Serotonin cell discoveries mean rethink of depression, anxiety, and SSRI's

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22 July 2010 by Linda Geddes
Magazine issue 2770.

IF YOU thought depression was caused by low serotonin levels, think again. It looks as if the brain chemistry of a depressed person is much more complex, with mounting evidence suggesting that too much serotonin in some brain regions is to blame.

If correct, it might explain some of the negative side-effects associated with selective serotonin re-uptake inhibitors (SSRIs), antidepressants like Prozac which increase the amount of the neurotransmitter serotonin in some parts of the brain.

The traditional view of depression was largely based on the observation that SSRIs boost mood- although why they do so is unknown. "Because antidepressants increase serotonin in some parts of the brain, people assumed that depression must be the result of low serotonin levels," says Christopher Lowry of the University of Boulder in Colorado. But the discovery of multiple types of serotonin-releasing neurons in the brain, along with high levels of serotonin recorded in people with depression, is prompting a rethink.

"What's more likely is that there are subgroups of serotonin neurons that are overactive in depressed patients, rather than underactive as we have all been assuming," says Lowry.

It's likely there are groups of serotonin neurons that are overactive, not underactive as assumed

One of the first clues that something might be amiss with the traditional theory came three years ago, when Murray Esler at the Baker Heart Research Institute in Melbourne, Australia, and colleagues found that the level of serotonin in the brains of people with panic disorder was four times higher than in healthy volunteers (Stress, DOI: 10.1080/10253890701300904), and in depressed people who were not receiving treatment it was two times higher than in volunteers (Archives of General Psychiatry, vol 65, p 38). They also showed that long-term use of SSRIs in people with depression and panic disorder seemed to decrease serotonin levels through an as yet unidentified mechanism.

Now, in studies of rats and mice, Lowry has found that there are multiple types of serotonin neurons that can be independently regulated. He presented his results at the Forum of European Neuroscience in Amsterdam, the Netherlands, last week.

This fits well with findings from other groups that there are two types of serotonin receptor in the amygdala, a brain region linked to emotion and anxiety: 5-HT2A receptors that inhibit anxiety, and 5-HT2C receptors that promote it. The roles of the receptors were identified by injecting drugs that either stimulated or inhibited each receptor and observing the animals' behavioural response.

Together, the findings might mean that while high levels of serotonin in some brain regions like the prefrontal cortex can lead to improved mood, high serotonin in other regions could have negative effects.

Evidence for this idea comes from Gina Forster at the University of South Dakota in Vermillion and colleagues, who injected a stress-related molecule into the brains of rats and found that it triggered two phases of serotonin release. An initial wave of serotonin appeared to increase fear-like behaviour in the rats, while a second wave decreased this behaviour, possibly because it activated a brain region called the medial prefrontal cortex, which is associated with calming of fears (Neuroscience, vol 141, p 1047).

The new findings have implications for how SSRI drugs work. In the long-term, SSRIs do tend to have a calming effect, although more research is needed to understand how they do this.
However, in the short-term some people taking SSRIs report feeling increased anxiety. This is "almost certainly due to the activation of one of these groups of serotonin neurons", says Lowry. The suicidal thoughts some people taking SSRIs claim to experience may also be linked to boosting serotonin, as suicide is thought to be associated with increased impulsivity. "It may be that certain types of SSRI are affecting these impulsivity circuits in the brain," says Lowry.

Learning more about these different groups of serotonin neurons could lead to better treatments for depression and anxiety disorders. "It might be possible to design very specific drugs that can turn on or off specific groups of neurons that are deregulated in anxiety or depression," says Lowry.