The profile of cortical neuroanatomical abnormalities in schizophrenia is not fully understood, despite hundreds of published structural brain imaging studies. This study presents the first meta-analysis of cortical thickness and surface area abnormalities in schizophrenia conducted by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Schizophrenia Working Group. The study included data from 4474 individuals with schizophrenia (mean age, 32.3 years; range, 11-78 years; 66% male) and 5098 healthy volunteers (mean age, 32.8 years; range, 10-87 years; 53% male) assessed with standardized methods at 39 centers worldwide. Compared with healthy volunteers, individuals with schizophrenia have widespread thinner cortex (left/right hemisphere: Cohen's d = -0.530/-0.516) and smaller surface area (left/right hemisphere: Cohen's d = -0.251/-0.254), with the largest effect sizes for both in frontal and temporal lobe regions. Regional group differences in cortical thickness remained significant when statistically controlling for global cortical thickness, suggesting regional specificity. In contrast, effects for cortical surface area appear global. Case-control, negative, cortical thickness effect sizes were two to three times larger in individuals receiving antipsychotic medication relative to unmedicated individuals. Negative correlations between age and bilateral temporal pole thickness were stronger in individuals with schizophrenia than in healthy volunteers. Regional cortical thickness showed significant negative correlations with normalized medication dose, symptom severity, and duration of illness and positive correlations with age at onset. The findings indicate that the ENIGMA meta-analysis approach can achieve robust findings in clinical neuroscience studies; also, medication effects should be taken into account in future genetic association studies of cortical thickness in schizophrenia.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Ingestion of cannabis can modulate anxiety levels, although the direction of this effect is variable. Long-term cannabis use has been associated with anxiety symptoms,^1-4 panic attacks,⁵ and an increased risk of anxiety disorders,^6-8 although the latter remains controversial.^9,10 Acute increases in anxiety can also occur following cannabis use.^11,12 However, cannabis use can also lead to sedation and relaxation, with users often reporting that they take the drug to alleviate psychosocial stress, anxiety, and agoraphobia,^2,13-15 increasing the likelihood of subsequent cannabis abuse.^11,16 Also, patients with psychotic disorders report that they use cannabis to reduce the anxiety associated with psychotic symptoms^17,18 and increased anxiety is a feature of withdrawal from regular cannabis use.¹⁹ There is thus evidence that cannabis can have both anxiogenic and anxiolytic effects. These apparently conflicting observations may partly reflect the fact that Cannabis sativa contains multiple compounds that may have different psychoactive properties.²⁰ In particular, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant and both can modulate anxiety. Immediate administration of Δ9-THC can increase anxiety²¹ but has also been reported to reduce anxiety and improve sleep.^22,23 This may parallel evidence from studies in experimental animals reporting that low doses of Δ9-THC have anxiolytic effects whereas high doses are anxiogenic.^24-26 In contrast, CBD has anxiolytic effects in both animals and humans,^27-31 and when coadministered with Δ9-THC, it can reduce the anxiety and psychotic symptoms induced by the latter cannabinoid.³² These differences in the behavioral effects of Δ9-THC and CBD are paralleled by differences in their mechanism of action at the molecular level. Δ9-Tetrahydrocannabinol binds to neuronal CB1 receptors,³³ which are found on GABAergic and glutamatergic neurons throughout the brain and are thought to be receptors for endogenous anandamide.^34-36 Since CBD has a very low affinity for the cannabinoid CB1 receptor^37,38 and does not bind to benzodiazepine receptors,²⁹ the molecular mechanisms underlying its anxiolyticlike activity are still unclear. It may activate vanilloid receptors and inhibit the cellular uptake and enzymatic hydrolysis of anandamide,^39,40 activate serotonin 5HT_1A receptors,⁴¹ and inhibit uptake of adenosine.⁴²