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Neural Plasticity
Volume 2015, Article ID 858251, 7 pages
Research Article

Lithium and Valproate Levels Do Not Correlate with Ketamine’s Antidepressant Efficacy in Treatment-Resistant Bipolar Depression

1New York Medical College, 40 Sunshine Cottage Road, Valhalla, NY 10595, USA
2National Institute of Mental Health, National Institutes of Health, Experimental Therapeutics and Pathophysiology Branch, 10 Center Drive, Building 10/CRC, Bethesda, MD 20892, USA
3Massachusetts General Hospital, Depression Clinical & Research Program, 1 Bowdoin Square, 6th Floor, Boston, MA 02114, USA
4Department of Psychiatry & Psychological Services, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA

Received 3 February 2015; Revised 21 March 2015; Accepted 13 May 2015

Academic Editor: Lin Xu

Copyright © 2015 Annie J. Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Ketamine and lithium both inhibit glycogen synthase kinase 3. In addition, lithium and ketamine have synergistic antidepressant-like effects at individually subeffective doses in rodents. We hypothesized that ketamine’s antidepressant effects would be improved by therapeutic doses of lithium versus valproate and that serum lithium levels would positively correlate with ketamine’s antidepressant efficacy. Thirty-six patients with treatment-resistant bipolar depression maintained on therapeutic-dose lithium (, 0.79 ± 0.15 mEq/L) or valproate (, 79.6 ± 12.4 mg/mL) received 0.5 mg/kg ketamine infusion in a randomized, double-blind, placebo-controlled, crossover trial. The primary depression outcome measure—the Montgomery-Åsberg Depression Rating Scale (MADRS)—was assessed before infusion and at numerous postinfusion time points. Both lithium (F1,118 = 152.08, , and ) and valproate (F1,128 = 20.12, , and ) significantly improved depressive symptoms, but no statistically significant difference was observed between mood stabilizer groups (F1,28 = 2.51, , and ). Serum lithium and valproate levels did not correlate with ketamine’s antidepressant efficacy. Although the study was potentially underpowered, our results suggest that lithium may not potentiate ketamine’s antidepressant efficacy in treatment-resistant bipolar depression.