Active Brain & Nervous System Mental Health

Lithium's mechanism in bipolar disorder: investigating the light hypersensitivity hypothesis.

Funder Wellcome Charity-funded
Associated organisations Northumbria University · University of Edinburgh Europe PMC affiliations are not treated as award recipients or mapped locations.
Funding £3.7M
Period Jun 2023 — May 2028

In plain English

AI plain-English summary

Lithium has been used for 70 years to treat bipolar disorder, but no one knows exactly how it works in the brain. Researchers now suspect lithium may act on the retina—the light-sensitive layer at the back of the eye—to stabilise the disrupted daily rhythms of mood, sleep, and activity that characterise the condition. People with bipolar disorder appear hypersensitive to evening light, which can throw their internal clocks out of sync. Lithium might increase the retina’s resilience to this light-induced disruption. This project will test that hypothesis directly, both in people exposed to controlled evening light stimuli and in lab-grown retinal organoid cells derived from individuals with bipolar disorder. If the hypothesis holds, it could shift treatment away from trial-and-error medication toward targeted chronotherapies—interventions that use light exposure timing, blue-light filters, or other retinal-focused strategies to manage mood. Patients would gain a clearer rationale for why lithium works, and clinicians could develop non-drug alternatives for those who cannot tolerate the drug’s side effects. People with lived experience are co-designing the study and its public engagement materials, ensuring the research stays grounded in real patient needs.

View original technical description
Lithium has been in use for 70 years and is the most effective treatment for bipolar disorder. It has many actions but the precise mechanism of action in bipolar disorder is uncertain. Recent evidence suggests that lithium may work by stabilizing aberrant circadian rhythms of mood, cognition and rest/activity, possibly via an action at the level of the retina. Specifically, individuals with bipolar disorder who are hypersensitive to the destabilizing effects of excess light in the evening may respond to lithium because it acts on the retina to make light-induced circadian disruption less likely. This is a plausible and exciting hypothesis that, if true, could herald a new era of chronotherapeutic approaches. We will test whether people with bipolar disorder are hypersensitive to evening light stimuli and whether lithium works by increasing retinal resilience to light-induced circadian disruption. In parallel, we will test the effect of light stimuli and lithium treatment on retinal organoid cells derived from individuals with bipolar disorder. People with bipolar disorder are involved in every aspect of this project, from design to dissemination, and we will also co-produce a range of knowledge exchange activities on the theme of ‘Bipolar Disorder, Lithium and Light’.

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Researchers

Iain Campbell (EPMC Awardee)Jasna Martinovic (EPMC Awardee)Nayantara Santhi (EPMC Awardee)

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Original classification

Directed Call - full

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