When they work, antidepressants can be a godsend. But they only work in about half of the patients who take them. And if the first attempt doesn't work, there are second- and third-line options to choose from.

But when it gets right down to it, all those options are pretty similar.

"The truth is that there hasn't been a medication for depression with a novel mechanism of action in decades," Robert Malenka told BioWorld Today. Even the last advance, the selective serotonin reuptake inhibitors, or SSRIs, was an improvement over the previous generation of antidepressants rather than a fundamental change in approach.

Malenka is a professor of psychiatry and behavioral sciences at Stanford University and the senior author of a paper in the July 12, 2012, issue of Nature that described the circuitry by which another receptor, the melanocortin receptor, affects depression.

For the potential development of antidepressants, however, the significance of the work is less in its identification of that circuitry. Malenka contended that from an industry perspective, the importance of the work is more in the light it sheds on the limits of the search for new antidepressants as it is currently conducted.

In their experiments, Malenka and his team looked at the nucleus accumbens, which is "a major part of the brain reward system circuitry," Malenka said. "And this circuitry, by definition, is no longer functioning normally in depression," because that is what depression is: the inability to feel pleasure.

To test the effects of the melanocortin receptor on that circuitry and how it is changed in depression, the team subjected mice to chronic stress and looked at how it affected their ability to enjoy food – one of the most rewarding stimuli out there.

They found that animals who were subjected to chronic stress ate less, and the effect could be blocked by inhibiting the melanocortin receptor. In electrophysiological studies, they showed that under normal conditions, stress activated the melanocortin receptor and weakened synapses that use dopamine, which is one of the main neurotransmitters that signals in response to rewarding stimuli. Normally rewarding stimuli were then unable to activate those neurons as strongly as they once had.

To make sure their effects were truly due to anhedonia, rather than any subtle metabolic effects, Malenka and his team also looked at the animals' ability to get pleasure from what might be the opposite of food – cocaine – and found the same effect.

Malenka said that although the work furthers the understanding of depression's neuroanatomy, and how different receptor types may interact to cause anhedonia, the role of the melanocortin receptor itself in depression was already well established. "A lot of people have been thinking of that receptor as a target" in obesity as well as depression. But like most brain receptors, the melanocortin receptor has many different roles in different brain regions. "It may well be too ubiquitous" to make a good target, although there may be other paths to preventing the depression-associated changes that do not target the melanocortin receptor. "Maybe we can start looking at the cell type and see what other targets are in that cell."

From a practical perspective, the most important aspect of the work, in Malenka's opinion, is that it neatly pinpoints a weakness of current antidepressant research. Though his team saw an effect on anhedonia when they blocked melanocortin receptors during chronic stress, two other tests – the forced swim test and the tail suspension test – did not show any effect of blocking those receptors.

Malenka said that forced swim and tail suspension tests, both of which are supposed to measure the animal equivalent of despair, are widely used in antidepressant research, came into favor because currently used antidepressants reduce the supposed depression-like behavior of mice in those tests.

But the assumption that other effective drugs also will show an effect in the same tests, he argued, is based on faulty logic. He described that logic as "'Because antidepressants work in this test, any other drug that works may also be an antidepressant.' Which may or may not be the case, but it's highly circular reasoning." And reasoning, one might add, that has not produced a novel class of antidepressants in a very long time.

"Does our work mean that these tests are useless? Absolutely not," Malenka stressed. But it does mean that they are not the be-all and end-all of antidepressant research. "If you are only using these common tests, you may end up missing something very important."