“Ketamine improved bipolar depression within minutes, study suggests,” read the headline in the May 30 Science Daily. The real story is far more complicated. Read on:

A team of researchers at the NIMH recruited 15 bipolar patients with depression (who were already on a mood stabilizer) and administered them either a small single intravenous dose of ketamine or a placebo. Two weeks later, the subjects were “crossed over,” ie those on the test drug now received the placebo and vice-versa.

The study found that 79 percent of those taking ketamine achieved “significant improvement” in symptoms within 40 minutes (including reduced suicidal thinking), and maintained this improvement over three days vs zero on the placebo. 

The study replicates a similar finding by the same researchers (using 15 patients), and supports two open-label (ie no placebo) studies on small patient groups. These studies build on similar studies done on patients with unipolar depression.

Before you shout “hallelujah,” we need to keep in mind that larger clinical trials (the type needed to win FDA approval) almost never replicate the optimistic findings of smaller studies. Moreover, test drugs are likely to fail for intolerable side effects. Indeed in a review article just published online, the study’s lead author Carlos Zarate notes that although future investigation is warranted, “due to its associated sedative and psychotomimetic [ie mimicking psychosis] effects, it is unlikely that ketamine will be adopted for widespread clinical use.”

So what is all the fuss about? One word: glutamate. Dr Zarate’s article spells it out:

Glutamate is an “excitatory” neurotransmitter that is widely distributed in the brain. It also regulates neuroplasticity, learning, and memory. More recently, imaging studies implicate elevated levels of glutamate in mood disorders and anxiety. What seems to be happening, according to Dr Zarate, is that excess glutamate transmission (from exposure to chronic stress) results in the loss of dendritic spines.

Dendrites are neural extensions at the receiving end of the synapse. Thus, when bombarded by excess glutamate (which results in over-excitation and the possibility of brain cell death), the brain goes into a sort of protective crouch. Dendrites retract, which reduces the number of receptors on the neuron. The neuron is now exposed to more normal levels of glutamate. 

The catch is that the neuron - indeed whole neural networks - are taken off-line. This is fine in emergencies, when the brain can reset to normal once the crisis is resolved, but under chronic stress the brain may experience great difficulty in resetting to normal. The dendritic spines - the basis of branching in neural networks - fail to grow back.

Not surprisingly, says Zarate, “the glutamatergic system likely plays a significant role as a primary mediator of psychiatric pathology.” Hence the quest to find drugs that work on glutamate. Ketamine is but one of many such agents under investigation.