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CB1 RECEPTOR SIGNALING, PREFRONTAL GABAERGIC TRANSMISSION AND ADOLESCENCE
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
INCREASING ENDOCANNABINOID LEVELS RESTORES ABERRANT DOPAMINE SYSTEM FUNCTION IN THE PCP MODEL OF SCHIZOPHRENIA Daniel Lodge UTHSCSA An augmented dopamine system function is one of the oldest hypothesis of schizophrenia and suggests that mesolimbic hyperactivity underlies the positive symptoms of the disease. As there is no overt pathology within the ventral tegmental area, it is thought that the pathology of schizophrenia lies upstream of the dopamine system. Increasing evidence from clinical and preclinical studies suggests that hyperactivity within hippocampal subfields underlies the augmented dopamine system function. Indeed, here we demonstrate that sub-chronic administration of the NMDA antagonist, phencyclidine (PCP) produces an increase in VTA dopamine neuron population activity. This is attributable to an increase in ventral hippocampal (vHipp) activity as tetrodotoxin inactivation of the vHipp completely normalizes the aberrant dopamine neuron activity. Given clinical evidence of a negative correlation between central endocannabinoid levels and positive symptom severity, we examined whether enhancing endocannabinoid tone could alter dopamine neuron activity in the PCP model. Endocannabinoid tone was increased by administration of the fatty acid amide hydrolase (FAAH) blocker, URB-597 (0.3mg/kg). Here we demonstrate that the increase in dopamine neuron population activity observed in PCP-treated rats is attenuated by URB-597 suggesting that increasing endocannabinoid tone may provide a potential therapeutic approach for psychosis.
MODULATION OF THE ENDOCANNABINOID SYSTEM AS A POTENTIAL NEW TARGET IN THE TREATMENT OF SCHIZOPHRENIA F. Markus Leweke 1,2 , Martin Hellmich 3 , Franziska Pahlisch 4 , Laura Kranaster 4 , Dagmar Koethe 5 1 Central Institute of Mental Health; 2 Heidelberg University, Germany; 3 Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany; 4 Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; 5 Department of General Psychiatry, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany Background:New pharmacological targets for the treatment of schizophrenia are urgently required. We initially identified one of the two major endocannabinoids, anandamide, as a counterbalancing if not protective factor in paranoid schizophrenia. Most recently, we reported that increasing levels of anandamide by blocking its metabolization by cannabidiol, a purified phytocannabinoid, significantly ameliorates psychotic symptoms in acute schizophrenia. Methods: We performed a randomized, double-blind, placebo-controlled, cross-over clinical trial in acute, antipsychotic-naive, first-break paranoid schizophrenia patients, fulfilling diagnostic criteria of DSM-IV. 29 patients were treated after written informed consent with either cannabidiol (600 mg per day) or placebo for 14 days and than switched to the corresponding cross-over condition. Additional patients to gain a total of 18 patients treated per protocol replaced dropouts. Results: Cannabidiol significantly improved psychotic symptoms in the cannabidiol-placebo condition during the first 14 days of treatment when compared to baseline. A MMRM analysis of all randomized patients (n=29) yielded a mean improvement of 2.4 points (standard error 3.0) on PANSS total in favor of cannabidiol (vs. placebo), albeit not statistically significant. Only one patient on sequence cannabidiol-placebo terminated treatment early (last seen at visit 3) whereas 10 patients terminated early on sequence placebo- cannabidiol. The most frequent reason given was worsening of symptoms (5/11 patients). In addition, cannabidiol was detectable in serum of almost all patients in the cannabidiol-placebo group. Side-effects of cannabidiol were on the level of placebo. Conclusions: Although limited by design issues (cross-over), duration of treatment (14 days), carry-over effects (serum levels of cannabidiol), and relevant placebo-response rates, this is the second study to provide evidence for antipsychotic properties of cannabidiol accompanied by a superior side-effect profile. Future placebo-controlled parallel-group trials studying the antipsychotic properties of cannabidiol in acute schizophrenia are nec-
S47
essary to provide further evidence for its efficacy in the treatment of this devastating disease.
CB1 RECEPTOR SIGNALING, PREFRONTAL GABAERGIC TRANSMISSION AND ADOLESCENCE Kuei Y. Tseng The Chicago Medical School at RFUMS Converging studies indicate that cannabis abuse during adolescence significantly increases the risk of developing psychosis and prefrontal cortex (PFC)-dependent cognitive impairments later in life. However, the mechanisms underlying the adolescent susceptibility to chronic cannabis exposure are poorly understood. Here I will summarize recent data showing how repeated exposure to the CB1 receptor agonist WIN during adolescence impacts the functional maturation of the PFC network. Using a non-contingent administration protocol in rats, we found conclusive evidence that exposure to a cannabinoid receptor 1 (CB1) agonist exclusively during early and mid-adolescence impairs prefrontal processing later in life. We further narrowed down this effect to a deficit in GABAergic transmission and uncovered that this prefrontal disinhibition could be normalized following single acute local infusion of the GABA-Aα1 positive allosteric modulator Indiplon. Thus, early and mid-adolescence are unique developmental periods during which the cannabinoid system predominantly interacts with the GABAergic system to regulate its proper functional maturation in the PFC. Together, these findings have direct implications in our understanding of the mechanisms that contribute to the long-term cognitive deficits observed in early adolescent onset cannabis abuse as well as the associated risk of developing psychiatric disorders such as schizophrenia. Supported by Rosalind Franklin University, the Brain Research Foundation and NIH R01-MH086507 grants.
Symposium UNDERSTANDING PATHWAYS TO CARE AS A MEANS OF ADVANCING EARLY INTERVENTION: FINDINGS FROM AROUND THE WORLD Chairperson: Michael T. Compton Discussant: John M. Kane Tuesday, 8 April 2014 2:00 PM – 4:00 PM Overall Abstract: Pathways to care can be defined as the contacts made during the period of time from the onset of illness until the first initiation of treatment. Although pathways to care among psychiatric patients in general have been an area of empirical examination for more than two decades, an emerging area of schizophrenia research is the examination of pathways to care in people experiencing a first episode of psychosis. The study of pathways to care represents a valuable field of inquiry for early psychosis research, especially in terms of how pathways may impact the duration of untreated psychosis (DUP) and illness outcomes. Understanding pathways to care in patients with first-episode psychosis informs efforts geared toward early recognition and intervention, thus reducing suffering and minimizing negative social consequences for those with psychosis. Concerning illness outcomes, the first contact that a first-episode patient has with psychiatric services is often essential in determining his/her subsequent adherence to treatment, and thus, outcomes of the illness. Studying when and where patients, during the course of an evolving psychotic disorder, make contacts for help can highlight where service improvements can be most effective. Understanding pathways to care may be particularly important for people’s initial treatment-seeking efforts, as patients and their families often will not know how to gain access to treatment. A growing body of literature examines the various pathways to mental health care among patients with first-episode psychosis in diverse countries. Pathways to care vary across countries, based on differences in health systems, criminal justice systems, and attitudes towards mental illnesses. This Symposium will provide attendees with the most recent data on pathways to care in the United States, the United Kingdom, Canada, and Switzerland.
INCREASING ENDOCANNABINOID LEVELS RESTORES ABERRANT DOPAMINE SYSTEM FUNCTION IN THE PCP MODEL OF SCHIZOPHRENIA Daniel Lodge UTHSCSA An augmented dopamine system function is one of the oldest hypothesis of schizophrenia and suggests that mesolimbic hyperactivity underlies the positive symptoms of the disease. As there is no overt pathology within the ventral tegmental area, it is thought that the pathology of schizophrenia lies upstream of the dopamine system. Increasing evidence from clinical and preclinical studies suggests that hyperactivity within hippocampal subfields underlies the augmented dopamine system function. Indeed, here we demonstrate that sub-chronic administration of the NMDA antagonist, phencyclidine (PCP) produces an increase in VTA dopamine neuron population activity. This is attributable to an increase in ventral hippocampal (vHipp) activity as tetrodotoxin inactivation of the vHipp completely normalizes the aberrant dopamine neuron activity. Given clinical evidence of a negative correlation between central endocannabinoid levels and positive symptom severity, we examined whether enhancing endocannabinoid tone could alter dopamine neuron activity in the PCP model. Endocannabinoid tone was increased by administration of the fatty acid amide hydrolase (FAAH) blocker, URB-597 (0.3mg/kg). Here we demonstrate that the increase in dopamine neuron population activity observed in PCP-treated rats is attenuated by URB-597 suggesting that increasing endocannabinoid tone may provide a potential therapeutic approach for psychosis.
MODULATION OF THE ENDOCANNABINOID SYSTEM AS A POTENTIAL NEW TARGET IN THE TREATMENT OF SCHIZOPHRENIA F. Markus Leweke 1,2 , Martin Hellmich 3 , Franziska Pahlisch 4 , Laura Kranaster 4 , Dagmar Koethe 5 1 Central Institute of Mental Health; 2 Heidelberg University, Germany; 3 Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany; 4 Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; 5 Department of General Psychiatry, Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany Background:New pharmacological targets for the treatment of schizophrenia are urgently required. We initially identified one of the two major endocannabinoids, anandamide, as a counterbalancing if not protective factor in paranoid schizophrenia. Most recently, we reported that increasing levels of anandamide by blocking its metabolization by cannabidiol, a purified phytocannabinoid, significantly ameliorates psychotic symptoms in acute schizophrenia. Methods: We performed a randomized, double-blind, placebo-controlled, cross-over clinical trial in acute, antipsychotic-naive, first-break paranoid schizophrenia patients, fulfilling diagnostic criteria of DSM-IV. 29 patients were treated after written informed consent with either cannabidiol (600 mg per day) or placebo for 14 days and than switched to the corresponding cross-over condition. Additional patients to gain a total of 18 patients treated per protocol replaced dropouts. Results: Cannabidiol significantly improved psychotic symptoms in the cannabidiol-placebo condition during the first 14 days of treatment when compared to baseline. A MMRM analysis of all randomized patients (n=29) yielded a mean improvement of 2.4 points (standard error 3.0) on PANSS total in favor of cannabidiol (vs. placebo), albeit not statistically significant. Only one patient on sequence cannabidiol-placebo terminated treatment early (last seen at visit 3) whereas 10 patients terminated early on sequence placebo- cannabidiol. The most frequent reason given was worsening of symptoms (5/11 patients). In addition, cannabidiol was detectable in serum of almost all patients in the cannabidiol-placebo group. Side-effects of cannabidiol were on the level of placebo. Conclusions: Although limited by design issues (cross-over), duration of treatment (14 days), carry-over effects (serum levels of cannabidiol), and relevant placebo-response rates, this is the second study to provide evidence for antipsychotic properties of cannabidiol accompanied by a superior side-effect profile. Future placebo-controlled parallel-group trials studying the antipsychotic properties of cannabidiol in acute schizophrenia are nec-
S47
essary to provide further evidence for its efficacy in the treatment of this devastating disease.
CB1 RECEPTOR SIGNALING, PREFRONTAL GABAERGIC TRANSMISSION AND ADOLESCENCE Kuei Y. Tseng The Chicago Medical School at RFUMS Converging studies indicate that cannabis abuse during adolescence significantly increases the risk of developing psychosis and prefrontal cortex (PFC)-dependent cognitive impairments later in life. However, the mechanisms underlying the adolescent susceptibility to chronic cannabis exposure are poorly understood. Here I will summarize recent data showing how repeated exposure to the CB1 receptor agonist WIN during adolescence impacts the functional maturation of the PFC network. Using a non-contingent administration protocol in rats, we found conclusive evidence that exposure to a cannabinoid receptor 1 (CB1) agonist exclusively during early and mid-adolescence impairs prefrontal processing later in life. We further narrowed down this effect to a deficit in GABAergic transmission and uncovered that this prefrontal disinhibition could be normalized following single acute local infusion of the GABA-Aα1 positive allosteric modulator Indiplon. Thus, early and mid-adolescence are unique developmental periods during which the cannabinoid system predominantly interacts with the GABAergic system to regulate its proper functional maturation in the PFC. Together, these findings have direct implications in our understanding of the mechanisms that contribute to the long-term cognitive deficits observed in early adolescent onset cannabis abuse as well as the associated risk of developing psychiatric disorders such as schizophrenia. Supported by Rosalind Franklin University, the Brain Research Foundation and NIH R01-MH086507 grants.
Symposium UNDERSTANDING PATHWAYS TO CARE AS A MEANS OF ADVANCING EARLY INTERVENTION: FINDINGS FROM AROUND THE WORLD Chairperson: Michael T. Compton Discussant: John M. Kane Tuesday, 8 April 2014 2:00 PM – 4:00 PM Overall Abstract: Pathways to care can be defined as the contacts made during the period of time from the onset of illness until the first initiation of treatment. Although pathways to care among psychiatric patients in general have been an area of empirical examination for more than two decades, an emerging area of schizophrenia research is the examination of pathways to care in people experiencing a first episode of psychosis. The study of pathways to care represents a valuable field of inquiry for early psychosis research, especially in terms of how pathways may impact the duration of untreated psychosis (DUP) and illness outcomes. Understanding pathways to care in patients with first-episode psychosis informs efforts geared toward early recognition and intervention, thus reducing suffering and minimizing negative social consequences for those with psychosis. Concerning illness outcomes, the first contact that a first-episode patient has with psychiatric services is often essential in determining his/her subsequent adherence to treatment, and thus, outcomes of the illness. Studying when and where patients, during the course of an evolving psychotic disorder, make contacts for help can highlight where service improvements can be most effective. Understanding pathways to care may be particularly important for people’s initial treatment-seeking efforts, as patients and their families often will not know how to gain access to treatment. A growing body of literature examines the various pathways to mental health care among patients with first-episode psychosis in diverse countries. Pathways to care vary across countries, based on differences in health systems, criminal justice systems, and attitudes towards mental illnesses. This Symposium will provide attendees with the most recent data on pathways to care in the United States, the United Kingdom, Canada, and Switzerland.