The effect of lithium on the structure and function of the human retina: a systematic review

Clinical Snapshot

Key Findings

• P Value: Not pooled; individual study p-values not extractable from abstract

• Effect Size: No pooled effect size calculable. Directional finding: 4 of 6 studies comparing lithium to valproate in bipolar disorder showed thicker RNFL in the lithium group; 2 of 2 larger studies comparing lithium-treated bipolar disorder to healthy controls showed no significant RNFL difference. All 10 functional studies reported a statistically significant effect of lithium on at least one functional measure.

• Primary Outcome: Structural retinal outcomes (RNFL thickness via OCT) and functional retinal outcomes (electrooculography, electroretinography, dark adaptation thresholds) in humans receiving lithium

• Nnt Or Sensitivity: Not applicable — no therapeutic or diagnostic accuracy data synthesised; no NNT, sensitivity, or specificity calculable from this review

• Confidence Interval: Not reported — no meta-analysis performed

Clinical Application

OCT is widely available in ophthalmology and increasingly in optometry settings, making structural retinal monitoring feasible in clinical practice. Electroretinography and electrooculography are more specialised and less routinely accessible. Routine retinal monitoring of lithium-treated patients is not currently standard practice, and this review does not provide sufficient evidence to mandate it. Lithium remains a first-line mood stabiliser for bipolar disorder in Australia, listed on the Pharmaceutical Benefits Scheme (PBS) for this indication. The Therapeutic Goods Administration (TGA) requires monitoring of renal and thyroid function during lithium therapy, but retinal monitoring is not currently included in standard Australian prescribing guidelines or RACGP recommendations. This review highlights a potential area for future guideline development if prospective evidence confirms clinically significant retinal effects. Australian psychiatrists and GPs managing long-term lithium therapy should be aware of the emerging — though currently inconclusive — evidence regarding retinal structural and functional changes, particularly in the context of the known association between bipolar disorder itself and RNFL thinning. Adults with bipolar disorder or depression receiving lithium therapy, particularly those undergoing long-term treatment where cumulative retinal effects may be clinically relevant. Patients with pre-existing retinal pathology or those being monitored for lithium toxicity may represent a priority subgroup for future prospective study.

Abstract

BACKGROUND: Bipolar disorder and depression are associated with structural and functional changes in the retina, including a thinner retinal nerve fibre layer (RNFL). Lithium is widely considered the most effective treatment for bipolar disorder, but its mechanism of action is not fully understood. We assessed research looking at the effect of lithium on structural or functional retinal outcomes in humans. METHODS: Searches using the terms 'Lithium' AND 'retina' were carried out to identify peer reviewed studies assessing the impact of lithium on retinal structure or function. These included those with or without a control group comparison, pre- and post- lithium comparisons and observational studies. There were no exclusions based on the quantity or preparation of lithium administered, or the length of administration. Risk of bias was assessed using the Joanna Briggs Institute (JBI) critical appraisal tool for Analytical Cross Sectional Studies, and a narrative synthesis and tabulated summary of the included studies was completed. RESULTS: Seven studies assessing structural outcomes and 10 reporting functional ones were identified, all highly heterogenous and with multiple limitations. Structural outcomes were derived exclusively from optical coherence tomography (OCT) with retinal nerve fibre layer (RNFL) being the most common measurement. There was no evidence of differences in the RNFL between participants with bipolar disorder taking lithium and healthy controls in two larger studies. In six studies looking at differences in those with bipolar disorder taking lithium and those taking valproate, two showed no signs of difference and four showed evidence of thicker RNFL in the lithium group. Studies reporting functional outcomes reported a statistically significant effect of lithium on at least one functional measure, derived from electrooculography, electroretinography, and dark adaptation thresholds. CONCLUSIONS: Current evidence suggests that lithium is likely to have an effect on the retina but limitations in all studies mean better designed and adequately powered prospective studies are required. REGISTRATION: PROSPERO database (Number-CRD42024516635).

References

1. 1.Needham, N., Grosset, D., Martin, J. T., MacGillivray, T., Dhillon, B., Martinovic, J., & Smith, D. J. (2026). The effect of lithium on the structure and function of the human retina: a systematic review. BMC Ophthalmology. https://doi.org/10.1038/nrneurol.2012.227