Antidepressants are one of the largest pharmaceutical markets. According to data from pharmaceutical market research firm IMS Health, the newest class of antidepressants, selective serotonin reuptake inhibitors (SSRIs), and their cousins, selective norepinephrine reuptake inhibitors, are the third-largest therapeutic class, with nearly 200,000 prescriptions in 2005 bearing a collective price tag of more than 12 billion dollars.

SSRI's major drawback is that they usually take weeks to become effective. This makes for a difficult - and in suicidal patients, dangerous - few weeks from prescription to therapeutic progress.

But research in the August issue of Archives of General Psychiatry shows that a single intravenous infusions of ketamine - a drug that, in higher doses than those used in the study, is approved as a human and animal sedative - can relieve depressive symptoms within two hours, and have effects lasting for up to a week.

The scientists, who are at the National Institute of Mental Health in Bethesda, Md., gave patients with treatment-resistant depression, who had been unsuccessfully treated with other antidepressants at least twice, either ketamine or a placebo infusion. Seventy percent of the patients who had received the ketamine responded to the drug, and 30 percent met criteria for remission from depression after one day, while none of the patients who received a placebo injection did.

The findings are somewhat surprising, since one common theory is that the time lag in antidepressant activity is because the growth of new neurons is necessary for their effects. Carlos Zarate, chief of the mood and anxiety disorders research unit at NIMH, told BioWorld Today that the neurogenesis hypothesis is "one of the theories out there," but other explanations for the delayed effects also exist.

Ketamine's rapid-onset effects are definitely too fast to be due to neurogenesis; Zarate said that the long-effect "most likely was maintained by plasticity changes" over the course of the week, since ketamine's target, the NMDA receptor, is a well-known player in the brain plasticity that accompanies learning and memory.

As for the rapid onset, Zarate said that plasticity also was a possible factor there, but "more likely, the early changes are due to the interplay between NMDA and AMPA receptors." The AMPA receptor is another glutamate receptor; ketamine not only blocks the NMDA receptor, but also leads to increased glutamate release, both factors that would increase the relative contribution of AMPA and decrease that of NMDA receptors to firing in response to glutamate.

Zarate and his colleagues concluded that "this line of research holds considerable promise for developing new treatments for depression with the potential to alleviate much of the morbidity and mortality associated with the delayed onset of action of traditional antidepressants." At least in one aspect, ketamine would present no progress over many other types of prescription medicine: With ecstasy-like effects, it clearly has abuse potential, as a generation of ravers who know the drug under the name Special K can testify. (If they can still testify to anything after taking it - among its effects are memory disruption.)

In the September issue of Nature Neuroscience, researchers from Centre National de la Recherche Scientifique campuses in Paris, Valbonne and Rouen, France, and McGill University in Montreal take aim at another type of ion channel: the potassium channel TREK-1, which is regulated by various neurotransmitters including serotonin and contributes to neuron's resting membrane potential, which regulates the ease of firing in response to stimuli.

The researchers created a TREK-1 knockout mouse, which lacked those potassium channels. While the mice showed few obvious abnormalities, they were quite resistant when compared to wild-type mice to four different behavioral methods used to induce depression-like symptoms in animals.

The scientists then injected knockout mice with various antidepressants, including both SSRIs and norepinephrine reuptake inhibitors, either acutely or, to better model the clinical situation, for several weeks. Knockout mice were insensitive to the effects of antidepressants, suggesting that the antidepressants usually act on the TREK channel as one of their targets. TREK1 knockouts showed better serotonin transmission than either wild-types or mice lacking a related potassium channel.

The authors concluded that "a search for selective blockers of the TREK-1 channel might potentially lead to a new type of antidepressant, which remains needed, as even with the latest generations of antidepressants, the clinical response of depressed patients remains limited, with one-third of the patients simply not responding to their treatment while only one-third obtain a full remission with an adequate treatment."