannabis during adolescence, a critical neurodevelopmental period. This symposium brings together researchers at the forefront of investigating the interactions between cannabis use or the endogenous cannabinoid system and schizophrenia to present new developments in understanding this interaction. Cecile Henquet will present data from epidemiological and observational studies that inform the gene-environment interactions that increase the risk of developing a psychotic illness when cannabis is used. Nadia Solowij will present data that shows that chronic cannabis users develop cognitive deficits, brain structural changes and
Nadia Solowij University of Wollongong, Wollongong, Australia; Schizophrenia Research Institute, Sydney, Australia
CANNABIS, COGNITION AND SCHIZOPHRENIA: STRUCTURAL BRAIN ALTERATIONS AND SYMPTOMATOLOGY
Chronic cannabis use has been found to result in cognitive deficits that resemble the cognitive endophenotypes of schizophrenia. We have conducted a number of studies in adult and adolescent cannabis users aimed at better understanding these cognitive deficits and their neural substrates. Deficits in verbal learning and memory are prominent and associated with the duration, frequency, dose and age of onset of cannabis use. The adolescent brain appears to be more vulnerable to the deleterious effects of cannabis. Our neuroimaging studies of chronic cannabis users have found significant dose-related reduction of the hippocampus, of a magnitude similar to that seen in schizophrenia, and this was associated with the development of subclinical positive psychotic symptoms. Negative symptoms and depressive symptoms were also elevated. Changes to the amygdala and cerebellum were
124
Abstracts
observed and suggest alterations in the functional circuitry of the brain in association with cannabis use and symptoms. Data examining cognition and brain structural alterations in people with first-episode psychosis or established schizophrenia and comorbid cannabis use will also be presented and discussed.
which may underlie their different symptomatic and behavioural effects, and is consistent with a potential therapeutic role for CBD in various neuropsychiatric conditions.
doi:10.1016/j.schres.2010.02.068 doi:10.1016/j.schres.2010.02.067
ACUTE NEURAL EFFECTS OF THE MAIN INGREDIENTS OF CANNABIS: IMPLICATIONS FOR PSYCHOSIS Sagnik Bhattacharrya Institute of Psychiatry, Kings College, London, United Kingdom Background: Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD), the two main ingredients of the cannabis sativa plant have distinct symptomatic and behavioural effects. THC can induce psychotic symptoms and anxiety, impair memory and psychomotor control in healthy individuals, exacerbate existing psychotic symptoms, anxiety and memory impairments in patients with schizophrenia and is thought to be the ingredient responsible for the increased risk of developing schizophrenia following regular cannabis use. In contrast, CBD has anxiolytic and possibly antipsychotic properties and does not impair memory or other cognitive functions. The neural basis for these distinct effects of THC and CBD on psychiatric symptoms and cognitive function is unclear. We combined functional magnetic resonance imaging (fMRI) in healthy volunteers and pharmacological challenge with oral THC and CBD to examine the neural correlates of the various symptomatic and cognitive effects of cannabis. We also examined whether THC and CBD had opposite effects on regional brain function. Methods: Fifteen healthy men with minimal previous exposure to cannabis were scanned while performing an oddball novelty processing task, a verbal learning task, a response inhibition task, a sensory processing task and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of 10 mg of THC, 600 mg of CBD or placebo. BOLD responses were measured using fMRI. Results: During the oddball novelty processing task, while responding to emotionally neutral target stimuli that were salient because of their deviance/frequency, participants found the ‘baseline’ stimuli inappropriately salient compared to the 'oddball' stimuli while under the influence of THC. This was accompanied by attenuation of activation in the striatum and hippocampus by THC, while CBD augmented activation in these regions relative to placebo. The effect of THC on striatum was inversely correlated with the psychotic symptoms it concurrently induced. During the verbal learning task, THC augmented activation in the parahippocampal gyrus during the encoding condition such that the normal linear decrement in activation across repeated encoding blocks was no longer evident. THC also attenuated the normal time-dependent change in ventrostriatal activation during the retrieval condition, which was directly correlated with concomitantly induced psychotic symptoms. THC and CBD also had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. Discussion: The modulation of medial temporal and striatal function by THC may underlie the effects of cannabis on verbal learning, stimulus salience and psychotic symptoms. Evidence that THC influences function in these regions, particularly in the context of altered processing of salience, provides a plausible mechanism for the increased risk of schizophrenia in regular cannabis users. THC and CBD can have opposite effects on regional brain function,
TRANSLATIONAL STUDIES ON (ENDO-)CANNABINOIDS IN SCHIZOPHRENIA: BENCH TO BEDSIDE
F. Markus Leweke Institute of Psychiatry, Kings College, London, United Kingdom Introduction: In the search of new mechanisms for antipsychotic drugs, translational approaches are of increasing relevance. These approaches include animal studies, mechanistic studies and clinical trials in healthy volunteers as well as innovatively designed phase IIa clinical trials. Methods: We report on an approach targeting the endogenous cannabinoid system for the treatment of acute schizophrenia. Endocannabinoids were measured by HPLC/MS in brain tissue of rats prior to and after administration of psychotomimetics and in cerebrospinal fluid and serum from clinically well characterized healthy volunteers and acute psychiatric patients. In addition, a randomized, double-blind, active controlled clinical trial of phase IIa was performed investigating cannabidiol, a phytocannabinoid, in acute schizophrenia. Results: In animal studies anandamide, a major endogenous agonist to the cannabinoid CB1-receptor, is significantly elevated in brain tissue under the influence of psychotomimetics. This is associated with respective behavioral data. In parallel, anandamide is markedly elevated in cerebrospinal fluid of acute first-episode antipsychotic-naïve schizophrenic patients and inversely correlated with psychotic symptoms. In our phase IIa clinical trial, cannabidiol showed significant antipsychotic properties associated with a mild side-effect profile and a characteristic mechanism of action. Discussion: Based on our findings, we suggest that the endocannabinoid system plays a significant pathophysiological role in schizophrenia and that modulation of its functioning may yield antipsychotic effects in this devastating disease. Thus, modulation of endocannabinoid functioning represents a promising new approach to the treatment of acute schizophrenia.
doi:10.1016/j.schres.2010.02.069
Symposium 11 THE MANY FACES OF PSYCHOSIS Co-Chairpersons: Charles Schulz, Carol Tamminga Monday, 12 April, 2010 - 1:30 pm - 3:30 pm Overall Abstract: The perplexing, but interesting, aspect of psychotic disorders is their complexity. Psychotic illnesses at times seem archetypal and at other times to present as a combination of disorders. To address the complexity of the study of psychosis the following presentations will be made:Inez MyinGermeys will present the impact of moments of negative emotional change on psychotic symptoms such as paranoia. The findings illustrate a mechanism for the co-occurrence of depressive and psychotic symptoms. Dr. Buckley will describe both preclinical and clinical research examining whether neurotrophins, specifically Brain Derived Neurotrophic Factor (BDNF), may be a neurobiological marker for vulnerability to psychosis. BDNF levels have been shown to be low in patients with first-episode psychosis and there is increased expression of c-Cbl in schizo-
imaging (DTI) demonstrated an overlay of middle temporal hyperactivations found during a semantic fluency task in minor allele carriers of DTNBP1 that was accompanied by reduced fractional anisotropy in the same region, among others. The data show that single susceptibility variants for schizophrenia exert an influence on behaviour and neural systems on a structural and functional basis that can already be detected in healthy subjects. These influences were found in regions that are also implied in schizophrenia. These results shed more light on the pathogenetic mechanisms underlying the aetiology of psychiatric disorders and could result ultimately in novel insights into diagnosis, classification and therapeutic strategies of schizophrenia. doi:10.1016/j.schres.2010.02.063
IMAGING GENETICS IN PSYCHIATRY: DISEASE PATH OR GARDEN PATH? Michael Owen University of Cardiff Cardiff United Kingdom Over the past few years there has been great interest in the use of endophenotypes, especially those based upon neuroimaging, both for risk gene discovery and for studying the function of established risk genes. This approach has been embraced enthusiastically but uncritically. In particular there are concerns about the two major assumptions underlying the use of endophenotypes: that the genetic architecture will be simpler than for disease and that endophenotypes necessarily lie upon the pathway between gene and clinical phenotype. With regard to the latter there have been few if any studies addressing the question of whether imaging endophenotypes mediate the effect of risk genes rather than indexing common risk mechanisms. Given the evidence for pleiotropy in psychiatric genetics this is of particular concern. These issues will be discussed in relation to research on schizophrenia and recommendations for future studies presented. doi:10.1016/j.schres.2010.02.064
123
subclinical psychotic symptoms, all of which resemble schizophrenia, and will also examine the effects of comorbid cannabis use in people with schizophrenia. Sagnik Bhattacharyya will present data from a series of studies that examined the effects of acute cannabinoid administration to healthy volunteers and show that different cannabinoids have markedly different effects on brain function and symptoms. Markus Leweke will then discuss the role of the endogenous cannabinoid system in schizophrenia and present evidence that cannabidiol may act as an efficacious antipsychotic medication. Our discussant, Robin Murray, will synthesise the evidence presented with regard to the neural substrates underlying the association between cannabis use and schizophrenia, drawing on his wealth of experience in this important area of research to lead a discussion around how advances in the field may serve to prevent those at risk from developing the disorder, as well as benefit people with schizophrenia who may also use cannabis. doi:10.1016/j.schres.2010.02.065
CROSS-SENSITISATION BETWEEN CANNABIS AND STRESS: GENE-ENVIRONMENT INTERACTIONS UNDERLYING PSYCHOSIS
Cecile Henquet Maastricht University, Maastricht, Netherlands Gene-environment interactions are likely to underlie the association between cannabis and psychosis. Epidemiological data and observational studies in daily life will be presented to further examine these underlying mechanisms of gene-environment interaction, as well as possible self-medication effects. In addition to the use of cannabis, the urban environment and traumatic experiences during childhood have been found to increase the risk for psychotic illness. It is unknown, however, whether these environmental factors may interact with cannabis use as well in increasing psychosis risk. Prospective data from the German EDSP study, the Greek National Perinatal survey and the Dutch NEMESIS study will be presented to show that the effects of cannabis may be particularly detrimental for those who are growing up in an urban environment or for individuals who have experienced childhood trauma.
Symposium 10 NEURAL SUBSTRATES OF THE ASSOCIATION BETWEEN CANNABIS AND SCHIZOPHRENIA Co-Chairpersons: Nadia Solowij, F. Markus Leweke Monday, 12 April, 2010 - 1:30 pm - 3:30 pm
doi:10.1016/j.schres.2010.02.066
Overall Abstract: Evidence for an association between cannabis use and schizophrenia has grown from large scale epidemiological studies as well as from clinical observation and laboratory studies. Cannabis use can trigger psychotic symptoms or overt schizophrenia in vulnerable individuals and significant recent research has aimed to understand the mechanisms by which this can occur and the inherent vulnerabilities. For example, there is some evidence that individuals with a specific polymorphism of the COMT gene are at risk of developing schizophrenia if they use cannabis during adolescence, a critical neurodevelopmental period. This symposium brings together researchers at the forefront of investigating the interactions between cannabis use or the endogenous cannabinoid system and schizophrenia to present new developments in understanding this interaction. Cecile Henquet will present data from epidemiological and observational studies that inform the gene-environment interactions that increase the risk of developing a psychotic illness when cannabis is used. Nadia Solowij will present data that shows that chronic cannabis users develop cognitive deficits, brain structural changes and
Nadia Solowij University of Wollongong, Wollongong, Australia; Schizophrenia Research Institute, Sydney, Australia
CANNABIS, COGNITION AND SCHIZOPHRENIA: STRUCTURAL BRAIN ALTERATIONS AND SYMPTOMATOLOGY
Chronic cannabis use has been found to result in cognitive deficits that resemble the cognitive endophenotypes of schizophrenia. We have conducted a number of studies in adult and adolescent cannabis users aimed at better understanding these cognitive deficits and their neural substrates. Deficits in verbal learning and memory are prominent and associated with the duration, frequency, dose and age of onset of cannabis use. The adolescent brain appears to be more vulnerable to the deleterious effects of cannabis. Our neuroimaging studies of chronic cannabis users have found significant dose-related reduction of the hippocampus, of a magnitude similar to that seen in schizophrenia, and this was associated with the development of subclinical positive psychotic symptoms. Negative symptoms and depressive symptoms were also elevated. Changes to the amygdala and cerebellum were
124
Abstracts
observed and suggest alterations in the functional circuitry of the brain in association with cannabis use and symptoms. Data examining cognition and brain structural alterations in people with first-episode psychosis or established schizophrenia and comorbid cannabis use will also be presented and discussed.
which may underlie their different symptomatic and behavioural effects, and is consistent with a potential therapeutic role for CBD in various neuropsychiatric conditions.
doi:10.1016/j.schres.2010.02.068 doi:10.1016/j.schres.2010.02.067
ACUTE NEURAL EFFECTS OF THE MAIN INGREDIENTS OF CANNABIS: IMPLICATIONS FOR PSYCHOSIS Sagnik Bhattacharrya Institute of Psychiatry, Kings College, London, United Kingdom Background: Delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD), the two main ingredients of the cannabis sativa plant have distinct symptomatic and behavioural effects. THC can induce psychotic symptoms and anxiety, impair memory and psychomotor control in healthy individuals, exacerbate existing psychotic symptoms, anxiety and memory impairments in patients with schizophrenia and is thought to be the ingredient responsible for the increased risk of developing schizophrenia following regular cannabis use. In contrast, CBD has anxiolytic and possibly antipsychotic properties and does not impair memory or other cognitive functions. The neural basis for these distinct effects of THC and CBD on psychiatric symptoms and cognitive function is unclear. We combined functional magnetic resonance imaging (fMRI) in healthy volunteers and pharmacological challenge with oral THC and CBD to examine the neural correlates of the various symptomatic and cognitive effects of cannabis. We also examined whether THC and CBD had opposite effects on regional brain function. Methods: Fifteen healthy men with minimal previous exposure to cannabis were scanned while performing an oddball novelty processing task, a verbal learning task, a response inhibition task, a sensory processing task and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of 10 mg of THC, 600 mg of CBD or placebo. BOLD responses were measured using fMRI. Results: During the oddball novelty processing task, while responding to emotionally neutral target stimuli that were salient because of their deviance/frequency, participants found the ‘baseline’ stimuli inappropriately salient compared to the 'oddball' stimuli while under the influence of THC. This was accompanied by attenuation of activation in the striatum and hippocampus by THC, while CBD augmented activation in these regions relative to placebo. The effect of THC on striatum was inversely correlated with the psychotic symptoms it concurrently induced. During the verbal learning task, THC augmented activation in the parahippocampal gyrus during the encoding condition such that the normal linear decrement in activation across repeated encoding blocks was no longer evident. THC also attenuated the normal time-dependent change in ventrostriatal activation during the retrieval condition, which was directly correlated with concomitantly induced psychotic symptoms. THC and CBD also had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. Discussion: The modulation of medial temporal and striatal function by THC may underlie the effects of cannabis on verbal learning, stimulus salience and psychotic symptoms. Evidence that THC influences function in these regions, particularly in the context of altered processing of salience, provides a plausible mechanism for the increased risk of schizophrenia in regular cannabis users. THC and CBD can have opposite effects on regional brain function,
TRANSLATIONAL STUDIES ON (ENDO-)CANNABINOIDS IN SCHIZOPHRENIA: BENCH TO BEDSIDE
F. Markus Leweke Institute of Psychiatry, Kings College, London, United Kingdom Introduction: In the search of new mechanisms for antipsychotic drugs, translational approaches are of increasing relevance. These approaches include animal studies, mechanistic studies and clinical trials in healthy volunteers as well as innovatively designed phase IIa clinical trials. Methods: We report on an approach targeting the endogenous cannabinoid system for the treatment of acute schizophrenia. Endocannabinoids were measured by HPLC/MS in brain tissue of rats prior to and after administration of psychotomimetics and in cerebrospinal fluid and serum from clinically well characterized healthy volunteers and acute psychiatric patients. In addition, a randomized, double-blind, active controlled clinical trial of phase IIa was performed investigating cannabidiol, a phytocannabinoid, in acute schizophrenia. Results: In animal studies anandamide, a major endogenous agonist to the cannabinoid CB1-receptor, is significantly elevated in brain tissue under the influence of psychotomimetics. This is associated with respective behavioral data. In parallel, anandamide is markedly elevated in cerebrospinal fluid of acute first-episode antipsychotic-naïve schizophrenic patients and inversely correlated with psychotic symptoms. In our phase IIa clinical trial, cannabidiol showed significant antipsychotic properties associated with a mild side-effect profile and a characteristic mechanism of action. Discussion: Based on our findings, we suggest that the endocannabinoid system plays a significant pathophysiological role in schizophrenia and that modulation of its functioning may yield antipsychotic effects in this devastating disease. Thus, modulation of endocannabinoid functioning represents a promising new approach to the treatment of acute schizophrenia.
doi:10.1016/j.schres.2010.02.069
Symposium 11 THE MANY FACES OF PSYCHOSIS Co-Chairpersons: Charles Schulz, Carol Tamminga Monday, 12 April, 2010 - 1:30 pm - 3:30 pm Overall Abstract: The perplexing, but interesting, aspect of psychotic disorders is their complexity. Psychotic illnesses at times seem archetypal and at other times to present as a combination of disorders. To address the complexity of the study of psychosis the following presentations will be made:Inez MyinGermeys will present the impact of moments of negative emotional change on psychotic symptoms such as paranoia. The findings illustrate a mechanism for the co-occurrence of depressive and psychotic symptoms. Dr. Buckley will describe both preclinical and clinical research examining whether neurotrophins, specifically Brain Derived Neurotrophic Factor (BDNF), may be a neurobiological marker for vulnerability to psychosis. BDNF levels have been shown to be low in patients with first-episode psychosis and there is increased expression of c-Cbl in schizo-