Presenting Author details:levkovit@netvision.net.il Alyat Hanoar, 94 Hod Hasaron, Israel, Tel.: +972 3 6354371; fax: +972 9 7405452. Background: Schizophrenia is characterized by negative symptoms and cognitive deficits related to rehabilitation outcome and quality of life. Current antipsychotics have a limited effect on these core symptoms, encouraging the development of drugs specifically targeting negative symptoms and cognitive deficits. Minocycline is a second-generation tetracycline, which has a beneficial effect in various neurological disorders. Recent findings from animal models of schizophrenia and case reports of human patients point towards minocycline's potential for the treatment of schizophrenia Methods: The current study examined the efficacy of minocycline as add-on treatment for alleviating negative and cognitive symptoms in early-phase schizophrenia. A double blind, randomized, placebo-controlled design was used. Consenting schizophrenia patients were randomly allocated to minocycline (n=36) or placebo (n=18) treatments. Subjects were followed-up for 6 months during which they underwent clinical and cognitive evaluations using a computerized assessment battery. Results: Minocycline was well tolerated with few adverse events. It showed a beneficial effect on negative symptoms and general outcome, evident in the Scale for the Assessment of Negative Symptoms (SANS), Clinical Global Impression (CGI) and insight scores. A similar pattern was found for cognitive functioning, mainly in executive functions (working memory, cognitive shifting and planning). Conclusions: Minocycline affected negative symptoms and executive functioning, both related to frontal lobe activity. These findings may be related to the effect of minocycline on the glutamatergic system, through inhibition of nitric oxide synthase and blocking of NO-induced neurotoxicity. The dopaminergic system may also be involved, as minocycline attenuates dopamine increase following NMDA antagonist administration. Overall, the findings support the beneficial effect of minocycline add on therapy in early phase schizophrenia. Acknowledgement: Stanley Research Foundation.