A cell culture study identifies a new molecular pathway that could lead to alternatives to lithium for bipolar disorder — but human trials are still years away

For decades, lithium has been the gold standard for treating bipolar disorder. But it doesn’t work for everyone. An estimated 30 to 50 percent of people with bipolar disorder don’t respond adequately to lithium, leaving them cycling through medications with limited options. Now, a study published in eBioMedicine (part of The Lancet family of journals) in June 2024 points to a new molecular target that could eventually change that.

Researchers at McGill University in Montreal found that activating a cellular energy sensor called AMPK (AMP-activated protein kinase) in neurons derived from bipolar patients produced protective effects similar to lithium. The study used induced pluripotent stem cells (iPSCs) — essentially, skin cells reprogrammed into neurons — from patients with bipolar I disorder to test the pathway in a controlled laboratory setting.

The key finding: when researchers activated AMPK in these lab-grown neurons, it reduced the hyperexcitability that characterizes bipolar neurons — the same overactive firing pattern that lithium helps control. In other words, AMPK activation appeared to do what lithium does, but through a different mechanism.

It’s important to be precise about what this study does and doesn’t show. This is a cell culture study — not a human clinical trial. The neurons were grown in a lab, not observed in living patients. No one took a pill. The leap from “this works in a dish” to “this works in a person” is enormous in neuroscience, and many promising lab findings never survive that translation. The researchers themselves note that extensive further research, including clinical trials, would be needed before any AMPK-targeting drug could be considered for patients.

Still, the finding matters for a specific reason: it identifies a new biological pathway that could be targeted independently of lithium. Current alternatives to lithium — anticonvulsants like valproate, or atypical antipsychotics — work through entirely different mechanisms and carry their own significant side effect profiles. If AMPK activation can be harnessed safely, it would represent a genuinely new class of treatment for bipolar disorder.

Some readers may have seen claims linking metformin, a common diabetes medication that activates AMPK, to mood benefits in bipolar patients. There is some preliminary evidence suggesting metformin may improve mood in bipolar patients who also have insulin resistance, but experts believe this effect is likely tied to reversing metabolic dysfunction rather than direct AMPK activation in the brain. Metformin’s ability to cross the blood-brain barrier is limited, and no controlled trial has established it as a mood stabilizer.

The broader context is encouraging. The fact that researchers can now grow neurons from individual patients and test drug pathways on them represents a shift toward personalized medicine in psychiatry.

A note from Robin Miller: I was one of the lucky ones — lithium worked for me, eventually. But I watched people in my support group try medication after medication, each one a new set of side effects and a new round of hope followed by disappointment. When I read about research like this, I think about them. The 30 to 50 percent number isn’t abstract to me. Those are people I know. Anything that opens a new door for treatment-resistant bipolar is worth paying attention to — even if it’s still in a lab.

Sources: eBioMedicine (The Lancet) | McGill University

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