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5-HT Receptors and Drugs

The 1990s look like being the decade of the neurotransmitter 5-HT – otherwise called serotonin. This was first isolated in the intestine in 1933 and called enteramine. It was rediscovered in blood vessels in 1947 and found to cause them to constrict, which led to it being called serotonin. In 1949, it was established that the chemical structure of serotonin was 5-hydroxytryptamine or 5-HT for short. Both names, 5-HT and serotonin have remained in use. Serotonin survives partly because SmithKline Beecham stumbled on the marketing appeal of the acronym SSRI – selective serotonin reuptake inhibitor – as part of their marketing of paroxetine.

Serotonin was discovered in the brain in 1953. Shortly before in 1948, LSD had been discovered and it had been recognised that there were structural similarities between 5-HT and LSD. This led, at the beginning of the psychopharmacological era, to great interest in the role brain 5-HT might play in mental illness (1, 2, 3).

The initial biochemical observations on antidepressants were that these drugs had effects on the 5-HT system. But despite this, 5-HT more or less disappeared from view for over 20 years. One important reason for this was the emergence of the catecholamine hypothesis for depression. Although antidepressants affected both catecholamines and 5-HT, in 1965, Joseph Schildkraut proposed that the effects on catecholamines were more important. This led to a focusing of research on the catecholamine system and a virtual ignoring of the 5-HT system, at least in terms of depression (see All You Need To Know About Antidepressants).

One consequence of this was that an association between 5-HT and anxiety developed. The reason for this was that by the early 1970s, it seemed that dopamine was the ‘psychosis’ neurotransmitter, noradrenaline the ‘mood’ neurotransmitter and acetylcholine the ‘dementia’ neurotransmitter. This left 5-HT without an accompanying psyhchiatric disorder and one disorder without a neurotransmitter – anxiety. Simplistic thought this may sound, it is to some extent how things appear to have happened.

There has been some evidence to support this parcelling out of disorders. In the case of 5-HT and anxiety, we noted in antidepressants and benzodiazepine anxiolytics articles before that the SSRIs appear to be anxiolytic. Clomipramine, fluoxetine and fluvoxamine are useful for phobic and obsessional states as well as depression. This applies to all antidepressants with 5-HT reputake inhibiting properties and far less so those antidepressants which do not inhibit 5-HT reuptake.

With the development of the SSRIs, there was increasing interest in the 5-HT system. This led during the 1980s to a sustained effort to characterise the receptors that 5-HT acts on and to develop drugs specific to each of these. A classification of where things have got to is given in table below.

Table of Contents

• 5-HT-1 Receptors
• Migraine
• 5-HT-2 Receptors
• 5-HT-3 Receptors
• 5-HT: What Kind of Anxiolysis?
• Side Effects of 5-HT Active Drugs
• References
• Help

5-HT-1 Receptors

As regards drugs active to 5-HT-1 site the picture is complex. Buspirone was launched under the trade name Buspar in 1985 in the USA, and 1988 in the UK, and marketed as anxiolytic. Given the degree of concern that there had been about the use of benzodiazepines in the treatment of anxiety, it seemed a safe bet that a non-benzodiazepine, non-dependence producing anxiolytic would sweep the market. It didn’t. There seem to be two reasons why not. Firstly buspirone just doesn’t seem to give the same pleasant feeling that the benzodiazepines produce, and consumers have accordingly not ‘gone for it’. Secondly, it does not work immediately, taking anything from 2-4 weeks for effects to appear, which is not much help for acutely anxious individuals.

On the positive side, it is an anxiolytic that does not cause dependence. This has not proved much of a selling point, though, as a common reaction among general practitioners has been – ‘Oh yes, we’ve heard that one before where anxiolytics are concerned, and look what happened?’. A decade later, however, there is still no evidence of dependence production.

In the treatment of anxiety, the dose of buspirone starts at 5 mg three times a day and works up to 30-60 mg/day for severely anxious individuals. The most prominent side effects are headache, nausea and dizziness. There seems some risk of akathisia and dyskinesias, generally although the risk is small and the intensity not great. In this there are similarities to the SSRIs.

Since the introduction of buspirone, a number of drugs that are more specific for the 5-HT-1 receptor have been developed – gepirone and flesinoxan. These compounds all show efficacy in screening tests for anxiolytic compounds and again appear anxiolytic without producing dependence. In general, they appear to have a significantly different profile to the benzodiazepines, being inactive in the screening tests used to detect benzodiazepine type anxiolysis. However, in contrast to buspirone, flesinoxan and gepirone are likely to be marketed as antidepressants. Why?

To appreciate this story in all its complexity, see Side Effects of Antidepressants. But briefly, there are reports that buspirone and the other 5-HT-1 agonists may be useful in depression. Like the antidepressants, these 5-HT-1 drugs seem to take anything from 2-4 weeks to take effect, which is quite unlike other anxiolytics. Are they then antidepressants, or are they essentially anxiolytics, but effective in depression because a good anxiolytic will suit many cases of depression well, or is their marketing as antidepressants a clever or perhaps even a cynical martketing exercise? There are no clear answers to these questions at present.

The latest twist to the story is that buspirone itself is now being remarketed as an antidepressant. There is some clinical trial evidence in support of this, but the real reason appears to be because the drug treatment of anxiety has acquire such a bad name, in the wake of the benzodiazepines that the very word anxiolytic has become a problem. General practitioners and others are much happier handing out antidepressants which they feel certain are not habit forming. This process is assisted by current education campaigns to bring home to general practitioners how often they miss the diagnosis of depression and how much misery they could alleviate if they got it right.

Migraine

Before leaving the 5-HT-1 receptor, some mention can be made of sumatriptan, even though it is neither antidepressant or anxiolytic. This was released worldwide in 1991, under the trade name, Imigran, for the treatment of migraine. The rationale for its use is that 5-HT is released into the bloodstream during the migraine attack. The traditional treatments for migraine hither to have dependent on compounds derived from the fungus, ergot, such as dihydroergotamine. These act on most 5-HT receptors, but do so weakly and at the same time act on a whole range of non-5HT receptors as well.

By acting on the 5-HT-1 receptors on arteries leading to the brain, sumatriptan appears to constrict cerebral arteries and thereby prevent the alternating constriction and dilation of arteries that gives rise to the throbbing headache of migraine.

At present, sumatriptan may be given by injection into the skin or taken orally. It works within minutes. It seems that its side effects are mainly nausea and fatigue. There is some concern about its possible effects on the cardiovascular system with reports of an increase in blood pressure with use. Caution is therefore recommended for patients with hypertension or angina.

5-HT-2 Receptors

As mentioned above, similarities between 5-HT and LSD led to early suggestions that 5-HT might play a role in mental illness. It is now clear that LSD binds to the 5-HT-2 receptor and that all hallucinogens of either the LSD or mescaline types exert their effects through this receptor. These effects can be blocked in animals by ketanserin, which is a 5-HT-2 antagonist. Perhaps surprisingly, however, neither ketanserin nor any other pure 5-HT-2 antagonists appear to be of much use in the treatment of psychotic conditions.

The issue is complex in that all current neuroleptics, in addition to having common actions on D-2 receptors, block 5-HT-2 receptors. It remains possible therefore that the tranquillising as opposed to the ’strait-jacketing’ effects of neuroleptics may be as much related to their actions on the 5-HT system as on the dopamine system. And as noted in the neuroleptics, clozapine, the neuroleptic that acts most potently on the 5-HT-2 receptor, is particularly useful down to this aspect of its actions and to the different balance of its effects between dopamine and 5-HT systems compared to other neuroleptics.

The presence on the list of 5-HT-2 antagonists of mianserin, nefazodone and trazodone, which have all been marketed as antidepressents is also of interest. Both mianserin and trazodone also have significant effects on adrenergic receptors but this is much less so with nefazodone. A compound related to trazodone, mCPP, which is an agonist for the 5-HT-2b receptor, is potently anxiogenic. Also of interest is that trazodone, cyproheptadine and nefazodone have aphrodisiac properties.

It seems likely that 5-HT-2 antagonism produces two further effects, one of which is weight gain. Neuroleptics such as chlorpromazine and clozapine, which act more potently at the 5-HT-2 receptor, probably produce weight gain for the same reason. Similarly, mianserin is particularly likely to cause weight gain. A second effect is sedation. Again, compared to other neuroleptics, clozapine and chlorpromazine are sedative. Trazodone and mianserin are also among the most sedative antidepressants, so much so that they are sometimes used as hypnotics (see Side Effects of Neuroleptics).

It remains somewhat unclear, however, just what role pure 5-HT-2 drugs or 5-HT-2 blockers have. While ketanserin and ritanserin are relatively pure antagonists, it is not clear whether they will be of any use in clinical practice. Initial trials have not revealed them to be particularly good anxiolytics, antidepressants or antipsychotics. One possibility is that they may be useful in the management of the dissociative symptoms of anxiety such as derealization or depersonalisation – symptoms which may be provoked by LSD. Another is that they may be somewhat cognitive enhancing.

5-HT-3 receptors

It was initially thought that there were only 5-HT-1 and 5-HT-2 type receptors, which drugs like buspirone binding to the former, and LSD or ketansering binding the latter. It now seems that, although at present the picture is most clear in the case of the additional 5-HT-3 receptor, there may be 5-HT-4 and 5-HT-5 receptors also.

With the discovery of the 5-HT-3 receptor and drugs that act on it, there was considerable excitement as early indications were that 5-HT-3 receptor antagonists may be effective for schizophrenia. This lead to the development of compounds such as ondansetron, granisetron and others. It has since become clear that 5-HT-3 receptor antagonists are anxiolytic not ‘antipsychotic’. This anxiolytic profile differs from that of benzodiazepines and 5-HT-1 agonists, although they are not at present being developed for this indication. Evidence from animal studies also shows that 5-HT-3 antagonists, like 5-HT-2 antagonists, enhance cognitive function.

At present, two 5-HT-3 antagonists have been released onto the market, ondansetron (Zofran) and granisetron (Kytril) for the management of severe nausea, such as is caused by cancer chemotherapy, for example. Previously, the drugs used for this purpose and for the management of nausea generally were dopamine antagonists, closely related to the neuroleptics. This points to a close relation between dopamine and 5-HT systems which will be commented on further below.

5-HT: What Kind of Anxiolysis?

Thus there seems to be a role for compounds acting on the 5-HT system in anxiety states. What role and why?

It appears that there is a substantial overlap between the 5-HT and dopamine systems. Both 5-HT-3 receptor antagonists and D-2 receptor antagonists are anti-emetic. Neuroleptics, SSRIs, and 5-HT-1 antagonists have been reported to produce akathisia and dyskinesias. More directly, it has been shown that 5-HT-3 receptor antagonists modulate dopamine release in the brain. One possibility, therefore, is that many of these compounds active on the 5-HT system are, as it were, atypical neuroleptics, that is, they will produce the benefits of neuroleptics without the same side effects.

Of note here are the reports of a possible benefit of clomipramine in OCD which suggest that it helps by producing a state of indifference to intrusive thoughts and imagery. In The Neuroleptics article, it was argued that the beneficial effects of neuroleptics also consist of an induction of a state of psychic indifference – although one appears to come on far more rapidly than induced by clomipramine.

Do drugs active on the 5-HT system, therefore, produce much the same type of anxiolysis as neuroleptics, although with a slower onset? There is a good case here for saying that the best scientific way forward with this question would be to enlist the takers of these various drugs to attempt to determine whether the effects of neuroleptics and the effects of drugs active on the 5-HT system are similar or if not in what way they differ. However, this is not the way the modern pharmaceutical industry works (see Side Effects of Antidepressants). Uncontrolled observations by users or clinicians are not welcome, and from the industry’s point of view, a recognition of similarities of this type would not help the marketing process which works better distinguishing difference and gearing up strategies around these differences.

Quite apart from the interaction between the 5-HT and dopamine systems, there is another possible interaction between the 5-HT system and the GABA system on which benzodiazepines work. Thus it may be that benzodiazepines exert their anxiolytic action through effects on the 5-HT system. While this is theoretically possible, it seems that the benzodiazepines and the drugs active on the 5-HT system bring about different kinds of anxiolysis. It is difficult to be more specific than this because, as with so many other drugs that have effects on behaviour, we know a lot about what brain receptors the various anxiolytics work on and a lot about the kind of patients that can be managed with these drugs and how quickly they respond, exactly what it feels like to have them and exactly what aspects of anxiety respond to particular anxiolytics.

This is surprising because this should be the easiest of all data to collect. It reflects the fact that we simply have not been in the habit of sitting down and listening to the reports of those who take pills. In part, it seems to me, this is because we appear to assume that taking pills for a psychiatric disorder of any sort must render the taker unfit to make objective observations. This, I believe, is an unfortunate and indeed dangerous assumption.

Side Effects of 5-HT Active Drugs

The side effects of the SSRIs have been detailed in the Side Effects of Antidepressants article. The most prominent are nausea and vomiting during early use and possible marked restlessness/akathisia. Similar effects are produced by the 5-HT-1 agonists, whereas the 5-HT-3 antagonists can block nausea and the 5-HT-2 antagonists produce weight gain.

In addition, there are marked effects on sexual functioning that have not yet been clearly established. Clomipramine seriously compromises sexual functions in over half the people who take it. Of note is that a compound called yohimbine, which acts on 5-HT receptors has been used as an aphrodisiac in the past. Also trazodone has been found to produce marked priapism in a proportion of cases. Far from being an unequivocal blessing, this has sometimes required surgical decompression. Cyproheptadine, a non-specific 5-HT antagonist appears helpful for impotence and a number of other 5-HT antagonists are being developed for this purpose.

In the case of buspirone, headaches, dizziness, nausea and ‘nervousness’/akathisia have been reported. It also appears that there may be stiffness (dystonia) and/or odd movements (dyskinesias). This is not unlike the neuroleptics, except that these effects seem less common and in general milder with drugs active on the 5-HT system. Such effects seem more likely to occur when drugs active on the 5-HT system, such as the SSRIs or 5-HT-1 agonists, are combined with neuroleptics. The use of drugs active on the 5-HT system in combination with a variety of other psychotropics also may lead to the development of a ’serotonin’ syndrome. This appears to be a mild version of the neuroleptic malignant syndrome (see Side Effects of Neuroleptics).

With all compounds active on the 5-HT system, there is a possibility of either stimulant or sedative effects. For the most part individuals will be neither stimulated nor sedated but a proportion of takers will either find sleep difficult or will find that they are so drowsy that they have to take their medication only at night. Oddly, in some cases, the takers of SSRIs complain about being drowsy while at the same time their performance on test of psychomotor function suggests that they are stimulated. As mentioned above, the 5-HT-2 antagonists are more clearly sedative.

References

1. Healy D: The marketing of 5-HT: depression or anxiety? Br J Psychiatry 1991, 157:747-752
2. Carllson A, Healy D: Early brain research in psychopharmacology: the impact on basic and clinical neuroscience: In The psychopharmacologists. Edited by Healy D. London: Chapman and Hall; 1996.
3. Healy D: The antidepressant era. Cambridge MA: Harward University Press; 1987.