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Aim: To evaluate antidepressant-like effect of memantine in a rat model., Methods: Male Wistar rats were treated intraperitoneally with either vehicle, memantine (10 mg/kg) or imipramine (20 mg/kg), for 3 wk. Twenty-four hour after the last treatment animals were challenged with quinpirole (0.3 mg/kg s.c.) and tested for motor activity. After 1 h habituation to the motility cages, the motor response was recorded for the following 45-min and the data were collected in 5-min time bins., Results: As expected, chronic treatment with imipramine potentiated the locomotor stimulant effect of quinpirole. On the contrary, chronic memantine administration failed to induce the behavioral supersensitivity to the dopamine agonist., Conclusion: The results show that memantine, at variance with antidepressant treatments, fails to induce dopaminergic behavioral supersensitivity. This observation is consistent with the results of preclinical and clinical studies suggesting that memantine does not have an acute antidepressant action but does have an antimanic and mood-stabilizing effect.

Unlabelled: We review preclinical and clinical evidences strongly suggesting that memantine, an old drug currently approved for Alzheimer's dementia, is an effective treatment for acute mania and for the prevention of manic/hypomanic and depressive recurrences of manic-depressive illness. Lithium remains the first line for the treatment and prophylaxis of bipolar disorders, but currently available treatment alternatives for lithium resistant patients are of limited and/or questionable efficacy. Thus, research and development of more effective mood stabilizer drugs is a leading challenge for modern psychopharmacology. We have demonstrated that 21 d administration of imipramine causes a behavioural syndrome similar to a cycle of bipolar disorder, i.e., a mania followed by a depression, in rats. Indeed, such treatment causes a behavioural supersensitivity to dopamine D2 receptor agonists associated with an increase sexual activity and aggressivity (mania). The dopamine receptor sensitization is followed, after imipramine discontinuation, by an opposite phenomenon (dopamine receptor desensitization) and an increased immobility time (depression) in the forced swimming test of depression. Memantine blocks the development of the supersensitivity and the ensuing desensitization associated with the depressive like behavior. On the basis of these observations we have suggested the use of memantine in the treatment of mania and in the prophylaxis of bipolar disorders. To test this hypothesis we performed several naturalistic studies that showed an acute antimanic effect and a long-lasting and progressive mood-stabilizing action (at least 3 years), without clinically relevant side effects. To confirm the observations of our naturalistic trials we are now performing a randomized controlled clinical trial. Finally we described the studies reporting the efficacy of memantine in manic-like symptoms occurring in psychiatric disorders other than bipolar., Limitations: A randomized controlled clinical trial is needed to confirm our naturalistic observations., Conclusion: We believe that this review presents enough pharmacological and clinical information to consider the administration of memantine in the treatment of bipolar disorders that no respond to standard mood stabilizers.