Trace-dosage of lithium for prevention of cognitive declining in mood illnesses: a randomized double-blind, placebo-controlled, study protocol
DOI:
https://doi.org/10.18203/2349-3259.ijct20251207Keywords:
Lithium trace doses, Mood disorders, Cognitive declining prevention, Dementia preventionAbstract
Background: Mood disorders [bipolar disorder (BD) and recurrent unipolar depression] are among the most common mental health conditions worldwide, and are recognized as significant risk factor for development of mild cognitive impairment (MCI) and dementia. Lithium, the gold standard treatment for these mood disorders, has also been suggested as a potential neuroprotective agent, even at trace doses. This study aims to evaluate the effect of trace doses of lithium in preventing cognitive decline in individuals with mood disorders.
Methods: This is randomized, double-blind, placebo-controlled trial involving 250 participants aged 55 to 75 years, all of whom have mood disorders and are not currently receiving lithium therapy. Participants will be randomized into either trace dose lithium (50 mg oral tablets daily) or placebo group, with 125 subjects in each group. All participants will continue their usual clinical treatment and will be followed every six month for five years. The primary outcome measure will be the incidence of MCI or worsening of pre-existing MCI, defined as change from baseline clinical dementia rating scale (CDR) score of 0 to 0.5 (MCI).
Conclusions: If this research demonstrates that trace doses of lithium can prevent the onset or progression of MCI or dementia in patients with mood disorders, it could offer a new therapeutic approach for addressing cognitive decline in this high-risk population, with significant public health implications.
Trial registration: clinicaltrials.gov: NCT06662526.
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References
Kessler RC, Hagop SA, Minnie A, Howard B, Paul G, Robert MAH, et al. Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers. Am J Psychiatry. 2006;163(9):1561-8. DOI: https://doi.org/10.1176/appi.ajp.163.9.1561
Vicente B, Robert K, Pedro R, Sandra S, Itzhak L, Silverio T. Lifetime and 12-month prevalence of DSM-III-R disorders in the Chile psychiatric prevalence study. Am J Psychiatry. 2006;163(8):1362-70. DOI: https://doi.org/10.1176/ajp.2006.163.8.1362
Gillis C, Mirzaei F, Potashman M, Ikram MA, Maserejian N. The incidence of mild cognitive impairment: A systematic review and data synthesis. Alzheimers Dement Amst Neth. 2019;11:248-56. DOI: https://doi.org/10.1016/j.dadm.2019.01.004
Petersen RC. Mild Cognitive Impairment. Contin Lifelong Learn Neurol. 2016;22:404-18. DOI: https://doi.org/10.1212/CON.0000000000000313
NA. Alzheimer’s Association 2024 Alzheimer’s Disease Facts and Figures. Alzheimers Dement. 2024;20(5):3708-821. DOI: https://doi.org/10.1002/alz.13809
Chen MH, Cheng-Ta L, Chia-Fen T, Wei-Chen L, Wen-Han C, Tzeng-Ji C, et al. Risk of subsequent dementia among patients with bipolar disorder or major depression: a nationwide longitudinal study in Taiwan. J Am Med Dir Assoc. 2015;16(6):504-8. DOI: https://doi.org/10.1016/j.jamda.2015.01.084
Da Silva J, Gonçalves-Pereira M, Xavier M, Mukaetova-Ladinska EB. Affective disorders and risk of developing dementia: systematic review. Br J Psychiatry J Ment Sci. 2013;202(3):177-86. DOI: https://doi.org/10.1192/bjp.bp.111.101931
Diniz BS, Antonio LT, Fei C, Ariel G, Jair CS, Meryl AB, et al. History of Bipolar disorder and the risk of dementia: a systematic review and meta-analysis. Am J Geriatr Psychiatry. 2017;25(4):357-62. DOI: https://doi.org/10.1016/j.jagp.2016.11.014
Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D. Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry. 2006;63(5):530-8. DOI: https://doi.org/10.1001/archpsyc.63.5.530
Velosa J, Delgado A, Finger E, Berk M, Kapczinski F, de Azevedo Cardoso T. Risk of dementia in bipolar disorder and the interplay of lithium: a systematic review and meta-analyses. Acta Psychiatr Scand. 2020;141(6):510-21. DOI: https://doi.org/10.1111/acps.13153
Wu KY, Chia-MC, Hsin-YL, Chi-Shin W, Erin CHW, Chia-Hsiang C, et al. Increased risk of developing dementia in patients with bipolar disorder: a nested matched case-control study. Bipolar Disord. 2013;15(7):787-94. DOI: https://doi.org/10.1111/bdi.12116
Pfennig A, Littmann E, Bauer M. Neurocognitive Impairment and Dementia in Mood Disorders. J Neuropsychiatry Clin Neurosci. 2007;19(4):373-82. DOI: https://doi.org/10.1176/appi.neuropsych.19.4.373
Yates JA, Clare L, Woods RT. Mild cognitive impairment and mood: a systematic review. Rev Clin Gerontol. 2013;23:317-56. DOI: https://doi.org/10.1017/S0959259813000129
Forlenza OV, Breno SD, Márcia R, Franklin SS, Leda LT, Wagner FG. Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry J Ment Sci. 2011;198(5):351-6. DOI: https://doi.org/10.1192/bjp.bp.110.080044
Forlenza OV, De-Paula VJR, Diniz BSO. Neuroprotective Effects of Lithium: Implications for the Treatment of Alzheimer’s Disease and Related Neurodegenerative Disorders. ACS Chem Neurosci. 2014;5:443-50. DOI: https://doi.org/10.1021/cn5000309
Kessing LV, Søndergård L, Forman JL, Andersen PK. Lithium treatment and risk of dementia. Arch Gen Psychiatry. 2008;65:1331-5. DOI: https://doi.org/10.1001/archpsyc.65.11.1331
Mauer S, Vergne D, Ghaemi SN. Standard and trace-dose lithium: a systematic review of dementia prevention and other behavioral benefits. Aust N Z J Psychiatry. 2014;48(9):809-18. DOI: https://doi.org/10.1177/0004867414536932
Singulani MP, Ana Flávia FF, Paulina SF, Iván CV, Leda LT, Luiz RB, et al. Lithium and disease modification: A systematic review and meta-analysis in Alzheimer’s and Parkinson’s disease. Ageing Res Rev. 2024;95:102231. DOI: https://doi.org/10.1016/j.arr.2024.102231
Haupt M, Bähr M, Doeppner TR. Lithium beyond psychiatric indications: the reincarnation of a new old drug. Neural Regen Res. 2021;16(12):2383. DOI: https://doi.org/10.4103/1673-5374.313015
Angst J, Gamma A, Gerber-Werder R, Zarate CA, Manji HK. Does long-term medication with lithium, clozapine or antidepressants prevent or attenuate dementia in bipolar and depressed patients? Int J Psychiatry Clin Pract. 2007;11:2-8. DOI: https://doi.org/10.1080/13651500600810133
Nunes PV, Forlenza OV, Gattaz WF. Lithium and risk for Alzheimer’s disease in elderly patients with bipolar disorder. Br J Psychiatr. 2007;190:359-60. DOI: https://doi.org/10.1192/bjp.bp.106.029868
Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Curr Alzheimer Res. 2013;10(1):104-7. DOI: https://doi.org/10.2174/156720513804871354
Figueroa LT, Barton S, Schull W, Razmilic B, Zumaeta O, Young A, et al. Environmental lithium exposure in the north of Chile-Tissue exposure indices. Epidemiol Biostat Public Health. 2014;149(2):280-90. DOI: https://doi.org/10.1007/s12011-012-9417-6
Dependencia Personas Mayores 2009. 2009.
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatr J Ment Sci. 1982;140:566-72. DOI: https://doi.org/10.1192/bjp.140.6.566
Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. Int Clin Psychopharmacol. 1996;11(3):89-95. DOI: https://doi.org/10.1097/00004850-199606003-00015
Posner K, Gregory KB, Barbara S, David AB, Kseniya VY, Maria AO, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatr. 2011;168:1266-77. DOI: https://doi.org/10.1176/appi.ajp.2011.10111704
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16(9):606-13. DOI: https://doi.org/10.1046/j.1525-1497.2001.016009606.x
Errazuriz A, Beltrán R, Torres R, Passi-Solar A. The Validity and Reliability of the PHQ-9 and PHQ-2 on Screening for Major Depression in Spanish Speaking Immigrants in Chile: A Cross-Sectional Study. Int J Environ Res Public Health. 2022;19(21):13975. DOI: https://doi.org/10.3390/ijerph192113975
Altman EG, Hedeker D, Peterson JL, Davis JM. The Altman Self-Rating Mania Scale. Biol Psychiatr. 1997;42(10):948-55. DOI: https://doi.org/10.1016/S0006-3223(96)00548-3
Shahin I, Bonnin CDM, Saleh E, Helmy K, Youssef UM, Vieta E. Validity of the Shahin Mixed Depression Scale: A Self-Rated Instrument Designed to Measure the Non-DSM Mixed Features in Depression. Neuropsychiatr Dis Treat. 2020;16:2209-19. DOI: https://doi.org/10.2147/NDT.S259996
Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: Psychometric properties. J Consult Clin Psychol. 1988;56(6):893-7. DOI: https://doi.org/10.1037//0022-006X.56.6.893
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53(4):695-9. DOI: https://doi.org/10.1111/j.1532-5415.2005.53221.x
Gaete M, Jorquera S, Bello-Lepe S, Mendoza YM, Véliz M, Alonso-Sanchez MF, et al. Resultados estandarizados del Montreal Cognitive Assessment (MoCA) para cribado neurocognitivo en población chilena. Neurología. 2020;38:246-55. DOI: https://doi.org/10.1016/j.nrl.2020.08.017
Torralva T, Roca M, Gleichgerrcht E, López P, Manes F. INECO Frontal Screening (IFS): A brief, sensitive, and specific tool to assess executive functions in dementia–corrected version. J Int Neuropsychol Soc. 2009;15(5):777-86. DOI: https://doi.org/10.1017/S1355617709990415
Ihnen J, Antivilo A, Muñoz-Neira C, Slachevsky A. Chilean version of the INECO Frontal Screening (IFS-Ch): Psychometric properties and diagnostic accuracy. Dement Neuropsychol. 2013;7(1):40-7. DOI: https://doi.org/10.1590/S1980-57642013DN70100007
Grober E, Hall C, Sanders AE, Lipton RB. Free and cued selective reminding distinguishes Alzheimer’s disease from vascular dementia. J Am Geriatr Soc. 2008;56:944-6. DOI: https://doi.org/10.1111/j.1532-5415.2008.01652.x
Rada I, Ortiz MS, Cabieses B. Calidad de vida relacionada con la salud en chilenos de comunas vulnerables. Gac Sanit. 2023;37:102328. DOI: https://doi.org/10.1016/j.gaceta.2023.102328
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatr. 1998;59(20):22-33.
Angst J, Gamma A, Neuenschwander M, Ajdacic-Gross V, Eich D, Rössler W, et al. Prevalence of mental disorders in the Zurich Cohort Study: a twenty year prospective study. Epidemiol Psychiatr Sci. 2005;14:68-76. DOI: https://doi.org/10.1017/S1121189X00006278
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