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Chapter 17 - Effects of Lithium on Brain Structure in Bipolar Disorder

from Section 5 - Therapeutic Applications of Neuroimaging in Mood Disorders

Published online by Cambridge University Press:  12 January 2021

Sudhakar Selvaraj
UTHealth School of Medicine, USA
Paolo Brambilla
Università degli Studi di Milano
Jair C. Soares
UT Harris County Psychiatric Center, USA
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Bipolar disorder is an episodic, highly impairing mood disorder that is estimated to have a prevalence of 2–3% in the general population and is one of the leading causes of years lived with a disability.(1) Lithium is the gold standard for the treatment of bipolar disorder, and although it is a simple element, its effects on the brain are very complex.(2) Lithium’s potential neurotrophic and neuroprotective effects raise the intriguing possibility that it can potentially ameliorate abnormalities in brain structure and thus alter the disease trajectory.

Mood Disorders
Brain Imaging and Therapeutic Implications
, pp. 219 - 235
Publisher: Cambridge University Press
Print publication year: 2021

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Ferrari, AJ, Stockings, E, Khoo, JP, Erskine, HE, Degenhardt, L, Vos, T, Whiteford, HA. The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013. Bipolar Disord. 2016 August; 18(5): 440450. DOI 10.1111/bdi.12423. PubMed PMID: 27566286.CrossRefGoogle ScholarPubMed
Machado-Vieira, R, Manji, HK, Zarate, CA Jr: The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord. 2009 June; 11 Suppl 2 : 92109.PMCID: 2800957.CrossRefGoogle ScholarPubMed
Suwalska, A, Sobieska, M, Rybakowski, JK. Serum brain-derived neurotrophic factor in euthymic bipolar patients on prophylactic lithium therapy. Neuropsychobiology. 2010; 62(4): 229234. Epub 2010 August 14. PMID: 20714172.CrossRefGoogle ScholarPubMed
Baldessarini, RJ, Tondo, L, Vázquez, GH. Pharmacological treatment of adult bipolar disorder. Mol Psychiatry. 2018 April 20. DOI 10.1038/s41380-018-0044-2. [Epub ahead of print] Review. PubMed PMID: 29679069.Google Scholar
Schaffer, A, Isometsä, ET, Tondo, L, et al. Epidemiology, neurobiology and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: Part I of a report of theInternational Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder. Aust N Z J Psychiatry. 2015 September; 49(9): 785802. DOI 10.1177/0004867415594427. Epub 2015 July 16. Review. PubMed PMID: 26185269; PubMed Central PMCID: PMC5116383.CrossRefGoogle Scholar
Hafeman, DM, Chang, KD, Garrett, AS, Sanders, EM, Phillips, ML. Effects of medication on neuroimaging findings in bipolar disorder: an updated review. Bipolar Disord. 2012 June;14(4): 375410. DOI 10.1111/j.1399-5618.2012.01023.x. Review. PubMed PMID: 22631621.CrossRefGoogle ScholarPubMed
Cousins, DA, Aribisala, B, Ferrier, IN, Blamire, AM. Lithium, gray matter, and magnetic resonance imaging signal. Biol Psychiatry. 2013; 73: 652657.CrossRefGoogle ScholarPubMed
Bearden, CE, Thompson, PM, Dutton, RA, et al. Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder. Neuropsychopharmacology. 2008 May; 33(6): 12291238. Epub 2007 August 8. PubMed PMID: 17687266.CrossRefGoogle ScholarPubMed
Foland, LC, Altshuler, LL, Sugar, CA, et al. Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport. 2008 January 22; 19(2): 221224. DOI 10.1097/WNR.0b013e3282f48108. PubMed PMID: 18185112; PubMed Central PMCID: PMC3299336.CrossRefGoogle ScholarPubMed
Hajek, T, Bauer, M, Simhandl, C, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med. 2014 February; 44(3): 507517. DOI 10.1017/S0033291713001165. Epub 2013 May 31. PubMed PMID: 23721695.CrossRefGoogle ScholarPubMed
Baykara, B, Inal-Emiroglu, N, Karabay, N, Increased hippocampal volumes in lithium treated adolescents with bipolar disorders: A structural MRI study. J Affect Disord. 2012 May; 138(3): 433439. DOI 10.1016/j.jad.2011.12.047. Epub 2012 February 9.CrossRefGoogle ScholarPubMed
Hajek, T, Cullis, J, Novak, T, et al. Hippocampal volumes in bipolar disorders: Opposing effects of illness burden and lithium treatment. Bipolar Disord. 2012 May; 14(3): 261270. DOI 10.1111/j.1399-5618.2012.01013.x.CrossRefGoogle ScholarPubMed
Hajek, T, Kopecek, M, Höschl, C, Alda, M. Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. J Psychiatry Neurosci. 2012 September; 37(5): 333343. DOI:10.1503/jpn.110143.CrossRefGoogle ScholarPubMed
Yucel, K, Taylor, VH, McKinnon, MC, et al. Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology. 2008 January; 33(2): 361367. Epub 2007 April 4. PubMed PMID: 17406649.CrossRefGoogle ScholarPubMed
Giakoumatos, CI, Nanda, P, Mathew, IT, et al. Effects of lithium on cortical thickness and hippocampal subfield volumes in psychotic bipolar disorder. J Psychiatr Res. 2015 February; 61: 180187. DOI 10.1016/j.jpsychires.2014.12.008. Epub 2014 December 23. PubMed PMID: 25563516; PubMed Central PMCID: PMC4859940.CrossRefGoogle ScholarPubMed
Hartberg, CB, Jørgensen, KN, Haukvik, UK, et al. Lithium treatment and hippocampal subfields and amygdala volumes in bipolar disorder. Bipolar Disord. 2015 August; 17(5): 496506. DOI:10.1111/bdi.12295. Epub 2015 March 24. PubMed PMID: 25809287.CrossRefGoogle ScholarPubMed
Bearden, CE, Thompson, PM, Dalwani, M, et al. Greater cortical gray matter density in lithium-treated patients with bipolar disorder. Biol Psychiatry. 2007 July 1; 62(1): 716. Epub 2007 January 19. PubMed PMID: 17240360; PubMed Central PMCID: PMC3586797.CrossRefGoogle ScholarPubMed
Germaná, C, Kempton, MJ, Sarnicola, A, et al. The effects of lithium and anticonvulsants on brain structure in bipolar disorder. Acta Psychiatr Scand. 2010 December; 122(6): 481487. DOI 10.1111/j.1600-0447.2010.01582.x. PubMed PMID: 20560901.CrossRefGoogle ScholarPubMed
López-Jaramillo, C, Vargas, C, Díaz-Zuluaga, AM, et al. Increased hippocampal, thalamus and amygdala volume in long-term lithium-treated bipolar I disorder patients compared with unmedicated patients and healthy subjects. Bipolar Disord. 2017 February; 19(1): 4149. DOI 10.1111/bdi.12467. Epub 2017 Feb 27. PubMed PMID: 28239952.CrossRefGoogle ScholarPubMed
Sassi, RB, Nicoletti, M, Brambilla, P, et al. Increased gray matter volume in lithium-treated bipolar disorder patients. Neurosci Lett. 2002 August 30; 329(2):243245. PubMed PMID: 12165422.CrossRefGoogle ScholarPubMed
Berk, M, Dandash, O, Daglas, R, et al. Neuroprotection after a first episode of mania: a randomized controlled maintenance trial comparing the effects of lithium and quetiapine on grey and white matter volume. Transl Psychiatry. 2017 January 24; 7(1): e1011. DOI 10.1038/tp.2016.281. Erratum in: Transl Psychiatry. 2017 February 21;7(2):e1041. PubMed PMID: 28117843; PubMed Central PMCID: PMC5545739.CrossRefGoogle ScholarPubMed
Yucel, K, McKinnon, MC, Taylor, VH, et al. Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: A longitudinal MRI study. Psychopharmacology (Berl). 2007 December; 195 (3): 357367. Epub 2007 August 20. PubMed PMID: 17705060.CrossRefGoogle ScholarPubMed
Selek, S, Nicoletti, M, Zunta-Soares, GB, et al. A longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment. J Affect Disord. 2013 September 5; 150(2): 629633. DOI 10.1016/j.jad.2013.04.020. Epub 2013 June 10. PubMed PMID: 23764385.CrossRefGoogle ScholarPubMed
Lyoo, IK, Dager, SR, Kim, JE, et al. Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: A longitudinal brain imaging study. Neuropsychopharmacology. 2010 July; 35(8): 17431750. DOI 10.1038/npp.2010.41. Epub 2010 March 31. PubMed PMID: 20357761; PubMed Central PMCID: PMC3055479.CrossRefGoogle ScholarPubMed
Moore, GJ, Bebchuk, JM, Wilds, IB, Chen, G, Manji, HK. Lithium-induced increase in human brain grey matter. Lancet. 2000 Oct 7;356(9237):1241–2. Erratum in: Lancet 2000 December 16;356(9247):2104.Menji HK [corrected to Manji HK]. PubMed PMID: 11072948.CrossRefGoogle ScholarPubMed
Moore, GJ, Cortese, BM, Glitz, DA, et al. A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. J Clin Psychiatry. 2009 April 21; 70(5): 699705. DOI:10.4088/JCP.07m03745. PubMed PMID: 19389332.CrossRefGoogle ScholarPubMed
Monkul, ES, Matsuo, K, Nicoletti, MA, et al. Prefrontal gray matter increases in healthy individuals after lithium treatment: A voxel-based morphometry study. Neurosci Lett. 2007 December 11; 429(1): 711. Epub 2007 October 10. PubMed PMID: 17996370; PubMed Central PMCID: PMC2693231.CrossRefGoogle ScholarPubMed
Phatak, P, Shaldivin, A, King, LS, Shapiro, P, Regenold, WT. Lithium and inositol: effects on brain water homeostasis in the rat, Psychopharmacology (Berl). 2006; 186: 4147.CrossRefGoogle ScholarPubMed
Necus, JM, Sinha, N, Smith, FE, et al. White matter microstructural properties in bipolar disorder and its relationship to the spatial distribution of lithium in the brain. Submitted doi: bioRxiv preprint first posted online Jun. 13, 2018.Google Scholar
Riadh, N, Allagui, MS, Bourogaa, E, et al. Neuroprotective and neurotrophic effects of long term lithium treatment in mouse brain. Biometals. 2011; 24: 747757. DOI 10.1007/s10534-011–9433-6.CrossRefGoogle ScholarPubMed
Vernon, AC, Natesan, S, Crum, WR, et al. Contrasting effects of haloperidol and lithium on rodent brain structure: A magnetic resonance imaging study with postmortem confirmation. Biol Psychiatry. 2012 May 15; 71(10): 855863. DOI 10.1016/j.biopsych.2011.12.004. Epub 2012 January 15. PubMed PMID: 22244831.CrossRefGoogle ScholarPubMed
Shim, SS, Hammonds, MD, Ganocy, SJ, Calabrese, JR. Effects of sub-chronic lithium treatment on synaptic plasticity in the dentate gyrus of rat hippocampal slices. Prog Neuropsychopharmacol Biol Psychiatry. 2007 March 30; 31(2): 343347.Epub 2006 November 9. PubMed PMID: 17097205.CrossRefGoogle ScholarPubMed
Pan, W, Banks, WA, Fasold, MB, Bluth, J, Kastin, AJ. Transport of brain-derived neurotrophic factor across the blood-brain barrier. Neuropharmacology. 1998 December; 37(12): 15531561. PubMed PMID: 9886678.CrossRefGoogle ScholarPubMed
Pillai, A, Kale, A, Joshi, S, et al. Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: correlation with plasma BDNF and psychopathology. Int J Neuropsychopharmacol. 2010 May; 13(4): 535539. Epub 2009 November 27. PubMed PMID: 19941699.CrossRefGoogle ScholarPubMed
Eker, C, Kitis, O, Taneli, F, et al. Correlation of serum BDNF levels with hippocampal volumes in first episode, medication-free depressed patients. Eur Arch Psychiatry Clin Neurosci. 2010 October; 260(7): 527533.DOI 10.1007/s00406-010-0110-5. Epub 2010 March 20.CrossRefGoogle ScholarPubMed
Rizos, E, Papathanasiou, M, Michalopoulou, P, et al. Association of serum BDNF levels with hippocampal volumes in first psychotic episode drug-naïve schizophrenic patients. Schizophr Res. 2011 July; 129(2–3): 201204.CrossRefGoogle ScholarPubMed
Erickson, KI, Voss, MW, Prakash, RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011 February 15; 108(7): 30173022. DOI 10.1073/pnas.1015950108. Epub 2011 January 31. PubMed PMID: 21282661; PubMed Central PMCID: PMC3041121.CrossRefGoogle ScholarPubMed
Fernandes, BS, Gama, CS, Ceresér, KM, et al. Brain-derived neurotrophic factor (BDNF) as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res. 2011 August; 45(8): 9951004. Epub 2011 May 6. Review. PubMed PMID: 21550050.CrossRefGoogle ScholarPubMed
Hammonds, MD, Shim, SS. Effects of 4-week treatment with lithium and olanzapine on levels of brain- derived neurotrophic factor (BDNF), B-cell CLL/lymphoma 2 and phosphorylated cyclic adenosine monophosphate response element-binding protein in the sub-regions of the hippocampus. Basic Clin Pharmacol Toxicol. 2009 August; 105(2): 113119. Epub 2009 April 17. PubMed PMID: 19486334.CrossRefGoogle Scholar
Jornada, LK, Moretti, M, Valvassori, SS, et al. Effects of mood stabilizers on hippocampus and amygdala BDNF levels in an animal model of mania induced by ouabain. J Psychiatr Res. 2010 un; 44(8): 506510. Epub 2009 December 1. PubMed PMID: 19954800.CrossRefGoogle Scholar
de Sousa, R, van de Bilt, M, Diniz, B, et al. Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: A preliminary 4-week study. Neurosci Lett. 2011 April 20; 494(1): 5456.CrossRefGoogle ScholarPubMed
Tramontina, JF, Andreazza, AC, Kauer-Sant’anna, M, et al. Brain-derived neurotrophic factor serum levels before and after treatment for acute mania. Neurosci Lett. 2009 March 13; 452(2):111113. Epub 2009 January 15.CrossRefGoogle ScholarPubMed
Pandey, GN, Rizavi, HS, Dwivedi, Y, Pavuluri, MN. Brain-derived neurotrophic factor gene expression in pediatric bipolar disorder: Effects of treatment and clinical response. J Am Acad Child Adolesc Psychiatry. 2008 September; 47(9): 10771085. PubMed PMID: 18664999.CrossRefGoogle ScholarPubMed
Frey, BN, Andreazza, AC, Ceresér, KM, et al. Effects of mood stabilizers on hippocampus BDNF levels in an animal model of mania. Life Sci. 2006 June 13; 79(3): 281286. Epub 2006 February 7. PubMed PMID: 16460767.CrossRefGoogle Scholar
Chen, G, Rajkowska, G, Du, F, Seraji-Bozorgzad, N., Manji, HK. Enhancement of hippocampal neurogenesis by lithium. J. Neurochem. 2000; 75: 17291734.CrossRefGoogle ScholarPubMed
Hanson, ND, Nemeroff, CB, Owens, MJ. Lithium, but not fluoxetine or the corticotropin-releasing factor receptor 1 receptor antagonist R121919, increases cell proliferation in the adult dentate gyrus. J Pharmacol Exp Ther. 2011 April; 337(1): 180186. DOI 10.1124/jpet.110.175372. Epub 2011 January 10. PubMed PMID: 21220416; PubMed Central PMCID: PMC3063735.CrossRefGoogle ScholarPubMed
Shim, SS, Hammonds, MD, Mervis, RF. Four weeks lithium treatment alters neuronal dendrites in the rat hippocampus. Int J Neuropsychopharmacol. 2013 July; 16(6): 13731382. DOI 10.1017/S1461145712001423. Epub 2013 January 18.CrossRefGoogle ScholarPubMed
Rhindress, K, Ikuta, T, Wellington, R, Malhotra, AK, Szeszko, PR. Delineation of hippocampal subregions using T1-weighted magnetic resonance images at 3 Tesla. Brain Struct Funct. 2015 November; 220(6): 32593272. DOI 10.1007/s00429-014-0854-1. Epub 2014 August 1.CrossRefGoogle ScholarPubMed
Kafantaris, V, Spritzer, L, Doshi, V, Saito, E, Szeszko, PR. Changes in white matter microstructure predict lithium response in adolescents with bipolar disorder. Bipolar Disord. 2017 November; 19(7): 587594. DOI 10.1111/bdi.12544. Epub 2017 October 9. PubMed PMID: 28992395.CrossRefGoogle ScholarPubMed
Markham, A, Cameron, I, Bains, R, et al. Brain-derived neurotrophic factor-mediated effects on mitochondrial respiratory coupling and neuroprotection share the same molecular signaling pathways. Eur J Neurosci. 2012 February; 35(3): 366374. PubMed PMID: 22288477.CrossRefGoogle Scholar
Rybakowski, JK, Czerski, P, Dmitrzak-Weglarz, M, et al. Clinical and pathogenic aspects of candidate genes for lithium prophylactic efficacy. J Psychopharmacol. 2012 March; 26(3): 368373. Epub 2011 Sep 2.CrossRefGoogle ScholarPubMed

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