Prozac (aka fluoxetine) is one of the most successful drugs of all time. Since its introduction as an antidepressant more than 20 years ago, Prozac has been prescribed to more than 80 million people around the world. Currently, approximately one in ten Americans are on an anti-depressant, with the vast majority taking SSRI’s like Prozac.
How does Prozac work? At first, the answer seemed simple: the drug is supposed to increase the brain’s supply of serotonin, a neurotransmitter, by blocking its reuptake. This inspired an elegant theory, known as the chemical hypothesis: Sadness is simply a lack of chemical happiness. The little blue pills cheer us up because they give the brain what it has been missing, which is a sufficient amount of serotonin. Here, for instance, is a Zoloft ad that summarizes this hypothesis.
Unfortunately, the serotonergic hypothesis is mostly wrong. After all, within hours of swallowing an antidepressant, the brain is flushed with excess serotonin. Yet nothing happens; the patient is no less depressed. Weeks pass drearily by. Finally, after a month or two of this agony, the torpor begins to lift.
But why the delay? If depression is simply a lack of serotonin, shouldn’t the effect of antidepressants be immediate? This is known as the Prozac lag, and it first led researchers to question the model of action behind SSRI’s.
A few years ago, I wrote about recent attempts to better understand what’s happening in the depressed brain, and why anti-depressants can sometimes reverse it. (Let’s not forget that, in cases of mild and moderate depression, the drugs barely outperform placebo.) It turns out that serotonin is only indirectly involved. Instead, the drug seems to promote plasticity, leading to younger neurons and an increase in neurogenesis:
Rather than seeing the disease as the result of a chemical imbalance, these researchers argue that the brain’s cells are shrinking and dying, as our response to stress spirals out of control. The effectiveness of Prozac, these scientists say, has little to do with the amount of serotonin in the brain. Rather, the drug works because it helps heal our neurons, allowing them to grow and thrive again.
In this sense, Prozac is simply a bottled version of other activities that have a similar effect, such as physical exercise. They aren’t happy pills, but healing pills.
These discoveries are causing scientists to fundamentally reimagine depression. While the mental illness is often defined in terms of its emotional symptoms – this led a generation of researchers to search for the chemicals, like serotonin, that might trigger such distorted moods – researchers are now focusing on more systematic changes in the depressed brain.
“The best way to think about depression is as a mild neurodegenerative disorder,” says Ronald Duman, a professor of psychiatry and pharmacology at Yale. “Your brain cells atrophy, just like in other diseases [such as Alzheimer’s and Parkinson’s]. The only difference with depression is that it’s reversible. The brain can recover.”
Consider, for instance, a 2008 paper by Italian researchers, published in the journal Science. The scientists were interested in seeing if fluoxetine, the active ingredient of Prozac, could increase the plasticity of brain cells in the adult rat. They studied animals with severe cases of “lazy eye,” a condition characterized by poor vision in one eye due to underdevelopment of the visual cortex. The scientists showed that fluoxetine gave brain cells the ability to take on new roles and form new connections, which erased the symptoms of the visual disorder.
A brand new paper by Japanese researchers extends this hypothesis, by looking at the response of mouse neurons to fluoxetine. Essentially, the antidepressant seemed to reverse the “maturation” of our hippocampal neurons:
Serotonergic antidepressant drugs have been commonly used to treat mood and anxiety disorders, and increasing evidence suggests potential use of these drugs beyond current antidepressant therapeutics. Facilitation of adult neurogenesis in the hippocampal dentate gyrus has been suggested to be a candidate mechanism of action of antidepressant drugs, but this mechanism may be only one of the broad effects of antidepressants. Here we show a distinct unique action of the serotonergic antidepressant fluoxetine in transforming the phenotype of mature dentate granule cells. Chronic treatments of adult mice with fluoxetine strongly reduced expression of the mature granule cell marker calbindin. The fluoxetine treatment induced active somatic membrane properties resembling immature granule cells and markedly reduced synaptic facilitation that characterizes the mature dentate-to-CA3 signal transmission. These changes cannot be explained simply by an increase in newly generated immature neurons, but best characterized as “dematuration” of mature granule cells. This granule cell dematuration developed along with increases in the efficacy of serotonin in 5-HT4 receptor-dependent neuromodulation and was attenuated in mice lacking the 5-HT4 receptor. Our results suggest that serotonergic antidepressants can reverse the established state of neuronal maturation in the adult hippocampus, and up-regulation of 5-HT4 receptor-mediated signaling may play a critical role in this distinct action of antidepressants.
In other words, the drugs do up-regulate serotonin, but that up-regulation is less important than the newfound youth and suppleness of our neurons, which (and this is the mostly speculative part) might help compensate for the damage caused by chronic stress.