Advances in the Management of Major Depressive Disorder - Episode 2

Glutamatergic Signaling and New Mechanisms of Action for Treatment of Depression

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Dr Andrew Cutler and Dr Greg Mattingly discuss newer mechanisms of action to treat patients with Major Depressive Disorder, in particular those with glutamatergic agents.


The conversation between Andrew Cutler, MD and Greg Mattingly, MD explores the newer mechanisms of action for treating depression, particularly focusing on glutamate and neural plasticity. Greg Mattingly emphasizes the significance of neural networks and the balance between excitatory glutamate and inhibitory Gaba in maintaining proper brain function.

They discuss the historical context of neural growth factor discovery in 1986 and its relevance to understanding how chronic stress and depression deplete certain chemicals in the brain, affecting neural connections. The conversation delves into the role of glutamate in neuroplasticity and the need for a balanced approach to modulating its levels.

Experts mention the impact of ketamine on glutamate Nmda receptors and its ability to quickly translate into clinical efficacy. The clinicians discuss the importance of balancing glutamate levels, avoiding overexcitation, and the potential of newer medications to enhance neural connectivity rapidly.

They touch upon the complexity of neural networks, including the default mode network and central executive network, highlighting how patients with depression may get stuck in rumination. Greg Mattingly notes that the new medicines show promise in shifting patients from one neural network to another, enhancing neural connectivity within hours to 24 hours.

The conversation extends to the exploration of various mechanisms, including psychedelic medicines, kappa opioid receptor antagonists, orexin system modulation, and inflammation modulation in treating depression. They emphasize the importance of moderation and safety in using glutamate medicines.

Finally, they discuss intranasal esketamine as a delivery method for ketamine, acknowledging its transformative potential despite some undesired side effects. The conversation ends with a mention of the REMS program due to dissociation, blood pressure issues, and sedation associated with ketamine use.

Summary was AI-generated and edited for clarity.