Eva Redei, the David Lawrence Stein Professor of Psychiatry at Northwestern’s Feinberg School has published new research which explains why antidepressants don’t work for so many people.
There are two prevailing theories about the causes of depression. One is that depression can be caused by stressful life events and the second is that depression results from an imbalance in neurotransmitters. However, medications based on those theories are treating effects, not causes.
Most animal models that are used by scientists to test antidepressants are based on the hypothesis that stress causes depression. “They stress the animals and look at their behavior,” she said. “Then they manipulate the animals’ behavior with drugs and say, ‘OK, these are going to be good anti-depressants.’ But they are not treating depression; they are treating stress.”
That is one key reason why current antidepressants aren’t doing a great job, Redei noted. She is now looking at the genes that differ in the depressed rat to narrow down targets for drug development.
She said another reason current antidepressants are often ineffective is that they aim to boost neurotransmitters based on the popular molecular explanation of depression, which is that it’s the result of decreased levels of the neurotransmitters serotonin, norepinephrine and dopamine. But that’s wrong, Redei said.
Redei examined the genes involved in both stress and depression. Of the 254 genes related to stress and the 1275 genes related to depression there is an overlap of only 5 genes.
“This overlap is insignificant, a very small percentage,” Redei said. “This finding is clear evidence that at least in an animal model, chronic stress does not cause the same molecular changes as depression does.”
If current medications are only treating effects then research should be focused on finding and treating the causes.
In the second part of the study, Redei found strong indications that depression actually begins further up in the chain of events in the brain. The biochemical events that ultimately result in depression actually start in the development and functioning of neurons.
“The medications have been focusing on the effect, not the cause,” she said. “That’s why it takes so long for them to work and why they aren’t effective for so many people.”
Her animal model of depression did not show dramatic differences in the levels of genes controlling neurotransmitters functions. “If depression was related to neurotransmitter activity, we would have seen that,” she said.
Unfortunately, although we now know those theories are wrong, we still do not have a theory that is right.