Schizophrenia interactome derived repurposable drugs and randomized control trials of two candidates.

There is a substantial unmet need for effective and patient-acceptable drugs to treat severe mental illnesses like schizophrenia. Computational analysis of genomic, transcriptomic, and pharmacologic data generated in the past two decades enables repurposing of drugs or compounds with acceptable safety profiles, namely those that are FDA-approved or reached late stages in clinical trials. We developed a rational approach to achieve this computationally for schizophrenia by studying drugs that target the proteins in its protein interaction network ('interactome'). This involved contrasting the transcriptomic modulations observed in the disorder and the drug; our analyses resulted in 12 candidate drugs, 9 of which had additional supportive evidence: their target networks were enriched for pathways relevant to schizophrenia etiology or for genes that had an association with diseases pathogenically similar to schizophrenia. To translate these computational results to the clinic, these shortlisted drugs must be tested empirically through randomized controlled trials (RCT), where their prior safety approvals obviate the need for time-consuming phase I and II studies. We selected two among the shortlisted candidates based on likely adherence and side effect profiles. We are testing them through adjunctive RCTs for patients with schizophrenia or schizoaffective disorder who experienced incomplete resolution of psychotic features with conventional treatment. The integrated computational analysis for identifying and ranking drugs for clinical trials can be iterated as additional data are obtained. Our approach could be expanded to enable disease subtype-specific drug discovery in future and should also be exploited for other psychiatric disorders.

Patterns of Tobacco Consumption among Indian Men with Schizophrenia Compared to Their Male Siblings

OBJECTIVE: Tobacco consumption among patients with schizophrenia has been investigated extensively in western countries, but there is a dearth of studies in India, where socio-economic and cultural variables are different. This study aims to investigate the patterns of tobacco consumption among schizophrenia patients compared with their non-psychotic siblings. METHODS: Consenting, successive male outpatients diagnosed with schizophrenia (n=100, DSM-IV criteria), and their non-psychotic brothers (n=100) were compared. Following a structured diagnostic interview, detailed information about tobacco consumption (including smokeless tobacco) was obtained using the Fagerstrom Test for Nicotine Dependence for smoked tobacco, and FTND-smokeless tobacco. The University of Pennsylvania Computerized Neurocognitive battery (CNB) was administered to a sub-group of patients (n=48). RESULTS: Schizophrenia patients initiated tobacco use at a significantly earlier age than their brothers, but there was no significant difference with regard to type, quantity or frequency of tobacco use (smoke or smokeless varieties). Patients who consumed tobacco had significantly higher positive symptom scores compared with non-users (p=0.043). There were no significant differences between nicotine dependent and non-dependent patients with regard to CNB domains except attention. CONCLUSION: Patterns of tobacco consumption were similar among schizophrenia patients and their non-psychotic brothers. Tobacco use was associated with increased positive symptom scores, but there were no significant differences in cognitive measures among nicotine dependent and non-dependent patients.

Is Familiality Associated with Downward Occupation Drift in Schizophrenia?

OBJECTIVE: Downward occupational drift has been extensively investigated in schizophrenia. It is known that certain illness related factors, such as severity, affect drift, but the impact of familial factors has not been investigated. METHODS: Occupation drift was studied among patients with schizophrenia/schizoaffective disorder (SZ/SZA)(n=523) and 130 affected sib pairs (ASPs). Drift was analyzed in relation to familiality as well as demographic and clinical variables. For comparison one proband (one of the affected siblings) from each ASP was selected. Occupation drift was measured in relation to the most responsible job held, and with regard to head of the household (HOH) occupation status. RESULTS: There was no significant difference between single affected and ASP probands in terms of occupational drift from the most responsible job (drifted 39.2% and 38% respectively) and with regard to HOH's occupation (drifted 88% and 82.8% respectively). A significant part of the sample remained unemployed in both single affected and ASP samples. Thus, there was no significant impact of familiality on these variables. However, marital status, pattern of severity, age at onset, gender were found to be associated with downward occupation drift in single affected probands while the only significant factor in familial probands was pattern of severity of severity when measuring in terms of downward drift from most responsible job. CONCLUSION: Though there is occupation drift in schizophrenia, there is no detectable impact of familial factors. Employment is associated with severity of delete.