09/09/2014 04:13 pm ET Updated Nov 09, 2014

Rethinking Serotonin's Role in Clinical Depression

There's no denying that depression is a form of mental-health epidemic in America. An estimated 17.5 million Americans suffer from some form of depression, with approximately 9.2 million of those cases classified as major or clinical depression. But what is depression exactly? What causes it? And, more importantly, how do we fix it?

Since the 1950s, clinical depression has been thought to be caused by a chemical imbalance in the brain, specifically an imbalance of the neurotransmitter serotonin. When selective serotonin-reuptake inhibitors, or SSRIs, like Prozac, Zoloft, and Paxil, hit the market, they were wildly popular. They were hailed as a miracle drug and chemical treatment for depression, and as many as one in 10 Americans over the age of 12 was prescribed antidepressants. SSRIs quickly became a multibillion-dollar industry, making the search for new and better treatments an unprofitable expense. However, the exact effects and usefulness of SSRIs have been heavily disputed, with two major issues persisting.

The first issue with SSRIs is that most cases of milder depression, and many cases of severe depression, simply don't respond to them. Treating what is believed to be the cause of depression doesn't actually result in a cure in most cases. The second issue is that how SSRIs are supposed to work, and the way they're observed to work, just don't add up. Serotonin is a neurotransmitter, which means certain neurons use it to signal other neurons. According to the traditional model of depression, depressed brains don't have enough serotonin. Either their neurons aren't releasing enough during signaling or not enough is being received by the other neurons. To fix this, SSRIs prevent some of the released serotonin from being removed after signaling. This results in more serotonin hanging out between neurons and makes serotonin signaling easier in the future. The implication is that taking SSRIs should have an alleviating effect within minutes, but research shows it takes as long as four to six weeks for their effects to actually be felt. So is serotonin imbalance actually responsible for depression?

A paper published in ACS Chemical Neuroscience last month suggests that no, depression is not cause by serotonin dysfunction. To show this, Mariana Angoa-Pérez and her fellow researchers at the Wayne State University School of Medicine genetically altered mice to lack the gene for the brain-specific form of tryptophan hydroxylase, TPH2. TPH2 is an enzyme necessary for the biosynthesis of serotonin, meaning a brain without TPH2 is a brain without serotonin. According to past theories of depression, these mice should be extremely depressed. However, this was not the case.

In the two main tests used to measure depression in mice, the mice lacking serotonin performed identically to normal mice in the first, and actually showed less of a depressive response in the second. Additionally, the serotonin-lacking mice showed no differences compared with normal mice in their responses to stress. In fact, after four weeks, the mice lacking serotonin spent less time grooming (a stress response) than they did initially, while the normal mice maintained constant grooming times. There was also no difference in weight gain. Finally, when tested on stress-induced anhedonia, or the inability to experience pleasurable things, normal mice experienced a greater reduction in the pleasure they got from sugar water than their serotonin-lacking counterparts. Together, this means that mice without any serotonin are no more depressed than mice with unaltered levels of serotonin.

So if serotonin isn't the culprit, what is? And if SSRIs can't solve the problem, what can? Unfortunately, these questions aren't currently answerable. It's possible that the collection of symptoms we call depression can result from a range of different imbalances, varying from person to person, with no single solution. If that's the case, a wider range of drugs and drug types is needed for effective treatment, each of which would be extremely expensive to research, create, and get to market. With the current, sustained profitability of SSRIs, diluting the market with different or better options is unlikely to be profitable. Hopefully, research institutions will continue to study depression and will be able to produce both better tests and better treatments.

But until then, if you are suffering from depression, seek help. Reach out to someone. In many cases, simply talking with a professional can help alleviate symptoms, and make things better. If you are in crisis, please call the National Suicide Prevention Hotline at 1-800-273-8255.