For more than three decades, antidepressants like selective serotonin reuptake inhibitors (SSRIs) have been the primary pharmacological intervention for people with depression. These drugs are based on the monoamine hypothesis, which posits that a deficiency of monoamine neurotransmitters, including serotonin, dopamine, and norepinephrine, are — at least in part — the cause of depression.
But these drugs are not without downsides. They often take weeks to work, they don’t work for everyone, and the side effects can sometimes be too much.
Scientists in China believe they have made progress toward solving at least some of those antidepressant downsides. In a recent study published in the journal Science, researchers outline how they discovered a small-molecular compound that, when tested in depressed mice, alleviated symptoms of depression two hours after treatment “without undesirable side effects.”
If they work, novel, fast-acting antidepressants could radically shift the pharmacological options for the estimated five percent of adults with depression worldwide.
The background— In the 1960s, scientists hypothesized that increasing serotonin (5-hydroxytryptamine) in the brain could help combat depression. While our more modern understanding of depression accounts for a variety of possible factors (or combination of factors) as the underpinnings of depression, it’s clear that for some people, increasing serotonin pharmacologically helps alleviate the symptoms of depression.
But the length of time some take to work is a major barrier. Qi-Gang Zhou, a researcher in the department of clinical pharmacology at Nanjing Medical University and one of the study authors tells Inverse that one such antidepressant, fluoxetine, typically takes 2-4 weeks to show efficacy. Further, traditional antidepressants don’t work for everyone, and for many people, they come with undesirable side effects.
Zhou and colleagues chalk some of these difficulties up to the interplay between the serotonin transporter (SERT) and the neuronal nitric oxide synthase (nNOS), a “low-output enzyme primarily expressed in neurons” in the dorsal raphe nucleus (DRN). The DRN is a main source of serotonin in the brain.
The brain's serotonin transporter is responsible for taking up serotonin released by serotonergic neurons. Previous research suggests that nNOS inhibits the delivery of SERT to the DRN. This not only results in the delayed onset of traditional antidepressants, it generally contributes to“other defects such as ineffectiveness and unstable efficacy in some patients,” Zhou says.
Zhou and his colleagues hypothesized that disrupting the interaction between the nNOS and the serotonin transport in the DRN would result in a rapid onset of antidepressant effects and mitigate the side effects and ineffectiveness some people experience with antidepressants.
What they found— The researchers used CRISPR-Cas9 gene editing technology to selectively disrupt the SERT-nNOS interaction in specific neurons in mice’s DRN. Once this was done, the mice quickly displayed signs of antidepressant behavior: when depressed mice are dangled by their tail, they won’t struggle. When they are not depressed, however, they will. Further tests showed that when the SERT-nNOS interaction was disrupted, it dramatically increased the amount of serotonin that was released into the mice's medial prefrontal cortex. That confirmed their hypothesis that disrupting the SERT-nNOS interaction on the DRN could result in the rapid uptake of serotonin and act as a rapid-onset antidepressant.
The researchers then screened their compound library for molecular compounds that could disrupt the same SERT-nNOS interaction in mice. They had previously disrupted the SERT-nNOS interaction through gene editing, something that we obviously wouldn’t do in humans. A small molecule compound, however, might serve as the active ingredient in a new class of antidepressant drugs. They found one such compound, ZZL-7, and tested it in mice. Within two hours, previously depressed mice started exhibiting antidepressant behaviors.
What it means for the future— The researchers hope this is the first step that might ultimately lead to a faster and more effective antidepressant for humans. While there’s a long way to go from a mouse study, the underlying confirmation of the SERT-nNOS interaction’s role in mitigating the effects of antidepressants may further our understanding of the biological underpinnings of depression.
