Science NOW points to an article from Monteggia and colleagues who find a new pathway that partially explains why the anti-depressant effects of low doses of ketamine (used at higher levels as an anesthetic and taken recreationally as a hallucinogen) start soon after it is taken, rather than requiring weeks, as with Zoloft or Paxil. Here is a clip from the Science summary:
...ketamine binds to, and blocks, a receptor in the brain called NMDAR, which triggers its anesthetic effects, so Monteggia's group used other compounds to block NMDARs in mice...the animals depression once again lessened, so the researchers knew that ketamine's antidepressant effects also depended on NMDAR. Next, the team studied how levels of certain proteins in the brain changed when mice were given ketamine. Blocking NMDARs with other compounds turns off production of some proteins, but ketamine causes the neurons to make more of a protein called BDNF (brain-derived neurotrophic factor)...The findings suggest a new set of molecules that ketamine and NMDAR affects, and that means a new set of molecules involved in depression.
There are two ways of activating NMDARs. Some turn on when the specific neurons fire to accomplish a task—be it learning, memorizing, or thinking. But other NMDARs are activated simply as background noise in the brain. Ketamine, the researchers showed, doesn't block the brain from activating NMDARs when it's using them to send a specific message. But it does block them from creating that background noise. Although scientists have long known about the brain's spontaneous level of background nerve firing, Monteggia's study is the first to suggest a link between such background noise and depression.