CNSPulse

ADVANCES IN DEPRESSION RESEARCH: A TRIBUTE TO NOLAN WILLIAMS

Charles Nemeroff — The University of Texas at Austin

2026 ASCP Annual Meeting

This panel presentation brings together four investigators who have worked closely with Nolan Williams over the last several years and is meant to present state of the art research relevant to mood disorders for which he was intimately involved and invested. Overall, they comprise four areas: 1. The role of a history of child abuse and neglect in treatment resistance in mood disorders; 2. Understanding the mechanism of action of ketamine with an emphasis on its action at the mu opiate receptor; 3. The use of low frequency focused ultrasound in the treatment of mood and anxiety disorders and 4. The promise of psychedelic medicines, more specifically ibogaine, in the treatment of traumatic brain injury and other neuropsychiatric disorders. In brief, childhood maltreatment has been conclusively shown to product reliable long term biological changes in the brain and body that are associated with increased vulnerability to several medical and psychiatric disorders. In addition such patients are relatively treatment resistant to conventional evidence-based treatments for mood disorders and this represents a clear confound in large scale phase II and III clinical trials. There are a number of preclinical studies that have demonstrated the the mu opioid antagonist naltrexone blocks the behavioral effects of ketamine and there are now clinical studies that have clearly shown that naltrexone pretreatment blocks the antidepressant and anti-suicide effects of IV ketamine. One unanswered question has been whether ketamine is acting as a mu opiate receptor agonist or is primarily releasing endogenous opioids that act on the mu opiate receptor. A combination of preclinical and clinical studies suggest the latter to be the case. This raises important questions about the development of opiate agonists in the treatment of treatment resistant major depression. Remarkable advances have occurred in the development of neuromodulation techniques for the treatment of mood disorders, largely transcranial magnetic stimulation, including the SAINT method originated at Stanford. One disadvantage of TMS is its inability to target deep subcortical structures. Low frequency focused ultrasound (FUS)has that capability and a pilot sham controlled study of FUS directed to the left amygdala during fMRI revealed a clear reduction in amygdala and it targets (hippocampal and insular) activity. In an uncontrolled study, 3 weeks of daily treatment resulted in significant reductions in mood and anxiety symptom severity scores with no serious side effects. There has been much recent attention on the potential of various psychedelic medications in the treatment of PTSD and mood disorders. In an open study of 30 male US servicemen with a history of traumatic brain injury (TBI) ibogaine administered with magnesium to mitigate cardiac side effects led to marked improvement of indices of TBI immediately, one month and 12 months later. In addition symptom severity of comorbid depression PTSD and anxiety were similarly improved. Structural brain imaging and resting state EEG measures showed significant post treatment changes. It appears that ibogaine may provide durable long terms effects in patients with TBI/PTSD. Taken together, these presentations provide a backdrop for the remarkable contributions that have been promulgated by Nolan Williams and will serve as a partial legacy to his enduring impact on the field.

Learning Objective 1: To understand the remarkable contributions made by Nolan Williams to the field of psychedelics and neuromodulation as evidenced by the trajectory of those two fields.

Learning Objective 2: To understand the recent developments of novel treatments for treatment refractory depression.

References

  1. Teicher MH, Gordon JB, Nemeroff CB. 2022. Recognizing the importance of childhood maltreatment as a critical factor in psychiatric diagnoses, treatment, research, prevention and education. Mol Psychiatry 27,1331-1338.
  2. Nemeroff CB. 2020. The State of Our Understanding of the Pathophysiology and Optimal Treatment of Depression: Glass Half Full or Half Empty? Amer J Psychiatry 177(8) 671-685.