Galantamine-ER for cognitive dysfunction in bipolar disorder and correlation with hippocampal neuronal viability: a proof-of-concept study

Abstract

Background: Many subjects with bipolar disorder experience significant cognitive dysfunction, even when euthymic, but few studies assess biological correlates of or treatment strategies for cognitive dysfunction.

Method: Nineteen subjects with bipolar disorder in remission, who reported subjective cognitive deficits, were treated with open-label galantamine-ER 8-24 mg/day for 4 months. Ten healthy volunteers matched for age and gender were also assessed. Mood and subjective cognitive questionnaires were administered monthly. At the beginning and the end of the trial all subjects were administered neuropsychological tests, including tests of attention (Conners CPT) and episodic memory (CVLT). Bipolar subjects underwent proton magnetic resonance spectroscopy (1H-MRS) measurements before and after treatment, healthy volunteers completed baseline 1H-MRS. We acquired 1H-MRS data at 4.0 T from voxels centered on the left and right hippocampus to measure hippocampal N-acetyl aspartate (NAA, a measure of neuronal viability) and choline containing compounds (Cho, a marker of lipid metabolism and membrane turn-over).

Results: Compared to healthy volunteers, bipolar subjects had higher baseline subjective cognitive deficits and lower scores on objective tests of attention (Conner's CPT) and verbal episodic memory (CVLT). After treatment, bipolar subjects experienced significant improvement of subjective cognitive scores and on objective tests of attention (Conner's CPT) and verbal episodic memory (CVLT). In the left hippocampus NAA increased and choline (Cho) decreased in bipolar subjects during treatment.

Conclusion: Bipolar subjects had cognitive dysfunction; treatment with Galantamine-ER was associated with improved cognition and with increases in neuronal viability and normalization of lipid membrane metabolism in the left hippocampus. This study was registered on ClinicalTrials.gov (NCT00181636).

Conflict of interest statement

Dr. Iosifescu has received research support from Aspect Medical Systems, Forest Laboratories and Ortho‐McNeil Neurologics; he has been a consultant for Forest Laboratories, Gerson Lehrman Group and Pfizer, Inc., and he has been a speaker for Eli Lilly & Co., Forest Laboratories, Pfizer, Inc and Reed‐Elsevier. Drs. Moore, Deckersbach and Ms. Tilley report no potential conflicts. Dr. Ostacher has received research support from Pfizer, and honoraria, Speaker Bureau or travel support from AstraZeneca, Bristol Myers‐Squibb, Concordant Rater Systems, Eli Lilly, Glaxo SmithKline. Dr. Nierenberg has received research support from Bristol‐Myers Squibb, Cederroth, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Lichtwer Pharma, Eli Lilly, Pfizer and Wyeth‐Ayerst; he has been a consultant for Abbott Laboratories, BrainCells Inc., Bristol‐Myers Squibb, Genaissance, GlaxoSmithKline, Innapharma, Janssen Pharmaceutica, Eli Lilly, Novartis, Pfizer, Sepracor, Shire and Somerset, and he has been a speaker for Bristol‐Myers Squibb, Cyberonics, Forest Pharmaceuticals, GlaxoSmithKline, Eli Lilly, and Wyeth‐Ayerst.

Figures

Figure 2

Typical proton spectroscopy (1H‐MRS) spectrum from a subject with bipolar disorder (A) and positioning of the spectroscopy voxel in the left hippocampus (B).

Figure 1

Changes in subjective cognitive scores (CPFQ) in bipolar subjects (BD) during treatment and comparison with healthy volunteers (HV).