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Cannabis use, gender and age of onset of schizophrenia: Data from the ÆSOP study
Psychiatry Research 215 (2014) 528–532
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Cannabis use, gender and age of onset of schizophrenia: Data from the ÆSOP study Kim Donoghue a,n, Gillian A. Doody b, Robin M. Murray c, Peter B. Jones d, Craig Morgan e, Paola Dazzan c, Jozella Hart e, Rodolfo Mazzoncini f, James H. MacCabe c Addictions Department, Institute of Psychiatry, King0 s College London, 4 Windsor Walk, London SE5 8BB, England, UK Division of Psychiatry, University of Nottingham, England, UK c Department of Psychosis Studies, Institute of Psychiatry, King0 s College London, England, UK d Department of Psychiatry, University of Cambridge, England, UK e Section of Social Psychiatry, Institute of Psychiatry, King0 s College London, England, UK f Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, Italy a
b
art ic l e i nf o
a b s t r a c t
Article history: Received 2 August 2013 Received in revised form 23 December 2013 Accepted 26 December 2013 Available online 4 January 2014
An earlier age of onset of schizophrenia has been identified as a poor prognostic indicator. The current study examines the interaction effect of gender and cannabis use on age of onset of schizophrenia and schizoaffective disorder. This research forms part of a two-centre epidemiological study of first-episode psychosis and included individuals with a diagnosis of schizophrenia or schizoaffective disorder and an age of onset between age 16 and 45. Kaplan–Meier curves and Cox proportional hazards regression were used to compare the effects of cannabis use and gender on age of first symptom of schizophrenia. Akaike0 s information criteria were used to find the model with the best fit to the data. Cannabis users had an earlier age of first symptom than non-users. There was an interaction with gender; the gender difference in age of onset was diminished in cannabis smokers compared with non-cannabis smokers. The model including cannabis use interacting with gender was the most parsimonious model, followed by cannabis use alone. The addition of other illegal drug use did not improve the model. Cannabis use is associated with an earlier age of onset of schizophrenia, and the gender difference in age of onset is reduced among cannabis smokers. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: First-episode Onset Positive symptoms Psychosis Substance misuse
1. Introduction A gender difference in age of onset of schizophrenia has been consistently reported and a recent meta-analysis has shown that males are on average 1.63 years younger when they first experience psychotic symptoms (Eranti et al., 2013). An earlier age of onset of schizophrenia has been associated with a poor prognosis, including greater cognitive and functional impairment, more severe symptoms, increased risk of relapse and re-hospitalisation, more days spent in hospital per year and less responsiveness to antipsychotics (DeLisi, 1992; Linszen et al., 1994; Rabinowitz et al., 2006; Rajji et al., 2009). Cannabis use is common in those with a first episode of psychosis, although more prevalent in males than females (e.g. Addington and Addington, 2007; Donoghue et al., 2011; Larsen et al., 2006; Sevy et al., 2010). Cannabis use has been found to be associated with an earlier age of onset of schizophrenia with
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Corresponding author. Tel.: +44 20 7848 0437; fax: +44 20 7848 0839. E-mail address: [email protected] (K. Donoghue).
0165-1781/$ - see front matter & 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.12.038
cannabis users developing the illness on average 2.70 years younger than non-cannabis users (Large et al., 2011). In further support of this relationship, an association has also been found between the age of initiation of cannabis use and the age of onset of schizophrenia (Leeson et al., 2012; Stefanis et al., 2013). The gender difference that is seen in age of onset may be confounded by differential cannabis use in males versus females, especially in countries with a high prevalence of cannabis use, such as the UK. The current study aims to study the gender differential for age of onset of schizophrenia, in a large first episode study in the UK, and to test the hypothesis that the gender difference in age of onset is confounded by cannabis use.
2. Method This research forms part of the Aetiology and Ethnicity of Schizophrenia and Other Psychoses (ÆSOP) study, a three-centre epidemiological study of firstepisode psychosis that took place in Nottingham, Bristol and South East London, although the Bristol sample lacked data on substance use so was not included in the current study. Ethical approval for the research was granted by the local Research Ethics Committees. Full details of entry criteria and study design have
K. Donoghue et al. / Psychiatry Research 215 (2014) 528–532 been reported elsewhere (Fearon et al., 2006; Kirkbride et al., 2006) therefore only those details relevant to the current research will be included here. All potential cases aged 16–64 who presented to mental health services with a first-episode of psychosis (ICD-10: F10–F29 and F30–F33) (WHO, 1992) between the years 1997 and 1999 were identified. All points of secondary mental health contact were monitored to identify all potential cases of first-episode psychosis. To further ensure that potential cases were not missed, a ‘leakage’ study was conducted using the methods of Cooper et al. (1987). This involved retrospectively scrutinising the electronic and paper information systems of mental health services to identify those patients who had been given a diagnosis of a psychotic syndrome. Case notes were reviewed and interviews with clinical staff were conducted to ensure these cases met the studies inclusion and exclusion criteria. Diagnoses were assigned for each participant subsequent to completed data collection by consensus meetings. A vignette that summarised the presenting complaint was presented in addition to clinical information from the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) or the Item Group Checklist (IGC) (WHO, 1994) for those that refused interview. Only participants who were aged younger than 45 at onset of psychotic symptoms and received a consensus diagnosis of schizophrenia or schizoaffective disorder according to the ICD-10 (F20, F25) were included in this paper. This is because late onset of schizophrenia may represent a distinct sub-sample of the disorder characterised by less severe positive symptoms, better cognitive function, lower dose antipsychotics, better every day functioning and increased prevalence in women (Vahia et al., 2010). Since there is no agreement on the cut-off age for late onset schizophrenia, the current study included only those individuals with a first episode of schizophrenia/ schizoaffective disorder presenting before age 45. The onset of psychosis was defined as the presence, for 1 week or more, of one of the following psychotic symptoms: delusions, hallucinations, marked thought disorder, marked psychomotor disorder (other than simple retardation or acceleration), and bizarre, grossly inappropriate and/or disorganised behaviour with a marked deterioration in function, and will be referred to as the onset of psychotic symptoms in the current study. Data relating to date of onset of psychosis was collated from interviews with the patient, a close relative, and clinical notes using the Personal and Psychiatric History Schedule (PPHS) (Jablensky et al., 1992). The age at which a person first came into contact with secondary mental health services with the presence of psychotic symptoms as described above will be referred to as the age of first contact in the current study. Duration of Untreated Psychosis (DUP) was defined as the period of time from the onset of psychosis to first contact with mental health services for psychosis. Information on drug use before the first presentation to mental health services was collected using three sources: (1) the PPHS, which included information provided by a relative or carer, (2) the SCAN and (3) clinical case notes. Data on drug use from these sources were collated retrospectively using an ad hoc secondary data collection schedule, which collated data on prevalence and type of substance use from all three sources. Where discrepancies between schedules were present, a hierarchical system was adopted: the information on drug use collected using the SCAN was deemed the most reliable, followed by the PPHS, and finally, clinical case notes. For the purposes of this study, a dichotomous variable for lifetime cannabis use or no use was created, where ‘use’ signified any use at all of cannabis before the first contact with mental health services. ‘No use’ represented those individuals who had not used cannabis before their first contact with mental health services. The variable ‘Other drug use’ was a dichotomous variable where ‘no use’ included those individuals who had never used an illegal substance (other than cannabis) in the time before their first contact with mental health services for psychosis.
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and a diagnosis of schizophrenia or schizoaffective disorder. Sixtyeight of these lacked data on cannabis use, leaving a sample of 143 for subsequent analyses. Key demographic data were compared for those with and without available information on cannabis use (Table 1), and there were no statistically significant differences between the two groups (p 40.05). Eighty five of the 143 participants included in the sample (59%) had a history of cannabis use in their lifetime. Cannabis users were younger at onset of psychotic symptoms and at first contact with mental health services compared to nonusers. A greater proportion of males had a history of cannabis use compared to females and a higher proportion of cannabis users had a history of other illegal drug use than those with no history of cannabis use. There was no difference between cannabis users and non-cannabis users for ethnicity, education level, employment status, DUP or Mode of Onset. Fig. 1 presents the Kaplan–Meier survival curve for the cumulative probability, by age, of the onset symptoms in males and females according to lifetime cannabis use. The mean age of psychotic symptom onset for males with no lifetime cannabis use was 27.07 (standard deviation (S.D.) ¼7.23) compared to a mean age of 30.76 (S.D. ¼8.15) for females. A similar mean age of psychotic symptom onset was found for males (mean¼25.52, S.D. ¼6.62) and females (mean¼26.03, S.D. ¼5.56) who had a history of cannabis use. Cox proportional hazards regression analysis was used to investigate the contribution of gender and cannabis use to age at symptom onset (Table 2). Male gender significantly contributed to age at symptom onset as did cannabis use. When age and gender were entered into a model together, cannabis use remained significant with a reduction in hazard ratio but male gender was no longer significant. The interaction between gender and cannabis use was significant. A large number of cannabis users (72.9%) also used other illegal drugs, therefore this variable was entered into a model, but this had little effect on the hazard ratios for the interaction for gender and cannabis use status. AIC was calculated to determine the best model (Table 3), the results of this analysis indicate that the model containing the interaction between cannabis use and gender only is the best with 28.7% probability. Adding information on other illegal drug use does not improve the fit. The model including gender alone fits the data much more poorly.
4. Discussion 2.1. Statistical analysis
4.1. Summary of findings 2
Independent samples t-tests, χ and Mann–Whitney U analysis were performed where appropriate to compare those for whom data on illegal drug use was available and for those for whom it was not. A Kaplan–Meier survival curve for age of onset of psychotic symptoms according to gender and cannabis use status was plotted. Cox proportional hazards regression was used to compare the effects of cannabis use and gender on age of onset of psychotic symptoms and expressed as hazard ratios. The proportional hazards assumption was checked using the scaled Schoenfeld residuals and no violation was detected. The Cox proportional hazards regression models were evaluated according to Akaike0 s information criteria (AIC) to determine the model that best fitted the data. AIC is a method of model selection, based on information theory, that compares the trade-off between the simplicity and goodness of fit of candidate models, aiming to find the model(s) with the best predictive validity in a future dataset. (Akaike, 1974). A smaller AIC indicates a better model. All analyses were conducted using Stata version 11 (StataCorp, 2009) and the alpha level was set at 0.05 (two-tailed).
3. Results Of the 511 participants included in the original AESOP study, 211 participants had an onset of symptoms before the age of 45
The use of cannabis is associated with an earlier age of onset of schizophrenia. There is a significant interaction between gender and cannabis use whereby the gender difference in age of onset is diminished in cannabis users. 4.2. Association of cannabis use with earlier age of onset The finding of an earlier age of onset in cannabis users is consistent with the results of a recent meta-analysis (Large et al., 2011). There are a number of potential explanations for an association between cannabis use and age of onset of schizophrenia (Large et al., 2011; Veen et al., 2004). A first possible explanation is of confounding by age; that cannabis use has no impact on age of onset of schizophrenia and the association seen is due to substance use being more common in younger, compared to older, individuals. However, the small age range of this population makes this explanation unlikely – furthermore, the finding that cannabis
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K. Donoghue et al. / Psychiatry Research 215 (2014) 528–532
Table 1 Sociodemographic data for those with and without cannabis use. No lifetime cannabis use, N ¼ 58
Lifetime cannabis use, N¼ 85
Missing data, N ¼68
Age at first contact, mean (S.D.)
30.1 (8.5)
26.4 (6.7)
29.28 (8.01)
Age at first psychotic symptom, mean (S.D.)
29.2 (7.9)
25.7 (6.3)
27.95 (7.48)
Gender, N (%) Male Female
25 (43.1) 33 (56.9)
62 (72.9) 23 (27.1)
49 (72.1) 19 (27.9)
Ethnicity, N (%) White British Black Caribbean Black African Other
17 18 14 9
(29.3) (31.0) (24.1) (15.5)
42 19 10 14
(49.4) (22.4) (11.8) (16.5)
24 20 12 12
(35.3) (29.4) (17.6) (17.6)
Education level, N (%) Higher Further GCSE No qualifications
9 15 18 16
(15.5) (25.9) (31.0) (27.6)
10 22 29 23
(11.9) (26.2) (34.5) (27.4)
8 20 13 24
(12.3) (30.8) (20.0) (36.9)
Employment status Employed Economically inactive Unemployed
15 (25.9) 11 (19.0) 32 (55.2)
23 (27.1) 8 (9.4) 54 (63.5)
Other drug use Other drug use No other drug use
3 (5.2) 55 (94.8)
62 (72.9) 23 (27.1)
DUP (days), median (interquartile range)
138 (29–546)
Mode of onset, N (%) Acute Insidious
10 (14.9) 9 (13.4) 48 (71.6)
86 (31–238)
21 (38.2) 34 (61.8)
163 (33–568)
34 (42.0) 47 (58.0)
19 (28.8) 47 (71.2)
Note: GCSE ¼ General Certificate of Higher Education or equivalent, further ¼qualifications achieved after compulsory education, and higher ¼academic and professional qualifications.
Percent of participants with psychotic symptoms
1.00
Table 2 Cox proportional hazards regression analysis.
0.75
0.50
0.25
0.00 10
20
30
40
50
Age (years) Male, no cannabis use Female, no cannabis use
Male, cannabis use Female, cannabis use
Fig. 1. Kaplan–Meier survival curve for the cumulative probability of age of the first psychotic symptom onset.
use, and illegal substance use in general is more prevalent in those with schizophrenia than in the general population (Mazzoncini et al., 2010) cannot be explained by confounding by age. A second explanation that has been advanced as a possible explanation for the association between cannabis use and schizophrenia is that of reverse causation: that individuals experiencing symptoms of schizophrenia smoke cannabis to self-medicate. While this explanation could explain the general association between cannabis use and schizophrenia, it is not clear how selfmedication could explain the association between cannabis use and earlier onset. This would require that individuals with earlier onset were more likely to self-medicate than those with a later onset. Furthermore, there is evidence from other studies that an
Hazard ratio
95% Confidence interval
p-Value
Cannabis
1.742
1.231–2.464
0.002
Male gender
1.542
1.090–2.183
0.014
Cannabis Male gender
1.573 1.293
1.081–2.290 0.889–1.881
0.018 0.179
Cannabis gender No cannabis use/male No cannabis use/female Cannabis use/male Cannabis use/female
1 (ref) 0.556 1.227 1.246
0.322–0.959 0.769–1.956 0.705–2.204
0.035 0.391 0.449
Cannabis gender No cannabis use/male No cannabis use/female Cannabis use/male Cannabis use/female
1 (ref) 0.558 1.059 1.068
0.323–0.965 0.624–1.796 0.571–1.999
0.037 0.832 0.836
Other illegal drug use
1.297
0.844–1.994
0.235
increase in cannabis use predates the onset of the prodrome in individuals who develop schizophrenia (Compton et al., 2009). A third explanation is that cannabis is a causal factor in the development of schizophrenia. There is growing evidence in favour of this hypothesis, for example, a meta-analysis found that there is a significant increased risk of developing a psychotic disorder in those who have used cannabis (Moore et al., 2007). The relationship has been found to be dose dependent (Di Forti et al., 2009) and the age of first cannabis use is associated with the age of onset of psychosis (Casadio et al., 2011).
K. Donoghue et al. / Psychiatry Research 215 (2014) 528–532
Table 3 The Akaike information criterion (AIC) to determine the Cox proportional hazards regression models which fit the data most parsimoniously. Model
AIC
Delta AIC
Likelihood ratio
Akaike0 s weight
Cannabis use gender Cannabis use Cannabis use, gender Cannabis use gender, other illegal drug use Gender
1133.230 1133.573 1133.739 1133.801
0 0.343 0.509 0.571
1 0.842 0.775 0.752
0.287 0.242 0.222 0.215
1137.493 4.263
0.119
0.034
Earlier age of onset of schizophrenia is generally associated with more severe illness: greater cognitive and functional impairment, more severe symptoms and greater risk of relapse (DeLisi, 1992; Linszen et al., 1994; Rabinowitz et al., 2006; Rajji et al., 2009). However, there is some evidence that individuals with schizophrenia and comorbid cannabis use have a different pattern. Schizophrenia patients who use cannabis have been shown to have better cognitive reserve (Donoghue and Doody, 2012), which is associated with better functional outcome (González-Blanch et al., 2010; Leeson et al., 2009; Malla et al., 2002; Milev et al., 2005) and fewer neurodevelopmental markers of schizophrenia, for example fewer neurological soft signs (Bersani et al., 2002; Ruiz-Veguilla et al., 2009). Leeson et al. (2012) suggested that cannabis use may trigger the onset of schizophrenia in individuals who would otherwise have had good prognostic features (i.e. higher premorbid IQ, better functional outcome and less severe symptoms). This raises the question of whether cannabis use may advance the onset of schizophrenia, in individuals where it would have occurred later, or perhaps not at all, without the presence of cannabis use or other illegal drug. Genetic variations have been explored with evidence to suggest that those with a psychometric of familial risk are more susceptible to cannabis use but there is little robust evidence at the molecular level (Decoster et al., 2012). Dysregulation of the endogenous endocannabinoid system has also received some attention to help explain the association between cannabis use and schizophrenia. For example, a recent study found greater global type 1 cannabinoid receptor binding in those with a diagnosis of schizophrenia compared to healthy controls, which was negatively correlated with negative symptoms in those who were antipsychotic free (Ceccarini et al., 2013). Those who use cannabis and subsequently develop schizophrenia may have a vulnerability to cannabis that is not present in those that use cannabis and do not develop schizophrenia. 4.3. Interactions between cannabis use and gender The current study has found that the use of cannabis results in an age of onset of psychotic symptoms for females that is comparable with males. These findings suggest that the use of cannabis may have a greater impact on females than males and would explain the narrowing of the gap in age of onset of psychosis between the genders. Oestrogen may have a neuroprotective role in women, leading to a later age of onset in noncannabis users (Kulkarni et al., 2012; Wise et al., 2001). There is a 20-fold increase on risk of onset of a first episode of psychosis or relapse of symptoms during the postpartum period when there is a dramatic reduction in oestrogen levels. There is a second spike in incidence of psychosis in women between the ages 45 and 54, with unusually severe symptomatology and treatment resistance, which is thought to be related to falling levels of oestrogen in older women (Begemann et al., 2012; Hayes et al., 2012). Furthermore, there is evidence to indicate that more severe psychotic symptoms are present during the phases of the menstrual cycle
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when oestrogen levels are low in female patients with schizophrenia (Bergemann et al., 2007). A number of animal models of schizophrenia have indicated that oestrogen is involved with the mechanisms of the neurotransmitters dopamine, glutamate and serotonin and resultant antipsychotic-like activity (Kulkarni et al., 2012). The association between oestrogen and schizophrenia has led to the exploration of using oestrogen therapeutically to augment antipsychotic medications. A Cochrane review of clinical research until 2005 found that adjunctive oestrogen therapy did not offer any additional therapeutic advantages (Chua et al., 2005). However, a more recent meta-analysis reported more promising findings but further, large, randomised controlled trials are required before recommendations for clinical application can be made (Begemann et al., 2012). The use of cannabis and other drugs may reduce or abolish the protective effect of oestrogen leading to a reduction in the age of onset in women to equal that of men. 4.4. The role of other illegal drugs Other illegal drug use was not a significant predictor of age of onset of psychotic symptoms when entered into a model with an interaction for the gender/cannabis use status and had little effect on the hazard ratios. This is in line with some previous research that has found that cannabis use was associated with age of onset of psychotic symptoms irrespective of other illegal drug use (Barnes et al., 2006; Barrigón et al., 2010; Dekker et al., 2012; González-Pinto et al., 2008; Öngür et al., 2009) but also in conflict with others (De Hert et al., 2011 González-Pinto et al., 2008; Veen et al., 2004). 4.5. Strengths and limitations Data for the current study was derived from a large, firstepisode epidemiological study of psychosis but there are a number of limitations of the current study that must be taken into account when interpreting its results. The data on substance misuse was collected retrospectively and relied on self-report. However, there is evidence to suggest that self-report data is reliable and consistent with urine drug screening in those with cannabis use (Martin et al., 1988) and with schizophrenia (Kedzior et al., 2006). Furthermore, the use of cannabis and other illegal substances was in many cases internally validated using a variety of sources including information from the participant, a relative or carer and clinical case notes. The current study did not have information available as to when use of illegal substances began, frequency and quantity of use. 4.6. Conclusion The current study lends further support to evidence that the use of cannabis is associated with of an earlier onset of schizophrenia, which is not explained by confounding whereby cannabis and other illegal drug use is more common in males. Cannabis use appears to shorten the gap in the age of onset of schizophrenia for males and females. References Addington, J., Addington, D., 2007. Patterns predictors and impact of substance use in early psychosis: a longitudinal study. Acta Psychiatrica Scandinavica 115, 304–309. Akaike, H., 1974. A new look at the statistical model identification. IEEE Transactions on Automatic Control 19, 716–723, http://dx.doi.org/10.1109/TAC.1974. 1100705. Barnes, T.R.E., Mutsatsa, S.H., Hutton, S.B., Watt, H.C., Joyce, E.M., 2006. Comorbid substance use and age at onset of schizophrenia. British Journal of Psychiatry 188, 237–242.
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Barrigón, M.L., Gurpegui, M., Ruiz-Veguilla, M., Diaz, F.J., Anguita, M., Sarramea, F., Cervilla, J., 2010. Temporal relationship of first-episode non-affective psychosis with cannabis use: a clinical verification of an epidemiological hypothesis. Journal of Psychiatric Research 44, 413–420. Bergemann, N., Parzer, P., Runnebaum, B., Resch, F., Mundt, C., 2007. Estrogen, menstrual cycle phases, and psychopathology in women suffering from schizophrenia. Psychological Medicine 37, 1427–1436. Begemann, M.J.H., Dekker, C.F., van Lunenburg, M., Sommer, I.E., 2012. Estrogen augmentation in schizophrenia: a quantitative review of current evidence. Schizophrenia Research 141, 179–184. Bersani, G., Orlandi, V., Gherardelli, D., Pancheri, P., 2002. Cannabis and neurological soft signs in schizophrenia: absence of relationship and influence on psychopathology. Psychopathology 34, 289–295. Casadio, P., Fernandes, C., Murray, R.M., Di Forti, M., 2011. Cannabis use in young people: the risk for Schizophrenia. Neuroscience and Behavioural Reviews 35, 1779–1787. Ceccarini, J., De Hart, M., Van Winkel, R., Peuskens, J., Bormans, G., Kranaster, L., Enning, F., Koethe, D., Leweke, F.M., Van Laere, K., 2013. NeuroImage 79, 304–312. Chua, W.L., de Lzquierdo, S.A., Kulkarni, J., Mortimer, A., 2005. Estrogen for schizophrenia. Cochrane Database for Systematic Reviews 19 (4). (art. no.: CD004719) pp. 1–37. Compton, M.T., Kelley, M.E., Ramsay, C.E., Pringle, M., Goulding, S.M., Esterberg, M. L., Stewart, T., Walker, E.F., 2009. Association of pre-onset cannabis, alcohol and tobacco use with age of onset of prodrome and age of onset of psychosis in first-episode patients. American Journal of Psychiatry 166, 1251–1257. Cooper, J.E., Goodhead, D., Craig, T., Harris, M., Howat, J., Korer, J., 1987. The incidence of schizophrenia in Nottingham. British Journal of Psychiatry 151, 619–626. Decoster, J., van Os, J., Myin-Germeys, I., De Hart, M., can Winkel, R., 2012. Genetic variation underlying psychosis-inducing effects of cannabis: critical review and future directions. Current Pharmaceutical Design 18, 5015–5023. De Hert, M., Wanpers, M., Jendricko, T., Franic, T., Vidovic, D., De Vriendt, N., Sweers, K., Peuskens, J., van Winkel, R., 2011. Effects of cannabis use on age at onset in schizophrenia and bipolar disorder. Schizophrenia Research 126, 270–276. Dekker, N., Meijer, J., Koeter, M., van den Brink, W., van Beveren, N., Kahn, R.S., Linszen, D.H., van Os, J., Wiersma, D., Bruggeman, R., Cahn, W., de Haan, L., Krabbendam, L., Myin-Germeys, I., GROUP Investigators, 2012. Age of onset of non-affective psychosis in relation to cannabis use, other drug use and gender. Psychological Medicine 42, 1903–1911. DeLisi, L.E., 1992. The significance of age of onset for schizophrenia. Schizophrenia Bulletin 18, 209–215. Di Forti, M., Morgan, C., Dazzan, P., Pariante, C., Mondelli, V., Marques, T.R., Handley, R., Luzi, S., Russo, M., Paparelli, A., Butt, A., Stilo, S.A., Wiffen, B., Powell, J., Murray, R.M., 2009. High-potency cannabis and the risk of psychosis. British Journal of Psychiatry 195, 488–491. Donoghue, K., Medley, I., Brewin, J., Glazebrook, C., Mason, P., Cantwell, R., Jones, P. B., Harrison, G., Doody, G.A., 2011. The association between substance misuse and first-episode psychosis in a defined UK geographical area during the 1990s. Social Psychiatry and Psychiatric Epidemiology 46, 137–142. Donoghue, K., Doody, G.A., 2012. Effect of illegal substance use on cognitive function in individuals with a psychotic disorder, a review and meta-analysis. Neuropsychology 26, 785–801. Eranti, S.V., MacCabe, J.H., Bundy, H., Murray, R.M., 2013. Gender differences in age of onset of schizophrenia: a meta-analysis. Psychological Medicine 43, 155–167. Fearon, P., Kirkbride, J.B., Morgan, C., Dazzan, P., Morgan, K., Lloyd, T., Hutchinson, G., Tarrant, J., Fung, W.L.A., Holloway, J., Mallett, R., Harrison, G., Leff, J., Jones, P. B., Murray, R.M., 2006. Incidence of schizophrenia and other psychoses in ethnic minority groups: results from the MRC funded ÆSOP study. Psychological Medicine 36, 1541–1550. González-Blanch, C., Perez-Iglesias, R., Pardo-Garciá, G., Rodríguez-Sánchez, J.M., Martínez-García, O., Vázquez-Barquero, J.L., Crespo-Facorro, B., 2010. Prognostic value of cognitive functioning for global recovery in first-episode schizophrenia. Psychological Medicine 40, 935–944. González-Pinto, A., Vega, P., Ibáñez, B., Mosquera, F., Barbeito, S., Gutiérrez, M., Ruiz de Azúa, S., Ruiz, I., Vieta, E., 2008. Impact of cannabis and other drugs on age of onset of psychosis. Journal of Clinical Psychiatry 69, 1210–1216. Hayes, E., Gavrilidis, E., Kulkarni, J., 2012. The role of oestrogen and other hormones in the pathophysiology and treatment of schizophrenia. Schizophrenia Research and Treatment, 1–8. Jablensky, A., Satorius, N., Ernberg, G., Anker, M., Korten, A., Cooper, J.E., Day, R., Bertelsen, A., 1992. Schizophrenia: manifestations, incidence and course in different cultures – a World Health Organisation ten-country study. Psychological Medicine Monograph Supplement 20, 1–97.
Kedzior, K.K., Badcock, J.C., Martin-Iverson, M.T., 2006. Validity and consistency of self-reports regarding substance use in general research volunteers, including regular cannabis users and schizophrenia patients. Substance Use and Misuse 41, 743–750. Kirkbride, J.B., Fearon, P., Morgan, C., Dazzan, P., Morgan, K., Tarrant, J., Lloyd, T., Holloway, J., Hutchinson, G., Leff, J.P., Mallett, R.M., Harrison, G.L., Murray, R.M., Jones, P.B., 2006. Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center ÆSOP study. Archives of General Psychiatry 63, 250–258. Kulkarni, J., Hayes, E., Gavrilidis, E., 2012. Hormones and schizophrenia. Current Opinion in Psychiatry 25, 89–95. Large, M., Sharma, S., Compton, M.T., Slade, T., Nielssen, O., 2011. Cannabis use and earlier onset of psychosis. Archives of General Psychiatry 68, 555–561. Larsen, T.K., Melle, I., Auestad, B., Fris, S., Haahr, U., Johannessen, J.O., Opjordsmoen, S., Rund, B.R., Simonsen, E., Vaglum, P., McGlashan, T.H., 2006. Substance abuse in first-episode non-affective psychosis. Schizophrenia Research 88, 55–62. Leeson, V.C., Barnes, T.R.E., Hutton, S.B., Ron, M.A., Joyce, E.M., 2009. IQ as a predictor of functional outcome in schizophrenia: a longitudinal four year study of first-episode psychosis. Schizophrenia Research 107, 55–60. Leeson, V.C., Harrison, I., Ron, M.A., Barnes, T.R.E., Joyce, E.M., 2012. The effect of cannabis use and cognitive reserve on age of onset and psychosis outcomes in first-episode schizophrenia. Schizophrenia Bulletin 38, 873–880. Linszen, D.H., Dingemans, P.M., Lenior, M.E., 1994. Cannabis abuse and the course of recent-onset schizophrenia disorders. Archives of General Psychiatry 51, 273–279. Martin, G.W., Wilkinson, D.A., Kapur, B.M., 1988. Validation of self-reported cannabis use by urine analysis. Addictive Behavior 13, 147–150. Malla, A.K., Norman, R.M.G., Manchanda, R., Townesend, L., 2002. Symptoms, cognition, treatment adherence and functional outcome in first-episode psychosis. Psychological Medicine 32, 1109–1119. Mazzoncini, R., Donoghue, K., Hart, J., Doody, G.A., Dazzan, P., Jones, P.B., Morgan, K., Murray, R.M., Fearon, P., 2010. Illicit substance use and its correlates in first episode psychosis. Acta Psychiatrica Scandinavica 121, 351–358. Milev, P., Ho, B.-C., Arndt, S., Andreasen, N.C., 2005. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry 162, 495–506. Moore, T.H., Zammit, S., Lingford-Hughes, A., Barnes, T.R., Jones, P.B., Burke, M., Lewis, G., 2007. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370, 319–328. Öngür, D., Lin, L., Cohen, B.M., 2009. Clinical characteristics influencing age of onset in psychotic disorders. Comprehensive Psychiatry 50, 13–19. Rabinowitz, J., Levine, S.Z., Hafner, H., 2006. A population based elaboration of the role of age of onset on the course of schizophrenia. Schizophrenia Research 88, 96–101. Rajji, T.K., Ismail, Z., Mulsant, B.H., 2009. Age of onset and cognition in schizophrenia: meta-analysis. British Journal of Psychiatry 195, 286–293. Ruiz-Veguilla, M., Gurpegui, M., Barrigon, M.L., Ferrin, M., Marin, E., Rubio, J.L., Gutierrez, B., Pintor, A., Cervilla, J., 2009. Fewer neurological soft signs among first episode psychosis patients with heavy cannabis use. Schizophrenia Research 107, 158–164. Sevy, S., Robinson, D.G., Napolitano, B., Patel, R.C., Gunduz-Bruce, H., Miller, R., McCormack, J., Lorell, B.S., Kane, J., 2010. Are cannabis use disorders associated with an earlier age of onset of psychosis? Schizophrenia Research 120, 101–107. StataCorp, 2009. Stata Statistical Software: Release 11. StataCorp LP, College Station, TX. Stefanis, N.C., Dragovic, M., Power, B.D., Jablensky, A., Castle, D., Morgan, V.A., 2013. Age at initiation of cannabis use predicts age of onset of psychosis: the 7- to 8year trend. Schizophrenia Bulletin, http://dx.doi.org/10.1093/schbul/sbs188. (advance access publication). Vahia, I.V., Palmer, B.W., Depp, C., Fellows, I., Golsham, S., Kraemer, H.C., Jeste, D.V., 2010. Is late-onset schizophrenia a subtype of schizophrenia? Acta Psychiatrica Scandinavica 122, 414–426. Veen, N.D., Selten, J.-P., van der Tweel, I., Feller, W.G., Hoek, H.W., Kahn, R.S., 2004. Cannabis use and age of onset of schizophrenia. American Journal of Psychiatry 161, 501–506. Wise, P.M., Dubal, D.B., Wilson, M.E., Rau, S.W., Böttner, M., 2001. Minireview: neuroprotective effects of oestrogen – new insights into mechanisms of action. Endocrinology 142, 969–973. World Health Organization, 1992. International Classification of Diseases, 10th Revision (ICD-10). World Health Organisation, Geneva, Switzerland. World Health Organization, 1994. Schedules for Clinical Assessment in Neuropsychiatry. World Health Organization, Geneva, Switzerland.
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Cannabis use, gender and age of onset of schizophrenia: Data from the ÆSOP study Kim Donoghue a,n, Gillian A. Doody b, Robin M. Murray c, Peter B. Jones d, Craig Morgan e, Paola Dazzan c, Jozella Hart e, Rodolfo Mazzoncini f, James H. MacCabe c Addictions Department, Institute of Psychiatry, King0 s College London, 4 Windsor Walk, London SE5 8BB, England, UK Division of Psychiatry, University of Nottingham, England, UK c Department of Psychosis Studies, Institute of Psychiatry, King0 s College London, England, UK d Department of Psychiatry, University of Cambridge, England, UK e Section of Social Psychiatry, Institute of Psychiatry, King0 s College London, England, UK f Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, Italy a
b
art ic l e i nf o
a b s t r a c t
Article history: Received 2 August 2013 Received in revised form 23 December 2013 Accepted 26 December 2013 Available online 4 January 2014
An earlier age of onset of schizophrenia has been identified as a poor prognostic indicator. The current study examines the interaction effect of gender and cannabis use on age of onset of schizophrenia and schizoaffective disorder. This research forms part of a two-centre epidemiological study of first-episode psychosis and included individuals with a diagnosis of schizophrenia or schizoaffective disorder and an age of onset between age 16 and 45. Kaplan–Meier curves and Cox proportional hazards regression were used to compare the effects of cannabis use and gender on age of first symptom of schizophrenia. Akaike0 s information criteria were used to find the model with the best fit to the data. Cannabis users had an earlier age of first symptom than non-users. There was an interaction with gender; the gender difference in age of onset was diminished in cannabis smokers compared with non-cannabis smokers. The model including cannabis use interacting with gender was the most parsimonious model, followed by cannabis use alone. The addition of other illegal drug use did not improve the model. Cannabis use is associated with an earlier age of onset of schizophrenia, and the gender difference in age of onset is reduced among cannabis smokers. & 2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: First-episode Onset Positive symptoms Psychosis Substance misuse
1. Introduction A gender difference in age of onset of schizophrenia has been consistently reported and a recent meta-analysis has shown that males are on average 1.63 years younger when they first experience psychotic symptoms (Eranti et al., 2013). An earlier age of onset of schizophrenia has been associated with a poor prognosis, including greater cognitive and functional impairment, more severe symptoms, increased risk of relapse and re-hospitalisation, more days spent in hospital per year and less responsiveness to antipsychotics (DeLisi, 1992; Linszen et al., 1994; Rabinowitz et al., 2006; Rajji et al., 2009). Cannabis use is common in those with a first episode of psychosis, although more prevalent in males than females (e.g. Addington and Addington, 2007; Donoghue et al., 2011; Larsen et al., 2006; Sevy et al., 2010). Cannabis use has been found to be associated with an earlier age of onset of schizophrenia with
n
Corresponding author. Tel.: +44 20 7848 0437; fax: +44 20 7848 0839. E-mail address: [email protected] (K. Donoghue).
0165-1781/$ - see front matter & 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.psychres.2013.12.038
cannabis users developing the illness on average 2.70 years younger than non-cannabis users (Large et al., 2011). In further support of this relationship, an association has also been found between the age of initiation of cannabis use and the age of onset of schizophrenia (Leeson et al., 2012; Stefanis et al., 2013). The gender difference that is seen in age of onset may be confounded by differential cannabis use in males versus females, especially in countries with a high prevalence of cannabis use, such as the UK. The current study aims to study the gender differential for age of onset of schizophrenia, in a large first episode study in the UK, and to test the hypothesis that the gender difference in age of onset is confounded by cannabis use.
2. Method This research forms part of the Aetiology and Ethnicity of Schizophrenia and Other Psychoses (ÆSOP) study, a three-centre epidemiological study of firstepisode psychosis that took place in Nottingham, Bristol and South East London, although the Bristol sample lacked data on substance use so was not included in the current study. Ethical approval for the research was granted by the local Research Ethics Committees. Full details of entry criteria and study design have
K. Donoghue et al. / Psychiatry Research 215 (2014) 528–532 been reported elsewhere (Fearon et al., 2006; Kirkbride et al., 2006) therefore only those details relevant to the current research will be included here. All potential cases aged 16–64 who presented to mental health services with a first-episode of psychosis (ICD-10: F10–F29 and F30–F33) (WHO, 1992) between the years 1997 and 1999 were identified. All points of secondary mental health contact were monitored to identify all potential cases of first-episode psychosis. To further ensure that potential cases were not missed, a ‘leakage’ study was conducted using the methods of Cooper et al. (1987). This involved retrospectively scrutinising the electronic and paper information systems of mental health services to identify those patients who had been given a diagnosis of a psychotic syndrome. Case notes were reviewed and interviews with clinical staff were conducted to ensure these cases met the studies inclusion and exclusion criteria. Diagnoses were assigned for each participant subsequent to completed data collection by consensus meetings. A vignette that summarised the presenting complaint was presented in addition to clinical information from the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) or the Item Group Checklist (IGC) (WHO, 1994) for those that refused interview. Only participants who were aged younger than 45 at onset of psychotic symptoms and received a consensus diagnosis of schizophrenia or schizoaffective disorder according to the ICD-10 (F20, F25) were included in this paper. This is because late onset of schizophrenia may represent a distinct sub-sample of the disorder characterised by less severe positive symptoms, better cognitive function, lower dose antipsychotics, better every day functioning and increased prevalence in women (Vahia et al., 2010). Since there is no agreement on the cut-off age for late onset schizophrenia, the current study included only those individuals with a first episode of schizophrenia/ schizoaffective disorder presenting before age 45. The onset of psychosis was defined as the presence, for 1 week or more, of one of the following psychotic symptoms: delusions, hallucinations, marked thought disorder, marked psychomotor disorder (other than simple retardation or acceleration), and bizarre, grossly inappropriate and/or disorganised behaviour with a marked deterioration in function, and will be referred to as the onset of psychotic symptoms in the current study. Data relating to date of onset of psychosis was collated from interviews with the patient, a close relative, and clinical notes using the Personal and Psychiatric History Schedule (PPHS) (Jablensky et al., 1992). The age at which a person first came into contact with secondary mental health services with the presence of psychotic symptoms as described above will be referred to as the age of first contact in the current study. Duration of Untreated Psychosis (DUP) was defined as the period of time from the onset of psychosis to first contact with mental health services for psychosis. Information on drug use before the first presentation to mental health services was collected using three sources: (1) the PPHS, which included information provided by a relative or carer, (2) the SCAN and (3) clinical case notes. Data on drug use from these sources were collated retrospectively using an ad hoc secondary data collection schedule, which collated data on prevalence and type of substance use from all three sources. Where discrepancies between schedules were present, a hierarchical system was adopted: the information on drug use collected using the SCAN was deemed the most reliable, followed by the PPHS, and finally, clinical case notes. For the purposes of this study, a dichotomous variable for lifetime cannabis use or no use was created, where ‘use’ signified any use at all of cannabis before the first contact with mental health services. ‘No use’ represented those individuals who had not used cannabis before their first contact with mental health services. The variable ‘Other drug use’ was a dichotomous variable where ‘no use’ included those individuals who had never used an illegal substance (other than cannabis) in the time before their first contact with mental health services for psychosis.
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and a diagnosis of schizophrenia or schizoaffective disorder. Sixtyeight of these lacked data on cannabis use, leaving a sample of 143 for subsequent analyses. Key demographic data were compared for those with and without available information on cannabis use (Table 1), and there were no statistically significant differences between the two groups (p 40.05). Eighty five of the 143 participants included in the sample (59%) had a history of cannabis use in their lifetime. Cannabis users were younger at onset of psychotic symptoms and at first contact with mental health services compared to nonusers. A greater proportion of males had a history of cannabis use compared to females and a higher proportion of cannabis users had a history of other illegal drug use than those with no history of cannabis use. There was no difference between cannabis users and non-cannabis users for ethnicity, education level, employment status, DUP or Mode of Onset. Fig. 1 presents the Kaplan–Meier survival curve for the cumulative probability, by age, of the onset symptoms in males and females according to lifetime cannabis use. The mean age of psychotic symptom onset for males with no lifetime cannabis use was 27.07 (standard deviation (S.D.) ¼7.23) compared to a mean age of 30.76 (S.D. ¼8.15) for females. A similar mean age of psychotic symptom onset was found for males (mean¼25.52, S.D. ¼6.62) and females (mean¼26.03, S.D. ¼5.56) who had a history of cannabis use. Cox proportional hazards regression analysis was used to investigate the contribution of gender and cannabis use to age at symptom onset (Table 2). Male gender significantly contributed to age at symptom onset as did cannabis use. When age and gender were entered into a model together, cannabis use remained significant with a reduction in hazard ratio but male gender was no longer significant. The interaction between gender and cannabis use was significant. A large number of cannabis users (72.9%) also used other illegal drugs, therefore this variable was entered into a model, but this had little effect on the hazard ratios for the interaction for gender and cannabis use status. AIC was calculated to determine the best model (Table 3), the results of this analysis indicate that the model containing the interaction between cannabis use and gender only is the best with 28.7% probability. Adding information on other illegal drug use does not improve the fit. The model including gender alone fits the data much more poorly.
4. Discussion 2.1. Statistical analysis
4.1. Summary of findings 2
Independent samples t-tests, χ and Mann–Whitney U analysis were performed where appropriate to compare those for whom data on illegal drug use was available and for those for whom it was not. A Kaplan–Meier survival curve for age of onset of psychotic symptoms according to gender and cannabis use status was plotted. Cox proportional hazards regression was used to compare the effects of cannabis use and gender on age of onset of psychotic symptoms and expressed as hazard ratios. The proportional hazards assumption was checked using the scaled Schoenfeld residuals and no violation was detected. The Cox proportional hazards regression models were evaluated according to Akaike0 s information criteria (AIC) to determine the model that best fitted the data. AIC is a method of model selection, based on information theory, that compares the trade-off between the simplicity and goodness of fit of candidate models, aiming to find the model(s) with the best predictive validity in a future dataset. (Akaike, 1974). A smaller AIC indicates a better model. All analyses were conducted using Stata version 11 (StataCorp, 2009) and the alpha level was set at 0.05 (two-tailed).
3. Results Of the 511 participants included in the original AESOP study, 211 participants had an onset of symptoms before the age of 45
The use of cannabis is associated with an earlier age of onset of schizophrenia. There is a significant interaction between gender and cannabis use whereby the gender difference in age of onset is diminished in cannabis users. 4.2. Association of cannabis use with earlier age of onset The finding of an earlier age of onset in cannabis users is consistent with the results of a recent meta-analysis (Large et al., 2011). There are a number of potential explanations for an association between cannabis use and age of onset of schizophrenia (Large et al., 2011; Veen et al., 2004). A first possible explanation is of confounding by age; that cannabis use has no impact on age of onset of schizophrenia and the association seen is due to substance use being more common in younger, compared to older, individuals. However, the small age range of this population makes this explanation unlikely – furthermore, the finding that cannabis
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Table 1 Sociodemographic data for those with and without cannabis use. No lifetime cannabis use, N ¼ 58
Lifetime cannabis use, N¼ 85
Missing data, N ¼68
Age at first contact, mean (S.D.)
30.1 (8.5)
26.4 (6.7)
29.28 (8.01)
Age at first psychotic symptom, mean (S.D.)
29.2 (7.9)
25.7 (6.3)
27.95 (7.48)
Gender, N (%) Male Female
25 (43.1) 33 (56.9)
62 (72.9) 23 (27.1)
49 (72.1) 19 (27.9)
Ethnicity, N (%) White British Black Caribbean Black African Other
17 18 14 9
(29.3) (31.0) (24.1) (15.5)
42 19 10 14
(49.4) (22.4) (11.8) (16.5)
24 20 12 12
(35.3) (29.4) (17.6) (17.6)
Education level, N (%) Higher Further GCSE No qualifications
9 15 18 16
(15.5) (25.9) (31.0) (27.6)
10 22 29 23
(11.9) (26.2) (34.5) (27.4)
8 20 13 24
(12.3) (30.8) (20.0) (36.9)
Employment status Employed Economically inactive Unemployed
15 (25.9) 11 (19.0) 32 (55.2)
23 (27.1) 8 (9.4) 54 (63.5)
Other drug use Other drug use No other drug use
3 (5.2) 55 (94.8)
62 (72.9) 23 (27.1)
DUP (days), median (interquartile range)
138 (29–546)
Mode of onset, N (%) Acute Insidious
10 (14.9) 9 (13.4) 48 (71.6)
86 (31–238)
21 (38.2) 34 (61.8)
163 (33–568)
34 (42.0) 47 (58.0)
19 (28.8) 47 (71.2)
Note: GCSE ¼ General Certificate of Higher Education or equivalent, further ¼qualifications achieved after compulsory education, and higher ¼academic and professional qualifications.
Percent of participants with psychotic symptoms
1.00
Table 2 Cox proportional hazards regression analysis.
0.75
0.50
0.25
0.00 10
20
30
40
50
Age (years) Male, no cannabis use Female, no cannabis use
Male, cannabis use Female, cannabis use
Fig. 1. Kaplan–Meier survival curve for the cumulative probability of age of the first psychotic symptom onset.
use, and illegal substance use in general is more prevalent in those with schizophrenia than in the general population (Mazzoncini et al., 2010) cannot be explained by confounding by age. A second explanation that has been advanced as a possible explanation for the association between cannabis use and schizophrenia is that of reverse causation: that individuals experiencing symptoms of schizophrenia smoke cannabis to self-medicate. While this explanation could explain the general association between cannabis use and schizophrenia, it is not clear how selfmedication could explain the association between cannabis use and earlier onset. This would require that individuals with earlier onset were more likely to self-medicate than those with a later onset. Furthermore, there is evidence from other studies that an
Hazard ratio
95% Confidence interval
p-Value
Cannabis
1.742
1.231–2.464
0.002
Male gender
1.542
1.090–2.183
0.014
Cannabis Male gender
1.573 1.293
1.081–2.290 0.889–1.881
0.018 0.179
Cannabis gender No cannabis use/male No cannabis use/female Cannabis use/male Cannabis use/female
1 (ref) 0.556 1.227 1.246
0.322–0.959 0.769–1.956 0.705–2.204
0.035 0.391 0.449
Cannabis gender No cannabis use/male No cannabis use/female Cannabis use/male Cannabis use/female
1 (ref) 0.558 1.059 1.068
0.323–0.965 0.624–1.796 0.571–1.999
0.037 0.832 0.836
Other illegal drug use
1.297
0.844–1.994
0.235
increase in cannabis use predates the onset of the prodrome in individuals who develop schizophrenia (Compton et al., 2009). A third explanation is that cannabis is a causal factor in the development of schizophrenia. There is growing evidence in favour of this hypothesis, for example, a meta-analysis found that there is a significant increased risk of developing a psychotic disorder in those who have used cannabis (Moore et al., 2007). The relationship has been found to be dose dependent (Di Forti et al., 2009) and the age of first cannabis use is associated with the age of onset of psychosis (Casadio et al., 2011).
K. Donoghue et al. / Psychiatry Research 215 (2014) 528–532
Table 3 The Akaike information criterion (AIC) to determine the Cox proportional hazards regression models which fit the data most parsimoniously. Model
AIC
Delta AIC
Likelihood ratio
Akaike0 s weight
Cannabis use gender Cannabis use Cannabis use, gender Cannabis use gender, other illegal drug use Gender
1133.230 1133.573 1133.739 1133.801
0 0.343 0.509 0.571
1 0.842 0.775 0.752
0.287 0.242 0.222 0.215
1137.493 4.263
0.119
0.034
Earlier age of onset of schizophrenia is generally associated with more severe illness: greater cognitive and functional impairment, more severe symptoms and greater risk of relapse (DeLisi, 1992; Linszen et al., 1994; Rabinowitz et al., 2006; Rajji et al., 2009). However, there is some evidence that individuals with schizophrenia and comorbid cannabis use have a different pattern. Schizophrenia patients who use cannabis have been shown to have better cognitive reserve (Donoghue and Doody, 2012), which is associated with better functional outcome (González-Blanch et al., 2010; Leeson et al., 2009; Malla et al., 2002; Milev et al., 2005) and fewer neurodevelopmental markers of schizophrenia, for example fewer neurological soft signs (Bersani et al., 2002; Ruiz-Veguilla et al., 2009). Leeson et al. (2012) suggested that cannabis use may trigger the onset of schizophrenia in individuals who would otherwise have had good prognostic features (i.e. higher premorbid IQ, better functional outcome and less severe symptoms). This raises the question of whether cannabis use may advance the onset of schizophrenia, in individuals where it would have occurred later, or perhaps not at all, without the presence of cannabis use or other illegal drug. Genetic variations have been explored with evidence to suggest that those with a psychometric of familial risk are more susceptible to cannabis use but there is little robust evidence at the molecular level (Decoster et al., 2012). Dysregulation of the endogenous endocannabinoid system has also received some attention to help explain the association between cannabis use and schizophrenia. For example, a recent study found greater global type 1 cannabinoid receptor binding in those with a diagnosis of schizophrenia compared to healthy controls, which was negatively correlated with negative symptoms in those who were antipsychotic free (Ceccarini et al., 2013). Those who use cannabis and subsequently develop schizophrenia may have a vulnerability to cannabis that is not present in those that use cannabis and do not develop schizophrenia. 4.3. Interactions between cannabis use and gender The current study has found that the use of cannabis results in an age of onset of psychotic symptoms for females that is comparable with males. These findings suggest that the use of cannabis may have a greater impact on females than males and would explain the narrowing of the gap in age of onset of psychosis between the genders. Oestrogen may have a neuroprotective role in women, leading to a later age of onset in noncannabis users (Kulkarni et al., 2012; Wise et al., 2001). There is a 20-fold increase on risk of onset of a first episode of psychosis or relapse of symptoms during the postpartum period when there is a dramatic reduction in oestrogen levels. There is a second spike in incidence of psychosis in women between the ages 45 and 54, with unusually severe symptomatology and treatment resistance, which is thought to be related to falling levels of oestrogen in older women (Begemann et al., 2012; Hayes et al., 2012). Furthermore, there is evidence to indicate that more severe psychotic symptoms are present during the phases of the menstrual cycle
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when oestrogen levels are low in female patients with schizophrenia (Bergemann et al., 2007). A number of animal models of schizophrenia have indicated that oestrogen is involved with the mechanisms of the neurotransmitters dopamine, glutamate and serotonin and resultant antipsychotic-like activity (Kulkarni et al., 2012). The association between oestrogen and schizophrenia has led to the exploration of using oestrogen therapeutically to augment antipsychotic medications. A Cochrane review of clinical research until 2005 found that adjunctive oestrogen therapy did not offer any additional therapeutic advantages (Chua et al., 2005). However, a more recent meta-analysis reported more promising findings but further, large, randomised controlled trials are required before recommendations for clinical application can be made (Begemann et al., 2012). The use of cannabis and other drugs may reduce or abolish the protective effect of oestrogen leading to a reduction in the age of onset in women to equal that of men. 4.4. The role of other illegal drugs Other illegal drug use was not a significant predictor of age of onset of psychotic symptoms when entered into a model with an interaction for the gender/cannabis use status and had little effect on the hazard ratios. This is in line with some previous research that has found that cannabis use was associated with age of onset of psychotic symptoms irrespective of other illegal drug use (Barnes et al., 2006; Barrigón et al., 2010; Dekker et al., 2012; González-Pinto et al., 2008; Öngür et al., 2009) but also in conflict with others (De Hert et al., 2011 González-Pinto et al., 2008; Veen et al., 2004). 4.5. Strengths and limitations Data for the current study was derived from a large, firstepisode epidemiological study of psychosis but there are a number of limitations of the current study that must be taken into account when interpreting its results. The data on substance misuse was collected retrospectively and relied on self-report. However, there is evidence to suggest that self-report data is reliable and consistent with urine drug screening in those with cannabis use (Martin et al., 1988) and with schizophrenia (Kedzior et al., 2006). Furthermore, the use of cannabis and other illegal substances was in many cases internally validated using a variety of sources including information from the participant, a relative or carer and clinical case notes. The current study did not have information available as to when use of illegal substances began, frequency and quantity of use. 4.6. Conclusion The current study lends further support to evidence that the use of cannabis is associated with of an earlier onset of schizophrenia, which is not explained by confounding whereby cannabis and other illegal drug use is more common in males. Cannabis use appears to shorten the gap in the age of onset of schizophrenia for males and females. References Addington, J., Addington, D., 2007. Patterns predictors and impact of substance use in early psychosis: a longitudinal study. Acta Psychiatrica Scandinavica 115, 304–309. Akaike, H., 1974. A new look at the statistical model identification. IEEE Transactions on Automatic Control 19, 716–723, http://dx.doi.org/10.1109/TAC.1974. 1100705. Barnes, T.R.E., Mutsatsa, S.H., Hutton, S.B., Watt, H.C., Joyce, E.M., 2006. Comorbid substance use and age at onset of schizophrenia. British Journal of Psychiatry 188, 237–242.
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Barrigón, M.L., Gurpegui, M., Ruiz-Veguilla, M., Diaz, F.J., Anguita, M., Sarramea, F., Cervilla, J., 2010. Temporal relationship of first-episode non-affective psychosis with cannabis use: a clinical verification of an epidemiological hypothesis. Journal of Psychiatric Research 44, 413–420. Bergemann, N., Parzer, P., Runnebaum, B., Resch, F., Mundt, C., 2007. Estrogen, menstrual cycle phases, and psychopathology in women suffering from schizophrenia. Psychological Medicine 37, 1427–1436. Begemann, M.J.H., Dekker, C.F., van Lunenburg, M., Sommer, I.E., 2012. Estrogen augmentation in schizophrenia: a quantitative review of current evidence. Schizophrenia Research 141, 179–184. Bersani, G., Orlandi, V., Gherardelli, D., Pancheri, P., 2002. Cannabis and neurological soft signs in schizophrenia: absence of relationship and influence on psychopathology. Psychopathology 34, 289–295. Casadio, P., Fernandes, C., Murray, R.M., Di Forti, M., 2011. Cannabis use in young people: the risk for Schizophrenia. Neuroscience and Behavioural Reviews 35, 1779–1787. Ceccarini, J., De Hart, M., Van Winkel, R., Peuskens, J., Bormans, G., Kranaster, L., Enning, F., Koethe, D., Leweke, F.M., Van Laere, K., 2013. NeuroImage 79, 304–312. Chua, W.L., de Lzquierdo, S.A., Kulkarni, J., Mortimer, A., 2005. Estrogen for schizophrenia. Cochrane Database for Systematic Reviews 19 (4). (art. no.: CD004719) pp. 1–37. Compton, M.T., Kelley, M.E., Ramsay, C.E., Pringle, M., Goulding, S.M., Esterberg, M. L., Stewart, T., Walker, E.F., 2009. Association of pre-onset cannabis, alcohol and tobacco use with age of onset of prodrome and age of onset of psychosis in first-episode patients. American Journal of Psychiatry 166, 1251–1257. Cooper, J.E., Goodhead, D., Craig, T., Harris, M., Howat, J., Korer, J., 1987. The incidence of schizophrenia in Nottingham. British Journal of Psychiatry 151, 619–626. Decoster, J., van Os, J., Myin-Germeys, I., De Hart, M., can Winkel, R., 2012. Genetic variation underlying psychosis-inducing effects of cannabis: critical review and future directions. Current Pharmaceutical Design 18, 5015–5023. De Hert, M., Wanpers, M., Jendricko, T., Franic, T., Vidovic, D., De Vriendt, N., Sweers, K., Peuskens, J., van Winkel, R., 2011. Effects of cannabis use on age at onset in schizophrenia and bipolar disorder. Schizophrenia Research 126, 270–276. Dekker, N., Meijer, J., Koeter, M., van den Brink, W., van Beveren, N., Kahn, R.S., Linszen, D.H., van Os, J., Wiersma, D., Bruggeman, R., Cahn, W., de Haan, L., Krabbendam, L., Myin-Germeys, I., GROUP Investigators, 2012. Age of onset of non-affective psychosis in relation to cannabis use, other drug use and gender. Psychological Medicine 42, 1903–1911. DeLisi, L.E., 1992. The significance of age of onset for schizophrenia. Schizophrenia Bulletin 18, 209–215. Di Forti, M., Morgan, C., Dazzan, P., Pariante, C., Mondelli, V., Marques, T.R., Handley, R., Luzi, S., Russo, M., Paparelli, A., Butt, A., Stilo, S.A., Wiffen, B., Powell, J., Murray, R.M., 2009. High-potency cannabis and the risk of psychosis. British Journal of Psychiatry 195, 488–491. Donoghue, K., Medley, I., Brewin, J., Glazebrook, C., Mason, P., Cantwell, R., Jones, P. B., Harrison, G., Doody, G.A., 2011. The association between substance misuse and first-episode psychosis in a defined UK geographical area during the 1990s. Social Psychiatry and Psychiatric Epidemiology 46, 137–142. Donoghue, K., Doody, G.A., 2012. Effect of illegal substance use on cognitive function in individuals with a psychotic disorder, a review and meta-analysis. Neuropsychology 26, 785–801. Eranti, S.V., MacCabe, J.H., Bundy, H., Murray, R.M., 2013. Gender differences in age of onset of schizophrenia: a meta-analysis. Psychological Medicine 43, 155–167. Fearon, P., Kirkbride, J.B., Morgan, C., Dazzan, P., Morgan, K., Lloyd, T., Hutchinson, G., Tarrant, J., Fung, W.L.A., Holloway, J., Mallett, R., Harrison, G., Leff, J., Jones, P. B., Murray, R.M., 2006. Incidence of schizophrenia and other psychoses in ethnic minority groups: results from the MRC funded ÆSOP study. Psychological Medicine 36, 1541–1550. González-Blanch, C., Perez-Iglesias, R., Pardo-Garciá, G., Rodríguez-Sánchez, J.M., Martínez-García, O., Vázquez-Barquero, J.L., Crespo-Facorro, B., 2010. Prognostic value of cognitive functioning for global recovery in first-episode schizophrenia. Psychological Medicine 40, 935–944. González-Pinto, A., Vega, P., Ibáñez, B., Mosquera, F., Barbeito, S., Gutiérrez, M., Ruiz de Azúa, S., Ruiz, I., Vieta, E., 2008. Impact of cannabis and other drugs on age of onset of psychosis. Journal of Clinical Psychiatry 69, 1210–1216. Hayes, E., Gavrilidis, E., Kulkarni, J., 2012. The role of oestrogen and other hormones in the pathophysiology and treatment of schizophrenia. Schizophrenia Research and Treatment, 1–8. Jablensky, A., Satorius, N., Ernberg, G., Anker, M., Korten, A., Cooper, J.E., Day, R., Bertelsen, A., 1992. Schizophrenia: manifestations, incidence and course in different cultures – a World Health Organisation ten-country study. Psychological Medicine Monograph Supplement 20, 1–97.
Kedzior, K.K., Badcock, J.C., Martin-Iverson, M.T., 2006. Validity and consistency of self-reports regarding substance use in general research volunteers, including regular cannabis users and schizophrenia patients. Substance Use and Misuse 41, 743–750. Kirkbride, J.B., Fearon, P., Morgan, C., Dazzan, P., Morgan, K., Tarrant, J., Lloyd, T., Holloway, J., Hutchinson, G., Leff, J.P., Mallett, R.M., Harrison, G.L., Murray, R.M., Jones, P.B., 2006. Heterogeneity in incidence rates of schizophrenia and other psychotic syndromes: findings from the 3-center ÆSOP study. Archives of General Psychiatry 63, 250–258. Kulkarni, J., Hayes, E., Gavrilidis, E., 2012. Hormones and schizophrenia. Current Opinion in Psychiatry 25, 89–95. Large, M., Sharma, S., Compton, M.T., Slade, T., Nielssen, O., 2011. Cannabis use and earlier onset of psychosis. Archives of General Psychiatry 68, 555–561. Larsen, T.K., Melle, I., Auestad, B., Fris, S., Haahr, U., Johannessen, J.O., Opjordsmoen, S., Rund, B.R., Simonsen, E., Vaglum, P., McGlashan, T.H., 2006. Substance abuse in first-episode non-affective psychosis. Schizophrenia Research 88, 55–62. Leeson, V.C., Barnes, T.R.E., Hutton, S.B., Ron, M.A., Joyce, E.M., 2009. IQ as a predictor of functional outcome in schizophrenia: a longitudinal four year study of first-episode psychosis. Schizophrenia Research 107, 55–60. Leeson, V.C., Harrison, I., Ron, M.A., Barnes, T.R.E., Joyce, E.M., 2012. The effect of cannabis use and cognitive reserve on age of onset and psychosis outcomes in first-episode schizophrenia. Schizophrenia Bulletin 38, 873–880. Linszen, D.H., Dingemans, P.M., Lenior, M.E., 1994. Cannabis abuse and the course of recent-onset schizophrenia disorders. Archives of General Psychiatry 51, 273–279. Martin, G.W., Wilkinson, D.A., Kapur, B.M., 1988. Validation of self-reported cannabis use by urine analysis. Addictive Behavior 13, 147–150. Malla, A.K., Norman, R.M.G., Manchanda, R., Townesend, L., 2002. Symptoms, cognition, treatment adherence and functional outcome in first-episode psychosis. Psychological Medicine 32, 1109–1119. Mazzoncini, R., Donoghue, K., Hart, J., Doody, G.A., Dazzan, P., Jones, P.B., Morgan, K., Murray, R.M., Fearon, P., 2010. Illicit substance use and its correlates in first episode psychosis. Acta Psychiatrica Scandinavica 121, 351–358. Milev, P., Ho, B.-C., Arndt, S., Andreasen, N.C., 2005. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. American Journal of Psychiatry 162, 495–506. Moore, T.H., Zammit, S., Lingford-Hughes, A., Barnes, T.R., Jones, P.B., Burke, M., Lewis, G., 2007. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370, 319–328. Öngür, D., Lin, L., Cohen, B.M., 2009. Clinical characteristics influencing age of onset in psychotic disorders. Comprehensive Psychiatry 50, 13–19. Rabinowitz, J., Levine, S.Z., Hafner, H., 2006. A population based elaboration of the role of age of onset on the course of schizophrenia. Schizophrenia Research 88, 96–101. Rajji, T.K., Ismail, Z., Mulsant, B.H., 2009. Age of onset and cognition in schizophrenia: meta-analysis. British Journal of Psychiatry 195, 286–293. Ruiz-Veguilla, M., Gurpegui, M., Barrigon, M.L., Ferrin, M., Marin, E., Rubio, J.L., Gutierrez, B., Pintor, A., Cervilla, J., 2009. Fewer neurological soft signs among first episode psychosis patients with heavy cannabis use. Schizophrenia Research 107, 158–164. Sevy, S., Robinson, D.G., Napolitano, B., Patel, R.C., Gunduz-Bruce, H., Miller, R., McCormack, J., Lorell, B.S., Kane, J., 2010. Are cannabis use disorders associated with an earlier age of onset of psychosis? Schizophrenia Research 120, 101–107. StataCorp, 2009. Stata Statistical Software: Release 11. StataCorp LP, College Station, TX. Stefanis, N.C., Dragovic, M., Power, B.D., Jablensky, A., Castle, D., Morgan, V.A., 2013. Age at initiation of cannabis use predicts age of onset of psychosis: the 7- to 8year trend. Schizophrenia Bulletin, http://dx.doi.org/10.1093/schbul/sbs188. (advance access publication). Vahia, I.V., Palmer, B.W., Depp, C., Fellows, I., Golsham, S., Kraemer, H.C., Jeste, D.V., 2010. Is late-onset schizophrenia a subtype of schizophrenia? Acta Psychiatrica Scandinavica 122, 414–426. Veen, N.D., Selten, J.-P., van der Tweel, I., Feller, W.G., Hoek, H.W., Kahn, R.S., 2004. Cannabis use and age of onset of schizophrenia. American Journal of Psychiatry 161, 501–506. Wise, P.M., Dubal, D.B., Wilson, M.E., Rau, S.W., Böttner, M., 2001. Minireview: neuroprotective effects of oestrogen – new insights into mechanisms of action. Endocrinology 142, 969–973. World Health Organization, 1992. International Classification of Diseases, 10th Revision (ICD-10). World Health Organisation, Geneva, Switzerland. World Health Organization, 1994. Schedules for Clinical Assessment in Neuropsychiatry. World Health Organization, Geneva, Switzerland.