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TOBACCO USE AND PSYCHOTIC EXPERIENCES IN UK TEENAGERS – EVIDENCE FROM THE ALSPAC LONGITUDINAL STUDY
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.
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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
S8
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
who do not use cannabis than there are cannabis users who do not use tobacco. This means that while collinearity is a problem when assessing cannabis’ independent association with PEs, this is not the case for tobacco. We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort (N=2050). Tobacco use at 16 was assessed via self-report questionnaire. PEs at 18 were assessed via semi-structured interview. Confounders (pre-birth: family history of mental illness, maternal education; childhood: childhood depression, borderline personality traits, conduct disorder; and teenage: alcohol (AUDIT), cannabis use and other illicit drug use) were measured by questionnaire or interview. Ordered logistic regression analyses were conducted to investigate the associations between frequency of tobacco use at 16 (never/experimenter/weekly/daily) and severity of PEs at 18 (none/suspected/definite/definite plus problems). Anyone who was deemed to have PEs at interview at age 12 was excluded. There was a strong association between frequency of tobacco use at 16 and severity PEs at 18 (Odds Ratio (OR) 1.66,95% CI:1.38, 2.00). Adjustment for pre-birth confounders did not alter the relationship. Further adjustment for childhood confounders attenuated the relationship slightly, although a strong association remained (OR 1.63,95% CI:1.34,1.98). Additional adjustment for teenage confounders further attenuated the relationship, but a strong association still remained (OR 1.49,95% CI:1.12,1.97). The association between tobacco and PEs was robust to confounding by all measured variables. This was unexpected, and contrary to findings in the same sample investigating cannabis’ effect on PEs, where adjustment for illicit drug or tobacco use greatly attenuated the previously similar relationship. There is little evidence as yet for a psychogenic effect of tobacco, so our findings may be due to confounding. If so, there are implications for interpreting cannabis and psychosis associations, as not all studies adjust for tobacco, and those that do often use crude measures. As there is a genetic basis for tobacco use, future research could employ Mendelian Randomisation to assess tobacco’s independent causal effect on PEs, without confounding from cannabis or other illicit drugs.
ANOTHER GOOD REASON TO STOP SMOKING: A CASE-CONTROL STUDY OF THE ASSOCIATION BETWEEN TOBACCO USE AND FIRST EPISODE PSYCHOSIS Marta Di Forti 1 , Arianna Marconi 2 , Pedro Gurillo Muñoz 3 , Francesca Bianconi 4 , Matteo Bonomo 4 , Saffron H. Mirza 4 , Anna Kolliakou 4 , James H. MacCabe 4 , Robin M. Murray 1 1 Institute of Psychiatry, King’s College London; 2 Department of Pediatrics and Child and Adolescent Neuropsychiatry; 3 Sapienza University of Rome; 4 Dept of Psychosis Studies, IoP, King’s College, London, UK The prevalence of tobacco smoking among people affected by schizophrenia is approximately three times that in the general population and two times that in people suffering from affective disorders. Two recent meta-analyses support the evidence of a consistent association. However, it is frequently suggested that the smoking is an attempt to self-medicate to ameliorate symptoms or antipsychotic side effects. To address this issue we analysed the association between tobacco use and psychosis at the time of the first onset comparing several measures of tobacco use between first episode psychosis patients (FEP) and a sample of healthy population controls. We also aimed to investigate the independent and combined contribution of tobacco smoking and cannabis use to the onset of psychosis. As part of the Genetics and Psychosis (GAP) case-control study, FEP patients who met ICD10 criteria for non-affective and affective psychosis were invited to participate. Socio-demographic data and history of tobacco and cannabis use were collected for 677 individuals (358 cases, 319 population controls) using the Medical Research Council Social Schedule, the Cannabis Experience Questionnaire, and the Nicotine Dependence Questionnaire. Gender, ethnicity and cannabis use were found to be differently distributed amongst smokers and non-smokers; therefore these variables were controlled for in the logistic regression analyses. Results FEP patients were almost four times more likely (OR=3.84; 95% CI: 2.74–5.38) to have been smoking tobacco at some point before onset and almost 4 times more likely to be current smokers compared to controls (OR=3.98; 95% CI: 2.43–6.53). When in the same model, we controlled for socio-demographic variables, and we analysed the effect of both life time tobacco and cannabis use, the probability of suffering from a psychotic disorder remained significantly increased for both life time history of tobacco use (OR=4.84; 95% CI: 3.04–7.71) and cur-
rent use (OR=3.59; 95% CI: 1.93–6.67). After controlling for life time history of tobacco use, the association with increased probability of experiencing a psychotic disorder was significant for daily cannabis use (OR=3.04; 95% CI: 1.91–7.76; p=0.020) and use of high potency cannabis (skunk) (OR=2.91; 95% CI: 1.52–3.45; p=0.001) but not for lifetime cannabis use (OR=0.91; 95% CI: 0.55–2.29; p=0.731). Conclusions: Both ever and current tobacco use are associated with a 4 fold increased probability to suffer from a psychotic disorder compared to never users and past users. When we analysed the effect of tobacco and cannabis use in the same model:1) Tobacco use both lifetime and current significantly increased the probability of suffering a psychotic disorders; 2) Daily cannabis use and skunk use were still significantly associated with an increased probability of suffering a psychotic disorder. Finally, as our data were collected from cases within few weeks of the onset of their first episode, this indicates that FEP patients tobacco consumption is unlikely to be merely an attempt to 1) counteract the effects of antipsychotic medications; or 2) ameliorate psychotic symptoms. Neither is it just a proxy for cannabis use.
SYSTEMATIC REVIEW AND META-ANALYSIS ON ASSOCIATIONS BETWEEN TOBACCO SMOKING AND BOTH THE DIAGNOSIS AND THE CLINICAL SYMPTOMS OF PSYCHOSIS? Pedro Gurillo Muñoz 1 , Sameer Jauhar 2 , Robin M. Murray 2 , James H. MacCabe 3 1 Marina Baixa’s Hospital (Alicante); 2 Institute of Psychiatry, King’s College, London, UK; 3 Dept of Psychosis Studies, IoP, King’s College, London, UK Background: Despite acknowledgement that a significant number of people with psychosis smoke cigarettes [1], it is still unclear whether smoking has a role in the aetiology of psychosis [2], and whether it has an effect on clinical symptoms in those with established psychosis. Methods: We conducted systematic reviews and meta-analyses of the published literature on cigarette smoking, incorporating prospective, crosssectional, case-control and retrospective studies reporting rates of smoking and clinical symptoms scores in people with psychosis. Specifically we wished to examine rates of daily cigarette smoking, age of initation of nicotine use and age of onset of psychosis in those with psychosis versus controls, and the effects of smoking on positive and negative symptoms in those with psychosis who smoked cigarettes versus those who did not. Statistical analysis Analysis was carried out using the metan command in Stata 11.2 Results: 29 studies and 32 samples were identified, that gave rates of daily cigarette smoking, with a total sample of 3328 smokers and 3010 non-smokers. Longitudinal Prospective Studies: overall risk ratio of new psychotic disorders in daily smokers versus non-smokers (RR)=1.33 (95% CI, 1.17–1.53). Case-Control Studies: overall odds ratio of first episode of psychosis in daily smokers versus non-smokers (OR)=1.77 (95% CI, 1.09–2.88). Age of onset of psychosis: people with psychosis who were daily smokers and developed psychotic illness at an earlier age than non-smokers (SMD=−0.2). Age of initiation of smoking: there was an earlier age of smoking cigarettes in those with psychosis compared to healthy controls (SMD=−0.34). 14 samples (from 13 studies) were identified with symptom data on people with psychosis by smoking status. These showed greater symptomatology in smokers tan non-smokers with a standardized mean difference of 0.43, (95% CI 0.34 to 0.52), z=9.26, p<0.001 for positive symptoms (taking data from PANSS, BPRS and SAPS), 0.089 for negative symptoms, (95% CIs 0.023–0.155), z=2.64, p=0.008 (taking data from PANSS, BPRS and SANS). Discussion and conclusions: Daily smoking is associated with a modestly increased risk of psychotic disorder. Smokers have an earlier onset of psychosis than non-smokers and people with psychosis have an earlier age of initiation of smoking that controls. Cigarette smoking is also linked to an increase in positive symptoms, though the cross sectional nature of the data means that causality cannot be inferred. References: [1] De Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophrenia research. 2005;76(2-3):135–57. [2] Myles N, Newall HD, Curtis J, Nielssen O, Shiers D, Large M. Tobacco Use Before, At, and After First-Episode Psychosis: A Systematic Meta-Analysis. The Journal of clinical psychiatry. 2012 73(4):468–7.
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.
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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
S8
Abstracts of the 4th Biennial Schizophrenia International Research Conference / Schizophrenia Research 153, Supplement 1 (2014) S1–S384
who do not use cannabis than there are cannabis users who do not use tobacco. This means that while collinearity is a problem when assessing cannabis’ independent association with PEs, this is not the case for tobacco. We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort (N=2050). Tobacco use at 16 was assessed via self-report questionnaire. PEs at 18 were assessed via semi-structured interview. Confounders (pre-birth: family history of mental illness, maternal education; childhood: childhood depression, borderline personality traits, conduct disorder; and teenage: alcohol (AUDIT), cannabis use and other illicit drug use) were measured by questionnaire or interview. Ordered logistic regression analyses were conducted to investigate the associations between frequency of tobacco use at 16 (never/experimenter/weekly/daily) and severity of PEs at 18 (none/suspected/definite/definite plus problems). Anyone who was deemed to have PEs at interview at age 12 was excluded. There was a strong association between frequency of tobacco use at 16 and severity PEs at 18 (Odds Ratio (OR) 1.66,95% CI:1.38, 2.00). Adjustment for pre-birth confounders did not alter the relationship. Further adjustment for childhood confounders attenuated the relationship slightly, although a strong association remained (OR 1.63,95% CI:1.34,1.98). Additional adjustment for teenage confounders further attenuated the relationship, but a strong association still remained (OR 1.49,95% CI:1.12,1.97). The association between tobacco and PEs was robust to confounding by all measured variables. This was unexpected, and contrary to findings in the same sample investigating cannabis’ effect on PEs, where adjustment for illicit drug or tobacco use greatly attenuated the previously similar relationship. There is little evidence as yet for a psychogenic effect of tobacco, so our findings may be due to confounding. If so, there are implications for interpreting cannabis and psychosis associations, as not all studies adjust for tobacco, and those that do often use crude measures. As there is a genetic basis for tobacco use, future research could employ Mendelian Randomisation to assess tobacco’s independent causal effect on PEs, without confounding from cannabis or other illicit drugs.
ANOTHER GOOD REASON TO STOP SMOKING: A CASE-CONTROL STUDY OF THE ASSOCIATION BETWEEN TOBACCO USE AND FIRST EPISODE PSYCHOSIS Marta Di Forti 1 , Arianna Marconi 2 , Pedro Gurillo Muñoz 3 , Francesca Bianconi 4 , Matteo Bonomo 4 , Saffron H. Mirza 4 , Anna Kolliakou 4 , James H. MacCabe 4 , Robin M. Murray 1 1 Institute of Psychiatry, King’s College London; 2 Department of Pediatrics and Child and Adolescent Neuropsychiatry; 3 Sapienza University of Rome; 4 Dept of Psychosis Studies, IoP, King’s College, London, UK The prevalence of tobacco smoking among people affected by schizophrenia is approximately three times that in the general population and two times that in people suffering from affective disorders. Two recent meta-analyses support the evidence of a consistent association. However, it is frequently suggested that the smoking is an attempt to self-medicate to ameliorate symptoms or antipsychotic side effects. To address this issue we analysed the association between tobacco use and psychosis at the time of the first onset comparing several measures of tobacco use between first episode psychosis patients (FEP) and a sample of healthy population controls. We also aimed to investigate the independent and combined contribution of tobacco smoking and cannabis use to the onset of psychosis. As part of the Genetics and Psychosis (GAP) case-control study, FEP patients who met ICD10 criteria for non-affective and affective psychosis were invited to participate. Socio-demographic data and history of tobacco and cannabis use were collected for 677 individuals (358 cases, 319 population controls) using the Medical Research Council Social Schedule, the Cannabis Experience Questionnaire, and the Nicotine Dependence Questionnaire. Gender, ethnicity and cannabis use were found to be differently distributed amongst smokers and non-smokers; therefore these variables were controlled for in the logistic regression analyses. Results FEP patients were almost four times more likely (OR=3.84; 95% CI: 2.74–5.38) to have been smoking tobacco at some point before onset and almost 4 times more likely to be current smokers compared to controls (OR=3.98; 95% CI: 2.43–6.53). When in the same model, we controlled for socio-demographic variables, and we analysed the effect of both life time tobacco and cannabis use, the probability of suffering from a psychotic disorder remained significantly increased for both life time history of tobacco use (OR=4.84; 95% CI: 3.04–7.71) and cur-
rent use (OR=3.59; 95% CI: 1.93–6.67). After controlling for life time history of tobacco use, the association with increased probability of experiencing a psychotic disorder was significant for daily cannabis use (OR=3.04; 95% CI: 1.91–7.76; p=0.020) and use of high potency cannabis (skunk) (OR=2.91; 95% CI: 1.52–3.45; p=0.001) but not for lifetime cannabis use (OR=0.91; 95% CI: 0.55–2.29; p=0.731). Conclusions: Both ever and current tobacco use are associated with a 4 fold increased probability to suffer from a psychotic disorder compared to never users and past users. When we analysed the effect of tobacco and cannabis use in the same model:1) Tobacco use both lifetime and current significantly increased the probability of suffering a psychotic disorders; 2) Daily cannabis use and skunk use were still significantly associated with an increased probability of suffering a psychotic disorder. Finally, as our data were collected from cases within few weeks of the onset of their first episode, this indicates that FEP patients tobacco consumption is unlikely to be merely an attempt to 1) counteract the effects of antipsychotic medications; or 2) ameliorate psychotic symptoms. Neither is it just a proxy for cannabis use.
SYSTEMATIC REVIEW AND META-ANALYSIS ON ASSOCIATIONS BETWEEN TOBACCO SMOKING AND BOTH THE DIAGNOSIS AND THE CLINICAL SYMPTOMS OF PSYCHOSIS? Pedro Gurillo Muñoz 1 , Sameer Jauhar 2 , Robin M. Murray 2 , James H. MacCabe 3 1 Marina Baixa’s Hospital (Alicante); 2 Institute of Psychiatry, King’s College, London, UK; 3 Dept of Psychosis Studies, IoP, King’s College, London, UK Background: Despite acknowledgement that a significant number of people with psychosis smoke cigarettes [1], it is still unclear whether smoking has a role in the aetiology of psychosis [2], and whether it has an effect on clinical symptoms in those with established psychosis. Methods: We conducted systematic reviews and meta-analyses of the published literature on cigarette smoking, incorporating prospective, crosssectional, case-control and retrospective studies reporting rates of smoking and clinical symptoms scores in people with psychosis. Specifically we wished to examine rates of daily cigarette smoking, age of initation of nicotine use and age of onset of psychosis in those with psychosis versus controls, and the effects of smoking on positive and negative symptoms in those with psychosis who smoked cigarettes versus those who did not. Statistical analysis Analysis was carried out using the metan command in Stata 11.2 Results: 29 studies and 32 samples were identified, that gave rates of daily cigarette smoking, with a total sample of 3328 smokers and 3010 non-smokers. Longitudinal Prospective Studies: overall risk ratio of new psychotic disorders in daily smokers versus non-smokers (RR)=1.33 (95% CI, 1.17–1.53). Case-Control Studies: overall odds ratio of first episode of psychosis in daily smokers versus non-smokers (OR)=1.77 (95% CI, 1.09–2.88). Age of onset of psychosis: people with psychosis who were daily smokers and developed psychotic illness at an earlier age than non-smokers (SMD=−0.2). Age of initiation of smoking: there was an earlier age of smoking cigarettes in those with psychosis compared to healthy controls (SMD=−0.34). 14 samples (from 13 studies) were identified with symptom data on people with psychosis by smoking status. These showed greater symptomatology in smokers tan non-smokers with a standardized mean difference of 0.43, (95% CI 0.34 to 0.52), z=9.26, p<0.001 for positive symptoms (taking data from PANSS, BPRS and SAPS), 0.089 for negative symptoms, (95% CIs 0.023–0.155), z=2.64, p=0.008 (taking data from PANSS, BPRS and SANS). Discussion and conclusions: Daily smoking is associated with a modestly increased risk of psychotic disorder. Smokers have an earlier onset of psychosis than non-smokers and people with psychosis have an earlier age of initiation of smoking that controls. Cigarette smoking is also linked to an increase in positive symptoms, though the cross sectional nature of the data means that causality cannot be inferred. References: [1] De Leon J, Diaz FJ. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophrenia research. 2005;76(2-3):135–57. [2] Myles N, Newall HD, Curtis J, Nielssen O, Shiers D, Large M. Tobacco Use Before, At, and After First-Episode Psychosis: A Systematic Meta-Analysis. The Journal of clinical psychiatry. 2012 73(4):468–7.