Greater white and grey matter changes associated with early cannabis use in adolescent-onset schizophrenia (AOS)
Introduction
The endocannabinoid system is involved in both neurodevelopmental and neurodegenerative processes (Basavarajappa et al., 2009), suggesting that the timing of the initiation of cannabis use may be crucial in cannabis-related disorders. Cannabis is the one of the most common drugs of misuse in the Western countries (Murray et al., 2008). Numerous epidemiological surveys have shown a link between cannabis use and the risk of schizophrenia (Andreasson et al., 1987, Arseneault et al., 2002, van Os et al., 2002, Zammit et al., 2004, Fergusson et al., 2003, Stefanis et al., 2004, Veen et al., 2004, Henquet et al., 2005a, Mauri et al., 2006, Konings et al., 2008), although this is contended by some (Macleod, 2007). There appears to be a dose dependent relationship (van Os et al., 2002, Zammit et al., 2004) with a higher risk of schizophrenia predicted by the earlier age of cannabis use; findings supported by meta-analyses (Semple et al., 2005, Henquet et al., 2005b, Moore et al., 2007). In healthy subjects the longer-term effects of cannabis include deficits in learning, memory and retrieval of information (Grant et al., 2003), and a loss of verbal IQ in those who started to use cannabis before age seventeen (Pope et al., 2003). Generally, schizophrenic patients perform worse on neuropsychological tests than healthy control subjects (White et al., 2006), however, some studies showed that regular cannabis use was found to improve cognitive functioning (Coulston et al., 2007, Jockers-Scherubl et al., 2007). Surprisingly, this was more evident in those who started using cannabis before age 17 (Jockers-Scherubl et al., 2007). A history of cannabis abuse/dependence has been shown to be associated with better full scale and verbal IQ scores in adolescents with treatment-refractory schizophrenia (Kumra et al., 2005).
Structural MRI studies of the effect of chronic cannabis use on normal subjects have provided controversial results: several studies found no effect (Tzilos et al., 2005, Jager et al., 2007), but others reported reduced grey matter volume when compared with matched controls (Matochik et al., 2005, Yucel et al., 2008). Diffusion tensor imaging studies have also been contradictory: two studies found no differences between cannabis users and controls (Gruber and Yurgelun-Todd, 2005, DeLisi, 2008), and one reported a significant reduction in mean diffusivity in the prefrontal section of the corpus callosum, but no decrease in fractional anisotropy (FA) associated with cannabis use (Arnone et al., 2008) A more recent study found reduced FA in the right superior longitudinal fasciculus and right and left hippocampus (Yucel et al., 2010b). In adolescents any reduction in FA is greater with binge drinking alone, than with marijuana and binge drinking combined (Jacobus et al., 2009).
In first-onset schizophrenia cases, cannabis use is associated with a loss of grey matter (GM) in the anterior cingulate (Szeszko et al., 2007), and an accelerated loss of GM generally (Rais et al., 2008). Hyperconnectivity, as reflected in greater diffusion coherence, has been reported in AOS, but with a study limitation of polydrug usage (Peters et al., 2009). A later study by the same group looking at age effects of cannabis (early age < 15 or late age > 17) found no effects of cannabis on FA (Dekker et al., 2011).
In this study we examined the effect of early cannabis use on the brain of patients with AOS. We hypothesised that the effects of chronic cannabis use in AOS would be particularly severe during a critical period of adolescent neurodevelopment.
Section snippets
Methods and subjects
The study was undertaken in accordance with the approval of the Oxford Psychiatric Research Ethics Committee. Written consent was obtained from all participants (and their parents if under the age of 16).
Sixteen AOS subjects (11 males, 5 females, aged 13 to 18) who were positive cannabis users (CAN+ve) were matched on age, sex and handedness with 16 AOS subjects non-users (CAN−ve). Subjects were recruited from the Oxford regional adolescent unit and surrounding units. All were diagnosed as
Results
There was no relationship with age, age of onset of psychosis, FSIQ, PIQ VIQ or medication dosage (chlorpromazine equivalents) with FA values in any cluster. Subjects with a positive family history of schizophrenia had lower FA values (F1,32 10.21, p = 0.003). However, there was no cannabis × family history interaction (F1,32 0.52, p = 0.47). Smoking was correlated with cannabis use; however, there was no main independent effect of smoking on FA values.
Comparison of control and schizophrenia subjects
Discussion
In this study we showed that subjects with AOS had widespread reduction of FA in the white matter and reduction of GM density in the cerebral cortex than control group. However, cannabis use appears to be associated with even greater reduction in GM and WM in AOS in these regions, suggesting cannabis affects regions that are particularly important in the pathology of AOS.
Previous reports (Rais et al., 2008) highlight an accelerated loss of GM associated with cannabis use in schizophrenia with,
Role of funding source
Funding for this study was provided by the MRC and the Oxford Hospital Services Research Committee (OHSCR).
Contributors
AJ and SJ designed the study and wrote the protocol. AJ, SJ, MH, MZ and PMM managed the literature searches and analyses. AJ, SN, LW and LB selected the sample and evaluated patients. AJ, MH and MZ undertook the statistical analysis. AJ, MZ, LB and PMM wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgements
We would like to thank the patients, their families, and the Donnington Health Centre, Oxford.
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