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Lithium Might Enable Ketamine's Antidepressant Activity

Helping ketamine-resistant patients.

Researchers have published results of experiments in rodents suggesting that lithium, a widely prescribed mood stabilizer, may have value as an adjunct to ketamine therapy in people who suffer from treatment-resistant depression (TRD).

The findings, published in Translational Psychiatry, are particularly interesting in view of disappointing results in a clinical trial published in 2019 that found no benefit from adding lithium to ketamine therapy in a group of patients with unipolar depression. In that study, importantly, all of the patients who participated showed an initial antidepressant response to a single ketamine treatment before being randomized into groups that received either ketamine plus lithium or ketamine plus placebo in three subsequent treatment sessions. The antidepressant response was not enhanced in those who received adjunctive lithium, an analysis indicated.

A team led by 2009 BBRF Young Investigator Susannah J. Tye, Ph.D., of the Mayo Clinic Depression Center and the University of Queensland, Australia, decided to further explore the possibility of lithium's potential value as an adjunct to ketamine therapy. 2006 BBRF Independent Investigator Mark A. Frye, M.D., also at the Mayo Clinic, was a member of the team. The first author of their paper was J. Blair Price, Ph.D.

The researchers noted that lithium is commonly prescribed as an adjunct to conventional treatments for treatment-resistant depression and "shares overlapping mechanisms of action with ketamine." Tye and colleagues also noted that lithium has been observed in rodent models of TRD to enhance the duration of ketamine's antidepressant effects.

One theory of ketamine's mechanism of action centers on its ability to increase the number and activity of AMPA receptors—cellular receptors for excitatory neurotransmitters—as well as "upregulate" the activity of the protein BDNF, a growth factor with various roles in the brain that are linked with neural and synaptic growth and antidepressant activity. The molecular pathways impacted by AMPA receptor activity and BDNF stimulation are also activated by lithium, the team noted, as well as other growth factors including insulin.

In a prior study using a rodent model of TRD, lithium augmentation of the tricyclic antidepressant medicine imipramine (Tofranil) was observed to boost insulin signaling and improve antidepressant response.

The theory the team tested in the rat model of TRD was that adjunctive lithium might generate an antidepressant response in animals that are not responsive to ketamine administration.

To create resistance to antidepressants in rats, the team administered a hormone called ACTH for 14 days, which helps boost the rodent equivalent of the stress hormone cortisol. Treatment-resistant rats were then divided into four groups of 12 each: one group was treated with ketamine, one with lithium, one received both ketamine and lithium, and the last received a placebo. Two kinds of behavioral tests were given to the rats once the treatments had been administered—standard tests that are widely used in rodent studies to gauge antidepressant activity.

Lithium treatment alone produced no antidepressant activity in ketamine-resistant animals. But those receiving lithium in addition to ketamine "displayed robust antidepressant responses," the researchers noted. "Of particular interest," they added, was the observation that animals receiving both drugs "expressed elevated biochemical markers" including plasma insulin levels accompanied by an increase in insulin signaling, which in past studies have been linked with antidepressant activity.

The ability of lithium plus ketamine to generate antidepressant responses in animals that were non-responders to ketamine alone is thought by the team to reflect lithium's impact on the molecular pathways responsible for increasing the plasticity of neurons, specifically, by boosting insulin levels and insulin signaling.

It is possible, the researchers said, that "lithium augmentation of ketamine may only be necessary and beneficial when there is an inherent deficit in critical modulators of [ketamine] response, such as insulin signaling."

The team said their approach has the potential to "reshape our understanding" not just of lithium augmentation of ketamine therapy, but more broadly of treatment-resistant depression. "Failed drug efficacy may have more to do with misalignment of drug target with [an individual's specific] physiology," they wrote.

The mere addition of lithium or the amount added to ketamine treatment may not be the most critical factor in future clinical applications, they said. Rather, future clinical trials might focus on testing how treatment response might be enhanced by "promoting molecular signaling cascades and bioenergetic pathways essential for enabling [any] antidepressant responsivity. Clinical studies using this precision medicine approach are needed."

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