Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms
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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.
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Verapamil may work as an adjunctive therapy or as monotherapy in women, but larger studies are needed before a conclusion can be made.
“While an initial small RCT did not show anti‐manic efficacy for verapamil,185 there is some evidence that it may work as an adjunctive therapy (level 4)186 or as monotherapy in women (level 4).187 Larger studies are needed before a conclusion can be made.”
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Cites
Hamilton, M. (1960) · Journal of Neurology, Neurosurgery & Psychiatry · doi:10.1136/jnnp.23.1.56 · Cited by 32,817 · see citing works
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442 · see citing works
Lithium amplifies agonist-dependent phosphatidylinositol responses in brain and salivary glands
Berridge, M. J., Downes, C. P., & Hanley, M. R. (1982) · Biochemical Journal · doi:10.1042/bj2060587 · Cited by 2,145 · see citing works
Hallcher, L. M., & Sherman, W. R. (1980) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)70391-3 · Cited by 1,102 · see citing works
Regulation of protein kinase C
Newton, A. C. (1997) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(97)80058-0 · Cited by 914 · see citing works
Two-Year Outcomes for Interpersonal and Social Rhythm Therapy in Individuals With Bipolar I Disorder
Frank, E., Kupfer, D. J., Thase, M. E., Mallinger, A. G., Swartz, H. A., Fagiolini, A. M., Grochocinski, V., Houck, P., Scott, J., Thompson, W., et al. (2005) · Archives of General Psychiatry · doi:10.1001/archpsyc.62.9.996 · Cited by 770 · see citing works
Self-citationBaum, A. E., Akula, N., Cabanero, M., Cardona, I., Corona, W., Klemens, B., Schulze, T. G., Cichon, S., Rietschel, M., Nöthen, M. M., et al. (2008) · Molecular Psychiatry · doi:10.1038/sj.mp.4002012 · Cited by 700 · see citing works
Lithium inhibits adrenergic and cholinergic increases in GTP binding in rat cortex
Avissar, S., Schreibert, G., Danon, A., & Belmaker, R. H. (1988) · Nature · doi:10.1038/331440a0 · Cited by 472 · see citing works
The Bech‐Rafaelsen Mania Scale and the Hamilton Depression Scale
Bech, P., Bolwig, T. G., Kramp, P., & Rafaelsen, O. J. (1979) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1979.tb04484.x · Cited by 405 · see citing works
Raskin, A., Schulterbrandt, J. G., Reatig, N., & McKeon, J. J. (1969) · The Journal of Nervous and Mental Disease · doi:10.1097/00005053-196901000-00010 · Cited by 372 · see citing works
Manji, H. K. (1995) · Archives of General Psychiatry · doi:10.1001/archpsyc.1995.03950190013003 · Cited by 330 · see citing works
Self-citationProtein kinase C overactivity impairs prefrontal cortical regulation of working memory
Birnbaum, S. G., Yuan, P. X., Wang, M., Vijayraghavan, S., Bloom, A. K., Davis, D. J., Gobeske, K. T., Sweatt, J. D., Manji, H. K., & Arnsten, A. F. T. (2004) · Science · doi:10.1126/science.1100021 · Cited by 318 · see citing works
Self-citationMammalian Diacylglycerol Kinases, a Family of Lipid Kinases with Signaling Functions
Topham, M. K., & Prescott, S. M. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.11447 · Cited by 283 · see citing works
Cellular Plasticity Cascades: Targets for the Development of Novel Therapeutics for Bipolar Disorder
Zarate, C. A., Singh, J. B., & Manji, H. K. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.10.021 · Cited by 276 · see citing works
Self-citationSherman, W. R., Leavitt, A. L., Honchar, M. P., Hallcher, L. M., & Phillips, B. E. (1981) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1981.tb10819.x · Cited by 270 · see citing works
Manji, H. K., & Lenox, R. H. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00235-8 · Cited by 241 · see citing works
Self-citationSignaling: cellular insights into the pathophysiology of bipolar disorder
Manji, H. K., & Lenox, R. H. (2000) · Biological Psychiatry · doi:10.1016/s0006-3223(00)00929-x · Cited by 209 · see citing works
Self-citationEfficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study
Zarate, C. A., Singh, J. B., Carlson, P. J., Quiroz, J., Jolkovsky, L., Luckenbaugh, D. A., & Manji, H. K. (2007) · Bipolar Disorders · doi:10.1111/j.1399-5618.2007.00530.x · Cited by 208 · see citing works
Self-citationAltered platelet protein kinase C activity in bipolar affective disorder, manic episode
Friedman, E., Hoau-Yan-Wang, Levinson, D. F., Connell, T. A., & Singh, H. (1993) · Biological Psychiatry · doi:10.1016/0006-3223(93)90006-y · Cited by 194 · see citing works
Increased Platelet Intracellular Calcium Concentration in Patients With Bipolar Affective Disorders
Dubovsky, S. L. (1989) · Archives of General Psychiatry · doi:10.1001/archpsyc.1989.01810070058010 · Cited by 186 · see citing works
Chronic Sodium Valproate Selectively Decreases Protein Kinase C α and ε In Vitro
Chen, G., Manji, H. K., Hawver, D. B., Wright, C. B., & Potter, W. Z. (1994) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1994.63062361.x · Cited by 171 · see citing works
Self-citationEnhanced protein kinase C activity and translocation in bipolar affective disorder brains
Wang, H.-Y., & Friedman, E. (1996) · Biological Psychiatry · doi:10.1016/0006-3223(95)00611-7 · Cited by 169 · see citing works
Lithium Decreases Membrane‐Associated Protein Kinase C in Hippocampus: Selectivity for the α Isozyme
Manji, H. K., Etcheberrigaray, R., Chen, G., & Olds, J. L. (1993) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1993.tb07474.x · Cited by 161 · see citing works
Self-citationCellular Plasticity Cascades: Genes-To-Behavior Pathways in Animal Models of Bipolar Disorder
Einat, H., & Manji, H. K. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.11.004 · Cited by 154 · see citing works
Self-citationA Preliminary Investigation of a Protein Kinase C Inhibitor in the Treatment of Acute Mania
Bebchuk, J. M., Arfken, C. L., Manji, S., Murphy, J., Hasanat, K., & Manji, H. K. (2000) · Archives of General Psychiatry · doi:10.1001/archpsyc.57.1.95 · Cited by 152 · see citing works
Self-citationOverview of the mechanism of action of lithium in the brain: fifty-year update.
Lenox, R. H., & Hahn, C.-G. (2000) · PubMed · Cited by 149 · see citing works
Emamghoreishi, M., Schlichter, L. C., Li, P. P., Parikh, S. V., Sen, J., Kamble, A., & Warsh, J. J. (1997) · American Journal of Psychiatry · doi:10.1176/ajp.154.7.976 · Cited by 142 · see citing works
Abnormal intracellular calcium ion concentration in platelets and lymphocytes of bipolar patients
Dubovsky, S. L., Murphy, J. R., Thomas, M. R., & Rademacher, J. (1992) · American Journal of Psychiatry · doi:10.1176/ajp.149.1.118 · Cited by 140 · see citing works
Einat, H., Yuan, P., Szabo, S. T., Dogra, S., & Manji, H. K. (2007) · Neuropsychobiology · doi:10.1159/000106054 · Cited by 119 · see citing works
Self-citationChronic lithium administration alters a prominent PKC substrate in rat hippocampus
Lenox, R. H., Watson, D. G., Patel, J., & Ellis, J. (1992) · Brain Research · doi:10.1016/0006-8993(92)90598-4 · Cited by 118 · see citing works
Kulkarni, J., Garland, K. A., Scaffidi, A., Headey, B., Anderson, R., de Castella, A. R., Fitzgerald, P. B., & Davis, S. R. (2005) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2005.11.001 · Cited by 113 · see citing works
Protein kinase C and dopamine transport—2. Effects of amphetamine in vitro
Giambalvo, C. T. (1992) · Neuropharmacology · doi:10.1016/0028-3908(92)90049-u · Cited by 105 · see citing works
Pazzaglia, P. J., Post, R. M., Ketter, T. A., Callahan, A. M., Marangell, L. B., Frye, M. A., George, M. S., Kimbrell, T. A., Leverich, G. S., Cora‐Locatelli, G., et al. (1998) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-199810000-00009 · Cited by 100 · see citing works
Self-citationClinical significance of reversed vegetative subtypes of recurrent major depression.
Thase, M. E., Carpenter, L. L., Kupfer, D. J., & Frank, E. (1991) · PubMed · Cited by 96 · see citing works
Self-citationLithium regulates PKC‐mediated intracellular cross‐talk and gene expression in the CNS in vivo
Chen, G., Masana, M. I., & Manji, H. K. (2000) · Bipolar Disorders · doi:10.1034/j.1399-5618.2000.20303.x · Cited by 90 · see citing works
Self-citationChronic Lithium Treatment Attenuates Intracellular Calcium Mobilization
Wasserman, M. J., Corson, T. W., Sibony, D., Cooke, R. G., Parikh, S. V., Pennefather, P., Li, P. P., & Warsh, J. J. (2004) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300400 · Cited by 88 · see citing works
Cowell, R. M., Kantor, L., Hewlett, G. H. K., Frey, K. A., & Gnegy, M. E. (2000) · European Journal of Pharmacology · doi:10.1016/s0014-2999(99)00828-6 · Cited by 78 · see citing works
Hough, C. J., Lu, S., Davis, C. L., et al. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00308-4 · Cited by 76 · see citing works
Iwata, S.-I., Hewlett, G. H. K., Ferrell, S. T., Kantor, L., & Gnegy, M. E. (1997) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37164-2 · Cited by 72 · see citing works
Watson, D. G., Watterson, J. M., & Lenox, R. H. (1998) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)37400-2 · Cited by 68 · see citing works
Protein kinase C and dopamine transport—1. Effects of amphetamine in vivo
Giambalvo, C. T. (1992) · Neuropharmacology · doi:10.1016/0028-3908(92)90048-t · Cited by 64 · see citing works
A review of randomized, controlled clinical trials in acute mania
Keck, P. E., Mendlwicz, J., Calabrese, J. R., FAWCETT, J. A., Suppes, T. M., Vestergaard, P., & Carbonell, C. (2000) · Journal of Affective Disorders · doi:10.1016/s0165-0327(00)00177-4 · Cited by 59 · see citing works
Calcium channel antagonists for the treatment of bipolar disorder
Levy, N. A., & Janicak, P. G. (2000) · Bipolar Disorders · doi:10.1034/j.1399-5618.2000.020204.x · Cited by 58 · see citing works
Wang, H.-Y., & Friedman, E. (2001) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01147-7 · Cited by 53 · see citing works
Verapamil: a new antimanic drug with potential interactions with lithium.
Dubovsky, S. L., Franks, R. D., & Allen, S. J. (1987) · PubMed · Cited by 52 · see citing works
Emerging trends in the treatment of rapid cycling bipolar disorder: a selected review
Post, R. M., Frye, M. A., Denicoff, K. D., Leverich, G. S., Dunn, R. T., Osuch, E. A., Speer, A. M., Obrocea, G. V., & Jajodia, K. (2000) · Bipolar Disorders · doi:10.1034/j.1399-5618.2000.020403.x · Cited by 49 · see citing works
Neurotoxicity Caused by Lithium‐Verapamil Synergism
Price, W. A., & Giannini, A. J. (1986) · The Journal of Clinical Pharmacology · doi:10.1002/j.1552-4604.1986.tb02980.x · Cited by 47 · see citing works
Wang, J., Asghari, V., Rockel, C. P., & Young, L. T. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00627-7 · Cited by 46 · see citing works
Berk, M., Bodemer, W., Oudenhove, T. V., & Butkow, N. (1995) · Human Psychopharmacology Clinical and Experimental · doi:10.1002/hup.470100304 · Cited by 44 · see citing works
Verapamil treatment for women with bipolar disorder
Wisner, K. L., Peindl, K. S., Perel, J. M., Hanusa, B. H., Piontek, C. M., & Baab, S. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(01)01338-5 · Cited by 41 · see citing works
Lithium affects G-protein receptor coupling
Drummond, A. H. (1988) · Nature · doi:10.1038/331388a0 · Cited by 37 · see citing works
Effect of verapamil on cardiac protein kinase C activity in diabetic rats
Yasushi, T., Kashiwagi, A., Ogawa, T., et al. (1991) · European Journal of Pharmacology · doi:10.1016/0014-2999(91)90595-h · Cited by 37 · see citing works
Phosphorylation of neuromodulin in rat striatum after acute and repeated, intermittent amphetamine
Gnegy, M. E., Hong, P., & Ferrell, S. T. (1993) · Molecular Brain Research · doi:10.1016/0169-328x(93)90055-t · Cited by 33 · see citing works
HOFFMAN, S., Gopalakrishna, R., Gundimeda, U., et al. (1998) · Experimental Eye Research · doi:10.1006/exer.1998.0491 · Cited by 32 · see citing works
Magnesium oxide augmentation of verapamil maintenance therapy in mania
Giannini, A. J., Nakoneczie, A. M., Melemis, S. M., Ventresco, J., & Condon, M. (2000) · Psychiatry Research · doi:10.1016/s0165-1781(99)00116-x · Cited by 31 · see citing works
Bipolar Medications: Mechanisms of Action.
Reti, I. M. (2001) · The Journal of Nervous and Mental Disease · doi:10.1097/00005053-200101000-00014 · Cited by 29 · see citing works
Lithium and calcium channel blockers: Possible neurotoxicity
Wright, B. A., & Jarrett, D. B. (1991) · Biological Psychiatry · doi:10.1016/0006-3223(91)90035-k · Cited by 22 · see citing works
Lithium‐Verapamil Toxicity in the Elderly
Price, W. A., & SHALLEY, J. E. (1987) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.1987.tb01353.x · Cited by 21 · see citing works
Post-receptor signaling pathways in the pathophysiology and treatment of mood disorders
Manji, H. K., & Chen, G. (2000) · Current Psychiatry Reports · doi:10.1007/s11920-000-0006-6 · Cited by 19 · see citing works
Self-citationCalcium channel blocker, nimodipine, for the treatment of bipolar disorder during pregnancy
Yingling, D. R., Utter, G. O., Vengalil, S., et al. (2002) · American Journal of Obstetrics and Gynecology · doi:10.1067/mob.2002.125279 · Cited by 14 · see citing works
Rapid cycling bipolar disease: New concepts and treatments
Dubovsky, S. L. (2001) · Current Psychiatry Reports · doi:10.1007/s11920-001-0038-6 · Cited by 11 · see citing works
Verapamil decreases lymphocyte protein kinase C activity in humans
DePetrillo, P. B., Abernethy, D. R., Wainer, I. W., et al. (1994) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.1994.8 · Cited by 10 · see citing works
Little, K. Y. (1989) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-198912000-00027 · Cited by 8 · see citing works
Choreoathetosis Induced by Verapamil and Lithium Treatment
&NA; (1989) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-198912000-00028 · Cited by 7 · see citing works
A link between lithium, lipids and receptors?
Michell, B. (1982) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(82)90177-3 · Cited by 6 · see citing works
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CACNA1C (Cav1.2) in the pathophysiology of psychiatric disease
Bhat, S., Dao, D. T., Terrillion, C. E., Arad, M., Smith, R. J., Soldatov, N. M., & Gould, T. D. (2012) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2012.06.001 · Cited by 271 · see citing works
Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature
Saxena, A., Scaini, G., Bavaresco, D. V., Leite, C., Valvassoria, S. S., Carvalho, A. F., & Quevedo, J. (2017) · Complex Psychiatry · doi:10.1159/000480349 · Cited by 85 · see citing works
- Authors
- Mallinger, A. G., Thase, M. E., Haskett, R., Buttenfield, J., Luckenbaugh, D. A., Frank, E., Kupfer, D. J., & Manji, H. K.
- Affiliations
- National Institutes of Health (US)
- University of Pittsburgh (US)
- Corresponding author
- Mallinger, Alan G
- Venue
- Bipolar Disorders
- Publisher
- Wiley
- Published
- 2008-11-18
- Volume
- 10
- Issue
- 8
- Pages
- 856-866
- ISSN
- 1398-5647 (ISSN-L)
- 1399-5618
- PMC
- PMC3387673
- OpenAlex
- W2047833434
- Cited by
- 44
- References
- 67
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 4 · 2013: 6 · 2012: 3
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bipolar Disorders (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01mh050634-03)
- National Institute of Mental Health (MH 29618, MH-50634, R01MH029618, R37MH029618)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- verapamil, lithium, mania, bipolar disorder, protein kinase C inhibition, adjunctive therapy, treatment-resistant mania, combination therapy, calcium channel blockers
- MeSH terms
- Adult, Bipolar Disorder, Calcium Channel Blockers, Double-Blind Method, Drug Resistance, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Perphenazine, Psychiatric Status Rating Scales, Antipsychotic Agents, Verapamil, Lithium Carbonate, Antimanic Agents
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