A brain region known as the amygdala could play a key role in predicting symptom improvement following ketamine therapy in patients with treatment-resistant anxious depression, according to new research published in the Journal of Affective Disorders.

“Since the antidepressant effects of ketamine in patients with anxious depression remain unclear, it is necessary to investigate the potential biomarkers predicting the antidepressant efficacy of ketamine in patients with anxious depression,” said study author Bin Zhang of the Affiliated Brain Hospital of Guangzhou Medical University.

“Previous studies have pointed out that functional connectivity differences in the amygdala are linked to depression improvement after ketamine treatment in depressed patients, but their role in anxious depression patients is uncertain. Therefore, we investigated the correlation between depression improvement after ketamine treatment and amygdala functional connectivity in anxious depression patients.”

For their study, the researchers examined neuroimaging data from 31 patients with anxious depression and 18 patients with non-anxious depression.

The researchers only included participants who had a diagnosis of major depression without comorbid psychotic symptoms, had a score greater than 17 on the Hamilton Depression Rating Scale, had previously failed to improve after at least two antidepressant treatments, had completed fMRI brain scans, and had undergone six ketamine infusions.

Among the patients with anxious depression, about 60% (20 patients) exhibited clinically significant reductions in depression symptoms following their sixth ketamine infusion. The remaining 11 patients with anxious depression were classified as non-responders.

The researchers found that, prior to the ketamine infusions, those who responded to the treatment tended to have greater functional connectivity between the left laterobasal amygdala and the left precuneus compared to non-responders. Additionally, the connectivity between the two brain regions was significantly reduced post-treatment among responders.

Patients with anxious depression also tended to have reduced connectivity between the right centriomedial amgydala and the right middle temporal gyrus compared to patients with non-anxious depression, which predicted treatment response.

“Corresponding to the crucial role of the amygdala in emotion regulation, especially in negative emotion, our study shown that the amygdala functional connectivity is associated with depression improvement to ketamine infusions in patients with anxious depression,” Zhang told PsyPost.

“The most surprising finding of the current study was that the baseline hyperconnectivity of the amygdala-precuneus found in the responders relative to the non-responders was significantly reduced on day 13 compared to baseline after six ketamine infusions. It may point to a potential neural underpinning by which ketamine exerts its antidepressant effect in patients with anxious depression.”

The results provide new insights into the mechanisms underlying ketamine’s antidepressant effects. But as with any study, the new research includes limitations. The researchers noted that their sample size was relatively small. Future research with larger samples should be conducted to validate the findings.

“Though the findings in our study may suggest that amygdala functional connectivity is a significant predictor of treatment response to ketamine infusions in patients with anxious depression, further validation is required,” Zhang said. “Moreover, further studies exploring the potential antidepressant mechanisms of ketamine may aid in the treatment of anxious depression patients.”

The study, “Functional connectivity differences in the amygdala are related to the antidepressant efficacy of ketamine in patients with anxious depression“, was authored by Shiqi Yuan, Xin Luo, Xiaoyu Chen, Mingqia Wang, Yiru Hu, Yanling Zhou, Yuping Ning, and Bin Zhang.