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NO SMOKE WITHOUT FIRE: COULD TOBACCO SMOKING HAVE A CAUSAL ROLE IN PSYCHOSIS?
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
and apomorphine) that have high D1 intrinsic activity, but these all are D2 selective and cause a host of dose-limiting D2-mediated pharmacological effects. These issues have provided a neuropsychopharmacological conundrum for decades, but recent advances in medicinal and computational chemistry have offered potential for the immediate future. The availability of high resolution crystal structures of relatively homologous receptors like the β-adrenergic receptor have, when combined with molecular manipulation of receptors, allowed a degree of study of ligand docking and activation mechanisms not previously possible. This, in turn, can permit the discovery or rationale modification of non-catechol-containing chemical backbones that may lead to novel drugs. In addition, has been widely recognized recently that it is possible to design novel drugs using two non-traditional strategies. One is the use of allosteric ligands that can affect signaling by interacting with the receptor and influence the actions of dopamine itself. The other is the ability to discover functionally selective ligands that would differentially activate signaling pathways mediated by the D1 receptor, leading to an improvement in therapeutic index. This presentation will report on several new directions in this area. We shall provide insights on how one can change the pharmacokinetic properties of molecules while retaining the desirable pharmacodynamic properties. One example to be presented will be the potential drug candidate EFF0311, in which a subtle chemical modification to dihydrexidine retained the desirable pharmacodynamic properties but provided a great improvement in pharmacokinetics. We shall also present data relating to the signaling properties of D1 receptor ligands, and how different signaling pathways affect functional responses in vivo. Finally, we shall summarize recent progress into the understanding and discovery of non-catechol D1 agonists. The therapeutic promise of D1 agonists has been extant for several decades. The utility for improving aspects of cognition has been suggested by animal studies for two decades, and as reported by others in this symposium, is now starting to be confirmed in human studies. Similarly, D1 agonists have been shown to have dramatic effects in the symptomatic treatment of Parkinson’s disease, and have been suggested as have potential in ADHD and substance abuse among other disorders. We believe that this presentation will show that contrary to a popular view, that the D1 receptor is druggable and may lead to important new symptomatic medicine.
DOPAMINE RECEPTORS AS TARGETS FOR COGNITIVE DEFICITS IN SCHIZOPHRENIA: LESSONS FROM ANIMAL MODELS Patricio O’Donnell Pfizer As current antipsychotics are inefficient against cognitive deficits in schizophrenia, there is intense effort to unveil approaches that could improve prefrontal cortical function in this disorder. A convergent observation in many different developmental and genetic animal models is the alteration in postnatal maturation of a subset of inhibitory cortical interneurons. Fast-spiking interneurons mature during adolescence in naïve animals, and this maturation is evidenced by a dramatic change in the manner they are modulated by dopamine. While in juvenile rats and mice D1 and D2 receptor activation has opposite effects on interneuron excitability, in adult animals both D1 and D2 activation strongly enhances excitability. This adolescent maturation is affected in several different models with genetic (DISC1 dominant negative) or developmental (neonatal ventral hippocampal lesion) manipulations. Our data indicate the adult profile of dopamine modulation of interneurons is critical for correct cognitive performance and suggests enhancing interneuron and pyramidal cell function by augmenting D1 receptor activity can be a useful strategy to restore excitation-inhibition balance in an altered cortical circuit.
S7
Symposium NO SMOKE WITHOUT FIRE: COULD TOBACCO SMOKING HAVE A CAUSAL ROLE IN PSYCHOSIS? Chairpersons: James H. MacCabe and Robin M. Murray Discussant: John J. McGrath Sunday, 6 April 2014 2:00 PM – 4:00 PM Overall Abstract: The emerging findings on cannabis as a risk factor for psychosis and psychotic symptoms are still stimulating debate. It is proving difficult to disentangle biological effects from confounding by social factors and reverse causality (self-medication). However, cigarette smoking has been largely overlooked, despite the very high (∼80%) prevalence of cigarette smoking in patients with schizophrenia. Almost all smokers of cannabis also smoke tobacco, but not vice-versa. However, cigarette smoking is rarely adjusted for, so any association between cannabis use and psychosis could, in theory, be almost entirely confounded by cigarette smoking. We present four recent studies on this topic, all of which show convergent and complementary findings. The first two studies concern subclinical psychotic symptoms. Dr Marco Boks of UMC Utrecht will present findings from a cross-sectional survey of 1,900 young adults in The Netherlands. Cigarette smoking was associated with psychotic symptoms as strongly as was cannabis, but when both were included in the same model, cigarette smoking remained significantly associated with psychotic symptoms, whereas cannabis smoking did not. Suzanne Gage (University of Bristol) will present longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Smoking cigarettes or cannabis at age 16 predicted psychosis-like experiences at age 18. The effect of cigarette smoking persisted after adjustment for confounders including cannabis, but the effect of cannabis did not persist after adjusting for cigarette smoking. But does tobacco smoking increase clinically significant psychosis? Dr Marta di Forti (Institute of Psychiatry, King’s College London) will present case-control data from a first episode study. Tobacco use was four times more common in cases than controls, and the association persisted almost unchanged after adjusting for lifetime cannabis use. Lifetime cannabis use, on the other hand, showed no association with psychosis; although more frequent cannabis use and the use of more potent forms did. Lastly, Dr Pedro Muños Gurillo (Hospital de al Marina Baixa, Alicante) will present a series of systematic reviews and meta-analyses examining associations between tobacco smoking and psychosis. The results show that tobacco smoking is more common in first episode psychosis than in controls, that tobacco smokers have an earlier onset of psychosis than non-smokers, that patients with psychosis have an earlier uptake of tobacco smoking that controls, and that patients who smoke tobacco have more positive symptoms than non-smoking patients. Taken together, these findings raise the possibility that tobacco smoking may be an independent risk factor for psychosis. Given the collinearity between cannabis and tobacco smoking, it is even plausible that the reported associations between cannabis and psychosis may be driven by nicotine rather than cannabis. Many of the epidemiological difficulties complicating the study of cannabis, such as the role confounding and reverse causality, apply equally well to tobacco, with the added problem of collinearity between tobacco and cannabis smoking. These factors make this area very difficult to study. However, we argue that the problem may be tractable, for example by studying people who smoke tobacco but not cannabis, or who take cannabis without tobacco. We conclude that epidemiological and biological research on associations between tobacco smoking and psychosis has been neglected for too long, and should be pursued.
TOBACCO USE AND PSYCHOTIC EXPERIENCES IN UK TEENAGERS EVIDENCE FROM THE ALSPAC LONGITUDINAL STUDY Suzanne H. Gage 1 , Matthew Hickman 1 , Jon Heron 1 , Marcus Munafo 1 , Glyn Lewis 2 , Stanley Zammit 2 1 University of Bristol; 2 University of Cardiff, UK A consistent association between cannabis use and psychotic experiences (PEs) has been described, but confounding by tobacco is hard to rule out due to the practice of smoking cannabis with tobacco. We attempt to assess the independent effect of tobacco on PEs, as there are more tobacco users
and apomorphine) that have high D1 intrinsic activity, but these all are D2 selective and cause a host of dose-limiting D2-mediated pharmacological effects. These issues have provided a neuropsychopharmacological conundrum for decades, but recent advances in medicinal and computational chemistry have offered potential for the immediate future. The availability of high resolution crystal structures of relatively homologous receptors like the β-adrenergic receptor have, when combined with molecular manipulation of receptors, allowed a degree of study of ligand docking and activation mechanisms not previously possible. This, in turn, can permit the discovery or rationale modification of non-catechol-containing chemical backbones that may lead to novel drugs. In addition, has been widely recognized recently that it is possible to design novel drugs using two non-traditional strategies. One is the use of allosteric ligands that can affect signaling by interacting with the receptor and influence the actions of dopamine itself. The other is the ability to discover functionally selective ligands that would differentially activate signaling pathways mediated by the D1 receptor, leading to an improvement in therapeutic index. This presentation will report on several new directions in this area. We shall provide insights on how one can change the pharmacokinetic properties of molecules while retaining the desirable pharmacodynamic properties. One example to be presented will be the potential drug candidate EFF0311, in which a subtle chemical modification to dihydrexidine retained the desirable pharmacodynamic properties but provided a great improvement in pharmacokinetics. We shall also present data relating to the signaling properties of D1 receptor ligands, and how different signaling pathways affect functional responses in vivo. Finally, we shall summarize recent progress into the understanding and discovery of non-catechol D1 agonists. The therapeutic promise of D1 agonists has been extant for several decades. The utility for improving aspects of cognition has been suggested by animal studies for two decades, and as reported by others in this symposium, is now starting to be confirmed in human studies. Similarly, D1 agonists have been shown to have dramatic effects in the symptomatic treatment of Parkinson’s disease, and have been suggested as have potential in ADHD and substance abuse among other disorders. We believe that this presentation will show that contrary to a popular view, that the D1 receptor is druggable and may lead to important new symptomatic medicine.
DOPAMINE RECEPTORS AS TARGETS FOR COGNITIVE DEFICITS IN SCHIZOPHRENIA: LESSONS FROM ANIMAL MODELS Patricio O’Donnell Pfizer As current antipsychotics are inefficient against cognitive deficits in schizophrenia, there is intense effort to unveil approaches that could improve prefrontal cortical function in this disorder. A convergent observation in many different developmental and genetic animal models is the alteration in postnatal maturation of a subset of inhibitory cortical interneurons. Fast-spiking interneurons mature during adolescence in naïve animals, and this maturation is evidenced by a dramatic change in the manner they are modulated by dopamine. While in juvenile rats and mice D1 and D2 receptor activation has opposite effects on interneuron excitability, in adult animals both D1 and D2 activation strongly enhances excitability. This adolescent maturation is affected in several different models with genetic (DISC1 dominant negative) or developmental (neonatal ventral hippocampal lesion) manipulations. Our data indicate the adult profile of dopamine modulation of interneurons is critical for correct cognitive performance and suggests enhancing interneuron and pyramidal cell function by augmenting D1 receptor activity can be a useful strategy to restore excitation-inhibition balance in an altered cortical circuit.
S7
Symposium NO SMOKE WITHOUT FIRE: COULD TOBACCO SMOKING HAVE A CAUSAL ROLE IN PSYCHOSIS? Chairpersons: James H. MacCabe and Robin M. Murray Discussant: John J. McGrath Sunday, 6 April 2014 2:00 PM – 4:00 PM Overall Abstract: The emerging findings on cannabis as a risk factor for psychosis and psychotic symptoms are still stimulating debate. It is proving difficult to disentangle biological effects from confounding by social factors and reverse causality (self-medication). However, cigarette smoking has been largely overlooked, despite the very high (∼80%) prevalence of cigarette smoking in patients with schizophrenia. Almost all smokers of cannabis also smoke tobacco, but not vice-versa. However, cigarette smoking is rarely adjusted for, so any association between cannabis use and psychosis could, in theory, be almost entirely confounded by cigarette smoking. We present four recent studies on this topic, all of which show convergent and complementary findings. The first two studies concern subclinical psychotic symptoms. Dr Marco Boks of UMC Utrecht will present findings from a cross-sectional survey of 1,900 young adults in The Netherlands. Cigarette smoking was associated with psychotic symptoms as strongly as was cannabis, but when both were included in the same model, cigarette smoking remained significantly associated with psychotic symptoms, whereas cannabis smoking did not. Suzanne Gage (University of Bristol) will present longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Smoking cigarettes or cannabis at age 16 predicted psychosis-like experiences at age 18. The effect of cigarette smoking persisted after adjustment for confounders including cannabis, but the effect of cannabis did not persist after adjusting for cigarette smoking. But does tobacco smoking increase clinically significant psychosis? Dr Marta di Forti (Institute of Psychiatry, King’s College London) will present case-control data from a first episode study. Tobacco use was four times more common in cases than controls, and the association persisted almost unchanged after adjusting for lifetime cannabis use. Lifetime cannabis use, on the other hand, showed no association with psychosis; although more frequent cannabis use and the use of more potent forms did. Lastly, Dr Pedro Muños Gurillo (Hospital de al Marina Baixa, Alicante) will present a series of systematic reviews and meta-analyses examining associations between tobacco smoking and psychosis. The results show that tobacco smoking is more common in first episode psychosis than in controls, that tobacco smokers have an earlier onset of psychosis than non-smokers, that patients with psychosis have an earlier uptake of tobacco smoking that controls, and that patients who smoke tobacco have more positive symptoms than non-smoking patients. Taken together, these findings raise the possibility that tobacco smoking may be an independent risk factor for psychosis. Given the collinearity between cannabis and tobacco smoking, it is even plausible that the reported associations between cannabis and psychosis may be driven by nicotine rather than cannabis. Many of the epidemiological difficulties complicating the study of cannabis, such as the role confounding and reverse causality, apply equally well to tobacco, with the added problem of collinearity between tobacco and cannabis smoking. These factors make this area very difficult to study. However, we argue that the problem may be tractable, for example by studying people who smoke tobacco but not cannabis, or who take cannabis without tobacco. We conclude that epidemiological and biological research on associations between tobacco smoking and psychosis has been neglected for too long, and should be pursued.
TOBACCO USE AND PSYCHOTIC EXPERIENCES IN UK TEENAGERS EVIDENCE FROM THE ALSPAC LONGITUDINAL STUDY Suzanne H. Gage 1 , Matthew Hickman 1 , Jon Heron 1 , Marcus Munafo 1 , Glyn Lewis 2 , Stanley Zammit 2 1 University of Bristol; 2 University of Cardiff, UK A consistent association between cannabis use and psychotic experiences (PEs) has been described, but confounding by tobacco is hard to rule out due to the practice of smoking cannabis with tobacco. We attempt to assess the independent effect of tobacco on PEs, as there are more tobacco users