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. 1998 Mar;23(2):109–117.

Calcitonin and bipolar disorder: a hypothesis revisited.

A Vik 1, L N Yatham 1
PMCID: PMC1188909  PMID: 9549251

Abstract

Double-blind trials conducted in the early 1980s showed that subcutaneous injections of salmon calcitonin in patients suffering from mania resulted in significant decreases in irritability, euphoria and hyperactivity. Although these results were promising, there were no follow-up studies in this area. A MEDLINE search into the effect of calcitonin on neuronal tissues revealed that calcitonin affects neuronal tissues in a manner similar to that of the currently accepted mood-stabilizing agents--namely by modulating intracellular second messenger signalling mechanisms, stabilizing neuronal membranes and inhibiting neuronal calcium influx. We suggest that these effects of calcitonin on neuronal tissues, combined with earlier clinical research showing its efficacy in treating the acute symptoms of mania, make calcitonin a candidate for further research in the treatment of bipolar disorder.

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Selected References

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  1. Allan E. Calcitonin in the treatment of intractable pain from advanced malignancy. Pharmatherapeutica. 1983;3(7):482–486. [PubMed] [Google Scholar]
  2. Bishop G. A. Calcitonin gene-related peptide modulates neuronal activity in the mammalian cerebellar cortex. Neuropeptides. 1995 Feb;28(2):85–97. doi: 10.1016/0143-4179(95)90080-2. [DOI] [PubMed] [Google Scholar]
  3. Casebolt T. L., Jope R. S. Chronic lithium treatment reduces norepinephrine-stimulated inositol phospholipid hydrolysis in rat cortex. Eur J Pharmacol. 1987 Aug 11;140(2):245–246. doi: 10.1016/0014-2999(87)90813-2. [DOI] [PubMed] [Google Scholar]
  4. Ceda G. P., Denti L., Ceresini G., Rastelli G., Dotti C., Cavalieri S., Valenti G., Hoffman A. R. Calcitonin inhibition of growth hormone-releasing hormone-induced GH secretion in normal men. Acta Endocrinol (Copenh) 1989 Apr;120(4):416–422. doi: 10.1530/acta.0.1200416. [DOI] [PubMed] [Google Scholar]
  5. Chakraborty M., Chatterjee D., Kellokumpu S., Rasmussen H., Baron R. Cell cycle-dependent coupling of the calcitonin receptor to different G proteins. Science. 1991 Mar 1;251(4997):1078–1082. doi: 10.1126/science.1847755. [DOI] [PubMed] [Google Scholar]
  6. Clementi G., Favit A., Curreri R., Nicoletti F., Scapagnini U. Repeated calcitonin treatment reduces the stimulation of inositol phospholipid by norepinephrine and serotonin in rat hippocampus and cerebral cortex. Brain Res. 1989 Jan 23;478(1):138–142. doi: 10.1016/0006-8993(89)91485-6. [DOI] [PubMed] [Google Scholar]
  7. Dubovsky S. L., Murphy J., Christiano J., Lee C. The calcium second messenger system in bipolar disorders: data supporting new research directions. J Neuropsychiatry Clin Neurosci. 1992 Winter;4(1):3–14. doi: 10.1176/jnp.4.1.3. [DOI] [PubMed] [Google Scholar]
  8. Dubovsky S. L., Thomas M., Hijazi A., Murphy J. Intracellular calcium signalling in peripheral cells of patients with bipolar affective disorder. Eur Arch Psychiatry Clin Neurosci. 1994;243(5):229–234. doi: 10.1007/BF02191579. [DOI] [PubMed] [Google Scholar]
  9. Dubovsky S. L., Thomas M. Serotonergic mechanisms and current and future psychiatric practice. J Clin Psychiatry. 1995;56 (Suppl 2):38–48. [PubMed] [Google Scholar]
  10. Dupuy B., Peuchant E., Vitiello S., Jensen R., Baghdiantz A., Blanquet P. Tryptophan and neutral amino acid concentrations in serum of rats after salmon calcitonin injection. Experientia. 1983 Mar 15;39(3):294–296. doi: 10.1007/BF01955312. [DOI] [PubMed] [Google Scholar]
  11. Egeland J. A., Gerhard D. S., Pauls D. L., Sussex J. N., Kidd K. K., Allen C. R., Hostetter A. M., Housman D. E. Bipolar affective disorders linked to DNA markers on chromosome 11. 1987 Feb 26-Mar 4Nature. 325(6107):783–787. doi: 10.1038/325783a0. [DOI] [PubMed] [Google Scholar]
  12. Epand R. M., Stafford A. R., Orlowski R. C. Calcitonin inhibits the rise of intracellular calcium induced by thyrotropin-releasing hormone in GH3 cells. Cell Calcium. 1989 Apr;10(3):145–149. doi: 10.1016/0143-4160(89)90068-7. [DOI] [PubMed] [Google Scholar]
  13. Fischer J. A., Sagar S. M., Martin J. B. Characterization and regional distribution of calcitonin binding sites in the rat brain. Life Sci. 1981 Aug 17;29(7):663–671. doi: 10.1016/0024-3205(81)90018-7. [DOI] [PubMed] [Google Scholar]
  14. Friedman E., Wang H. Y. Receptor-mediated activation of G proteins is increased in postmortem brains of bipolar affective disorder subjects. J Neurochem. 1996 Sep;67(3):1145–1152. doi: 10.1046/j.1471-4159.1996.67031145.x. [DOI] [PubMed] [Google Scholar]
  15. Gaggi R., Chirivi L., Roncada P., Gianni A. M. Calcitonin enhances the effects of nimodipine on biogenic amines of rat brain. Gen Pharmacol. 1992 May;23(3):561–563. doi: 10.1016/0306-3623(92)90128-7. [DOI] [PubMed] [Google Scholar]
  16. Gaggi R., De Iasio R., Gianni A. M. Relationships between the effects of peripherally administered salmon calcitonin on calcaemia and brain biogenic amines. Jpn J Pharmacol. 1989 Nov;51(3):309–320. doi: 10.1254/jjp.51.309. [DOI] [PubMed] [Google Scholar]
  17. Gerber U., Felix D., Felder M., Schaffner W. The effects of calcitonin on central neurons in the rat. Neurosci Lett. 1985 Oct 10;60(3):343–348. doi: 10.1016/0304-3940(85)90601-9. [DOI] [PubMed] [Google Scholar]
  18. Goltzman D., Mitchell J. Interaction of calcitonin and calcitonin gene-related peptide at receptor sites in target tissues. Science. 1985 Mar 15;227(4692):1343–1345. doi: 10.1126/science.2983422. [DOI] [PubMed] [Google Scholar]
  19. Henke H., Tobler P. H., Fischer J. A. Localization of salmon calcitonin binding sites in rat brain by autoradiography. Brain Res. 1983 Aug 8;272(2):373–377. doi: 10.1016/0006-8993(83)90587-5. [DOI] [PubMed] [Google Scholar]
  20. Hoovers J. M., Redeker E., Speleman F., Höppener J. W., Bhola S., Bliek J., van Roy N., Leschot N. J., Westerveld A., Mannens M. High-resolution chromosomal localization of the human calcitonin/CGRP/IAPP gene family members. Genomics. 1993 Mar;15(3):525–529. doi: 10.1006/geno.1993.1104. [DOI] [PubMed] [Google Scholar]
  21. Judd A. M., Kubota T., Kuan S. I., Jarvis W. D., Spangelo B. L., Macleod R. M. Calcitonin decreases thyrotropin-releasing hormone-stimulated prolactin release through a mechanism that involves inhibition of inositol phosphate production. Endocrinology. 1990 Jul;127(1):191–199. doi: 10.1210/endo-127-1-191. [DOI] [PubMed] [Google Scholar]
  22. Kusumakar V., Yatham L. N. An open study of lamotrigine in refractory bipolar depression. Psychiatry Res. 1997 Sep 19;72(2):145–148. doi: 10.1016/s0165-1781(97)00082-6. [DOI] [PubMed] [Google Scholar]
  23. Laurian L., Oberman Z., Graf E., Gilad S., Hoerer E., Simantov R. Calcitonin induced increase in ACTH, beta-endorphin and cortisol secretion. Horm Metab Res. 1986 Apr;18(4):268–271. doi: 10.1055/s-2007-1012291. [DOI] [PubMed] [Google Scholar]
  24. Lenox R. H., Watson D. G. Lithium and the brain: a psychopharmacological strategy to a molecular basis for manic depressive illness. Clin Chem. 1994 Feb;40(2):309–314. [PubMed] [Google Scholar]
  25. Levine A. S., Morley J. E. Reduction of feeding in rats by calcitonin. Brain Res. 1981 Oct 5;222(1):187–191. doi: 10.1016/0006-8993(81)90957-4. [DOI] [PubMed] [Google Scholar]
  26. Looij B. J., Jr, Roelfsema F., Frölich M. The effect of calcitonin on growth hormone secretion in acromegaly. Clin Endocrinol (Oxf) 1989 Nov;31(5):573–579. doi: 10.1111/j.1365-2265.1989.tb01281.x. [DOI] [PubMed] [Google Scholar]
  27. Maeda Y., Nakamura T., Hasegawa T., Furukawa H., Nabeshima T. Effect of salmon calcitonin on the lethality of quinolinic acid, an excitatory amino acid. Res Commun Chem Pathol Pharmacol. 1992 Aug;77(2):191–199. [PubMed] [Google Scholar]
  28. Manji H. K., Potter W. Z., Lenox R. H. Signal transduction pathways. Molecular targets for lithium's actions. Arch Gen Psychiatry. 1995 Jul;52(7):531–543. doi: 10.1001/archpsyc.1995.03950190013003. [DOI] [PubMed] [Google Scholar]
  29. Masana M. I., Bitran J. A., Hsiao J. K., Mefford I. N., Potter W. Z. Lithium effects on noradrenergic-linked adenylate cyclase activity in intact rat brain: an in vivo microdialysis study. Brain Res. 1991 Jan 11;538(2):333–336. doi: 10.1016/0006-8993(91)90450-a. [DOI] [PubMed] [Google Scholar]
  30. Mathé A. A., Agren H., Lindström L., Theodorsson E. Increased concentration of calcitonin gene-related peptide in cerebrospinal fluid of depressed patients. A possible trait marker of major depressive disorder. Neurosci Lett. 1994 Dec 5;182(2):138–142. doi: 10.1016/0304-3940(94)90782-x. [DOI] [PubMed] [Google Scholar]
  31. Mitsuma T., Nogimori T., Chaya M. Peripheral administration of eel calcitonin inhibits thyrotropin secretion in rats. Eur J Pharmacol. 1984 Jun 15;102(1):123–128. doi: 10.1016/0014-2999(84)90344-3. [DOI] [PubMed] [Google Scholar]
  32. Moore E. E., Kuestner R. E., Stroop S. D., Grant F. J., Matthewes S. L., Brady C. L., Sexton P. M., Findlay D. M. Functionally different isoforms of the human calcitonin receptor result from alternative splicing of the gene transcript. Mol Endocrinol. 1995 Aug;9(8):959–968. doi: 10.1210/mend.9.8.7476993. [DOI] [PubMed] [Google Scholar]
  33. Morimoto S., Nishimura J., Miyauchi A., Takai S., Okada Y., Onishi T., Fukuo K., Lee S., Kumahara Y. Calcitonin in plasma and cerebrospinal fluid from normal subjects and patients with medullary thyroid carcinoma: possible restriction of calcitonin by the blood-brain barrier. J Clin Endocrinol Metab. 1982 Sep;55(3):594–596. doi: 10.1210/jcem-55-3-594. [DOI] [PubMed] [Google Scholar]
  34. Mørk A., Geisler A. Effects of lithium ex vivo on the GTP-mediated inhibition of calcium-stimulated adenylate cyclase activity in rat brain. Eur J Pharmacol. 1989 Sep 22;168(3):347–354. doi: 10.1016/0014-2999(89)90796-6. [DOI] [PubMed] [Google Scholar]
  35. Nakhla A. M., Latif A. Response of rat brain to calcitonin alteration. Brain Res. 1982 Apr 29;238(2):489–493. doi: 10.1016/0006-8993(82)90129-9. [DOI] [PubMed] [Google Scholar]
  36. Nakhla A. M., Nandi Majumdar A. P. Calcitonin-mediated changes in plasma tryptophan and brain 5-hydroxytryptamine and acetylcholinesterase activity in rats. Biochem J. 1978 Feb 15;170(2):445–448. doi: 10.1042/bj1700445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Nicoletti F., Clementi G., Patti F., Canonico P. L., Di Giorgio R. M., Matera M., Pennisi G., Angelucci L., Scapagnini U. Effects of calcitonin on rat extrapyramidal motor system: behavioral and biochemical data. Brain Res. 1982 Nov 4;250(2):381–385. doi: 10.1016/0006-8993(82)90436-x. [DOI] [PubMed] [Google Scholar]
  38. Nicosia S., Guidobono F., Musanti M., Pecile A. Inhibitory effects of calcitonin on adenylate cyclase activity in different rat brain areas. Life Sci. 1986 Dec 8;39(23):2253–2262. doi: 10.1016/0024-3205(86)90404-2. [DOI] [PubMed] [Google Scholar]
  39. Nussenzveig D. R., Thaw C. N., Gershengorn M. C. Inhibition of inositol phosphate second messenger formation by intracellular loop one of a human calcitonin receptor. Expression and mutational analysis of synthetic receptor genes. J Biol Chem. 1994 Nov 11;269(45):28123–28129. [PubMed] [Google Scholar]
  40. Okamoto Y., Kagaya A., Shinno H., Motohashi N., Yamawaki S. Serotonin-induced platelet calcium mobilization is enhanced in mania. Life Sci. 1995;56(5):327–332. doi: 10.1016/0024-3205(94)00955-4. [DOI] [PubMed] [Google Scholar]
  41. Olgiati V. R., Guidobono F., Netti C., Pecile A. Localization of calcitonin binding sites in rat central nervous system: evidence of its neuroactivity. Brain Res. 1983 Apr 18;265(2):209–215. doi: 10.1016/0006-8993(83)90334-7. [DOI] [PubMed] [Google Scholar]
  42. Overgaard K., Agnusdei D., Hansen M. A., Maioli E., Christiansen C., Gennari C. Dose-response bioactivity and bioavailability of salmon calcitonin in premenopausal and postmenopausal women. J Clin Endocrinol Metab. 1991 Feb;72(2):344–349. doi: 10.1210/jcem-72-2-344. [DOI] [PubMed] [Google Scholar]
  43. Pietrowsky R., Dentler M., Fehm H. L., Born J. Effects of calcitonin on human auditory and visual evoked brain potentials. Psychopharmacology (Berl) 1992;107(1):50–54. doi: 10.1007/BF02244964. [DOI] [PubMed] [Google Scholar]
  44. Post R. M., Weiss S. R., Chuang D. M. Mechanisms of action of anticonvulsants in affective disorders: comparisons with lithium. J Clin Psychopharmacol. 1992 Feb;12(1 Suppl):23S–35S. doi: 10.1097/00004714-199202001-00005. [DOI] [PubMed] [Google Scholar]
  45. Prato A., Scapagnini U., Rapisarda E., Giuffrida R., Palmeri A., Caruso A., Clementi G. Analgesic activity of a synthetic analogue of eel-calcitonin and its effect on the spontaneous activity of brainstem neurons in the rat. Neurosci Lett. 1987 Oct 29;81(3):303–308. doi: 10.1016/0304-3940(87)90400-9. [DOI] [PubMed] [Google Scholar]
  46. Sawada M., Ichinose M., Ishikawa S., Sasayama Y. Calcitonin induces a decreased Na+ conductance in identified neurons of Aplysia. J Neurosci Res. 1993 Oct 1;36(2):200–208. doi: 10.1002/jnr.490360210. [DOI] [PubMed] [Google Scholar]
  47. Shah G. V., Kennedy D., Dockter M. E., Crowley W. R. Calcitonin inhibits thyrotropin-releasing hormone-induced increases in cytosolic Ca2+ in isolated rat anterior pituitary cells. Endocrinology. 1990 Aug;127(2):613–620. doi: 10.1210/endo-127-2-613. [DOI] [PubMed] [Google Scholar]
  48. Skofitsch G., Jacobowitz D. M. Calcitonin and calcitonin gene-related peptide receptor binding sites in the rat central nervous system. Ann N Y Acad Sci. 1992 Jun 30;657:420–422. doi: 10.1111/j.1749-6632.1992.tb22788.x. [DOI] [PubMed] [Google Scholar]
  49. Sobaniec W., Kułak W. Anticonvulsive properties of calcitonin in rats. Eur Neuropsychopharmacol. 1992 Dec;2(4):443–446. doi: 10.1016/0924-977x(92)90007-u. [DOI] [PubMed] [Google Scholar]
  50. Sortino M. A., Aleppo G., Scapagnini U., Canonico P. L. Ipriflavone inhibits phosphoinositide hydrolysis and Ca2+ uptake in the osteoblast-like UMR-106 cells. Eur J Pharmacol. 1992 Jul 1;226(3):273–277. doi: 10.1016/0922-4106(92)90072-4. [DOI] [PubMed] [Google Scholar]
  51. Sortino M. A., Canonico P. L., Clementi G. Bimodal action of [Asu1,7]eel-calcitonin on phosphoinositide hydrolysis in cultured anterior pituitary cells. Eur J Pharmacol. 1991 Aug 14;207(4):345–350. doi: 10.1016/0922-4106(91)90009-7. [DOI] [PubMed] [Google Scholar]
  52. Tannenbaum G. S., Goltzman D. Calcitonin gene-related peptide mimics calcitonin actions in brain on growth hormone release and feeding. Endocrinology. 1985 Jun;116(6):2685–2687. doi: 10.1210/endo-116-6-2685. [DOI] [PubMed] [Google Scholar]
  53. Twery M. J., Cooper C. W., Mailman R. B. Calcitonin depresses amphetamine-induced locomotor activity. Pharmacol Biochem Behav. 1983 Jun;18(6):857–862. doi: 10.1016/s0091-3057(83)80005-7. [DOI] [PubMed] [Google Scholar]
  54. Twery M. J., Moss R. L. Calcitonin and calcitonin gene-related peptide alter the excitability of neurons in rat forebrain. Peptides. 1985 May-Jun;6(3):373–378. doi: 10.1016/0196-9781(85)90098-1. [DOI] [PubMed] [Google Scholar]
  55. Ustdal M., Dogan P., Soyuer A., Terzi S. Treatment of migraine with salmon calcitonin: effects on plasma beta-endorphin, ACTH and cortisol levels. Biomed Pharmacother. 1989;43(9):687–691. doi: 10.1016/0753-3322(89)90088-7. [DOI] [PubMed] [Google Scholar]
  56. Van Houten M., Posner B. I. Circumventricular organs: receptors and mediators of direct peptide hormone action on brain. Adv Metab Disord. 1983;10:269–289. doi: 10.1016/b978-0-12-027310-2.50015-3. [DOI] [PubMed] [Google Scholar]
  57. Young L. T., Warsh J. J., Kish S. J., Shannak K., Hornykeiwicz O. Reduced brain 5-HT and elevated NE turnover and metabolites in bipolar affective disorder. Biol Psychiatry. 1994 Jan 15;35(2):121–127. doi: 10.1016/0006-3223(94)91201-7. [DOI] [PubMed] [Google Scholar]
  58. Zofková I., Bednár J. Calcitonin inhibits TRH-induced TSH secretion. Exp Clin Endocrinol. 1984 May;83(3):263–268. [PubMed] [Google Scholar]
  59. de Beaurepaire R. Antagonism of calcitonin-induced anorexia by chronic, but not acute, tricyclic antidepressants in the rat. Brain Res. 1992 May 22;581(1):165–167. doi: 10.1016/0006-8993(92)90358-g. [DOI] [PubMed] [Google Scholar]

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