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Researchers Crack Codes for Lithium, Electroshock

How two long-time therapies for brain disorders work are finally being understood by the medical community, creating a path to safer alternatives.

While they have been widely used for decades, no one knew exactly why two mainstays of psychiatric treatment—lithium chloride for bipolar disorder and electroconvulsive (or electroshock) therapy for major depression—worked.

But new discoveries are illuminating how these treatments affect brain function, answering old questions and opening the door to new, more effective therapies that may have fewer side effects.

Research fellow Qing-Jun Meng and a team at the University of Manchester found that lithium blocks the activity of an enzyme that affects the brain’s master clock—the part in charge of our circadian rhythms. They reported their results in the journal PLoS One.

Scientists already knew that people with bipolar disorder suffer disruptions of circadian rhythms. “The most obvious [effects] are the sleep disorders, because that’s controlled by our body clock,” Meng says. “During a depressive episode they will experience insomnia, and during the very high moods they will feel a lot of energy, and they don’t feel a need to sleep.”

In bipolar patients, the genes behind the machinery of the master clock are under-active. That, Meng reasoned, could explain the disrupted sleep patterns and other symptoms.

“That got me to thinking that lithium might change the robustness of the rhythm,” he says. In working with mice, he showed that by blocking the enzyme known as glycogen synthase kinase, or GSK3, lithium boosts the master clock’s strength threefold.

Understanding this mechanism, Meng says, companies are already developing drugs that can block GSK3, but which would be unlikely to trigger lithium's unwelcome effects such as nausea, dry mouth, tremor, weakness and weight gain.

In the mid 30s, a dozen years before an Australian psychiatrist first documented lithium’s benefit for bipolar patients, electroconvulsive therapy was used to treat disorders such as major depression and schizophrenia. Controversial because of its side effects, including disrupting people’s memories, electroconvulsive therapy is still viewed as an effective alternative for people who don’t respond to antidepressant medications. But, like lithium, there wasn’t a lot of understanding of how the treatment actually worked.

University of Aberdeen researchers recently conducted before-and-after functional MRI scans of nine depressed people treated with electroshock therapy. In measuring the connectivity of 25,000 brain areas, researchers found one – the left dorsolateral prefrontal cortex – that appeared to be “hyperconnected” in patients before treatment.

This bolstered an earlier hypothesis, says research fellow Jennifer Perrin, which suggested that in depressed people, cortical structures involved in thinking are too connected to the limbic system that focuses on emotional processing. Electroconvulsive therapy decreased that hyperconnection, she says, restoring the brain to balanced functioning.

Unraveling the mysteries of ECT and lithium seem likely to hasten their departure from the therapeutic arsenal as better understanding should lead to better treatments. Scans to detect signs of brain hyperconnectivity could, for example, enable earlier treatment to head off relapses of depression in high-risk patients. Some day pop culture references in movies like “One Flew Over the Cuckoo’s Nest” and songs like Nirvana’s “Lithium” will be echoes of the past.