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Major depressive disorder (MDD) or depression is a heterogeneous mental illness which have direct effect on patient's behavior and cognition; causing constant feeling of unhappiness and loss of concern in earlier enjoyed events. Vortioxetine (VOR) is a new atypical serotonergic antidepressant reported for the treatment of major MDD and has its use in various psychological disorders. Despite its therapeutic potential, it has poor water solubility which creates problem in delivery. Nanocrystal based orally disintegrating tablets (ODTs) are proposed to enhance water solubility and dissolution rate of VOR. Nanosuspension was prepared by nanoprecipitation method after optimizing various parameters. The formulated nanosuspension was effectively converted to solid powder by the lyophilization technique with emphasis on parameters like nature/concentration of cryoprotectants. Prepared nanocrystals were characterized for solid state of drug present, morphology and size after re-dispersion. The powders were then subsequently compressed into ODTs and dissolution profiles of the tablets were compared. The dissolution profile of the ODTs prepared from nanocrystals showed superior dissolution profile in comparison to ODTs prepared from untreated drug.