TALK OF THE NATION: Almost as soon as it was introduced in 1987, the antidepressant Prozac, which selectively targets the chemical serotonin, became a blockbuster. “Prozac just blew everything else out of the water,” Frazer says. This had less to do with the efficacy of Prozac (it is not better at treating depression than tricyclics, the earlier generation of antidepressants) than with the fact that the drug had relatively few side effects. “It was very free of side effects,” says Pedro Delgado. “And so it began to be used very widely, and there was a lot of enthusiasm for it.” That understates the case. In a very short time, Prozac became wildly popular, and again, Prozac worked on just one chemical in the brain: serotonin. And really, it is because of the popularity of Prozac that the low-serotonin story took hold, even though, Frazer argues, the scientific research has not borne that out. “I don’t think there’s any convincing body of data that anybody has ever found that depression is associated to a significant extent with a loss of serotonin,” he says. Delgado also makes this argument. In the 1990s, he carried out a study that showed that if you take a normal person and deplete them of serotonin, they will not become depressed. He says he feels this demonstrates that low serotonin doesn’t cause depression. Coyle is less absolute in his dismissal of the evidence on serotonin. His take is that while low serotonin probably doesn’t cause depression, some abnormality in the serotonin system clearly plays a role. But most researchers have moved on, he says, and are looking at more fundamental issues like identifying the genes that might put people at risk for developing depression. “What’s being looked at are processes that are much more fundamental than just serotonin levels,” he says. “We need to move beyond serotonin, and I think the field is.” MORE
TALK OF THE NATION: Traditional antidepressants like Prozac work on a group of chemical messengers in the brain called the serotonin system. Researchers once thought that a lack of serotonin was the cause of depression, and that these drugs worked simply by boosting serotonin levels. Recent research suggests a more complicated explanation. Serotonin drugs work by stimulating the birth of new neurons, which eventually form new connections in the brain. But creating new neurons takes time — a few weeks, at least — which is thought to explain the delay in responding to antidepressant medications. Ketamine, in contrast, activates a different chemical system in the brain – the 
glutamate system. Researcher Ron Duman at Yale thinks ketamine rapidly increases the communication among existing neurons by creating new connections. This is a quicker process than waiting for new neurons to form and accomplishes the same goal of enhancing brain circuit activity. MORE
GAWKER: K is a form of Ketamine, which is usually manufactured for street use from horse or cat tranquilizers. It usually comes in a chunky powder that is a very pale yellow. You snort it. There is a really gross aftertaste. As Wikipedia will tell you, “Like other drugs of this class such as tiletamine and phencyclidine (PCP), it induces a state referred to as ‘dissociative anesthesia’ and is used as a recreational drug.” MORE
TALK OF THE NATION: A growing number of scientists think it won’t be long before psychiatric care is transformed. And they are particularly excited about an experimental drug that is being tried in the NeuroPsychiatric Center next to Ben Taub hospital. It’s here that drug researchers are studying a drug that’s unlike anything now used to treat depression. And they’re giving it to patients who haven’t done well on existing drugs. One of these patients is Heather Merrill, who speaks to me in a small conference room that is part of the large and very busy outpatient clinic. Merill is 41, with three kids and a nice house in the suburbs. “I’ve suffered from depression for most of my adult life,” she says. “It got to the point where I kind of felt like there wasn’t going to be anything that was going to be able to help me.” At times her depression gets so bad that she can’t take care of her family or even herself, she says. And that’s how she was feeling the day before, she says, when doctors placed an IV in her arm and began to administer a drug. Because it was part of an experiment, there were two possibilities. The drug could have been just a sedative. Or it might have been something called ketamine. Ketamine has been used for decades as an anesthetic. It also has become a wildly popular but illegal club drug known as “Special K.” Mental health researchers got interested in ketamine because of reports that it could make depression vanish almost instantly. In contrast, drugs like Prozac take weeks or even months. And the frustrating thing is that depression medications really haven’t changed much since Prozac arrived in the 1970s, says Sanjay Mathew from Baylor College of Medicine, who is in charge of the ketamine study at Ben Taub. MORE
GAWKER: I remember one night at a gay discotheque in Washington D.C. when I was still in college being slumped up against the DJ booth while he played a Madonna track. It seemed like the song was going on for hours, being played on repeat over and over and over again. In the span of three minutes, I thought I lived an entire evening. I thought I was dancing, and I thought Madonna was there. I thought I was dancing with Madonna. I was sure I was, flailing my limbs about as the Material Girl kept time with me, coaxing me to enjoy the party, matching me beat for beat as the lights did slow pirouettes around us. And she laughed at my jokes and told me she liked my outfit. Madge and I were friends! Everything was amazing and spectacular, but on the outside I was a drooling mess, unable to move, and embarrassing myself. When my friends finally carted me away, I started to hit them, shouting in as loud of a voice as I could muster. “Stop it. I don’t want to leave. I’m dancing with Madonna. Madonna! Madonna!” This is why K is so incredibly stupid. MORE
PSYCHIATRY ONLINE: Subjects who were maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on two test days two weeks apart. The ketamine dose was based on the researchers’ previous study of subjects with treatment-resistant major depression, as well as several other studies. The Montgomery-Asberg Depression Rating Scale (MADRS) was used to rate subjects at baseline and at 40, 80, 110, and 230 minutes and on days 1, 2, 3, 7, 10, and 14 post-infusion. Within 40 minutes after receiving a placebo, subjects’ depressive symptoms lessened a little. But within 40 minutes after receiving ketamine, their depressive symptoms lessened significantly more. This improvement remained significant through day 3. The drug-difference effect size was largest on day 2. Seventy-one percent of subjects responded to ketamine, and 6 percent responded to placebo at some point during the trial. Ketamine was generally well tolerated; the most common adverse effect was the appearance of dissociative symptoms, though only at the 40-minute point on the first day. Dissociation is a common side effect of ketamine. “These findings are particularly noteworthy because a substantial proportion of study participants had been prescribed complex polypharmacy regimens in the past, with substantial treatment failures,” the researchers said in their report. “The mean number of past antidepressant trials was seven, and more than 55 percent of participants had failed to respond to electroconvulsive therapy. The toll of this protracted and refractory illness on the subjects was evident in that two-thirds of participants were on psychiatric disability, and nearly all were unemployed.” Zarate said, however, that at this point their findings do not have clinical implications. “The optimal dose of ketamine for treatment-resistant depression has not yet been established,” he said. “It is possible that lower doses of ketamine than what we used in our study would avoid the side effects.” He added that the results, “while encouraging, warrant further research in larger controlled studies to determine ketamine’s efficacy and safety profile in this population.” MORE