BACKGROUND: We have recently provided preliminary clinical observations indicating that memantine, as augmenting agent, was associated with a meaningful antimanic and mood-stabilizing effect in treatment-resistant bipolar disorders. To further investigate the therapeutic and prophylactic action of the drug we administered memantine, as augmenting agent, to 40 treatment-resistant bipolar disorder patients, monitored and evaluated for 12 months. METHODS: The sample population encompassed 40 treatment-resistant bipolar disorder patients monitored for 12 months. Memantine, at the dose of 10-30 mg/day, was added to the ongoing treatment, which was left unmodified. The severity of the patients' condition before memantine and the changes after memantine addition were evaluated on the Clinical Global Impression Bipolar (CGI-BP) Overall Bipolar Illness Scale. The severity of patients' condition was scored before memantine and the change was evaluated after memantine addition at 6 and 12 months. LIMITATIONS: The present study has the limitations of an open clinical study and the observed effects require testing in a blinded, randomized, controlled trial which is planned. RESULTS: The average CGI-BP score of the patients was 6.7 (SD=0.58, range: 5-7) before the addition of memantine. After 6 months of memantine treatment, 72.5% of patients were very much or much improved. Among the rapid cyclers 68.4% of patients reached stability, defined by the absence of recurrences. Patients very much or much improved were 72.5% at 12 months; while 12.5% discontinued memantine or were lost to follow-up. CONCLUSIONS: The results confirm our previous observations and strongly suggest that memantine, as augmenting agent, was associated with a clinically substantial antimanic and sustained mood-stabilizing effect, with excellent safety and tolerability profile.