Janusz Rybakowski: Lithium The Amazing Drug in Psychiatry

Janusz K. Rybakowski’s reply to Samuel Gershon’s comment on Rybakowski’s reply to Barry Blackwell’s comment

        Thanks, Sam, for touching on this important problem. I should underline that my suggestions on the benefits of lithium for dementia are not related to personal experiences but the literature on this subject in the recent decade. As to my practice with elderly patients on lithium, I did not notice particularly adverse effect on cognition, if lithium concentration is kept within reasonable levels, i.e., 0.4-0.6 mmol/l.

        Possible beneficial lithium effects for dementia have been suggested by population studies which have shown an association between lithium treatment and a reduction of the risk for dementia (Donix and Bauer 2016). Employing the Danish nationwide register of lithium prescriptions, it was observed that subjects taking lithium for a long time had the dementia rate the same as the general population. On the other hand, in patients receiving anticonvulsant drugs, such a rate was higher with a longer duration of treatment (Kessing, Sondergard, Forman and Andersen 2008).  While long-term treatment with lithium resulted also in a lower rate of dementia in bipolar patients, the opposite was obtained for such treatment with anticonvulsants, antidepressants and antipsychotics (Kessing, Forman and Andersen 2010). In a Danish study, an inverse association between dementia incidence and concentration of lithium in drinking water was found (Kessing, Gerds, Knudsen et al. 2017) and the results of American research demonstrated that changes in Alzheimer’s disease (AD) mortality was inversely related to trace lithium in drinking water (Fajardo, Fajardo, LeBlanc and MacPherson 2018).

        The first single-blind, randomized, placebo-controlled multi-center trial investigating the effects of lithium treatment on CSF dementia biomarkers and cognitive performance included 71 patients with early AD treated with a lithium level of 0.5 – 0.8 mmol/l over 10 weeks. No significant changes in CSF biomarkers or cognitive parameters were found (Hampel, Ewers, Burger et al. 2009). However, secondary data analysis showed associations of lithium treatment with increased concentration of Brain Derived Neurotrophic Factor (BDNF) and a further subgroup analysis demonstrated that patients showing higher BDNF concentrations also had cognitive improvement (Leyhe, Eschweiler, Stransky et al. 2009).

        Two years later Forlenza, Diniz, Radanovic et al. (2011) investigated the effects of a low dose lithium treatment (0.25–0.5 mmol/l) on cognitive parameters and CSF biomarkers of dementia in 45 patients with amnestic mild cognitive impairment (aMCI). After 12 months, lithium-treated patients who did not convert to AD showed a significantly reduced concentration of hyperphosphorylated tau protein. In the lithium group, the conversion rate to AD was similar to non-lithium-treated patients, although converters showed a less cognitive decline. Nunes, Viel and Buck (2013) studied the effects of a lithium microdose of 300 μg per day in a randomized, placebo-controlled trial lasting 15 months in 113 patients with AD. The patients receiving lithium did not display impaired results in the mini-mental state examination test, on the other hand, the control group showed a decreased performance.

        Recently, the results of a randomized, double-blind, placebo-controlled four-year trial were published. The therapeutic effects of low-dose lithium (0.25–0.5 mmol/l) in 61 patients with amnestic MCI were examined. Within the lithium group, patients showed stable cognitive and functional scores after 24 months whereas patients in the placebo group demonstrated slightly, but significantly worsened scores. There were no significant differences in the concentration of hyperphosphorylated tau- and total tau protein. In the lithium group, there was a trend towards a diminished conversion into AD (Forlenza, Radanovic, Talib and Gattaz 2019).

        Two meta-analyses suggested possible pro-cognitive effects of lithium in patients with MCI and AD. The first, including three clinical trials with a total of 232 patients, demonstrated a significant slowing of cognitive decline associated with lithium treatment (Matsunaga, Kishi, Annas et al. 2015). The second included five randomized controlled trials investigating the effects of lithium and tideglusib, an inhibitor of GSK-3, on cognition in patients with MCI and AD. In the subgroup of lithium-treated patients, some beneficial effects on cognitive parameters were found,  correlating with treatment duration (Matsunaga, Fujishiro and Takechi 2019).

        Therefore, possible preventing and therapeutic effects of lithium in dementia are promising and the issue is worth further studies.

References:

Donix M, Bauer M. Population studies of association between lithium and risk of neurodegenerative disorders. Curr Alzheimer Res 2016;13:873-8. 

Fajardo VA, Fajardo VA, LeBlanc PJ, MacPherson REK. Examining the relationship between trace lithium in drinking water and the rising rates of age-adjusted Alzheimer's disease mortality in Texas. J Alzheimers Dis 2018;61:425-34. 

Forlenza OV, Diniz BS, Radanovic M, Santos FS, Talib LL, Gattaz W. Disease-modifying properties of longterm lithium treatment for amnestic mild cognitive impairment: randomised controlled trial. Br J Psychiatry 2011;198:351-6. 

Forlenza OV, Radanovic M, Talib LL, Gattaz WF. Clinical and biological effects of longterm lithium treatment in older adults with amnestic mild cognitive impairment: randomised clinical trial. Br J Psychiatry  2019;215:668-74.  

Hampel H, Ewers M, Burger K, Annas P, Mörtberg A, Bogstedt A,  Frölich L, Schröder J, Schönknecht P, Riepe MW, Kraft I, Gasser T, Leyhe T, Möller H-J, Kurz A, Basun H. Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry 2009;70 922-31. 

Kessing LV, Sondergard L, Forman JL, Andersen PK. Lithium treatment and the risk of dementia. Arch Gen Psychiatry 2008;65:1331-5.

Kessing LV, Forman JL, Andersen PK. Does lithium protect against dementia? Bipolar Disord 2010;12:87-94.

Kessing LV, Gerds TA, Knudsen NN, Jørgensen LF, Kristiansen SM, Voutchkova D, Ernstsen V, Schullehner J, Hansen B, Andersen PK, Ersbøll AKjær. Association of lithium in drinking water with the incidence of dementia. JAMA Psychiatry 2017;74:1005-10.

Leyhe T, Eschweiler GW, Stransky E, Gasser T, Annas P, Basun H, Laske C. Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease. J Alzheimers Dis 2009;16:649-56. 

Matsunaga S, Kishi T, Annas P, Basun H, Hampel H, Iwata N. Lithium as a treatment for Alzheimer's disease: A systematic review and meta-analysis. J Alzheimers Dis 2015;48:403-10.  

Matsunaga S, Fujishiro H, Takechi H. Efficacy and safety of Glycogen Synthase Kinase 3 inhibitors for Alzheimer's Disease: A systematic review and meta-analysis. J Alzheimers Dis 2019;69;1031-9.  

Nunes MA, Viel TA, Buck HS. Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer's disease. Curr Alzheimer Res 2013;10:104-7.

September 23, 2021