Lithium’s Mechanism of Action – A Focus on Neuroprotection
Bipolar disorder, also known as manic-depressive illness, is an illness characterised by periods of recurrent depression and mania. As bipolar disorder progresses, the time between episodes gradually gets shorter (kindling phenomenon) with increasing functional impairments as well as increased suicide and hospitalisation rates.
Patients with bipolar disorder have higher rates of medical co-morbidities, attempted and completed suicide and higher rates of mortality resulting in a lower life expectancy compared to the general population.
Studies show that there are serial neuroanatomical changes that are associated with gradually worsening symptoms and treatment resistance. Although neuroimaging data is inconsistent, bipolar symptoms appear to be associated with decreased cortical and subcortical structures in addition to increases in the lateral ventricular volume.
Current treatments for bipolar disorder include antipsychotic medications, mood stabilisers and antidepressants. Lithium has compelling evidence in the treatment of mania, acute bipolar depression and prophylaxis in bipolar disorder.
A meta-analysis by Geddes et al., showed that Lithium therapy reduces the overall risk of relapse in bipolar disorder by 40-61% and its effectiveness in preventing manic episodes is greater than for depression. (40% vs. 22%). 
A real-world effectiveness study in a Finnish cohort of 18018 patients found that lithium use was associated with the lowest risk of rehospitalisation because of mental or physical illness compared to antipsychotics or other mood stabilisers.
Lithium also has anti-suicidal properties. The seminal study by Cipriani et al., showed that Lithium reduces the risk of death and suicide by 60% and the risk of self-harm by 70%. . The lead author Cipriani updated this by carrying out a meta-review of all systematic reviews and meta-analyses of RCTs of lithium and suicide and self-harm published between January 1980 and June 2017. The authors state-
The evidence to date is overwhelmingly in favour of lithium as an antisuicidal agent, even balanced against any potential disadvantages of its use in regular clinical practice…..Given this evidence, however, the use of lithium is still underrepresented in clinical practice and should be incorporated more assertively into current guidelines.
Evidence also suggests that starting Lithium early in the course of the disorder reduces the rate of treatment non-response. Despite the benefits, Lithium use amongst clinicians is declining.
Despite abundant evidence regarding the efficacy of lithium and its effectiveness in the treatment of bipolar disorders, its use is declining at the beginning of the 21st century. It is of paramount importance to keep reminding psychiatrists and educating physicians about the unique properties of lithium and about monitoring patients treated with lithium, since it has been suggested that lithium should once again become the first-line treatment for bipolar disorders. (Zivanovic, 2017) 
Geddes, J. R., Burgess, S., Hawton, K., Jamison, K., & Goodwin, G. M. (2004). Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of randomized controlled trials. American Journal of Psychiatry, 161(2), 217-222.
Cipriani, A., Hawton, K., Stockton, S., & Geddes, J. R. (2013). Lithium in the prevention of suicide in mood disorders: updated systematic review and meta-analysis. Bmj, 346, f3646.
Berk M 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. Translational Psychiatry. 2017
Beyer J et al., Hyperintense MRI lesions in bipolar disorder: A meta-analysis and review. International Review of Psychiatry. 2014
Forlenza O et al., Neuroprotective effects of lithium: implications for the treatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chemical Neuroscience. 2014
Lewandowski K et al., Myelin vs axon abnormalities in white matter in bipolar disorder. Neuropsychopharmacology. 2015