Major depressive disorder is one of the most common mental disorders in the United States, affecting more than 8% of adults. If you’re lucky, regular antidepressants take about a month to show signs of improvement – assuming you’ve found the right one. For some people, antidepressants don’t work at all. Therefore, scientists are constantly looking for new strategies to treat depression, ideally a fast-acting drug with fewer side effects. Now, according to a recent study in mice, scientists have identified an antidepressant compound that works differently than any other on the market and takes effect in as little as two hours.
Current treatments for depression
In the 1950s, scientists accidentally discovered antidepressants while developing iproniazid, a treatment for tuberculosis. During clinical trials, patients overwhelmingly reported pleasurable side effects, including euphoria, psychostimulation, and improved sleep. Later studies found that iproniazid increased a group of neurotransmitters: serotonin, dopamine, epinephrine, and norepinephrine. Over the next few decades, experts believed that low levels of these neurotransmitters must cause depression. In the 1990sit became clear that this wasn’t quite right, but that hasn’t stopped pharmaceutical companies from promoting drugs that increase neurotransmitter levels.
The most commonly prescribed type of antidepressant is selective serotonin reuptake inhibitors (SSRIs), which include Prozac, Zoloft and Paxil. These drugs prevent neurons from removing serotonin by blocking a transporter protein, allowing more of the neurotransmitter to interact with neurons for longer. This effect occurs almost immediately; however, the neuropsychological effects of SSRIs take about a month to develop. This is because more serotonin is not always better.
The dorsal raphe nucleus (DRN) is the main source of serotonin in the brain. Like neurons in many brain regions, DRN neurons communicate via serotonin. However, the consequence of this communication is opposite to that of other regions of the brain. Serotonin repressed the triggering of DRN neurons, while it active neuronal discharge in other parts of the brain. Additionally, because the DRN is an essential producer of serotonin, serotonin signaling is reduced throughout the brain when the DRN stops firing. In other words, too much serotonin in the DRN can make symptoms of depression worse. So why are SSRIs the most commonly prescribed treatment for depression? If DRN neurons are bombarded with serotonin for a long time (about a month), they become immune to the suppressive effects of the neurotransmitter and return to normal. Essentially, higher levels of serotonin in the brain make a person feel better and no longer interfere with DRN activity.
A more targeted approach
A team of scientists from Nanjing Medical University wanted to try a different approach. Instead of largely inhibiting all serotonin transporters (what SSRIs do to increase serotonin levels), and if they could specifically activate DRN serotonin transporters (which would allow DRN neurons to mop up serotonin, reduce its level and allow DRN neurons to function normally)? If they could, the antidepressant effects would be evident within hours. Unfortunately, serotonin transporters in the DRN are identical to serotonin transporters in other regions of the brain. Therefore, any molecule that directly activates one would activate the others.
Fortunately, a 2008 study provided a clue. The study found that the serotonin transporter binds to nitric oxide synthase (nNOS), a protein found primarily in DRN neurons, but not in other brain regions associated with depression. When the transporter and the nNOS combine, the transporter ceases to function. Blocking this interaction (and allowing the transporter to function) would be a great way to decrease serotonin in the DRN, but first the researchers needed to determine if DRN neurons expressed nNOS during the depressive episode. To do this, they needed clinically depressed mice.
Decreasing serotonin in DNS increases it in other regions
The chronic unpredictable mild stress (CMS) protocol is a common way to induce depression in rodents. The scientists exposed the animals to random mild stressors, including restraint in tubes, forced swimming in cold water, water deprivation and pairing with another stressed animal. After four weeks, the mice, unsurprisingly, exhibited behavioral and neurological changes associated with depression. More importantly, nNOS was significantly increased in the DRN but not in other brain regions. So the big question became, “Does nNOS blockade alleviate depression?”
In order to answer this, the researchers injected a chemical directly into the mice’s DRN to separate the serotonin transporter and nNOS. Within two hours, they saw the activity of the serotonin transporter increase (meaning the level of serotonin in the DRN decreased). More importantly, the increase in serotonin in other brain regions led to improved behavior, suggesting that blocking the transporter-nNOS complex has a fast-acting antidepressant effect.
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Unsurprisingly, most people don’t want an injection into their brain. Thus, the researchers have developed a molecule that can be injected into a vein. Again they gave it to a group of depressed mice and again the depressive behaviors were reversed within two hours of dosing. The authors urge human trials to determine whether blocking the transporter-nNOS complex also works to alleviate depression in humans.