1. Will We Have Rapid-Onset
Antidepressants? How Might They Work?
Selective antagonists of the N-methyl-D-aspartate receptor may quickly ease depressive
symptoms — but much work remains before they become clinically useful.
Virtually all classes of current antidepressant medications must be taken for a frustratingly
long time, usually several weeks, before the drugs even begin to offer symptom relief. This
delay has been attributed to an "initiation and adaptation" paradigm, in which
antidepressants are thought to simply initiate a complex cascade of events that ultimately
lead to adaptations in neurotrophic signaling and in the glutamatergic system.
Recently, encouraging glimmers have appeared regarding potential faster-onset
antidepressants that act more directly on these downstream processes, and researchers have
started to elucidate the drugs' potential mechanisms of action. The N-methyl-D-aspartate
(NMDA) receptor (particularly its NR2 subunit, the major glutamate receptor in the brain)
may play a role in major depressive disorder (MDD). NMDA receptor antagonists have
been shown to reverse depression-like behaviors in animals, and researchers have now
conducted several clinical trials.
Antidepressant effects were robust and rapid in two government-funded, randomized,
placebo-controlled, double-blind, crossover studies of ketamine (a nonselective NMDA
receptor antagonist and dissociative anesthetic), given as a single intravenous infusion in a
subanesthetic dose. Each study enrolled 18 patients. In one, a study of treatment-resistant
MDD (Arch Gen Psychiatry 2006; 63:856), effect sizes were initially very large and
remained large after 1 week. On day 1, 71% of patients on ketamine responded and 29%
met remission criteria; 35% of ketamine recipients maintained response for at least a week.
At 40 minutes only, positive and manic symptoms were significantly worse in patients on
ketamine than in patients on placebo. The other study involved patients with treatment-
resistant bipolar depression who took ketamine adjunctively with valproate or lithium
(Arch Gen Psychiatry 67:793). Significant improvements occurred within 40 minutes and
lasted 3 days. Dissociative symptoms were significantly higher with ketamine than placebo
at 40 minutes only; manic symptoms occurred in one patient on ketamine at 40 minutes and
in one patient on placebo at day 10.
The psychotomimetic effects of open-channel NMDA receptor blockers such as ketamine
might be avoided in antagonists of the NR2B subunit NMDA receptor. The NR2B subunit
is localized primarily in the forebrain, including the hippocampus, which is involved in
MDD. These more-selective agents have high affinity for the endoplasmic reticulum
protein sigma-1 receptors in the brain, which have also been implicated in the pathogenesis
of MDD (J Clin Psychopharmacol 2009; 29:411).
CP-101,606, an antagonistic agent selectively targeting the NR2B subunit, was the focus of
a manufacturer-funded proof-of-concept study (J Clin Psychopharmacol 2008; 28:631) of
30 depressed patients who did not respond to paroxetine (20 mg/day escalated to 40

2. mg/day). The patients continued paroxetine and were randomized to CP-101,606 or placebo
in a double-blind phase. The agent was associated with significant improvement in
depressive symptoms; some improvement persisted for a week in 78% of patients.
Dissociative reactions were noted in two placebo recipients and six CP-101,606 recipients
(2 with severe symptoms). A potential mechanism for this antidepressant type has been
identified. Using rat models of despair (forced swim tests and learned helplessness),
investigators identified cellular signaling pathways in the prefrontal cortex that are rapidly
activated by ketamine (JW Psychiatry Oct 8; and Science 329:913). Ketamine infusion in
rats rapidly induced expression of synaptic proteins and increased dendritic spine density
and synaptic activity, possibly through its activation of the "mammalian target of
rapamycin" (mTOR), a specific protein kinase involved in protein synthesis and synaptic
plasticity. Inhibition of the mTOR pathway in the medial prefrontal cortex prevented
ketamine's antidepressant effects.
Before scientists develop clinically useful medications based on these findings, several
practical problems must be solved. Researchers need to develop agents with lower adverse
effect profiles (possibly, selective NRB2 antagonists) and protocols with safe, tolerable,
and effective dosing capable of achieving sustained effects (see also Arch Gen Psychiatry
67:1110). Because mTOR signaling involves diverse biological processes including cancer,
manipulation of this system requires judicious experimentation.
— Joel Yager, MD
Published in Journal Watch Psychiatry January 3, 2011