The antidepressant potential of (2R,6R)-hydroxynorketamine: A detailed review of pre-clinical findings

Depression affects hundreds of millions globally, and in 2019, esketamine, an S-enantiomer of ketamine, was approved for treatment-resistant depression (TRD). While effective, esketamine carries risks, including abuse potential and adverse effects even at low doses. As a result, ketamine's metabolite, (2R,6R)-hydroxynorketamine ((2R,6R)-HNK), has garnered attention for its potential antidepressant effects without these drawbacks. This selective review evaluates preclinical behavioral evidence for (2R,6R)-HNK's antidepressant properties, focusing on rodent studies that used established depression models. Results showed that (2R,6R)-HNK reduced behavioral despair, anhedonia, anxiety, and social avoidance in both stressed and non-stressed rodents. Antidepressant effects were observed at doses between 5and 125 mg/kg, with rapid onset (30 min) and long-lasting effects (up to 21 days). However, some studies failed to demonstrate significant antidepressant effects at doses below 40 mg/kg, often in models with pre-induced depression. No significant adverse effects were reported, but data on side effects were limited. In conclusion, (2R,6R)-HNK shows promise as a next-generation antidepressant. However, further research is needed to fully understand its long-term safety and mechanisms, and to determine its advantages over existing treatments like esketamine, particularly for TRD patients.