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Long term lithium therapy: a neuroprotective or neurotoxic factor? A systematic review of existing data


Lithium is an effective medication for the treatment of bipolar disorder, but it is unclear whether its long-term use may result in protective or in toxic consequences.

Materials and methods

The MEDLINE was searched with the combination of the word: 'Lithium' with key words that referred to every possible effect on the central nervous system. The papers were classified into those supporting a neuroprotective effect, those in favor of a neurotoxic effect and those neutral. The papers were classified in research in humans, animal and in vitro research, case reports, and review/opinion articles.


The MEDLINE search returned 913 papers. This number concerns February 2005. The scanning of the abstracts selected 238 papers for further reviewing.

95 papers supported the neuroprotective effect (6 human research, 63 animal/in vitro, 0 case reports, 26 reviews/opinion articles).

135 papers supported the neurotoxic effect (18 human research, 21 animal/in vitro, 74 case reports, 22 reviews/opinion articles).

8 papers supported no hypothesis (5 human research, 2 animal/in vitro, 0 case reports, 1 reviews/opinion articles).


Although more papers are in favor of the neurotoxic effect, the great difference in the type of papers that support either hypothesis, along with publication bias and methodological issues make conclusions difficult. It seems that there is a possibility of a toxic effect in real-life clinical practice even in well-followed patients.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Fountoulakis, K., Vieta, E., Bouras, C. et al. Long term lithium therapy: a neuroprotective or neurotoxic factor? A systematic review of existing data. Ann Gen Psychiatry 5 (Suppl 1), S329 (2006).

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