IT STARTED out as LY110141. Its inventor, Eli Lilly, was not sure what to do with it. Eventually the company found that it seemed to make depressed people happier. So, with much publicity and clever branding, Prozac was born. Prozac would transform the treatment of depression and become the most widely prescribed antidepressant in history. Some users described it as “bottled sunshine”. It attained peak annual sales (in 1998) of $3 billion and at the last count had been used by 54m people in 90 countries. And, along the way, it embedded into the public consciousness a particular idea about how depression works—that it is caused by a chemical imbalance in the brain, which the drug corrects. Unfortunately, this idea seems to be only part of the story.

In science it is good to have a hypothesis to frame one’s thinking. The term “chemical imbalance” is just such a thing. It is a layman’s simplification of the monoamine hypothesis, which has been the prevalent explanation for depression for almost 50 years. Monoamines are a class of chemical that often act as messenger molecules (known technically as neurotransmitters) between nerve cells in the brain. Many antidepressive drugs boost the level of one or other of these chemicals. In the case of Prozac, the monoamine in question is serotonin.

The monoamine hypothesis, though, is under attack. One long-standing objection is that, although drugs such as Prozac raise levels of their target monoamine quite quickly, the symptoms of depression may take weeks, or even months to abate—if, indeed, they do abate, for many patients do not respond to such drugs at all. Now, to add to that, a second objection has emerged. This is the discovery that ketamine, a drug long used as an anaesthetic and which is also popular recreationally, works, too, as a fast-acting antidepressant. Ketamine’s mode of action is not primarily on monoamines, so the race is on to use what knowledge there is of the way it does work to design a new class of antidepressant. This is a change of direction so radical that some think it heralds a revolution in psychiatry.

Special K

Ketamine works for 75% of patients who have been resistant to other forms of treatment, such as Prozac (which works in 58% of patients). Moreover, it works in hours, sometimes even minutes, and its effects last for several weeks. A single dose can reduce thoughts of suicide. As a result, although it has not formally been approved for use in depression, it is widely prescribed “off label”, and clinics have sprouted up all over America, in particular, to offer infusions of the drug (which must be taken intravenously, if it is to work). Anecdotal reports suggest that it has already saved many lives.

Ketamine’s rise has been gradual. The discovery of its efficacy against depression happened a decade ago. Conducting clinical trials of new uses for drugs whose patents have expired is not a high priority for pharmaceutical companies, which generally prefer to test new molecules whose patents they own—and without such trials, formal approval for a new use cannot be forthcoming. Now, though, novel ketamine-related treatments are emerging.

One such is esketamine. Normal ketamine is a mixture of two molecules that are mirror images of each other. Esketamine is just one of these “optical isomers”. Though it, too, is off-patent, Johnson & Johnson, a large American drug company that is developing it for use, hopes it will have the same positive effects as the unsorted isomeric mixture, but without side-effects such as hallucinations, dizziness and “dissociation”—a feeling of being awake but detached from one’s surroundings.

By changing its formulation so that it can be administered in the form of a nasal spray, the firm both makes esketamine easier to use than isomerically mixed ketamine and creates something patentable. Preliminary evidence suggests esketamine does indeed work, and the firm is seeking approval for it to be used to treat two conditions: major depressive disorder with imminent risk of suicide, and treatment-resistant depression.

Other companies, though, are taking a different approach, by studying ketamine’s mode of action and attempting to imitate the way it works. Many people think ketamine affects the action of a common neurotransmitter called glutamate, by blocking the activity of receptors for this molecule. One hypothesis is that it interacts with a glutamate receptor called NMDA that had never previously been thought to be involved in depression. Several firms are therefore seeking to mimic the effect of ketamine by aiming at the NMDA receptor.

One such is Allergan, an Irish company that last year paid $560m to buy Naurex, an American biotech firm whose NMDA-blocking drug rapastinel is intended as a once-a-week intravenous treatment. Evidence from an early trial shows rapastinel is well tolerated, does not induce hallucinations and seems to work quickly. Allergan plans to start more extensive trials later this year. Nor is Allergan alone in its interest in the NMDA route. Other firms working on molecules that interact with this receptor, or with a special flavour of it called NR2B, include AstraZeneca, Avanir Pharmaceuticals and Cerecor.

Reception committee

It would be a mistake, though, to think that science has now reached a neat conclusion about how depression acts in the brain. One surprise came earlier this year in the form of work published by Carlos Zarate of America’s National Institutes of Health, who is a pioneer in the field. This study suggests that, in mice at least, ketamine is not working directly on the NMDA receptor, but rather on another glutamate receptor. This finding will not matter to Johnson & Johnson, because esketamine mimics the effects of normal ketamine, which is known to work. But it may mean those taking the NMDA route with other molecules are barking up the wrong tree.

As to the specifics of Dr Zarate’s study, Husseini Manji, the head of neuroscience at Johnson & Johnson, says it is possible that this work identified an additional way to generate antidepressive effects. Even if ketamine is found to work via another receptor, this does not preclude it working via NMDA. Armin Szegedi, who runs clinical development of the drug rapastinel at Allergan, makes the same argument. He explains that all the glutamate receptors seem to interact with each other as well, and act as a complicated system.

Time will tell who is correct, but such minutiae will matter less than whether one of these new approaches works. Lots of drugs, for many indications, work well, even though no one knows precisely how. The important point, though, is that ketamine has opened up a new line of attack on a horrible illness—and that this attack is being pressed relentlessly home.