5-HT₃ receptor antagonists ameliorate fatigue: so much potential, so little knowledge!

Despite a high prevalence with massive socioeconomic implications, fatigue per se, or as a symptom of a diagnosed condition, remains poorly understood. Much of the evidence available arises from measurement of biochemicals or proteins; alterations in which may be primary or secondary to the symptom, or indeed associated with another aspect of an underlying disease. However, an increasing body of evidence implicates an altered central 5-HT (5-hydroxytryptamine; serotonin) system. Although apparent inconsistencies are evident (for example, see Hartz and colleagues¹), elevated 5-HT neurotransmission appears most likely.^2–5 Numerous distinct receptors have evolved to transduce 5-HT signalling. The majority of these receptors (at least 13) are G protein coupled receptors (GPCRs) but, unusual for monoamine neurotransmitters, an additional receptor, the 5-HT₃ receptor, is a member of the cys-cys loop ligand gated ion channel superfamily; other members being the nicotinic acetylcholine receptor, the GABA_A receptor, and the glycine receptor.⁶ The 5-HT₃ receptor is predominantly expressed by central neurones and peripheral nerves and is known to mediate fast synaptic neurotransmission in the brain.

The clinical availability of 5-HT₃ receptor antagonists offers an opportunity to probe further for roles for this receptor. In this issue of Gut, Piche and colleagues⁷ provide further support for the use of 5-HT₃ receptor antagonists to alleviate fatigue, in this case arising from hepatitis C infection (see page 1169). This builds on previous observations where these compounds have reduced fatigue in uncontrolled studies with small numbers of patients.^8,9 The double blind placebo controlled trial with originally 36 patients demonstrated that chronic administration of the selective 5-HT₃ receptor antagonist ondansetron (Zofran; a relatively low oral dose of 4 mg twice daily for 30 days) improved the level of fatigue in patients relative to placebo (although a significant positive placebo response was also evident at one of the time points). As acknowledged by the authors, they selected patients with relatively high levels of fatigue, which may have allowed a greater scope for the detection of drug induced effects in this symptom that is notoriously difficult to quantify. Interestingly, depressive symptoms in patients also improved. Given the strong association of fatigue as a symptom of depressed patients, it would be pertinent to investigate whether the ondansetron induced reduction in the two symptoms are interrelated. Of further note, both the reduction in fatigue and depression were also evident 30 days after discontinuation of the drug treatment, suggesting that plastic changes may have occurred, as has been postulated for more traditional antidepressant therapies. It may be relevant, however, that another symptom often associated with hepatic disease, pruritus, also likely to be centrally mediated, appears responsive to 5-HT₃ receptor antagonists.^10,11

From their early development in the mid- to late 1980s, the selective 5-HT₃ receptor antagonists have been hailed for their potential clinical utility. Much of the initial impetus for their synthesis and development came from the antiemetic efficacy of metoclopramide. At high dosage, metoclopramide afforded additional protection from the nausea and vomiting associated with aggressive anticancer treatment that appeared to correlate with the relatively low affinity to antagonise 5-HT₃ receptors (for review see Barnes and colleagues¹²). The strategy was vindicated with the substantial antiemetic efficacy of selective 5-HT₃ receptor antagonists such as ondansetron (Zofran), granisetron (Kytril), and tropisetron (Navoban).

Soon after the availability of selective 5-HT₃ receptor antagonists, pioneering work by Costall and Naylor, as well as others, demonstrated that these compounds displayed therapeutic potential in numerous animal models predictive of, for instance, anxiolytic, antipsychotic, and cognitive enhancing actions. The subsequent clinical trials however were largely disappointing and curtailed the development of these compounds for these indications (for reviews see Barnes and Sharp⁶ and Costall and Naylor¹³). Clear reasons for these failures remain to be elucidated. Perhaps the animal models simply did not accurately mimic the human diseases? An often quoted explanation is that the unusual bell shaped dose-response curve often evident with 5-HT₃ receptor antagonists (that is, efficacy is lost at higher dosages) necessitates a wide dose range to prove the negative (that is, to prove that there really is no effect). This phenomenon still awaits a mechanistic rationalisation.

However, perhaps the failure simply reflects the different pattern of forebrain expression in humans compared with laboratory animals. For instance, the human cerebral cortex displays relatively low levels of 5-HT₃ receptor binding sites, unlike rodents.^14–18 In contrast, human extrapyramidal regions such as the caudate nucleus and putamen display relatively high levels of 5-HT₃ receptor binding sites, whereas little corresponding expression is evident in rodents.^14–18 The area is further complicated by the apparent species specific expression of individual 5-HT₃ receptor subunits. Thus central expression of the biophysical 5-HT_3B subunit is apparent in human but not rodent brain.^19–22 The presence of at least three further purported 5-HT₃ receptor subunits (5-HT_3C, 5-HT_3D, and 5-HT_3E subunits²¹) within the human genome, with no corresponding genes identified in rodents, further highlights interspecies differences in the potential expression of different 5-HT₃ receptor isoforms. This area has received little investigation to date, yet in terms of pharmacology, at least the homomeric 5-HT_3A receptor and the heteromeric 5-HT_3A/3B receptor appear nearly identical,²³ although major functional differences are apparent—for instance, the differing ionic selectivity of the ion channel integral with the receptor, with homomeric 5-HT_3A receptors displaying high permeability to Ca²⁺ relative to the heteromeric 5-HT_3A/3B receptor complex. A further difference is the single channel conductance, which is an order of magnitude higher for heteromeric 5-HT_3A/3B receptors relative to homomeric 5-HT_3A receptors.^19,24

Given these major pattern of expression and functional differences between the human 5-HT₃ receptor isoforms and their rodent counterparts, it is perhaps not surprising that the behavioural consequences of antagonising forebrain 5-HT₃ receptors appear to be species dependent. In terms of investigating clinical utility, clearly this problem is bypassed by direct evaluation of 5-HT₃ receptor function in human volunteers or patients; this strategy identifying the ability of 5-HT₃ receptor antagonists to reduce fatigue.^7–9

The growing evidence that 5-HT₃ receptor blockade will benefit patients with fatigue requires support from large multicentre trials. However, the encouraging signs will further promote research to determine the mechanism(s) underlying this widespread clinically important symptom and suggests that further therapies may be derived from targeting the 5-HT system, a strategy that has already reaped rich rewards.²⁵