Only about one third of patients achieve remission after 14 weeks of SSRI (Selective Serotonin Reuptake Inhibitors) antidepressant treatment and around 30% of patients remain ‘treatment resistant’, even after trying multiple treatment approaches. When SSRIs are effective, they require chronic administration to achieve therapeutic efficacy and it can take several weeks for depressive symptoms to fully resolve. SSRIs selectively block serotonin transporters, which results in an increase in 5-HT levels at all post-synaptic serotonin receptor subtypes. This indirect activation of a broad range of receptors is likely to contribute not only to the therapeutic action, but also to the unwanted aspects of SSRIs. In particular, early activation of 5-HT1A autoreceptors by SSRIs results in a paradoxical decrease in 5-HT cell firing, and is thought to contribute to the slow onset of the clinical action of SSRIs. Equally, activation of post-synaptic 5-HT2C receptors has been associated with the increase in anxiety that can characterise initiation of SSRI treatment.
More selective activation of specific 5-HT receptors has the potential to produce better tolerated, faster acting treatments. Preclinical studies suggest that the 5-HT4 receptor is a particularly promising therapeutic target for this approach. In animal models, 5-HT4 receptor activation has antidepressant effects across a range of behavioural paradigms. Intriguingly, the onset of antidepressant effects following 5-HT4 receptor agonism is more rapid than that seen with SSRIs, and is accompanied by early molecular and cellular changes that mirror those seen following chronic administration of conventional antidepressants. On this issue, eesearchers have found that SSRI have the potential to improve certain cognitive functions, such as verbal memory. They measured brain function in patients before and after taking the SSRI escitalopram and correlated this to a drop in the level of one of the serotonin receptors in the brain and to cognitive improvements during treatment.
Serotonin is often described as a ‘feel good’ chemical, and higher levels of serotonin circulating in the brain contribute to a sense of well-being, and can ease clinical depression in most sufferers. There are several serotonin receptors in the brain, and all will serve to regulate well-being by regulating circulating serotonin’s interaction with the brain. However, this work concentrated on only one serotonin receptor, the 5HT4 receptor. The researchers began by scanning the brains of 90 depressed patients, to measure the quantity of 5HT4 receptor which serotonin binds to. At the same time, patients were given a series of tests to measure mood and cognitive abilities. Patients were given daily doses of escitalopram, and at the end of an 8-week period, 40 patients were rescanned to measure the quantity of 5HT4 receptor in the brain. The mood of the patients had improved, but the team also found that the levels of 5HT4 receptor had dropped by around 9% possibly due to adaptations to increased levels of serotonin.
When they asked these patients to undertake more cognitive tests, they found that their performance had improved, so that the less the 5HT4 receptor had changed the better the cognitive outcome. This phenomenon was particularly prominent for the ability to recall words. This is potentially significant. It seems that the SSRI medication contributes to an improvement on cognitive function, at the same time as helping improve mood. The investigation ties the improvement in cognitive function to the specific 5HT4 receptor. The researchers note that this was a real-world study, so there is no placebo control. The team’s next step is to treat patients with drugs which specifically stimulates the 5HT4 receptor to see the effect on cognitive function; interestingly, serotonin is also found in the gut, and there are drugs available to treat irritable bowel syndrome which specifically bind to and stimulate 5HT4 , which the team may repurpose in these trials.
To date, the evidence that the 5-HT4 receptor might be a useful treatment target mainly comes from preclinical studies, and it is important that these findings are translated into human studies. Human PET imaging studies using the [11C]-SB 207145 ligand have provided some initial support for a role of the 5-HT4 receptor in the pathophysiology of depression. However, it remains to be established whether activation of 5-HT4 receptors in humans has effects that mirror the antidepressant and pro-cognitive effects seen in animals, and therefore whether this is a viable antidepressant target. Beside, the role of this receptor well correlates with the hyopothised connection between constipation and depression. For example, a recen work from Oxford University showed that the 5-HT4 receptor stimulant, prucalopride, a drug licensed for the treatment of constipation, improves memory in both healthy participants and people at risk of depression.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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