Friday, October 14, 2016

Novel Drugs for Depression

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.

by The Economist |  Read more:
Image: Dave Simonds