The 11th Peter Miller Musser, Lecture in depression grand rounds: Towards Rational Treatment Discovery in Depression: Ketamine and Photobiomodulation

Major depressive disorder (MDD) is a severe illness affecting 21 million Americans (~10%) per year (Kessler et al, 2012) and is the second leading cause of global disability (GBD Disease and Injury Incidence and Prevalence, 2015). Although effective treatments exist, a large proportion (~30%) of MDD patients do not improve, even after several antidepressant treatments (Voineskos et al, 2020). Until very recently, treatment discovery in MDD has been largely serendipitous. There is a clear need for novel treatments focused on specific biological abnormalities present in MDD.

We will review two novel treatments for MDD (ketamine and photobiomodulation) that were developed based on insights regarding associated biological abnormalities. First, data on glutamate system abnormalities in MDD justified the development of ketamine and its enantiomer esketamine (both NMDA glutamate receptors antagonists) as rapid-acting antidepressant treatments. Also, significant evidence of abnormal brain mitochondrial energy metabolism in MDD led to the development of transcranial photobiomodulation (t-PBM), which stimulates the mitochondrial respiratory chain; early data suggest that t-PBM may be an effective treatment in MDD.