Objective: Cannabis use/abuse is a common co-morbid problem in patients experiencing a first episode of psychotic illness (FEP). The relationship between the clinical presentation of FEP and cannabis abuse is complex and warrants further investigation, especially within the South African context. Method: We tested associations between recent/current cannabis use and duration of untreated psychosis (DUP), age of onset (AO), PANSS-rated (Positive and Negative Syndrome Scale) positive, negative and general psychopathology symptoms and depressive symptoms (Calgary Depression Scale for Schizophrenia) in a sample of 54 patients with FEP. Results: Mean DUP was 34.4 weeks, while mean AO was 24.7 years. Co-morbid cannabis use occurred in 35% of the sample and was significantly associated with shorter DUP (Mann-Whitney U, p=0.026). While not significant, there was also a trend association between cannabis use and lower negative symptoms (Mann-Whitney U, p=0.051). Conclusion: Current/recent cannabis use was associated with clinical features of psychosis onset that previously have been associated with better outcome. Medium and long-term outcome for cannabis users however, is likely to depend on whether or not cannabis use is ongoing.

The pharmacogenomic network responsible for the rapid antidepressant action of ketamine and concomitant adverse events in patients has been poorly defined. Integrative, multiscale biological data analytics helps explain ketamine's action. Using a validated computational pipeline, candidate ketamine-response genes and regulatory RNAs from published literature, binding affinity studies, and single nucleotide polymorphisms (SNPs) from genomewide association studies (GWAS), we identified 108 SNPs associated with 110 genes and regulatory RNAs. All of these SNPs are classified as enhancers, and additional chromatin interaction mapping in human neural cell lines and tissue shows enhancer-promoter interactions involving other network members. Pathway analysis and gene set optimization identified three composite sub-networks within the broader ketamine pharmacogenomic network. Expression patterns of ketamine network genes within the postmortem human brain are concordant with ketamine neurocircuitry based on the results of 24 published functional neuroimaging studies. The ketamine pharmacogenomic network is enriched in forebrain regions known to be rapidly activated by ketamine, including cingulate cortex and frontal cortex, and is significantly regulated by ketamine (p=6.26E-33; Fisher's exact test). The ketamine pharmacogenomic network can be partitioned into distinct enhancer sub-networks associated with: (1) glutamate neurotransmission, chromatin remodeling, smoking behavior, schizophrenia, pain, nausea, vomiting, and post-operative delirium; (2) neuroplasticity, depression, and alcohol consumption; and (3) pharmacokinetics. The component sub-networks explain the diverse action mechanisms of ketamine and its analogs.These results may be useful for optimizing pharmacotherapy in patients diagnosed with depression, pain or related stress disorders. GRIA4 (12), and many other known (8,13) and unknown pharmacodynamic targets within human brain. Ketamine and its metabolites strongly induce the expression of the CYP2B6 gene in human brain, which encodes a drug metabolizing enzyme that contributes to first-and second-pass metabolism of the drug and its metabolites (14). Recent genomewide association studies (GWAS) in humans demonstrate association of ketamine response and adverse events with enhancers of genes and long non-coding RNAs (lncRNAs) related to the roundabout guidance receptor 2 (ROBO2) gene, whose product binds members of the slit guidance ligand family (SLIT1, SLIT2) that are involved in dendrite guidance and synaptic plasticity (15,16). Like phencyclidine, a structurally related compound, ketamine induces acute dissociation, with both drugs exhibiting species-specific differences in response. In sum, the central nervous system (CNS) pathway(s) responsible for the rapid antidepressant effects of ketamine and its enantiomers in patients diagnosed with treatment-resistant depression (TRD) remain poorly defined, including emergence of on-and off-target effects and individual differences in response and adverse eve...