The marketing of 5-hydroxytryptamine: depression or anxiety?

D Healy

The British Journal of Psychiatry 1991 158: 737-742 Access the most recent version at doi:10.1192/bjp.158.6.737

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The Marketing of S-Hydroxytryptamine: Depression or Anxiety?

DAVID HEALY

The discoverythat tricycic antidepressants blocked the the market for phobic/anxious depressions was at re-uptake of both noradrenaline and 5-hydroxy this time targeted by producers of monoamine tryptamine (5-HT) waS a significant step on the oxidase inhibitors (MAOIs), whose sales had slumped road to the development of the monoamine hypo as a result of both the MRC comparative trial of theses of depression (Healy, 1987). The subsequent antidepressants in 1965 and the recognition of the demonstration that the de-aminated metabolites of ‘¿cheeseeffect'.Clomipramine was subsequently amitriptyline and imipramine, nortriptyline and marketed as anti-obsessional and it was for this desipramine, were antidepressants tilted the balance indication that it was licensed by the FDA in 1990. toward noradrenaline as the pertinent neuro Whether the promotion of clomipramine as anti transmitter, as these latter drugs were clearly obsessional was as market orientated as this analysis inhibitors of noradrenergic rather than 5-HT uptake. may suggest is uncertain, but the outcome today is In 1964, Ciba Geigy chlorinated imipramine, in that it and other 5-HT re-uptake inhibitors are an attempt to produce a more effective antidepressant. marketed as specific for obsessive—compulsivedis However, not only was the resulting chlor-imipramine orders (OCD). It has been suggested that a large part no more effective, it seemed to be markedly more of this impression derives from the fact that drugs toxic (Pinder, 1987), so much so that it was only which block 5-HT re-uptake are almost the only ones licensed by the Food and Drugs Administration to have been studied properly in OCD (Marks et al, (FDA, Washington, DC) for use in the USA in 1988). There has not been, for example, a proper 1990. study of neuroleptics in OCD, although prior to the During the J970s, Astra consulted Arvid Carlsson introduction of clomipramine, neuroleptics appear regarding the development of an antidepressant. He to have been the standard treatment for OCD. noted that, although a rational appraisal of the situation While there is some dispute about just how useful might suggest that desipramine and nortriptyline clomipramine is in OCD (Marks et al, 1988), there must be the core tricyclic antidepressants, clinicians is an emerging consensus that it, and other 5-HT re appeared to prefer amitriptyline and imipramine uptake inhibitors, in contrast to the non-5-HT (Carlsson, 1990). He pinpointed 5-HT re-uptake re-uptake inhibiting antidepressants, are of some use. blockade as the effect that tertiary amine tricycics Are 5-HT re-uptake inhibitors then in some way have which their metabolites do not, and suggested anxiolytic rather than, or in addition to, being accordingly that drugs specific for 5-HT re-uptake antidepressant? To try and focus further on this inhibition should be developed and tested for issue, I consider firstly the evidence in favour antidepressant efficacy. Clomipramine, then the of a necessary action of antidepressants on 5-HT most specific 5-HT re-uptake inhibitor, was used as systems, and secondly the likely profiles of action a basis to design zimelidine, which was marketed in of a number of recently developed 5-HT receptor the early 1980s. Clinical trials suggested that it was agonists and antagonists. an antidepressant but it was later withdrawn because of side-effects. Since then other 5-HT re-uptake inhibitors have followed. Antidepressants and 5-HT Meanwhile, given the dominance of amitriptyline By the mid-l980s increasing interest had developed and imipramine in clinical settings, Ciba Geigy were about a possible role of 5-HT receptor functioning faced with a marketing problem for clomipramine. in depression. There were several reasons for this. They produced a parenteral preparation of clom Firstly, it had been shown that antidepressant ipramine and encouraged prescribers to look at induced changes in adrenergic receptors did not take alternative indications. This led to its being given in place, unless there was an intact 5-HT system (Sulser, large doses intravenously in a number of single-blind 1984). Secondly, antidepressant treatment was shown and non-placebo-controlled studies for phobic and either to sensitise post-synaptic 5-HT2 receptors (Dc obsessional states (for review see Healy, 1990). It Montigny etal, 1988;Healy et al, 1985)or to influence appeared to be in some way anxiolytic - if anything receptor number (Cowen et a!, 1986). Thirdly, it was more anti-phobic than anti-obsessional. However, also known from animal work that lithium has

737 Thie One I@@III@IIU@IUI@I@flhIIDhI@1111I@IIIllIII@I KG23-E45- FF9R 738 HEALY pre-synaptic effects on the 5-HT system and sensitises et a! in 1974,on 45 clearly endogenouslydepressed post-synaptic 5-HT receptors (Price et a!, 1990). In subjects, who were randomly given a tricycic anti an attempt to study this effect in humans, Dc depressant and lithium or a tricycic antidepressant Montigny et a! (1981) and Henninger et a! (1983) and placebo. They concluded that lithium appeared added lithium to the tricycic antidepressant regimes to enhance the effects of tricydic antidepressants but of treatment-resistant depressives and reported a the differences between lithium and placebo groups rapid and remarkable improvement in mood. This were not significant. was put down to the ability of lithium to sensitise 5-HT2 receptors, with the implication that effective 5-HT receptor agonists and antagonists antidepressant treatment in general worked by this means (Dc Montigny et a!, 1988). The initial monoamine depletion hypotheses gave Finally, based on this effect of lithium, a variety way in the late 1970s to a variety of adrenergic of treatment cocktails have been developed; the most receptor hypotheses, notably the alpha-2 super notable of these have been the combinations of sensitivity and the post-synaptic beta receptor clomipramine, L-tryptophan and lithium (Hale eta!, supersensitivityhypotheses (Healy, 1987).Comparable 1987) and phenelzine, L-tryptophan and lithium hypotheses, implicating 5-HT receptors, were held (Barker et a!, 1987). A common feature of these up by technical difficulties in identifying receptor regimes has been an attempt to selectively influence subtypes. the 5-HT system (Leonard, 1988). The recent In 1979, using radioligand binding methods, withdrawal of L-tryptophan from the market has led, Peroutka & Snyder distinguished between a 5-HT1 it would seem, to a number of patients on such and 5-HT2 receptor. The development of selective regimes relapsing (Ferrier et a!, 1990). agonist and antagonist radioligands to further It is, however, far from certain that there is any distinguish between 5-HT receptor subtypes has specific effect of manipulating the 5-HT system in subsequently produced a profusion of new receptor treatment resistance. It is almost impossible to subtypes. Some of these experimental compounds compare adequately the addition of lithium to the have been successfully refmed further for use in man. effect of adding another antidepressant or neuroleptic It is with the behavioural profile of these latter drugs to an apparently ineffective regime. The initial claims that we are now concerned. in favour of lithium did not capture attention From Table 1 it will be clear that there is by virtue of any proven specificity to the 5-HT some overlap between the 5-HT1@receptor and system or even to treatment resistance, but rather the 5-HT2 receptor; it seems likely that these may by a seemingly dramatic induction of clinical in future be designated as 5-HT@ and 5-HT2b. A change - within 48 hours. This in turn appears to 5-HTIb receptor exists only in animals. A 5-HT1d have done more than anything else to confer the and 5-HT4 receptor have been proposed but at impression of specificity to the 5-HT system. Such rapid responses are not now cited and would seem Table 1 to have been a chance phenomenon. 5-HT receptor agonists and antagonists In one of the largest studies of treatment resistance AgonistAntagonist5.HT,,8-OHDPAT Shapira et a! (1988) gave clomipramine and/or lithium to a group of 12 electroconvulsive therapy resistant depressed subjects but found that the mean Buspirone Spiperone Propranolol5-HT,@mCPPRitansennGepirone time to recovery was 2.2 months. Such delay hardly Ipsapirone suggests a specific role for manipulations of the 5-HT FlesinoxanMethsergide system. Reviewing all studies in the area, Price (1989) has recently concluded that lithium augmentation Miansenn5-HT2d-LSDKetanserin brings about a response in around 50% of cases and that the mean time to response may be about three Ritanserin Rispendone weeks. This suggests that there may be little Mianserin difference between adding lithium to an ineffective Trazodone regime or adding another antidepressant, such as neuroleptics5-HT32-methoxy-5-HTOndansetronAll mianserin, or a judicious dose of a neuroleptic. Treatment-resistant subjects are also a difficult Granisetron group from which to extrapolate. It can perhaps be Zacopride noted that what in effect was the first study of This table is based on the guidelinesof the serotonin receptor club lithium augmentation was conducted by Lingjaerde nomenclature committee. December 1989. THE MARKETINGOF 5-HT 739 present remain radiolabelled binding sites only, receptors, also block 5-HT2 receptors (Glennon, without an obvious functional correlate (Peroutka, 1990). The difference between their actions on these 1988; Gonzalez-Heydrich & Peroutka, 1990). two receptor systems is that the doses used clinically If the antidepressant action of 5-HT re-uptake for the different neuroleptics correlate closely with inhibitors is mediated through the 5-HT system —¿it their ability to bind to D-2 receptors, whereas this is not a foregone conclusion that this is necessarily is not so in the case of their binding to 5-HT2 the case —¿thenpresumably this must be effected receptors. indirectly by altering the availability of 5-HT to one The presence on this list of mianserin and or other of these receptors. If 5-HT has a role in trazodone, which have both been marketed as either depression or anxiety, it might be expected antidepressants, is of interest. In the case of then that drugs acting more directly on one or other mianserin, however, this agent also has a significant of these receptors would be either clearly anxiolytic effect on adrenergic receptors. In the case of or antidepressant. trazodone, of interest is the fact that one of its derivatives —¿mCPP,which is an agonist for the 5-HT1J5HT@, receptor - is potently anxiogenic 5-HT1 (Zohar et a!, 1988). The picture as regards drugs active at the 5-HT1 site is complex. The recently introduced buspirone, which is a partial agonist for the 5@HTiasite, has been 5-11T3 marketed as an anxiolytic. Since its introduction a Several years ago, it appeared that 5-HT3 receptor number of more specific agonists for this site have antagonists might be effective in schizophrenia, based been developed - ipsapirone, gepirone and flesinoxan. on tests in animal models of schizophrenia (Costall These compounds all show efficacy in animal et a!, 1988). This led to the developmentof a screening tests for anxiolytic compounds. They number of compounds such as Glaxo's ondansetron, appear, however, to have a significantly different Smith Kline Beecham's granisetron and others proffle to the benzodiazepines, being inactive in some which are shortly due to come onto the market. It of the screening tests used to detect benzodiazepine has since become clearer that 5-HT3 receptor an type anxiolysis (Gonzalez-Heydrich & Peroutka, tagonists have an anxiolytic profile that differs from 1990; Glennon, 1990). that of both benzodiazepines and 5@HTiaagonists In contrast to buspirone, however, flesinoxan and (Jones et a!, 1988). ipsapirone, which also appear in early pre-release Of particular note is that 5-HT3 receptor an studies to be anxiolytic in man, are currently being tagonists appear, in animals, to reverse effectively tested as antidepressants. One rationale offered for the anxiety that is induced by benzodiazepine this stems from the finding that the prototypical discontinuation (Costall et a!, 1990). 5HT1a agonist, 8-OHDPAT, potently reverses some of the behaviours in animals that constitute learned helplessness (Gonzalez-Heydrich & Peroutka, 1990). As this is a model of depression rather than anxiety, The marketing of 5-HT the inference drawn has been that 5@HTiaagonists might be antidepressant. There are other ways, In addition to perhaps 20 to 30 new 5-HT re-uptake inhibitors, there are a great number of new however, to interpret this switch in indications which compounds, with relatively specific actions on will be developed below. the 5-HT system, that have begun to appear on the market. Are they anxiolytic or antidepressant or 5-HT2 both? The overview, above, of the behavioural effects mediated through 5-HT receptors suggests In the case of the 5-HT2 receptor, it appears that that 5-HT has more to do with anxiety than the hallucinogenic effects of LSD and mescaline are depression. This, however, is an issue that is likely mediated through the 5-HT2 receptor (Davis, 1987). to be confounded greatly by the efforts of drug These effects can be blocked in animals by ketanserin companies to market their products. and ritanserin (Davis, 1987). There is also some For example, the relative failure of buspi evidence that 5-HT2 antagonists such as ritanserin rone to make major inroads in the marketplace or risperidone are of benefit in schizophrenia suggests that it will be very difficult to market (Gelders, 1989). All current neuroleptics, further a general anxiolytic, in the post-benzodiazepine more, in addition to having common actions on D-2 era. Such a compound would have to be both 740 HEALY as effectively anxiolytic as the benzodiazepines Hamilton scale score. The 5-HT re-uptake inhibitors and remarkably safe. The safety factor comes do just this. Are such agents specifically anti into play when one considers that broad-spectrum depressant? Against this possibility is the fact that anxiolytics may end up being prescribed for sub there is no relationship between potency in inhibiting stantial sections of the population, so that the 5-HT re-uptake and antidepressant efficacy. Indeed, potential liability to the company should anything the recently developed and apparently antidepressant go wrong is considerable. tianeptine appears to promote 5-HT uptake (Fattacini This must be one reason why so many 5-HT re et a!, 1990). It must be rememberedaswell that uptake inhibitors are being produced - and why the the original of the species, clomipramine, had a temptation to market them as antidepressants is all much wider range of actions than the more specific but irresistible. These compounds can be produced compounds currently being introduced. easily. They are far safer than the earlier tricycics There is a further possibility. It appears that and MAOIs. They are so safe that it becomes a there is a substantial overlap between the 5-HT feasible proposition to take the current fmdings from and dopaminergic systems. Both 5-HT3 receptor social psychiatry and advise general practitioners that antagonists and D-2 receptor antagonists are anti there are many more untreated depressives than was emetic (Costall et a!, 1988). Neuroleptics, 5-HT formerly thought; often conditions presenting as re-uptake inhibitors and 5-HT15 agonists increase anxiety stem from an underlying depression, and prolactin levels. Both neuroleptics and fluoxetine current evidence suggests that antidepressants (in have beeii reported to produce akathisia (Lipinski contrast to anxiolytics) need to be taken chronically, et a!, 1989).5-HTld receptorsarefoundprincipally in order to reduce the risk of relapse. Marketing as in the basal ganglia (Peroutka, 1988). 5-HT3 receptor antidepressants also produces a different (and more antagonists modulate mesolimbic dopamine release useful) set of expectations in both prescribers and (Tricklebank, 1989). There are grounds, therefore, consumers - that the drugs will not do much in the to believe that drugs active on the 5-HT system may short term. There is, therefore, a good marketing modulate dopaminergic systems or vice versa. rationale for producing 5-HT re-uptake inhibiting Of note here is the fact that the first report of a ‘¿antidepressants'.Fromthe beach-head of depression, possible benefit of clomipramine in OCD suggested raids can subsequently be launched on the hinter that it helped by producing a state of indifference lands of anxiety, following the well-established to intrusive thoughts and imagery (Cordoba & precedent of the MAOIs and clomipramine. Lopez-Ibor, 1967; Healy, 1990). I have argued, Are 5-HT re-uptake inhibitors, therefore, not elsewhere (Healy, 1989), that the beneficial effects antidepressant? Currently in clinical trials for of neuroleptics also follow from the induction of a antidepressants, the Hamilton Rating Scale for state of psychic indifference - although one that Depression (HRSD) is the most commonly used appears to come on far more rapidly than that instrument. A problem with the HRSD is that a induced by clomipramine, albeit with the drawback@ considerable part of the total score may derive from of being often accompanied by counterproductive questions that are concerned with anxiety. An side-effects. Without more precise phenomenological effective anxiolytic agent may substantially reduce descriptions from patients, it is not possible to say total scores and such reductions are then often whether these effects differ, other than in the time uncritically interpreted as evidence of antidepressant course of their onset. efficacy. A case can be made therefore that manipulating On this basis all neuroleptics have been ‘¿shown'5-HT functioning may, in certain circumstances, be to be antidepressants (Robertson & Trimble, 1982). indirectly neuroleptic. On this basis, current cocktails Lundbeck, in particular, have conducted a successful for treatment-resistant depressions, which manipulate marketing campaign for flupenthixol, using such 5-HT systems, may be equivalent to adding a data to suggest that it is in someway both a neuroleptic to an established antidepressant neuroleptic and an antidepressant (for review see regime. Healy, 1990). Both diazepam and alprazolam have comparable antidepressant credentials (Tiller et a!, The way forward? 1989; Rickels eta!, 1985); the companies concerned have, however, had other marketing targets (Healy, When new compounds are produced, there is aprima 1990). fade casefor conductinga seriesof open studies Many of the more recently developed compounds in clinical populations to establish their actual active at 5-HT receptors will also provide substantial effects in man as opposed to the effects proposed benefits for depressed patients as rated by the total by current theories or by extrapolation from animal THE MARKETING OF 5-HT 741 experiments. This, however, is not the way the controlled studies. These smallernumberscould then modern pharmaceutical industry works. consist of clearly endogenomorphically depressed The production of a drug requires a prior subjects; the kind of individuals who would seem determination of market returns balanced against least likely to respond to an anxiolytic. liabilities. This initial requirement tends to act as a Finally, Quitkin et a! (1984) and Kravitz et a! mould into which subsequentdevelopments must be (1990) have suggested that a true antidepressant fitted. This will often apparently lead to companies response can be differentiated on the basis of a ignoring information about unexpected clinical pattern analysis as opposed to a consideration of benefits which might complicate the figures. A recent overall success rates compared to placebo. A clear example concerns calcium-entry blocking agents delay in responseof up to two weeks has traditionally (Healy, 1990). Company information, until recently, been taken to be characteristic of antidepressants as suggested that these agents do not cross the blood opposed to anxiolytics or neuroleptics. Ironically, brain barrier. However, it was observed that such this may indicate the best basis for claiming that the agents may ameliorate tardive dyskinesia (Barrow & 5HT1a agonists are antidepressants, in that re Childs, 1986),an observation subsequently replicated, sponse to these compounds takes two to three weeks which has not, it would seem, been taken up and to appear. promoted by the companies concerned. This is presumably because the balance-sheet of gains and liabilities might be incalculably disrupted by Acknowledgement doing so. I am grateful to Brian Leonard (Dept of Pharmacology, University This example of clinicians noting the effects of a College Gaiway, Ireland) for many fruitful discussions we have had drug on a condition other than the one it was on the clinical, biochemical and marketing aspects of antidepressant drugs, which have helped to form the basis of this article. prescribed for contains an important pointer. To date, all significant developments in psycho pharmacology have happened serendipitously (see References Sneader, 1990; Kuhn, 1990; Sandier, 1990 and for B4@Itxna,W. A., Scorr, J. S. & EccLEsToN, D. (1987) The review Healy, 1990). None have been the result of Newcastle chronic depression study: results of a treatment a double-blind placebo-controlledstudy. At present, regime. International Clinical Psychopharmacology, 2,261-272. B4'@xaow,N.& CHILDS,A. (1986) Anti-tardive dyskinesia effect of the interpenetrationof psychopharmacologywith the verapamil.AmericanJournalof Psjichlatry,143, 1485. pharmaceutical industry, although of immense CAIU.ssoN,A. (1990) Early psychopharmacology and the rise of benefit in many respects, tends to obscure this and modern brain research. Journal of Psychopharmacology, 4, to suggest instead that all the significant researchhas 120-126. CORDoBA,E.E. & Lopsz-Iaoa, J. J. (1967) Monochlorimipramine been done before a drug comes to the marketplace- in psychiatric patients resistant to other forms of treatment. apart from the formality of a set of clinical trials. ActasLuso-EspanolasdeNeurologia,Psyquiatricay ciencas This is simply not the case. All too often the clinical Afines, 26, 119—147. trial, today, merely sets the seal on a marketing COSTALL, B., NAYLOR, R. J. & Tymts, M. B. (1988) Recent advances in the neuropharmacology of 5HT-3 agonists and process rather than acts an independent piece of antagonists. Reviews in the Neurosclences, 2,41-65. research. & —¿ (1990) The psychopharmacology of 5HT Clinicians need to research ‘¿independently'the receptors. Pharmacology and Therapeutics, 47, 181—202. effects of these new compounds. We need also to Cowar@i,P. J., GEANEY,D. P., Sca@csrrEa, M., et a! (1986) Desmethylimipramine treatment in normal subjects: effects on come up with operational criteria for antidepressants neuroendocrine responses to L-tryptophan and platelet 5HT (and other psychotropic drugs), so that simply related receptors. Archives of General Psychiatry, 43, 61-67. achieving effects in clinical trials cannot be passed DAVIS,M. (1987) Mescaline: excitatory effects on acoustic startle off as evidence that the drug in question is an are blocked by serotonin-2 antagonists. Psychopharmacology, 93, 286—291. imipramine-equivalent, for example. There are a DE MownoNy, C., GRuNBERo,F.,MAYER,A.,et a! (1981) Lithium number of recent developments that perhaps may induces rapid relief of depression in tricycic antidepressant drug help in this. One has been the development of rating nonresponders. British Journal of Psychiatry, 13$, 252-256. scales, such as the Montgomery-Asberg Depression —¿, Csi*ptrr, Y. & BLIER, P. (1988) Lithium augmentation of antidepressant treatments: evidence for an involvement of the Rating Scale (MADRS), which are much less likely 5HT system. In New Concepts in Depression (eds M. Briley & to throw up false positives with anxiolytics. 0. Fillion), pp. 144-160. Basingstoke: Macmillan Press. Another is the development of multiple-baseline FATrACINI, C. M., Bo@os-Jnas@z, F., GozI.AN, H., et al(1990) methods, which could potentially replace the placebo Tianeptine stimulates uptake of 5-hydroxytryptamine in vivo in the rat brain. Neuropharmacology, 29, 1-8. controlled trial (Kazdin, 1982). 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David Healy, MD, MRCPsych, Senior Lecturer in Psychological Medicine, Academic Sub-Department of PsychologicalMedicine,North WalesHospital, Denbigh, Clwyd LLJ6 SSS