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Caution urged in interpreting a negative study of cannabis use and schizophrenia
Schizophrenia Research 154 (2014) 119–120
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Caution urged in interpreting a negative study of cannabis use and schizophrenia
Dear Editor, The recent publication by Proal et al. (2014) on psychosis and cannabis use concludes “while cannabis may modify the illness onset, severity and outcome, there is no evidence from this study that it can cause the psychosis” despite an earlier admission in the discussion that “the current study, however, is not able to address whether cannabis can interact with a genetic predisposition to cause schizophrenia”. The distinction made between causality and interaction with a genetic predisposition is a false dichotomy, as even tobacco use interacts with genotype when causing lung cancer. What matters is quantifying the impact and its direction. A more accurate and helpful summation of their paper would be that while the study was able to demonstrate the presence of a relatively strong family history of schizophrenia in cannabis-using schizophrenia patients, it was actually underpowered to definitively determine whether and to what degree the cannabis use might have promoted the presence of disease in that group. Because the public health implication of the research is potentially enormous and the likelihood is high that non-scientists will access their paper, the phrasing they chose for their final conclusion is unfortunate. On the one hand the authors were willing to accept prior research relating to effects on illness age of onset for which there is also no evidence in the current study, but on the other hand they were unwilling to mention a study demonstrating cannabis use increased the risk for schizophrenia by a factor of 1.5 to 2.2-fold when genetic background effects were controlled for (McGrath et al., 2010) or one demonstrating the purified active ingredient of cannabis to be psychotomimetic in previously mentally healthy individuals (D'Souza et al., 2004). My second concern relates to suggestive evidence in the data overlooked by the authors. In Sample 3 (schizophrenia patients with no cannabis use), the schizophrenia risk to relatives falls off steeply with decreasing degree of relationship (significant trend, p = 0.09), at a rate similar to that described in prior studies and consistent with a pattern thought to be reflective of multiple genetic contributions (Table 1, Gottesman and Shields, 1967; Table 1, Risch, 1990). Yet the Sample 4 patients (schizophrenia patients with cannabis use) look very different in that the schizophrenia risk to relatives slopes more gradually downward from the first degree relatives to the group including more distant relatives, a result incompatible with a predominantly multigene/small environmental factor model (Risch, 1990) and more consistent with a multigene disease that was strongly modified in this patient group by one or more environmental factors effective above a certain threshold of genetic load. As a point of comparison, a similar flattening of the risk curve for degree of relationship can be seen in the difference
http://dx.doi.org/10.1016/j.schres.2014.02.014 0920-9964/© 2014 Elsevier B.V. All rights reserved.
between relatives of NIDDM versus IDDM diabetes patients (weaker and stronger environmental components, respectively; Rich, 1990). In the Proal et al. (2014) study with the issue here, the dominant differential environmental component known to the authors was cannabis use and thus finding the slopes of risk with degree of relatedness differed between the groups should have been discussed and its potential relevance highlighted. Clearly, the key data point for a determination of the relative impact of cannabis is the morbid risk for schizophrenia in first degree relatives of Sample 3 versus Sample 4 patients. The morbid risk reported for the relatives of the non-cannabis-using patients (Sample 3) was actually 1.4-fold higher than the cannabis using patients (Sample 4), but the study did not have enough power to statistically confirm or refute a less than 2-fold difference. An increase in sample size would be required to do so, and if the observed difference were to be confirmed, it would explain not only why the Sample 4 data fits poorly with a multigene/ small environmental impact model but also would give weight to the premise that cannabis use significantly contributes to the development of this disease. Finally, it is important to emphasize that should cannabis be shown to cause psychosis only in those with a substantial family history, such causality would still be important. You need look no further than the discordance of schizophrenia in identical twins (as high as 56%; Gottesman and Shields, 1967) to realize that even for individuals with the highest genetic risk, causal environmental triggers can make the difference between leading a normal life and not. Destiny is not preordained by the genes in schizophrenia. Role of funding source The author declares no role for an external funding source. Contributors The author is the sole contributor to this letter to the editor. Conflict of interest The author has no conflict of interest to declare.
References D'Souza, D.C., Perry, E., MacDougall, L., Ammerman, Y., Cooper, T., Wu, Y.T., Braley, G., Gueorguieva, R., Krystal, J.H., 2004. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29, 1558–1572. Gottesman, I.I., Shields, J., 1967. A polygenic theory of schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 58, 199–205. McGrath, J., Welham, J., Scott, J., Varghese, D., Degenhardt, L., Hayatbakhsh, M.R., Alati, R., Williams, G.M., Bor, W., Najman, J.M., 2010. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch. Gen. Psychiatry 67, 440–447. Proal, A.C., Fleming, J., Galvez-Buccollini, J.A., Delisi, L.E., 2014. A controlled family study of cannabis users with and without psychosis. Schizophr. Res. 152, 283–288. Rich, S.S., 1990. Mapping genes in diabetes genetic epidemiological perspective. Diabetes 39, 1315–1319.
120
Letter to the Editor
Risch, N., 1990. Linkage strategies for genetically complex traits I. Multilocus models. Am. J. Hum. Genet. 46, 222–228.
Christine L. Miller MillerBio, 6508 Beverly Rd, Baltimore, MD 21239, United States Tel.: +1 443 520 0485. E-mail address: [email protected].
11 January 2014
Contents lists available at ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Caution urged in interpreting a negative study of cannabis use and schizophrenia
Dear Editor, The recent publication by Proal et al. (2014) on psychosis and cannabis use concludes “while cannabis may modify the illness onset, severity and outcome, there is no evidence from this study that it can cause the psychosis” despite an earlier admission in the discussion that “the current study, however, is not able to address whether cannabis can interact with a genetic predisposition to cause schizophrenia”. The distinction made between causality and interaction with a genetic predisposition is a false dichotomy, as even tobacco use interacts with genotype when causing lung cancer. What matters is quantifying the impact and its direction. A more accurate and helpful summation of their paper would be that while the study was able to demonstrate the presence of a relatively strong family history of schizophrenia in cannabis-using schizophrenia patients, it was actually underpowered to definitively determine whether and to what degree the cannabis use might have promoted the presence of disease in that group. Because the public health implication of the research is potentially enormous and the likelihood is high that non-scientists will access their paper, the phrasing they chose for their final conclusion is unfortunate. On the one hand the authors were willing to accept prior research relating to effects on illness age of onset for which there is also no evidence in the current study, but on the other hand they were unwilling to mention a study demonstrating cannabis use increased the risk for schizophrenia by a factor of 1.5 to 2.2-fold when genetic background effects were controlled for (McGrath et al., 2010) or one demonstrating the purified active ingredient of cannabis to be psychotomimetic in previously mentally healthy individuals (D'Souza et al., 2004). My second concern relates to suggestive evidence in the data overlooked by the authors. In Sample 3 (schizophrenia patients with no cannabis use), the schizophrenia risk to relatives falls off steeply with decreasing degree of relationship (significant trend, p = 0.09), at a rate similar to that described in prior studies and consistent with a pattern thought to be reflective of multiple genetic contributions (Table 1, Gottesman and Shields, 1967; Table 1, Risch, 1990). Yet the Sample 4 patients (schizophrenia patients with cannabis use) look very different in that the schizophrenia risk to relatives slopes more gradually downward from the first degree relatives to the group including more distant relatives, a result incompatible with a predominantly multigene/small environmental factor model (Risch, 1990) and more consistent with a multigene disease that was strongly modified in this patient group by one or more environmental factors effective above a certain threshold of genetic load. As a point of comparison, a similar flattening of the risk curve for degree of relationship can be seen in the difference
http://dx.doi.org/10.1016/j.schres.2014.02.014 0920-9964/© 2014 Elsevier B.V. All rights reserved.
between relatives of NIDDM versus IDDM diabetes patients (weaker and stronger environmental components, respectively; Rich, 1990). In the Proal et al. (2014) study with the issue here, the dominant differential environmental component known to the authors was cannabis use and thus finding the slopes of risk with degree of relatedness differed between the groups should have been discussed and its potential relevance highlighted. Clearly, the key data point for a determination of the relative impact of cannabis is the morbid risk for schizophrenia in first degree relatives of Sample 3 versus Sample 4 patients. The morbid risk reported for the relatives of the non-cannabis-using patients (Sample 3) was actually 1.4-fold higher than the cannabis using patients (Sample 4), but the study did not have enough power to statistically confirm or refute a less than 2-fold difference. An increase in sample size would be required to do so, and if the observed difference were to be confirmed, it would explain not only why the Sample 4 data fits poorly with a multigene/ small environmental impact model but also would give weight to the premise that cannabis use significantly contributes to the development of this disease. Finally, it is important to emphasize that should cannabis be shown to cause psychosis only in those with a substantial family history, such causality would still be important. You need look no further than the discordance of schizophrenia in identical twins (as high as 56%; Gottesman and Shields, 1967) to realize that even for individuals with the highest genetic risk, causal environmental triggers can make the difference between leading a normal life and not. Destiny is not preordained by the genes in schizophrenia. Role of funding source The author declares no role for an external funding source. Contributors The author is the sole contributor to this letter to the editor. Conflict of interest The author has no conflict of interest to declare.
References D'Souza, D.C., Perry, E., MacDougall, L., Ammerman, Y., Cooper, T., Wu, Y.T., Braley, G., Gueorguieva, R., Krystal, J.H., 2004. The psychotomimetic effects of intravenous delta-9-tetrahydrocannabinol in healthy individuals: implications for psychosis. Neuropsychopharmacology 29, 1558–1572. Gottesman, I.I., Shields, J., 1967. A polygenic theory of schizophrenia. Proc. Natl. Acad. Sci. U. S. A. 58, 199–205. McGrath, J., Welham, J., Scott, J., Varghese, D., Degenhardt, L., Hayatbakhsh, M.R., Alati, R., Williams, G.M., Bor, W., Najman, J.M., 2010. Association between cannabis use and psychosis-related outcomes using sibling pair analysis in a cohort of young adults. Arch. Gen. Psychiatry 67, 440–447. Proal, A.C., Fleming, J., Galvez-Buccollini, J.A., Delisi, L.E., 2014. A controlled family study of cannabis users with and without psychosis. Schizophr. Res. 152, 283–288. Rich, S.S., 1990. Mapping genes in diabetes genetic epidemiological perspective. Diabetes 39, 1315–1319.
120
Letter to the Editor
Risch, N., 1990. Linkage strategies for genetically complex traits I. Multilocus models. Am. J. Hum. Genet. 46, 222–228.
Christine L. Miller MillerBio, 6508 Beverly Rd, Baltimore, MD 21239, United States Tel.: +1 443 520 0485. E-mail address: [email protected].
11 January 2014