NCDEU Poster Session 2012

The Efficacy of Memantine for Cognitive Deficits in Euthymic Subjects With Bipolar Disorder

Dan V. Iosifescu, MD, MSc; William S. Gilmer, MD; Alexander Fan, MD; Atilla Gonenc, PhD; Constance Moore, PhD; Christopher Randolph, PhD; Mark Hyman Rapaport, MD; Thilo Deckersbach, PhD; and Andrew A. Nierenberg, MD
From Massachusetts General Hospital and Harvard Medical School, Boston (Drs Deckersbach, Iosifescu, and Nierenberg); Mount Sinai School of Medicine, New York, New York (Dr Iosifescu); Northwestern University Feinberg School of Medicine, Chicago, Illinois (Dr Gilmer); McLean Hospital, Belmont, Massachusetts (Dr Gonenc); the University of Massachusetts, Worcester (Dr Moore); Loyola University Medical Center, Chicago, Illinois (Dr Randolph); and Emory University, Atlanta, Georgia (Dr Rapaport).

This poster presentation was supported by Forest Laboratories (via grants to Drs Nierenberg, Iosifescu, and Rapaport).

Background: Subjects with bipolar disorder experience significant cognitive dysfunction, even when euthymic, but few studies have evaluated potential treatments for such deficits.

Methods: We randomized 72 euthymic subjects with bipolar disorder, who reported subjective cognitive deficits. Subjects were assigned flexible doses (5-20 mg/day) of memantine or placebo (using a ratio 2:1 respectively) for a 12-week treatment study. At baseline and endpoint all subjects were administered neuropsychological tests, including tests of attention (the Rapid Visual Information Processing Task, RVIP of CANTAB), short-term/working memory (the Spatial Working Memory, SWM of the CANTAB), verbal and episodic memory (the California Verbal Learning Test, CVLT-II and the Delayed Matching to Sample, DMS of the CANTAB). We also administered the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which includes five subscales (attention, immediate memory, visuospatial construction skills, delayed memory and language). Mood scales and subjective cognitive questionnaires were administered monthly. We collected proton magnetic resonance spectroscopy (1H-MRS) data from a subset of patients before and after treatment. MRS data was acquired from two 15x15x15 mm voxels centered on left and right hippocampus. Study completers were offered open label treatment with memantine for additional 12 weeks; neuropsychological tests were again administered at the end of the follow-up.

Results: Over 12 weeks, the memantine group showed significant improvements over placebo in spatial and working memory (SWM: Between errors, Strategy, Total Errors), verbal and episodic memory (DMS: Percent correct and Total correct; CVLT: Trial 2; Trial 4; Recognition hits; Recognition of false positives), total RBANS score and three of five RBANS indexes (attention, language and delayed memory). Compared to placebo (N=3), memantine-treated subjects (N=6) had increases in left hippocampus NAA, a measure of neuronal viability, and in the right hippocampus choline (Cho). The initial improvements in neuropsychological tests during randomized treatment were maintained over 12 weeks of open follow-up.

Conclusions: Memantine was associated with acute improvements on several cognitive domains in euthymic bipolar subjects over 12 weeks and such improvements persisted with ongoing treatment for an additional three months. Memantine was also associated with MRS measures of increased hippocampus neuronal viability.

Learning Objectives:
Understand the importance of cognitive deficits for the functional disability in bipolar disorder

Discuss the potential efficacy of memantine as a potential treatment for cognitive dysfunction in bipolar patients

References
Malhi GS, Ivanovski B, Hadzi-Pavlovic D, et al. Neuropsychological deficits and functional impairment in bipolar depression, hypomania and euthymia. Bipolar Disord. 2007;9(1–2):114–125. PubMed

Iosifescu DV, Moore CM, Deckersbach T, et al. Galantamine-ER for cognitive dysfunction in bipolar disorder and correlation with hippocampal neuronal viability: a proof-of-concept study. CNS Neurosci Ther. 2009;15(4):309–319. PubMed

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