Treatment resistant depression (TRD) is a major public health problem. Current therapeutic
options for this patient population remain limited. With all available treatments, only a
sub-set of those patients who achieve an antidepressant response are likely to achieve
treatment-induced remission. The need for antidepressant medication that can provide both
rapid and long lasting relief of TRD symptoms is widely recognized. There is new evidence
that drugs that block NMDA glutamate receptors (NMDA antagonists) are promising candidates
for meeting this need. Existing studies in TRD have used only a low-dose, brief infusion of
ketamine that would not be expected to re-sensitize the NMDA receptor; in agreement with this
theory, these prior studies have found only temporary improvements of depression. Our key
hypothesis is that a higher-dose, longer-term ketamine infusion, such as that used in chronic
pain studies, would provide a more robust and lasting improvement from depression.
Accordingly, we will be test whether a 100-hour ketamine infusion would be more effective
than the standard 40-minute ketamine infusion currently used in other TRD studies. We will
randomize subjects to one of 2 arms: (1) 100-hour (+/- 4 hours) ketamine infusion plus
clonidine for the entire infusion (2) 40-minute ketamine infusion (plus clonidine) following
a 100+/- hour saline infusion. All subjects will receive clonidine, an alpha-2 agonist, to
minimize side effects of ketamine (namely, brief/mild psychotic and cognitive symptoms).
A subset of patients with TRD will also receive a 100-hour (+/- 4-hours) ketamine infusion
with two head MRIs pre-infusion and one head MRI post-infusion and/or weekly maintenance IM
injections of either ketamine or active CNS placebo, lorazepam for up to 16 weeks. Little
research has been done on the mechanism of ketamine's putative antidepressant action. There
is now a consensus that, in the early stages of the novel treatment development for
depression, clinical studies should be paired with mechanistic studies (neuroimaging) to
understand the underlying mechanism and validate this as a treatment target. Ketamine is
thought to have an antidepressant effect by increasing synaptic connections and therefore
increasing connectivity in critical cognitive/emotional circuits.