A team of researchers has published results of experiments in patients with treatment-resistant depression that provides direct evidence of at least one important mechanism through which ketamine exerts its powerful antidepressant effects.

As an experimental drug administered in low, “subanesthetic” doses, ketamine years ago demonstrated its rapid-acting antidepressant effects in severely depressed individuals who had not been helped by conventional depression treatments. In 2019, esketamine (Spravato), a chemical cousin of ketamine, was approved by the FDA for treating refractory depression and depression with acute suicidal ideation. Over 90 BBRF grants supported the early work on ketamine, led by distinguished scientists including John H. Krystal, M.D., Dennis Charney, M.D., and Carlos Zarate, M.D., all current or past members of BBRF’s Scientific Council.

The approved drug is designed to be administered in approved medical settings, as ketamine can have dissociative side effects (the sensation of an out-of-body experience). At high dose, ketamine is also an addictive compound. Its beneficial effects, in depression, are dramatic and can potentially save lives, but usually do not last longer than a few weeks. For these reasons, researchers have been trying to develop drugs which mimic ketamine’s rapid and intense antidepressant impact while minimizing side effects and prolonging its benefits.

Such efforts are supported by research like that just reported by a team in Japan, appearing in Molecular Psychiatry. The team was led by Takuya Takahashi, M.D., Ph.D., of Yokohama City University Graduate School of Medicine. Dr. Takahashi received a BBRF Young Investigator grant in 2005 to support his research on a type of cellular receptor for glutamate, the most pervasive and important of the brain’s excitatory neurotransmitters. Called AMPA receptors, they are at the center of the newly reported findings about how ketamine exerts its remarkable antidepressant effects.

Numerous experiments in animals have pointed to AMPA receptors as playing an important role in ketamine’s mechanism of action. But it has been difficult to translate such findings to humans, in part because until now it has been very difficult if not impossible to closely observe these receptors in action in the living human brain. That problem has been successfully addressed by Dr. Takahashi and colleagues, who have developed and tested a radioactive tracer administered in very small doses that enables researchers to observe AMPA receptors in real-time in people, using PET imaging (positron emission tomography).

The team’s work is based on data gathered in a multi-part clinical trial in Yokohama, involving 34 individuals with treatment-resistant major depression and 49 healthy individuals, who served as controls. The depressed patients were divided into 2 groups, one receiving an intravenous subanesthetic dose of ketamine (0.5 mg/kg) twice a week for two weeks, and the other receiving placebo injections on the same schedule. Most participants were between 30 and 50 years old, about two-thirds were male, and among those who were depressed, many had lived with the illness for over a decade. Before and after the trial, each participant received a PET scan to map AMPA receptor density and distribution throughout the brain.

Participants in the trial with refractory depression had widespread abnormalities in AMPA receptor density compared with healthy participants, the team reported.

The analysis of PET scans made before and after ketamine was administered in the depressed participants showed a variety of changes on a brain-wide basis. Improvements in depressive symptoms after ketamine treatment were linked to what the team called dynamic, region-specific adjustments in the density of AMPA receptors on the surface of excitatory glutamate neurons. In the cortex, some subregions showed increased receptor density, while reductions were seen in brain regions associated with the processing of rewards, especially the habenula. These region-specific shifts, both involving increases and decreases in AMPA receptors depending on the location, were strongly correlated with improvements in patient symptoms.

The team suggests that their results support “the well-established notion that there are distinct biological processes” underlying resistance to treatment in major depression. In the habenula, for instance, where fewer AMPA receptors on neuronal cell surfaces corresponded with greater symptom improvement following ketamine treatment, the findings offer a clue about how ketamine affects the reward system. The habenula is acutely responsive to negative rewards, i.e., negative reinforcement, in which a particular behavior is encouraged by removing something undesirable or unpleasant. This can be a positive thing, but repetitive negative rewards have been linked with depression, and are used to induce depression in animal models. The decrease in cell-surface AMPA receptor density in the habenula in ketamine-treated patients who were treatment-resistant is consistent with the acute effect of ketamine on the lateral habenula in animal models. The team finds this correspondence “highly promising and critically important,” in view of the longstanding difficulty of translating results from animal models of illness to the human setting.

The observed relation between observed AMPA receptor changes and ketamine’s efficacy varied in different locations. An example is brain areas that are part of the default-mode network (DMN)—a broad brain network that is active when the brain is not focused on a particular task, and whose state, as measured by functional brain scans, is among the indices of depression. “Our findings suggest that ketamine may increase AMPA receptor density in association with depressive symptom improvement within specific DMN regions, potentially shifting them toward a normalized functional connectivity,” the team noted.

Other findings indicated that ketamine, by inducing regional AMPA changes, may suppress hyperactivity in the lateral portion of the habenula, “thereby activating reward-related neural circuits.” The totality of evidence suggests that ketamine appears to regulate AMPA receptor dynamics in a way that reverses abnormalities in AMPA receptor cell-surface density specifically seen in patients with treatment-resistant depression, helping to account for its efficacy in those patients.

In broad terms, Dr. Takahashi and colleagues concluded, “our findings demonstrate that AMPA receptor distribution is altered in patients with treatment-resistant depression, and that ketamine partially normalizes these abnormalities in association with its antidepressant effects.” Not only, therefore, might AMPA receptors help mediate ketamine’s beneficial effects; they may also be biomarkers of treatment response in depression, the team said.