- Whereas several well-controlled studies have established the selective serotonin reuptake inhibitors (SSRIs) as the recommended first-line pharmacotherapeutic agents for acute and chronic post-traumatic stress disorder (PTSD), drug interventions in the acute postexposure phase have not been studied to the same extent and tend to be largely speculative. This study employed an animal model which assesses prevalence of individual stress–response behavior patterns in order to assess the short-term effects of a brief treatment regimen with an SSRI (sertraline) administered immediately after stress–exposure, with those of an identical delayed regimen and of saline. Prevalence rates of rats displaying extreme anxiety-like behavioral responses to predator stress, compared to partial and minimal responses, were assessed in the elevated plus maze and startle response paradigms, with and without intraperitoneal administration of sertraline for 7 days immediately postexposure, or 7 days after exposure. Immediate postexposure administration of sertraline reduced anxiety-like and avoidant behavior, decreased hyperarousal responses and diminished the overall incidence of extreme (PTSD-like) behavioral responses, compared to the delayed treatment regimen and to saline controls. Brief immediate poststress exposure treatment with sertraline reduced prevalence rates of extreme behavioral disruption in the short-term. SSRI drugs are thus worthy of further investigation as agents of secondary prevention in the acute aftermath of stress–exposure.