Several effective pharmacological therapies for panic disorder (PD) are available, but they have some drawbacks, and unsatisfactory outcomes can occur. Expanding the variety of anti-panic medications may allow for improving PD treatment. The authors performed an updated systematic review of preclinical and clinical (Phase I-III) pharmacological studies to look for advances made in the last six years concerning novel-mechanism-based anti-panic compounds or using medications approved for nonpsychiatric medical conditions to treat PD. The study included seven published articles presenting a series of preclinical studies, two Phase I clinical studies with orexin receptor (OXR) antagonists, and two clinical studies investigating the effects of D-cycloserine (DCS) and xenon gas in individuals with PD. The latest preclinical findings confirmed and expanded previous promising indications of OXR1 antagonists as novel-mechanism-based anti-panic compounds. Translating preclinical research into clinical applications remains in the early stages. However, limited clinical findings suggested the selective OXR1 antagonist JNJ-61393115 may exert anti-panic effects in humans. Overall, OXR1 antagonists displayed a favorable profile of short-term safety and tolerability. Very preliminary suggestions of possible anti-panic effects of xenon gas emerged but need confirmation with more rigorous methodology. DCS did not seem promising as an enhancer of cognitive-behavioral therapy in PD. Future studies, including objective panic-related physiological parameters, such as respiratory measures, and expanding the use of panic vulnerability biomarkers, such as hypersensitivity to CO₂ panic provocation, may allow for more reliable conclusions about the anti-panic properties of new compounds.