mTOR is a cellular kinase that acts as a master switch regulating anabolism and catabolism. It controls processes like protein synthesis and response to stress and nutrients. Recent research has shown mTOR plays a role in psychiatric conditions like depression. Ketamine, which has rapid antidepressant effects, works by activating mTOR, promoting catabolism and increasing dendritic spines within minutes. Inhibition of mTOR by rapamycin blocks these ketamine-induced changes. This suggests targeting the mTOR pathway may be a promising avenue for developing new fast-acting antidepressant treatments.

1. What is mTOR and why is it a “hot topic” in psychiatry today?
The micro-universe that we are all made of, the cell, can be in two metabolic states, anabolism or
catabolism. In times of famine(caloric restriction), catabolism prevails-also called autophagy. In
times of plenty, anabolism prevails, manifested by protein synthesis, glucose uptake,
angiogenesis and cell proliferation.
The scientists were able to locate in the cells, including neurons, the master molecular switch
between anabolism and catabolism.
Mammalian target of rapamycin (mTOR), a kinase, is the cells’ master switch for
anabolism/catabolism, protein synthesis, caloric intake and response to stress. For this
reason it is of interest to oncologists, psychiatrists and aging researchers alike.
mTOR IS THE CELLULAR ANABOLISM/CATABOLISM SWITCH
Rapamycin is able to turn the metabolic switch OFF (catabolism), while ketamine turns the
switch ON (anabolism).
Longevity specialists acknowledge only two life-extending interventions in mammals: calorie
restriction and genetic manipulation. Inhibition of mTOR by rapamycin mimics calorie
restriction by shutting down the same molecular pathway as restricted caloric intake does.
Experiments showed increased longevity (10% -28%) in mice fed a special diet containing
rapamycin.

2. Currently rapamycin is in clinical trials for Alzheimer’s disease and other neurodegenerative
diseases. By increasing brain autophagy (catabolism) , rapamycin seems to clear out amyloid
plaques.
Rapamycin (Sirolimus) is an immunosuppressant drug used for preventing rejection in organ
transplantation. In addition to its immunosuppressant action rapamycin has antiproliferative
properties and is used in cancer therapy.
IMPLICATIONS FOR PSYCHIATRY
Several clinical studies showed that a single sub-anesthetic dose of ketamine( activator of
mTOR) caused a rapid antidepressant effect within hours of administration in treatment-
refractory patients with major depression.
Ketamine is known to produce psychosis as well as cognitive impairment (by blocking NMDA
receptors), yet it can improve depression in at least a subset of patients.
Ketamine is an antagonist at NMDA receptors. It works at the same site (inside
the channel) where PCP also binds.

3. Hints about NMDA receptor antagonists causing improvement in depression existed since 1959
(reported by Crane).
In 2000 Berman et al. reported antidepressant effects from NMDA receptor antagonists.
More recently Carlos Zarate, at NIMH, reported in 2010 that “ robust and rapid antidepressant
effects resulted from a single intravenous dose of ketamine”.
On August 30, 2010 Ron Duman from Yale identified cellular signaling pathway in rat prefrontal
cortex activated by ketamine with a rapid and direct influence on behavior. This group reported
that a single dose of ketamine activates the mammalian target of the rapamycin (mTOR)
signaling pathway, resulting in increased synaptic protein expression within 2 hours and
increased dendritic spine density and synaptic activity within 24 hours.
On the other hand inhibition of mTOR through infusion of rapamycin completely blocked
ketamine’s influence on synaptic protein synthesis, synaptogenesis, and dendritic spine
formation.
Depression seems to occur when dendritic spine formation is inhibited, while increased
dendritic spine formation has been associated with euthymic states. Ketamine leads to
increased dendritic spine density within minutes from infusion, by turning ON the mTOR switch
to catabolism.
Dendritic spines grow within minutes from ketamine infusion causing improvement in depressive
symptoms.

4. Available antidepressants cause growth of dendritic spines.
Aberant TOR activity was found not only in depression, but also in diabetes, obesity, heart disease,
muscle degeneration and cancer.
Reason enough for excitement among many specialties.
A.Sfera