ª 2010 The Authors
Bipolar Disorders 2010: 12: 348–349
Letter to the Editor
Antimanic and mood-stabilizing effect of
memantine as an augmenting agent in
treatment-resistant bipolar disorder
To the Editor:
Memantine is a selective, uncompetitive N-methyl-
D-aspartate (NMDA) receptor antagonist, cur-
rently used in the treatment of AlzheimerÕs disease.
Many clinical trials have demonstrated its tolerabil-
ity and safety. We have suggested that antidepres-
sants induce mania and rapid cycling by sensitizing
dopamine D2 receptors (1) and demonstrated that
the sensitization induced by antidepressants requires
the stimulation of NMDA receptors (2). It is
tempting to suggest that the phenomenon of sensi-
tization could underlie the spontaneous develop-
ment 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 writ-
ten informed consent for the treatment and the
publication of the data, we administered memantine
10–30 mg ⁄day (according to the doses used for
AlzheimerÕs disease and in many 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 2 men)]. 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 average of 21.5 years (SD = 12, range:
5–47) and had been resistant to very intense
standard treatments, including lithium, antiepilep-
tics, typical and atypical antipsychotics, electrocon-
vulsive 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
348
Journal compilation ª 2010 Blackwell Munksgaard
BIPOLAR DISORDERS
severity of the patientsÕ condition before meman-
tine 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 im-
proved), 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 constipa-
tion. 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.
Athanasios Koukopoulosa, Daniela Reginaldia,
Giulia Serraa, Alexia Koukopoulosa, Gabriele Sania
and Gino Serrab
a b
Centro Lucio Bini, Roma, Dipartimento di Scienze del
Farmaco, Università di Sassari, Sassari, Italy
Corresponding author:
Gino Serra, M.D.
Dipartimento di Scienze del Farmaco
Università di Sassari
Via Muroni 23⁄A
07100 Sassari, Italy
Fax: 0039079228715
E-mail: dsfserra@uniss.it
doi: 10.1111/j.1399-5618.2010.00803.x

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Letter to the Editor
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Key words: bipolar disorder – memantine – treatment
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