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The serotonin effect

7 December 2006

Exploring the lesser-known roles of the neurotransmitter serotonin.

Being stuck in traffic and already late; your first day at school; being unable to find a copy of your usual newspaper and having to read the only one left which just happens to swing in the opposite political direction.  We all have different ideas of what causes stress and anxiety.  Biochemically, however, it is regulated through the same molecular processes in all of us.

A chemical intermediate that is believed to be involved in this regulation is a neurotransmitter called serotonin, low levels of which are associated with depression. One form of treatment for individuals who suffer from depression and anxiety disorders is to prescribe a drug that allows the available serotonin in the body to be used more efficiently. Such drugs work by preventing the reuptake of the serotonin back into the cells, hence the name SSRI – Selective Serotonin Reuptake Inhibitor. Beyond all this however, other roles that serotonin has in modulating response to stress and anxiety –and thus other possible therapeutic effects for SSRIs – are relatively unclear.

Serotonin is synthesised in the body from an amino acid (the building blocks of proteins) called tryptophan. Dr Potokar and colleagues, including Dr Simon Davies, are utilising this metabolic feature in a paradigm that allows them to investigate not only psychological responses to altered levels of serotonin, but also physiological ones.

One property of serotonin is that it cannot pass through the blood brain barrier, thus serotonin in the brain must be produced from tryptophan that is obtained through diet. When a patient is given a drink that contains large neutral amino acids but not tryptophan, the neutral amino acids stimulate protein production sucking up the tryptophan in the peripheral system; this leads to an 80 per cent reduction of tryptophan in five hours. The knock on effect of this is a reduction of serotonin in both the peripheral (e.g. plasma) and central (e.g. brain) systems of the body. Similarly the peripheral tryptophan levels can be increased by giving the same drink, but supplemented with tryptophan.

The tryptophan depletion paradigm is well established in psychiatric research as a method for assessing the effects that altered levels of serotonin have on mood and anxiety symptoms. Studies have previously shown that giving a tryptophan depleting drink to patients who have suffered from depression, but who have responded well to SSRI’s, causes the depressive symptoms to return. In similar studies Dr Potokar has focussed on panic disorder and social phobia. Patients with these disorders who are also taking SSRIs for treatment are set challenges that are designed to induce stress – for example being asked to speak in public. The results of these studies showed that on the days when the patients were tryptophan depleted versus the days where the tryptophan levels were increased, the levels of stress and anxiety were higher when undergoing the set challenges. When the body is depleted of tryptophan it cannot produce as much serotonin as per normal and the low levels, even when SSRI’s are being taken, lead to changes in mood and anxiety; which as Potokar suggests, emphasises that SSRIs work by increasing the throughput of serotonin.

Is serotonin function related to other stress related disorders?

Irritable Bowel Syndrome (IBS) is a common condition occurring in about 10 to 15 per cent of the population and can prove to be quite distressing for the individual if severe. It is characterised by abdominal pain and changes in bowel habits, however there is also evidence of mood and anxiety disorders being coupled with IBS. The colon itself has a vast supply of nerves that connect it to the brain, which is why high stress levels can often affect gastrointestinal function. Another significant point is that roughly 90 to 95 per cent of serotonin resides in the gut.

Studies are now emerging that suggest SSRIs have some efficacy in patients with IBS. Dr Potokar in collaboration with Dr Chris Probert and Dr Jon Shufflebotham, have been following on from this by employing the tryptophan depletion paradigm to further investigate acute changes in serotonin on gastrointestinal and mood symptoms in irritable bowel syndrome. Their research, recently published in the American Journal of Gastroenterology, showed that compared to normal control patients, IBS patients reported more gastrointestinal symptoms on the acute tryptophan increase days compared with the depletion day, and reported less anxiety on acute tryptophan increase days. This information suggests that IBS suffers have aberrant serotonergic functioning, providing evidence to support the hypothesis that serotonin dysfunction is involved in IBS.

Does serotonin mediate more than just psychological response to stress?

Work by Dr Potokar’s group, in particular that of Dr Davies, has won awards including the Anxiety Disorders Poster Award at the European College of Neuropsychopharmacology in Amsterdam, and the American College of Neuropsychopharmacology Exchange Fellowship to Waikoloa, Hawaii. Their research investigates the impact of serotonin not only on emotional tone, but also on physiological parameters such as cardiovascular aspects. People who suffer from anxiety disorders, especially panic attacks, can carry higher risks of cardiovascular problems such as high blood pressure. In Potokar’s and Davies’s studies, patients with anxiety disorders who are being treated with SSRIs, are subjected to conditions that induce stress. The results from these studies show that when peripheral levels of serotonin are reduced (through using the tryptophan depletion method), a larger than normal increase in blood pressure is observed.

The evidence gathered in the above studies clarifies that the neurotransmitter serotonin, is indeed a major player in the regulation of tone and psychological response to stress. But perhaps more interestingly, it reveals its regulatory roles in physiological responses to situations where these factors are put upon, such as in patients with anxiety disorders and those who suffer from panic attacks. What is of particular clinical and ultimately therapeutic relevance, is its involvement in physiological diseases that frequently coexist with anxiety disorders. These being cardiovascular related disorders such as hypertension and the previously discussed gastrointestinal condition, irritable bowel syndrome.   

Dr Potokar’s findings not only improve our understanding of how serotonin functions, but also support the use of SSRIs in managing aspects of cardiovascular disease and IBS, where stress and anxiety are often associated.     

Dr John Potokar/Psychiatry

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