There is no shortage of psychological and pharmacological therapies to combat the world’s most widespread mental health issue, major depressive disorder (MDD). However, a significant portion of the affected population fail to respond to many of these traditional therapies. For this reason, new drugs must be tested and validated. One promising candidate is ketamine –famously but somewhat improperly known as a horse tranquilizer.
However, the manner by which ketamine acts is not well known, meaning that clinicians are still circumspect regarding its use in treating MDD. Recently, researchers in New York look at how ketamine affects the subgenual anterior cingulate cortex (sgACC), a region of the brain whose hyperactivity has proven ties to MDD. The recent study, which appeared in Neuropsychopharmacology, helps bridge this gap in the literature.
In the study, 28 patients with MDD and 20 healthy controls underwent function MRI (fMRI) scans both at rest and while completing a monetary incentive-based task. The goal of the incentive task was to activate the sgACC, known to be implicated in reward anticipation.
The results of the study demonstrate a more complex relation between the sgACC and MDD than has been previously suspected. The authors evoke the existence of a “double dissociation whereby sgACC hyper-activation to positive feedback is associated with anhedonia [inability to feel happiness], whereas hyper-activation to negative feedback is associated with anxiety.”
This also enabled them to uncover what may be an important physiological distinction in the region, where the posterior region was more closely related to symptoms of anhedonia and the anterior region to anxiety.
In terms of a pharmacological treatment, ketamine was shown to operate by reducing sgACC hyperactivation to positive feedback. If this seems counterintuitive, it is important to remember that many brain centers are inhibitory by nature, meaning that the more active they are, the more strongly they inhibit other areas—thus producing, for example, a reduced response to positive feedback. Interestingly, the ketamine treatment blunted sgACC hyperactivation in response to positive feedback, but not negative feedback.
The neurological underpinnings of MDD are still not well understood. The same can be said for many of the drugs used in treating it. Rigorous clinical testing and exploratory studies like the present are thus essential in improving our understanding of both this disease and treatment options.
The study, “Ketamine normalizes subgenual cingulate cortex hyper-activity in depression“, was authored by Laurel S. Morris, Sara Costi, Aaron Tan, Emily R. Stern, Dennis S. Charney, and James W. Murrough.