Acute Antidepressant-Like Effects and Biphasic Dose–Response Profiles of Melissa officinalis and Nepeta menthoides in Mice

Introduction: Depression remains a major global health challenge, with many patients poorly responding to standard monoaminergic antidepressants. This has prompted exploration of alternative treatments possessing antioxidant and neuroprotective effects. Melissa officinalis (MO) and Nepeta menthoides (NM), medicinal plants rich in rosmarinic acid and flavonoids, are traditionally used in Persian medicine for mood disorders and have demonstrated antidepressant potential in preclinical models. However, their acute dose–response effects have not been thoroughly studied. This study aimed to assess the acute antidepressant actions and define the therapeutic windows of MO and NM aqueous extracts in mice. Methods: Sixty-six male N-MRI mice were randomly assigned to 11 groups receiving single oral doses of NM (100–1200 mg/kg) or MO (350–950 mg/kg), fluoxetine (20 mg/kg), imipramine (10 mg/kg), or saline. Behavioral assessments included the Open Field Test (OFT), Tail Suspension Test (TST), and Forced Swim Test (FST). Results: Both extracts demonstrated dose-dependent biphasic behavioral effects, with antidepressant-like activity observed at lower doses. NM (100 mg/kg) and MO (550 mg/kg) produced the greatest reductions in immobility time, comparable to fluoxetine and imipramine. In contrast, higher doses showed diminished or reversed efficacy. Locomotor activity findings indicated that the reduced immobility observed at effective doses was not attributable to hyperactivity. Conclusion: These findings establish the optimal acute effective doses for NM and MO and emphasize the critical importance of dose selection in herbal antidepressant therapy. Future studies should assess chronic effects and elucidate underlying biochemical mechanisms.