The authors report no conflicts of interest related to the subject of this work. MET has received compensation from AstraZeneca, Bristol-Myers Squibb, Cephalon, Cyberonics, Eli Lilly & Co., GlaxoSmithKline, Janssen Pharmaceutica, MedAvante, Neuronetics, Novartis, Organon, Sepracor, Shire US, Supernus Pharmaceuticals, Wyeth Pharmaceuticals, Sanofi-aventis, Jones Day (Wyeth Litigation), Phillips Lytle (GlaxoSmithKline Litigation), American Psychiatric Publishing, Guilford Publications, and Herald House; and reports equity holdings in MedAvante, Inc., but has received no financial compensation to date. RH has received compensation from Eli Lilly & Co., GlaxoSmithKline, Wyeth Pharmaceuticals, and Abbott. DAL has received compensation from NIMH through Kelly Services, Inc. (a contracting agency); from Yale University through investigator Dr. Alex Neumeister; and from UCLA through a grant from the Stanley Foundation and administered by Dr. Lori Altshuler. EF has received compensation from Pfizer, Eli Lilly & Co., Novartis, Servier, Forest Research Institute, the Pittsburgh Foundation, Guilford Press, and Lundbeck. DJK has received compensation from Eli Lilly & Co., Forest Pharmaceuticals, Pfizer, Solvay/Wyeth Pharmaceuticals, and Servier Amerique.
Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms
Article first published online: 18 NOV 2008
© 2008 The Authors. Journal compilation © 2008 Blackwell Munksgaard
Volume 10, Issue 8, pages 856–866, December 2008
How to Cite
Mallinger, A. G., Thase, M. E., Haskett, R., Buttenfield, J., Luckenbaugh, D. A., Frank, E., Kupfer, D. J. and Manji, H. K. (2008), Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms. Bipolar Disorders, 10: 856–866. doi: 10.1111/j.1399-5618.2008.00636.x
- Issue published online: 18 NOV 2008
- Article first published online: 18 NOV 2008
- Received 9 August 2007, revised and accepted for publication 29 April 2008
- bipolar disorder;
- protein kinase C;
Objectives: Attenuation of protein kinase C (PKC) is a mechanism common to both established (lithium, valproate) and some novel (tamoxifen) antimanic agents. Verapamil, although primarily known as a calcium channel blocker, also has PKC inhibitory activity. Verapamil has shown antimanic activity in some but not all studies. Therefore, we investigated verapamil, used alone or as an adjunctive treatment, in manic patients who did not respond to an initial adequate trial of lithium.
Methods: Each study phase lasted three weeks. Subjects were treated openly with lithium in Phase 1 (n = 45). Those who failed to respond were randomly assigned to double-blind treatment in Phase 2 with either verapamil (n = 10) or continued-lithium (n = 8). Phase 2 nonresponders (n = 10) were assigned to combined verapamil/lithium in Phase 3.
Results: Response in Phase 2 did not differ significantly between verapamil and continued-lithium. During Phase 3, response to combined treatment was significantly better than overall response to monotherapy in Phase 2 (Fisher’s Exact test, p = 0.043). Mania ratings improved during combined treatment in Phase 3 by 88.2% (linear mixed model analysis, F = 4.34, p = 0.013), compared with 10.5% improvement during Phase 2.
Conclusions: In this preliminary investigation, verapamil monotherapy did not demonstrate antimanic efficacy. By contrast, the combination of verapamil plus lithium was highly efficacious. Our findings thus suggest that verapamil may have potential utility as an adjunct to lithium. This effect may be mediated by additive actions on PKC inhibition, which may be an important mechanism for antimanic agents in general.