Abstract The introduction of pharmacotherapies for treatment-resistant depression is hindered by translational challenges with existing preclinical screening models that fail to adequately model the clinical features of this syndrome. This research sought to screen antidepressants in two selected genetic lines previously identified as stress-vulnerable and -resilient in the chick anxiety-depression model. Separate groups of socially-raised 5–6day-old Black Australorps (stress-vulnerable) and Production Reds (stress-resilient) were administered imipramine (0–20mg/kg), fluoxetine (0–10mg/kg), maprotiline (0–10mg/kg) or ketamine 0–15mg/kg) IP (1ml/kg) and placed into isolation for 90min. Distress vocalizations (DVoc) were recorded. Onset of behavioral despair and Dvoc rates during the depression-like phase (30–90min) were calculated. Black Australorps entered behavioral despair approximately 25% faster than Productions Reds highlighting stress-vulnerability in this Black Australorp line. In the depression-like phase, Black Australorps were insensitive to imipramine and fluoxetine but sensitive to ketamine, a finding that parallels stress-vulnerable, treatment resistant depressive disorder. The chick anxiety-depression model using the Black Australorp line may prove useful in pre-clinical screening of novel antidepressant targets for use in treatment-resistant depression.