Antimanic and mood-stabilizing effect of memantine as an augmenting agent in treatment-resistant bipolar disorder.

Memantine is a selective, uncompetitive N-methylD-aspartate (NMDA) receptor antagonist, currently used in the treatment of Alzheimer s disease. Many clinical trials have demonstrated its tolerability and safety. We have suggested that antidepressants induce mania and rapid cycling by sensitizing dopamine D2 receptors (1) and demonstrated that the sensitization inducedbyantidepressants requires the stimulation of NMDA receptors (2). It is tempting to suggest that the phenomenon of sensitization could underlie the spontaneous development and the course of mania as well. Thus, blockade of NMDA receptors would prevent and suppress mania. These considerations prompted us to use memantine (the only safe NMDA receptor antagonist available for clinical use) as an antimanic and mood-stabilizing agent in a naturalistic setting (which according to Italian rules does not require Ethical Committee approval). After obtaining written informed consent for the treatment and the publication of the data, we administeredmemantine 10–30 mg ⁄day (according to the doses used for Alzheimer s disease and inmany off-label uses of the drug in other psychiatric disorders) to 18 bipolar disorder patients [(mean age= 42, SD= 11, range: 24–61): 13 bipolar I disorder (11 women and 2 men) and 5 bipolar II disorder (3 women and 2men)]. Ten of these 18 patients were rapid cyclers, 5 were continuous circular with long cycles, and 3 had a course with free intervals. Thirteen patients exhibited psychotic symptoms. These patients had been ill for an averageof 21.5 years (SD=12, range: 5–47) and had been resistant to very intense standard treatments, including lithium, antiepileptics, typical and atypical antipsychotics, electroconvulsive therapy, and antidepressants. These patients had been under our care for a mean duration of 9 years (SD = 11, range: 1–33). The 10 rapid cyclers had a mean duration of rapid-cycling course of 11 years (SD = 7.6, range: 3–29). The memantine treatment was added to the ongoing treatment, which was left unmodified. The severity of the patients condition before memantine and the change after memantine addition was evaluated on the Clinical Global Impression– Bipolar (CGI-BP) (3) Overall Bipolar Illness scale. All patients were monitored for 24 weeks. The average CGI-BP score was 6.6 (range: 5–7) before the addition of memantine. Compared to the preceding phases of illness, at 24 weeks, 9 patients scored 1 (very much improved), 4 patients scored 2 (much improved), 2 patients scored 3 (minimally improved), and 3 patients scored 4 (remained unchanged). Among the 10 rapid cyclers, 6 reached stability. Thus, after 24 weeks of memantine treatment, 72.2% of patients were very much or much improved. The mean time to improvement was 55 days (SD = 48.4, range: 6–132). These results suggest a meaningful antimanic and mood-stabilizing effect of memantine. The improvement was obtained in patients who had been resistant for many years to all available treatments and at relatively small doses. With regard to side effects, one patient complained of dizziness and another of constipation. Controlled clinical studies are warranted in order to confirm our preliminary observations and establish the safety and efficacy of memantine in combination with other treatments for bipolar disorder before a widespread use of memantine in patients with treatment-resistant bipolar disorder.