Neuron
March 1, 2019
J. Krystal, C. Abdallah, G. Sanacora et al.
443 citations
Ketamine represents a new class of rapid-acting antidepressants effective for treatment-resistant mood disorders. Its development grew from a revised understanding of depression's biology. Research into how ketamine works is providing fresh insights into antidepressant mechanisms and challenging established views on the neurobiology of depression. The drug's fast, strong, and lasting effects on depressive symptoms appear ready to change how depression is treated.
Neuropsychopharmacology
February 24, 2020
C. Abdallah, L. Averill, R. Gueorguieva et al.
181 citations
Ketamine produces rapid antidepressant effects within 24 hours, thought to involve mTORC1 activation. In a double-blind crossover trial, 20 depressed patients received either rapamycin (an mTORC1 inhibitor) or placebo before ketamine. Rapamycin did not block ketamine's 24-hour antidepressant effects. Over two weeks, rapamycin prolonged ketamine's benefits: response rates were 41% with rapamycin versus 13% with placebo, and remission rates were 29% versus 7%. These findings question whether systemic or local mTORC1 blockade matters and suggest rapamycin may extend ketamine's effects, potentially informing mechanisms of depression relapse.
Expert Opinion on Investigational Drugs
February 1, 2022
L. Averill, C. Abdallah
Only two FDA-approved medications exist for PTSD, both SSRIs, which have limited efficacy: 40% of patients do not respond, only 20-30% achieve remission, and the advantage over placebo is 10-20%. Psychotherapy also has high dropout rates, with 55.8% for Prolonged Exposure and 46.6% for Cognitive Processing Therapy. There is an urgent need for novel treatments. Psychoplastogens such as ketamine, MDMA, psilocybin, and 5-MeO-DMT, which rapidly promote neural plasticity, show potential for fast and robust improvements in trauma-related symptoms. Ketamine's rapid-acting antidepressant effects have prompted a paradigm shift toward targeting synaptic dysconnectivity underlying chronic stress pathology, rather than focusing on single neurotransmitter systems.