Numerous small clinical studies consistently demonstrate that a single sub-dose of ketamine, an ionotropic glutamatergic NMDA (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder and active suicidality. Patients who have undergone ketamine infusion treatment report the alleviation of depressive and suicidal symptoms within hours of a single infusion— with effects lasting from several days, up to two weeks.
Beating Depression with Ketamine
The NMDA receptor antagonist ketamine has attracted enormous interest in mental health research due to its rapid antidepressant actions, but its mechanism of action is not fully understood. In this novel research by Yang Y, Cui Y, et al show that blockade of NMDA receptor-dependent bursting activity in the lateral habenula (LHb) also known as the “anti-reward center”, mediates the rapid antidepressant actions of ketamine in rodent trials.
The LHb gets major inputs from the habenula-projecting globus pallidus and the medial prefrontal cortex (mPFC), sending efferent signals to the dopaminergic ventral tegmental area (VTA), serotonergic dorsal raphe nuclei (SNc) and the GABAergic rostromedial tegmental nucleus. This anti reward action results from rapid burst signals from the LHb neurons, which inhibit downstream monaminergic reward centers. The research team found that a local blockade of NMDA receptors in the LHb with ketamine is sufficient to induce rapid antidepressant effects. In short, releasing the brain’s natural reward centers from strong, efferent anti-reward signals will improve mood and sense of well-being.
Why Does This Matter?
This finding provides a framework for developing new rapid-acting antidepressants and the possibility of discovering new and novel targets for other psychiatric illness. For those of us in the addiction field, drugs of abuse elevate dopamine and other monoaminergic neurotransmitters that effect reward and mood. Substance Use Disorder changes the reward threshold, whereby naturally rewarding stimuli is no longer rewarding.
Substance Use Disorders ultimately reduce the bioavailability of monoamines and degrade the reward circuitry between the midbrain and the PFC. As a result anhedonia, depression and suicidality may emerge—which enslaves users to a life in which their mood and well-being is dependent upon the consumption of psychoactive substances. In other words, better life through better chemistry.
It is important to understand the role that the anti-reward system plays as a reinforcement and survival. Early on in life, disease or physical pain is a primary teacher of safe versus unsafe behavior. The ventral pallidum (VP) plays a critical role in processing both rewarding and aversive stimuli. Activation patterns in VP neuronal subpopulation specifically encode reward and motivation signals via phasic bursts of excitation and plays an important role in the larger mesocorticolimbic processing. Recent experiments show that lesioning in the VP causes dramatic changes in reward, specifically “liking”. It has been demonstrated that liking sugar, for example, can be changed to disliking, via lesioning in the VP. Finding less intrusive means to mediate this complicated reward system may eventually help those suffering from Substance Use Disorders, depression, and other addictive behaviors.
Yang Y, Cui Y, et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature. 2018 Feb 14;554(7692):317-322. doi: 10.1038/nature25509.