Antidepressants,　having　been　applied　for　the　treatment　of　major　depressive　disorder　and　other　conditions　for　decades,　are　among　the　most　commonly　detected　human　pharmaceuticals　in　the　aquatic　environment.　This　study　evaluated　the　immunotoxicity　of　acute　exposure　to　environmentally　relevant　concentrations　of　amitriptyline,　fluoxetine　and　mianserin　using　an　in　vitro　primary　macrophage　model　isolated　from　red　common　carp　(Cyprinus　carpio),　and　also　explored　their　potential　mechanisms　of　action.　A　potential　suppressive　immunoregulatory　effect　of　antidepressant　exposure　was　suggested　based　on　the　observed　suppressive　effects　on　oxidative　stress　parameters,　bactericidal　activity,　NO　production,　and　NO　synthase　activity,　as　well　as　pro-inflammatory　cytokine　gene　expression,　and　a　significant　stimulatory　effect　on　anti-inflammatory　interleukin-10　and　interferon　cytoldne　gene　expression　and　ATPase　activities　in　macrophages　after　6　h-exposure　to　three　individual　antidepressants　and　a　combination　thereof.　Notably,　we　also　found　these　effects　were　significantly　associated　with　a　corresponding　decrease　in　nuclear　factor-kappa　B　(NF-kappa　B)　activity　after　antidepressants　exposure,　and　the　NF-kappa　B　antagonist　significantly　restrained　the　effects　of　antidepressants　on　gene　expression　of　cytokines,　indicating　that　antidepressants　could　alter　the　response　of　various　immune-associated　components　via　the　inhibition　of　NF-kappa　B.　Moreover,　time-dependent　lethal　concentrations　of　three　antidepressants　on　primary　macrophages　were　firstly　determined　at　mg/L　levels,　and　the　synergetic　effects　of　antidepressant　mixtures　were　suggested　and　in　particular,　for　some　parameters　including　total　antioxidant　capacity　and　cytokine　genes　expression,　they　could　be　significantly　affected　by　antidepressants　exposure　at　concentrations　as　low　as　10　ng/L,　which　together　thereby　revealed　the　potential　risk　of　antidepressants　to　aquatic　life.　(C)　2017　Elsevier　Inc.　All　rights　reserved.