Why this “molecule of interest” may provide a new treatment for depression
FDA approval and the emergence of selective serotonin absorption inhibitors (SSRIs) in the late 1980s transformed psychiatry. Finally, there was an effective and inexpensive drug for depression, one of the world’s leading causes of disability. Today, SSRIs are among the most prescribed drugs.
However, as scientists report in a recent article published in the Journal of Neuroscience, interest in SSRIs within the research community has waned. This is because these drugs, known by brand names like Prozac and Zoloft, exhibit “variable clinical effectiveness” – they don’t work for everyone. A growing number of people suffer from treatment-resistant depression, or TRD.
This sparked a revolution in mental health research, prompting scientists to explore taboo substances like ketamine and MDMA as therapies for depression.
But in the Journal of Neuroscience paper, researchers at Imperial College London and the University of South Carolina argue that one way forward does not necessarily mean counting SSRIs, but fine-tuning their application. Their argument stems from one of the most basic reactions the body experiences: inflammation.
Why? The study team found that histamines, molecules involved in the immune system and found in the brain, are an important link between depression and inflammation due to their effect on serotonin. In the long term – and more research is needed to be sure – this work suggests that antidepressants like SSRIs may work more effectively for some when paired with new drugs that lower histamine in the brain.
Histamine, explains co-author, post-doctoral fellow and project leader student Melinda Hersey, plays a role in both mediating the immune response (such as the release of cytokines) and the ability to modulate monoamine neurotransmitters. (like serotonin) which is believed to be impaired in people with depression.
It is “an important molecule of interest”, she says Reverse. And it’s a bridge between two competing ideas for the cause and treatment of depression.
Competing depression hypotheses
To understand why the histamine connection is new, you need to know the two classic hypotheses of depression: the monoamine hypothesis and the cytokine hypothesis. (These are eloquently explained in an accompanying review written by Hersey and colleagues in the European Journal of Neuroscience.)
1. The monoamine hypothesis of depression
This is the explanation for depression that you are probably familiar with. It’s the idea that monoamines – the neurotransmitters dopamine, serotonin, and norepinephrine – are deregulated during depression. This theory arose when researchers examined the blood, urine, and cerebrospinal fluid of depressed patients and found that monoamines and their metabolites were reduced.
This hypothesis is also supported by the fact that SSRIs still work for many. These drugs are designed to allow serotonin to circulate in the brain longer and improve mood. Yet there is a growing appreciation that for some people SSRIs are not helpful enough and / or come with unwanted side effects.
“There is an emerging appreciation that the heterogeneity of response to antidepressant drugs that target the monoamine system reflects the overall heterogeneity of depressive illness,” the team writes.
2. The cytokine hypothesis of depression
Studies also indicate that pro-inflammatory cytokines are a factor in the development and progression of depression. Historically, scientists believed that the brain was not influenced by cytokines, because of the blood-brain barrier. (Inflammatory cytokines signal molecules that promote inflammation.)
Now, researchers know he’s not immune: Inflammatory cytokines can influence brain chemistry associated with psychiatric disorders.
Meanwhile, a number of diseases characterized by chronic inflammation, such as rheumatoid arthritis, are now understood to be accompanied by depression. Depression itself is associated with a chronic low-grade inflammatory response.
“It’s pretty well established that depression is associated with inflammation, as most patients with depression have also been shown to have high markers of inflammation,” Hersey explains.
An acute immune response known to produce “disease behavior” in humans and rodents is also accompanied by “symptoms that reflect depression or depressive-like phenotypes,” Hersey adds.
Depressed patients with severe inflammation are among the most likely to not respond to SSRIs.
But two factors prevent an “a-ha” moment: this inflammation hypothesis alone cannot “sufficiently explain the pathophysiological depression”. SSRIs also have anti-inflammatory properties.
What is possible, argues the study team, is that these hypotheses overlap.
Enter the histamines, to the left of the stage.
The experience – The team had a hunch that it was the relationship between serotonin and histamine that made it difficult for people with DRT to benefit from SSRIs.
So they took mice and implanted biocompatible microelectrodes measuring serotonin in the hippocampus of their brain. This allowed scientists to measure the levels of serotonin in the brain without harming the brain.
Then, half of the mice were injected with an inflammation-causing toxin, the rest being left as a control. Within minutes, brain serotonin levels dropped in the injected mice. Because this toxin is known to be unable to cross the blood-brain barrier, it was clear that it was not the direct cause.
What could cause the drop, however, is histamine: Analysis found that the inflammatory response triggered the release of histamine, which in turn attached to neurons and inhibited the release of serotonin.
When they gave SSRIs to the mice, they still couldn’t increase serotonin levels. It was not until the administration of histamine-lowering drugs that serotonin levels returned to normal. (These drugs are not the same as antihistamines.)
What happens after – While this work is considered preclinical data – it involved mice, not humans – the team is hopeful that it can eventually provide a new route of treatment, taking the form of therapy targeting both histamine. and serotonin. They want to “alleviate depressive symptoms, even in people with treatment-resistant depression,” says Hersey.
The next chapter will focus on three main areas, she says:
- Explore how chronic inflammation can affect the serotonin-histamine relationship
- Perform an in-depth characterization of histamine in the brain
- Observation of the dynamics of histamine and serotonin in human stem cells
But questions remain, including a chicken-and-egg situation: Does inflammation lead to depression, or does depression lead to inflammation?
It’s probably both. Depression, explains Hersey, “is a very heterogeneous disease”, so it is possible that “the pathology of the disease can evolve in various ways on a case-by-case basis.”