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Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response

Published online by Cambridge University Press:  31 May 2013

T. Hajek*
Affiliation:
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada Prague Psychiatric Center, Department of Psychiatry and Medical Psychology, 3rd School of Medicine, Charles University, Prague, Czech Republic
M. Bauer
Affiliation:
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
C. Simhandl
Affiliation:
Psychiatrische Abteilung, Krankenhaus Neunkirchen, Austria
J. Rybakowski
Affiliation:
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poland
C. O'Donovan
Affiliation:
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
A. Pfennig
Affiliation:
Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany
B. König
Affiliation:
Psychiatrische Abteilung, Krankenhaus Neunkirchen, Austria
A. Suwalska
Affiliation:
Department of Adult Psychiatry, Poznan University of Medical Sciences, Poland
K. Yucel
Affiliation:
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
R. Uher
Affiliation:
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
L. T. Young
Affiliation:
Department of Psychiatry, University of Toronto, ON, Canada
G. MacQueen
Affiliation:
Department of Psychiatry, University of Calgary, AB, Canada
M. Alda
Affiliation:
Department of Psychiatry, Dalhousie University, Halifax, NS, Canada Prague Psychiatric Center, Department of Psychiatry and Medical Psychology, 3rd School of Medicine, Charles University, Prague, Czech Republic
*
*Address for correspondence: T. Hajek, M.D., Ph.D., Department of Psychiatry, Dalhousie University, QEII HSC, Abbie J. Lane Bldg, Room 3093, 5909 Veteran's Memorial Lane, Halifax, NS B3H 2E2, Canada. (Email: tomas.hajek@dal.ca)

Abstract

Background

Neuroimaging studies have demonstrated an association between lithium (Li) treatment and brain structure in human subjects. A crucial unresolved question is whether this association reflects direct neurochemical effects of Li or indirect effects secondary to treatment or prevention of episodes of bipolar disorder (BD).

Method

To address this knowledge gap, we compared manually traced hippocampal volumes in 37 BD patients with at least 2 years of Li treatment (Li group), 19 BD patients with <3 months of lifetime Li exposure over 2 years ago (non-Li group) and 50 healthy controls. All BD participants were followed prospectively and had at least 10 years of illness and a minimum of five episodes. We established illness course and long-term treatment response to Li using National Institute of Mental Health (NIMH) life charts.

Results

The non-Li group had smaller hippocampal volumes than the controls or the Li group (F2,102 = 4.97, p = 0.009). However, the time spent in a mood episode on the current mood stabilizer was more than three times longer in the Li than in the non-Li group (t51 = 2.00, p = 0.05). Even Li-treated patients with BD episodes while on Li had hippocampal volumes comparable to healthy controls and significantly larger than non-Li patients (t43 = 2.62, corrected p = 0.02).

Conclusions

Our findings support the neuroprotective effects of Li. The association between Li treatment and hippocampal volume seems to be independent of long-term treatment response and occurred even in subjects with episodes of BD while on Li. Consequently, these effects of Li on brain structure may generalize to patients with neuropsychiatric illnesses other than BD.

Type
Original Articles
Copyright
Copyright © Cambridge University Press 2013 

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References

Ahrens, B, Muller-Oerlinghausen, B (2001). Does lithium exert an independent antisuicidal effect? Pharmacopsychiatry 34, 132136.CrossRefGoogle ScholarPubMed
Atmaca, M, Ozdemir, H, Cetinkaya, S, Parmaksiz, S, Belli, H, Poyraz, AK, Tezcan, E, Ogur, E (2007). Cingulate gyrus volumetry in drug free bipolar patients and patients treated with valproate or valproate and quetiapine. Journal of Psychiatric Research 41, 821827.Google Scholar
Baldessarini, RJ, Tondo, L, Davis, P, Pompili, M, Goodwin, FK, Hennen, J (2006). Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disorders 8, 625639.Google Scholar
Bauer, M, Alda, M, Priller, J, Young, LT (2003). Implications of the neuroprotective effects of lithium for the treatment of bipolar and neurodegenerative disorders. Pharmacopsychiatry 36 (Suppl. 3), S250S254.Google Scholar
Bearden, CE, Thompson, PM, Dutton, RA, Frey, BN, Peluso, MA, Nicoletti, M, Dierschke, N, Hayashi, KM, Klunder, AD, Glahn, DC, Brambilla, P, Sassi, RB, Mallinger, AG, Soares, JC (2008). Three-dimensional mapping of hippocampal anatomy in unmedicated and lithium-treated patients with bipolar disorder. Neuropsychopharmacology 33, 12291238.CrossRefGoogle ScholarPubMed
Berk, M, Kapczinski, F, Andreazza, AC, Dean, OM, Giorlando, F, Maes, M, Yucel, M, Gama, CS, Dodd, S, Dean, B, Magalhaes, PV, Amminger, P, McGorry, P, Malhi, GS (2011). Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neuroscience and Biobehavioral Reviews 35, 804817.CrossRefGoogle ScholarPubMed
Beyer, JL, Kuchibhatla, M, Payne, ME, Moo-Young, M, Cassidy, F, MacFall, J, Krishnan, KR (2004). Hippocampal volume measurement in older adults with bipolar disorder. American Journal of Geriatric Psychiatry 12, 613620.Google Scholar
Coppen, A, Montgomery, SA, Gupta, RK, Bailey, JE (1976). A double-blind comparison of lithium carbonate and maprotiline in the prophylaxis of the affective disorders. British Journal of Psychiatry 128, 479485.CrossRefGoogle ScholarPubMed
Cousins, DA, Aribisala, B, Nicol Ferrier, I, Blamire, AM (2013). Lithium, gray matter, and magnetic resonance imaging signal. Biological Psychiatry 73, 652657.Google Scholar
da Silva, J, Goncalves-Pereira, M, Xavier, M, Mukaetova-Ladinska, EB (2013). Affective disorders and risk of developing dementia: systematic review. British Journal of Psychiatry 202, 177186.Google Scholar
Ebdrup, BH, Skimminge, A, Rasmussen, H, Aggernaes, B, Oranje, B, Lublin, H, Baare, W, Glenthoj, B (2011). Progressive striatal and hippocampal volume loss in initially antipsychotic-naive, first-episode schizophrenia patients treated with quetiapine: relationship to dose and symptoms. International Journal of Neuropsychopharmacology 14, 6982.Google Scholar
Foland, LC, Altshuler, LL, Sugar, CA, Lee, AD, Leow, AD, Townsend, J, Narr, KL, Asuncion, DM, Toga, AW, Thompson, PM (2008). Increased volume of the amygdala and hippocampus in bipolar patients treated with lithium. Neuroreport 19, 221224.CrossRefGoogle ScholarPubMed
Forlenza, OV, Diniz, BS, Radanovic, M, Santos, FS, Talib, LL, Gattaz, WF (2011). Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. British Journal of Psychiatry 198, 351356.Google Scholar
Gallelli, KA, Wagner, CM, Karchemskiy, A, Howe, M, Spielman, D, Reiss, A, Chang, KD (2005). N-Acetylaspartate levels in bipolar offspring with and at high-risk for bipolar disorder. Bipolar Disorders 7, 589597.CrossRefGoogle ScholarPubMed
Garcia, M, Huppertz, HJ, Ziyeh, S, Buechert, M, Schumacher, M, Mader, I (2009). Valproate-induced metabolic changes in patients with epilepsy: assessment with H-MRS. Epilepsia 50, 486492.Google Scholar
Garver, DL, Holcomb, JA, Christensen, JD (2005). Cerebral cortical gray expansion associated with two second-generation antipsychotics. Biological Psychiatry 58, 6266.Google Scholar
Germana, C, Kempton, MJ, Sarnicola, A, Christodoulou, T, Haldane, M, Hadjulis, M, Girardi, P, Tatarelli, R, Frangou, S (2010). The effects of lithium and anticonvulsants on brain structure in bipolar disorder. Acta Psychiatrica Scandinavica 122, 481487.Google Scholar
Gould, TD, Picchini, AM, Einat, H, Manji, HK (2006). Targeting glycogen synthase kinase-3 in the CNS: implications for the development of new treatments for mood disorders. Current Drug Targets 7, 13991409.Google Scholar
Grof, P, Duffy, A, Alda, M, Hajek, T (2009). Lithium response across generations. Acta Psychiatrica Scandinavica 120, 378385.CrossRefGoogle Scholar
Hajek, T, Bauer, M, Pfennig, A, Cullis, J, Ploch, J, O'Donovan, C, Bohner, G, Klingebiel, R, Young, LT, MacQueen, GM, Alda, M (2012 a). Large positive effect of lithium on prefrontal cortex N-acetylaspartate in patients with bipolar disorder: 2-centre study. Journal of Psychiatry and Neuroscience 37, 185192.Google Scholar
Hajek, T, Cullis, J, Novak, T, Kopecek, M, Hoschl, C, Blagdon, R, O'Donovan, C, Bauer, M, Young, LT, MacQueen, G, Alda, M (2012 b). Hippocampal volumes in bipolar disorders: opposing effects of illness burden and lithium treatment. Bipolar Disorders 14, 261270.Google Scholar
Hajek, T, Kopecek, M, Hoschl, C, Alda, M (2012 c). Smaller hippocampal volumes in patients with bipolar disorder are masked by exposure to lithium: a meta-analysis. Journal of Psychiatry and Neuroscience 37, 333343.Google Scholar
Hallahan, B, Newell, J, Soares, JC, Brambilla, P, Strakowski, SM, Fleck, DE, Kieseppa, T, Altshuler, LL, Fornito, A, Malhi, GS, McIntosh, AM, Yurgelun-Todd, DA, LaBar, KS, Sharma, V, MacQueen, GM, Murray, RM, McDonald, C (2011). Structural magnetic resonance imaging in bipolar disorder: an international collaborative mega-analysis of individual adult patient data. Biological Psychiatry 69, 326335.Google Scholar
Hampel, H, Ewers, M, Burger, K, Annas, P, Mortberg, A, Bogstedt, A, Frolich, L, Schroder, J, Schonknecht, P, Riepe, MW, Kraft, I, Gasser, T, Leyhe, T, Moller, HJ, Kurz, A, Basun, H (2009). Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. Journal of Clinical Psychiatry 70, 922931.Google Scholar
Kessing, LV, Forman, JL, Andersen, PK (2010). Does lithium protect against dementia? Bipolar Disorders 12, 8794.CrossRefGoogle ScholarPubMed
Kessing, LV, Sondergard, L, Forman, JL, Andersen, PK (2008). Lithium treatment and risk of dementia. Archives of General Psychiatry 65, 13311335.Google Scholar
Khorram, B, Lang, DJ, Kopala, LC, Vandorpe, RA, Rui, Q, Goghari, VM, Smith, GN, Honer, WG (2006). Reduced thalamic volume in patients with chronic schizophrenia after switching from typical antipsychotic medications to olanzapine. American Journal of Psychiatry 163, 20052007.Google Scholar
Lauterbach, EC, Mendez, MF (2011). Psychopharmacological neuroprotection in neurodegenerative diseases, part III: criteria-based assessment: a report of the ANPA committee on research. Journal of Neuropsychiatry and Clinical Neurosciences 23, 242260.CrossRefGoogle ScholarPubMed
Lenox, RH, Hahn, CG (2000). Overview of the mechanism of action of lithium in the brain: fifty-year update. Journal of Clinical Psychiatry 61 (Suppl. 9), 515.Google Scholar
Leung, M, Cheung, C, Yu, K, Yip, B, Sham, P, Li, Q, Chua, S, McAlonan, G (2011). Gray matter in first-episode schizophrenia before and after antipsychotic drug treatment. Anatomical likelihood estimation meta-analyses with sample size weighting. Schizophrenia Bulletin 37, 199211.CrossRefGoogle ScholarPubMed
Leyhe, T, Eschweiler, GW, Stransky, E, Gasser, T, Annas, P, Basun, H, Laske, C (2009). Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease. Journal of Alzheimer's Disease 16, 649656.Google Scholar
Licht, RW, Vestergaard, P, Kessing, LV, Larsen, JK, Thomsen, PH (2003). Psychopharmacological treatment with lithium and antiepileptic drugs: suggested guidelines from the Danish Psychiatric Association and the Child and Adolescent Psychiatric Association in Denmark. Acta Psychiatrica Scandinavica. Supplementum 419, 122.Google Scholar
Lyoo, IK, Dager, SR, Kim, JE, Yoon, SJ, Friedman, SD, Dunner, DL, Renshaw, PF (2010). Lithium-induced gray matter volume increase as a neural correlate of treatment response in bipolar disorder: a longitudinal brain imaging study. Neuropsychopharmacology 35, 17431750.Google Scholar
Macdonald, A, Briggs, K, Poppe, M, Higgins, A, Velayudhan, L, Lovestone, S (2008). A feasibility and tolerability study of lithium in Alzheimer's disease. International Journal of Geriatric Psychiatry 23, 704711.Google Scholar
Machado-Vieira, R, Manji, HK, Zarate, CA Jr. (2009). The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disorders 11 (Suppl. 2), 92109.CrossRefGoogle ScholarPubMed
McKinnon, MC, Yucel, K, Nazarov, A, MacQueen, GM (2009). A meta-analysis examining clinical predictors of hippocampal volume in patients with major depressive disorder. Journal of Psychiatry and Neuroscience 34, 4154.Google ScholarPubMed
Molina, V, Reig, S, Sanz, J, Palomo, T, Benito, C, Sanchez, J, Sarramea, F, Pascau, J, Desco, M (2005). Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia. Schizophrenia Research 80, 6171.Google Scholar
Moncrieff, J, Leo, J (2010). A systematic review of the effects of antipsychotic drugs on brain volume. Psychological Medicine 40, 14091422.Google Scholar
Monkul, ES, Matsuo, K, Nicoletti, MA, Dierschke, N, Hatch, JP, Dalwani, M, Brambilla, P, Caetano, S, Sassi, RB, Mallinger, AG, Soares, JC (2007). Prefrontal gray matter increases in healthy individuals after lithium treatment: a voxel-based morphometry study. Neuroscience Letters 429, 711.Google Scholar
Moore, GJ, Bebchuk, JM, Wilds, IB, Chen, G, Manji, HK (2000). Lithium-induced increase in human brain grey matter. Lancet 356, 12411242.Google Scholar
Moore, GJ, Cortese, BM, Glitz, DA, Zajac-Benitez, C, Quiroz, JA, Uhde, TW, Drevets, WC, Manji, HK (2009). A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients. Journal of Clinical Psychiatry 70, 699705.Google Scholar
Moorhead, TW, McKirdy, J, Sussmann, JE, Hall, J, Lawrie, SM, Johnstone, EC, McIntosh, AM (2007). Progressive gray matter loss in patients with bipolar disorder. Biological Psychiatry 62, 894900.CrossRefGoogle ScholarPubMed
Roy-Byrne, P, Post, RM, Uhde, TW, Porcu, T, Davis, D (1985). The longitudinal course of recurrent affective illness: life chart data from research patients at the NIMH. Acta Psychiatrica Scandinavica. Supplementum 317, 134.Google Scholar
Silverstone, PH, Wu, RH, O'Donnell, T, Ulrich, M, Asghar, SJ, Hanstock, CC (2003). Chronic treatment with lithium, but not sodium valproate, increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients. International Clinical Psychopharmacology 18, 7379.Google Scholar
Stip, E, Mancini-Marie, A, Letourneau, G, Fahim, C, Mensour, B, Crivello, F, Dollfus, S (2009). Increased grey matter densities in schizophrenia patients with negative symptoms after treatment with quetiapine: a voxel-based morphometry study. International Clinical Psychopharmacology 24, 3441.Google Scholar
Tariot, PN, Schneider, LS, Cummings, J, Thomas, RG, Raman, R, Jakimovich, LJ, Loy, R, Bartocci, B, Fleisher, A, Ismail, MS, Porsteinsson, A, Weiner, M, Jack, CR Jr., Thal, L, Aisen, PS (2011). Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Archives of General Psychiatry 68, 853861.CrossRefGoogle ScholarPubMed
Vernon, AC, Natesan, S, Crum, WR, Cooper, JD, Modo, M, Williams, SC, Kapur, S (2012). Contrasting effects of haloperidol and lithium on rodent brain structure: a magnetic resonance imaging study with postmortem confirmation. Biological Psychiatry 71, 855863.CrossRefGoogle ScholarPubMed
Willner, P, Scheel-Kruger, J, Belzung, C (2012). The neurobiology of depression and antidepressant action. Neuroscience Biobehavioral Reviews Published online. 19 12 2012 . doi:10.1016/j.neubiorev.2012.12.007 . Google Scholar
Yucel, K, McKinnon, MC, Taylor, VH, Macdonald, K, Alda, M, Young, LT, MacQueen, GM (2007). Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology (Berlin) 195, 357367.Google Scholar
Yucel, K, Taylor, VH, McKinnon, MC, Macdonald, K, Alda, M, Young, LT, MacQueen, GM (2008). Bilateral hippocampal volume increase in patients with bipolar disorder and short-term lithium treatment. Neuropsychopharmacology 33, 361367.Google Scholar
Zarate, CA Jr., Singh, J, Manji, HK (2006). Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biological Psychiatry 59, 10061020.CrossRefGoogle ScholarPubMed