Copyright ª Blackwell Munksgaard 2003 Bipolar Disorders 2003: 5: 1–7 BIPOLAR DISORDERS ISSN 1398-5647

Hypothesis Paper F Mood-stabilizers: the archeology of the concept O

Harris M, Chandran S, Chakraborty N, Healy D. Mood-stabilizers: the Margaret Harris, SummitO Chandran, archeology of the concept. Nabonita Chakraborty and David Bipolar Disord 2003: 5: 1–7. ª Blackwell Munksgaard, 2003 Healy R North Wales Department of Psychological Objective: To review the history of Ômood-stabilizingÕ treatments. Medicine, Hergest Unit, Bangor, UK Method: We have reviewed primary source data on the origin of the P use of current mood-stabilizers.

Results: This historical record on the origins of the mood-stabilizers 2 points to a more ambiguous picture as regards pharmacotherapeutic Key words: specificity to bipolar disorders than is commonly conceded. DReceived 28 October 2002, revised and accepted Conclusions: This review suggests a need for alternative formulations for publication 13 February 2003 of the concept of a mood-stabilizer. An alternative to the currentlyE Corresponding author: David Healy, North Wales dominant paradigm is that these agents have treatment effects, which Department of Psychological Medicine, Hergest need to be matched more precisely with patientsÕ constitutional types in Unit, Bangor, UK LL57 2PW. order to optimize outcomes. T 1 e-mail: [email protected] C In recent years the treatment of bipolar mood drug is a mood-stabilizer? Will defining a drug as a disorders has changed dramatically with sodium mood-stabilizer then lead to people who respond valproate, carbamazepine, lamotrigine, and otherE to that drug being diagnosed as bipolar patients? anticonvulsants now used regularly in addition to Would this be appropriate? or in lieu of lithium. There is a general acknow- This paper attempts to shed light on these ledgement that pharmaceutical company interestR in questions by charting aspects of the development the area of bipolar disorders has played some part of anticonvulsants for mood disorders. An accom- in sustaining a wider interest. But this wider panying paper will provide comparative data on interest has also led to the emergenceR of conceptual the incidence and prevalence of service utilization models challenging traditional notions in this for patients diagnosed as having bipolar mood therapeutic domain. For example antidepressants disorders and other data such as inter-illness are routinely used in the depressed phase of a intervals from the pre- and postlithium periods. bipolar disorder, but there isO in fact very little evidence to support this practice (1) and some The archeology of mood-stabilization reason to believe that antidepressants paradoxic- ally may make the problemC worse (2, 3). There are The initial use of lithium for mania created an clear implications of such perspectives for the impression that the manic pole of manic-depressive theoretical models that underpin clinical practice. illness might almost involve a lithium deficiency A great deal hingesN on the concept of a mood- state. The possibility of what would now be termed stabilizer. For three decades, lithium stood as what mood-stabilizing effects arose in the late 1960s. would now be called a mood-stabilizer in contrast Two studies by Schou and Baastrup laid the basis to the ÔantidepressantsU Õ. The answer to the question for claims that lithium was prophylactic for manic- what is a mood-stabilizer was simple – it was depressive episodes (4–6). But the response to these lithium. The emergence of other compounds forces claims was vigorous with critics of the concept us to go further. What does it now take to show a arguing that the results of the naturalistic studies 1 BDI 069 Dispatch: 21.10.03 Journal: BDI CE: Svalli Journal Name Manuscript No. B Author Received: No. of pages: 7 PE: Sri Harris et al. that formed the basis for claims for lithium’s patients – from 10 to 20%. This gave a ready prophylactic effects might simply reflect a regres- population in which to try out a new anticonvul- sion to the mean, or the effects of a withdrawal sant. Borselli and Lambert initially found valpro- syndrome. A Ômirror-imageÕ service utilization mide intensely sedative, particularly when added to study of patients before and after lithium by other anticonvulsants such as phenobarbitone. Angst, Weiss, Grof, Baastrup and Schou in 1970 When valpromide was finally administered onF its (7), and a randomized controlled trial (8) appeared own, it became clear that it had psychotropic in to settle the issue – lithium was what would now be addition to neurotropic effects. This has been termed a mood-stabilizer. described by Lambert as follows ÔpatientsO felt more However, the data on service utilization from the themselves, the mental stickiness, viscosity that had study by Angst et al., which did so much to lay sometimes been there on older agents, was less. We the basis for the concept of a mood-stabilizer in the saw the disappearance of tendenciesO to depression, 1970s, from the perspective of the present look less sometimes even a mild euphoriaÕ (13). clear-cut than standard interpretations of the study Epilepsy was then thought to predispose to both suggest. In part, this is because by 1970, the Ômood- schizophreniform developments,R and an epileptic stabilizingÕ properties of valpromide had already personality disorder. Epileptic patients were seen been discovered, and reports were just about to as importunate, manipulative and viscous in emerge of lithium’s benefits in conditions other their personalities. TheseP patients were frequently than manic-depressive illness. detained in hospital not because of their convul- sions but because of the social disturbances they caused. They were thought to have impulse control The origins of valproate/valpromide disorders, which underlay their inability to adapt The origins of valproate and valpromide lie in the to normal socialD life. The other feature of their Second World War and efforts by German scien- personalities was a certain obsessionality. On tists to produce butter substitutes (9). These efforts valpromide, these social disturbances and the led to the synthesis of valproic acid. After the war characteristicE importunate behavior of hospitalized valproic acid was used as a common diluent for epileptics appeared to change. Female patients in other drugs. In 1963 George Carraz of the Labo- particularT were less likely to end up in conflicts, less ratoire Berthier at Grenoble, when asked to test likely to provoke others in their surroundings, and out a new product for possible anticonvulsant less likely to self-harm. This led Lambert and properties dissolved the new compound in valproic CBorselli to ask whether valpromide reduced self- acid. Testing failed to show any correlation harm tendencies; was it anti-masochistic? between different doses of the experimental com- These issues return in the case of the discovery of pound and anticonvulsant activity but yet theE carbamazepine and pose a real question. The mixture was anticonvulsant. Carraz realized that degree of control of convulsions is not significantly the anticonvulsant properties stemmed from valp- better now compared with before but it is clear that roic acid and titrating the dose of this demonstra-R epileptic patients do not end up in mental hospitals ted the issue conclusively. in a way that they did before. Is this because of Carraz synthesized valproate (Depakine) and a beneficial effect of these drugs on personality valpromide (Depamide) derivativesR of valproic and general integration that has been all but acid. The conventional wisdom of the time had it un-investigated? Is this beneficial effect what that an azote moiety would enhance the psycho- underpins mood-stabilization? tropic properties of a compound, and it was this At this time, lithium was unavailable in France that led to the synthesis of valpromide.O Valpromide or was more generally thought of as being ineffec- in fact protects animals from epileptic convulsions tive. There was a premium therefore on finding triggered by strychnine where valproate does not. effective treatments for manic-depressive disorder. Valpromide also crossesC the blood brain barrier The standard maintenance regimes at the time more readily leading to higher CNS concentrations involved the use of antipsychotics such as chlor- than valproate. promazine or levomepromazine. The sedative Carraz had a linkN with Sergio Borselli a psychi- properties of valpromide led to its use in combi- atric trainee with Pierre Lambert at Bassens Hospi- nation with chlorpromazine for agitated and manic tal in Rhoˆ ne-Alpe. This led to the primary tests of patients, just as phenobarbitone had been used. On the anticonvulsantU properties of both valproate and recovery, patients left on valpromide alone showed valpromide in Bassens Hospital (10–12). an enhanced compliance compared with patients At that point in time most large asylums in on chlorpromazine. Altogether Lambert et al. Europe had significant populations of epileptic studied the drug in approximately 250 patients 2 Mood-stabilizers: the archeology of the concept and concluded that valpromide had distinct psych- that therefore there was no evidence of efficacy for otropic effects that were of benefit in the treatment carbamazepine (19). This was during a period of both acute manic states and in the maintenance when megadose regimes of neuroleptic agents were treatment of manic depressive illness (14). This led used in the West against which a 250 mg dose of to a study looking more closely at 32 patients and chlorpromazine may well have looked indistin- at the impact of valpromide on rates of hospita- guishable to placebo as a comparator. The proto-F lization before and after exposure to this agent. In col used however was exactly the same protocol line with the earlier findings of Angst et al. for used to investigate lithium and these results were lithium, there appeared on valpromide to be a fall not contested. The results of carbamazepineO and in the number of manic episodes by 50% and a lithium indeed appeared to be comparable (24, 25). decrease of 60% in the duration of hospitalization Carbamazepine however did not emerge into (15). wider use in the West until its psychotropicO effects Valpromide at this stage, however, was not were documented by Ballenger and Post in 1980. promoted by Laboratoire Berthier as valproate By the time it emerged into wider use, it was clear was selling well as an anticonvulsant both in that carbamazepine had interestingR psychotropic France and abroad. Valproate also began to be properties. It had been used in Japan for a wide used for mood disorders and in 1980 Emrich et al. range of conditions and it was noted to be useful in (16) reported on its usefulness for the management stabilizing aggressiveP outbursts in young men. of mania without knowing about the prior use of Young men with impulse control disorders repor- valpromide. ted that a break was interposed between them and their impulses so that they were allowed a pause for reflection that they did not have before. This use of The origins of carbamazepine carbamazepineD entered into the Western literature In the early 1970s lithium was not available in as a use in the management of episodic dyscontrol Japan. This led to the use of a wider variety of syndrome (19, 26). agents to manage manic-depressive disorders than E were being used in countries where lithium was Parallel developments available. Japanese hospitals were also in the T process of institutionalizing with a large increase Lithium was undergoing a parallel evolution. in the hospital population following the discovery When first introduced in the 1950s, it had appeared of chlorpromazine in contrast to the reductions Cto be a specific treatment for manic-depressive elsewhere (17). Japanese psychiatry was neuropsy- illness. From there, it migrated during the 1960s to chiatrically oriented and the treatment of epilepsy become a prophylactic treatment. In the early lay within the domain of psychiatrists. This meantE 1970s, a study by Sheard in prisoners demonstrated that a considerable number of patients were treated an anti-irritability, or anti-impulsive action that led in asylums for epileptic or related conditions. As a to a reduction in violent behavior among prison result, carbamazepine, a tricyclic agent, cameR into inmates (27). This study, which was immediately use within the asylum following its release as an replicated (28), questioned the basis for the sup- anticonvulsant during the 1960s. posed specificity of lithium’s effects to manic- The availability of and sedativeR properties of depressive illness. Paradoxically at the same time carbamazepine almost inevitably led to its use the concept of bipolar disorder was broadening out in lieu of other sedative agents such as the to encompass anyone who might respond to a barbiturates in manic patients. In an echo of mood stabilizer. The licensing of lithium in the the valpromide story, it was notedO that the use of United States in conjunction with other historical carbamazepine contributed something distinctive processes was leading to a re-diagnosis to manic- to the management of both epileptic and manic depressive illness of many patients formerly diag- patients (18, 19). C nosed as having schizophrenia (29, 30). These factors laid the basis for a clinical trial of But there is another neglected history here. carbamazepine in the treatment of manic-depres- Through the 1960s a variety of other anticonvul- sive illness (20–22).N When written up in English, sants were also used for non-epileptic indications. this trial in which carbamazepine was compared These included diphenylhydantoin (31, 32), becla- with chlorpromazine demonstrated comparable mide (33) and sulthiame (34, 35). These drugs were results to chlorpromazineU (23). However the article used a variety of psychotic and behavioral condi- had a poor reception in the Western literature with tions including what were later called conduct the criticism that almost homeopathic doses of disorders in children and are now liable to be chlorpromazine had been used (250 mg/day) and diagnosed as juvenile onset bipolar disorders. This 3 Harris et al. use of drugs like sulthiame and diphenylhydantoin, with selective effects on limbic systems will be however, unlike the use of carbamazepine and found to be useful, whereas others will not. An valproate did not get linked to bipolar disorders at alternative, however, is that these differences in the time and did not lead to the concept of mood- efficacy may be parsimoniously explained in terms stabilization. of differential functional effects of lithium, carb- amazepine, valproate, valpromide and lamotrigine.F While slow to emerge, the notion of mood- The emergence of mood-stabilization stabilization has all but replaced the earlier notion Based on reports of the effectiveness of carbamaze- of prophylaxis. If we ask whether any ofO the newer pine for mood disorders, Post et al. (36–38) mood-stabilizing agents can be demonstrated to be suggested that the efficacy of this tricyclic anticon- truly prophylactic, we reach the paradox at the vulsant might be explained if episodes of mood heart of the mood-stabilizationO debate. Mood- disorder were conceptualized as convulsive equiv- stabilizers are agents, which ideally would show alents. Mood stabilization might then involve a prophylactic effects without evidence of benefits in reduction of the kindling effects that primed the acute state. However, currentRÔmood-stabilizersÕ subsequent episodes. While Schou almost 20 years are only on the market because of demonstrable earlier had talked about mood-normalizers (39), benefits in acute states. Post’s formulations, which linked a proposed This sets up a numberP of paradoxes. Antipsych- mechanism of action with prophylactic effects, otics and antidepressants demonstrably produce inaugurated a new era of mood-stabilization, treatment effects in the depressive and manic poles although the concept was nevertheless slow to take of bipolar disorder. Chlorpromazine was first used shape – the term mood-stabilizer in fact only in the management of mania and neuroleptics have appears sporadically in the literature until the early been the standardD agents for the management of to mid-1990s. manic states ever since. If by an antidepressant is As this new concept took shape, the proposed meant an agent that demonstrates a treatment effect of mood-stabilizers was relatively disease- effect inE a trial with depressed patients, then most specific and furthermore was one that should occur neuroleptics are antidepressants (41), although it regardless of any beneficial non-specific functional shouldT be noted that despite this evidence of short- effects such agents might also have. In addition, it term effects, few clinicians would regard these followed from Post’s proposals that the longer agents as antidepressants in the longer run. These the period the person was left untreated and the Cfindings in fact may do more to demonstrate the greater the number of episodes they had the greater pitfalls of short-term trials than anything else. The the propensity to future episodes would be. This functional effects that these agents produce have conceptualization coincided with contemporaryE face validity as therapeutic principles in the man- thinking about lithium and it mandated early agement of both depressive and manic states. intervention. Evidence that valproate had similar Indeed ironically, while antidepressants may mood stabilizing properties to carbamazepineR cause manic reactions, one of the only controlled appeared to endorse the kindling hypothesis. trials done of imipramine in mania demonstrated The kindling model put a premium on investi- that it had beneficial effects in some patients (39). It gating other anticonvulsants. BeneficialR psycho- was a consideration of results such as these in fact tropic effects in patients being treated for epilepsy, that led Schou to the concept of a mood normalizer echoing those previously seen with valproate and in 1963. carbamazepine, were also described for lamotri- gine, gabapentin, vigabatrin andO other anticonvul- Mood or psyche stabilizers? sants. However, not all anticonvulsants appear to be of benefit in manic-depressive disorders. The The dominant conception of a mood-stabilizer at current status of gabapentinC is uncertain (40), and present appears to be that such a drug attacks a it would seem that vigabatrin is unhelpful, tiaga- specific underlying physiological abnormality with- bine may be of limited utility and topiramate is not out necessarily producing any obvious functional routinely helpful, althoughN it may have some utility effect. The implication is that all mood-stabilizers in refractory cases. are in some way modifying the same mechanism. The findings that some anticonvulsants have Secondary messengers appear to be the favorite minimal effectsU for mood disorders suggest that the target at present, but there are no common specific notion that agents that reduce kindling will neces- effects reported to date. sarily be beneficial in manic-depressive orders While this conception can draw on histor- needs to be reviewed. One possibility is that agents ical notions about the specificity of lithium, the 4 Mood-stabilizers: the archeology of the concept subsequent history of lithium as well as the First, in addition to the possible deleterious effects discoveries of the first psychotropic properties of of antidepressants on bipolar mood disorders, the valpromide and carbamazepine point to a need for possibility has also been raised that antidepressants a new term such as a psycho-stabilizer. The may have equally problematic effects in the unipo- standard model is now a nosolytic one, in which lar domain. Fava in particular has argued that benefits are specific and nosolytic. A psycho- antidepressants while efficacious in resolvingF acute stabilizer, in contrast, would produce a serenic, disorders may in fact lead to further episodes by a sedative or anti-irritability effect that would have sensitization process (43). demonstrable benefits across a range of syndromes. A related area of interest in the treatmentO of The literature on lithium culminating in Sheard’s unipolar disorders has lain in the notion that 1971 trial now suggests that far from being specific treatment should aim at restoring well-being rather for manic-depressive illness lithium may be an than simply ameliorating the mainO features of agent that among other things reduces the sensi- acute episodes. This domain links to the issue tivity to events in the environment so that the of relapse to antidepressants in that the existence of disruptive impact of these events on internal mood subclinical or residual symptomsR is the biggest states is minimized. Such an effect has a clear single predictor of future relapse (44). functional utility that conceivably could produce In a study that bears on both these points benefits across a range of psychosyndromes, other Tranter et al. (45) haveP recently provided evidence than manic-depressive illness. Carbamazepine and that subjects may be constitutionally predisposed valproate appear to produce somewhat different to respond optimally to agents selective to partic- but broadly serenic effects. For this alternative ular systems and that these agents have distinctive model to attract support it would be necessary to functional effects. The implication of these data is specify the differences between these agents and that individualsD may respond less well if at all to lithium in sufficient detail to account for the agents acting primarily on the wrong system for conventional clinical wisdom and trial evidence them. Such sub-optimal responses can be expected that carbamazepine and valproate may be more to be moreE likely to lead to further illness episodes useful than lithium for mixed mood disorders and than would optimal responses. There is no reason less beneficial in classic manic-depressive illness. to believeT that similar considerations will not also This latter formulation of course stems from a apply to the mood-stabilizers. period when lithium was viewed of as being all but specific to manic-depressive illness in a way that CPerspectives for the future was never the case for carbamazepine or valproate. Some specification of differential functional A number of consequences stem from the above effects is possible. Valpromide and valproate wereE formulation. It has proven all but impossible to discovered initially through their use in mania and demonstrate prophylactic efficacy for agents, other because of their particular ÔsedativeÕ properties. than perhaps lithium, in the case of manic-depres- Sedation is a therapeutic principle that makesR sense sive disorders. A proper trial demonstrating such in the management of manic states. Lamotrigine in effects would run for many years and would contrast appears to be more effective in the depres- demonstrate a reduced frequency of episodes, an sive poles of manic-depressive disorderR and this is an increase in the inter-illness interval compared with agent that far from being sedating is more likely to placebo and would also demonstrate that these be described in terms of its euphoriant properties effects outweigh any disruption produced by with- (42). There is some basis therefore for arguing that drawal syndromes on discontinuation. In practice lithium, carbamazepine, valproateO and lamotrigine it has proved impossible to sustain a seriously ill all have functional effects that have face validity in patient group in such a trial. terms of managing various phases of manic-depres- However another method of evaluating treat- sive disorders. The implicationC of this formulation ments opens up if the focus switches to their more however is that while these agents are now thought immediate functional effects. If patients on any of of as being a homogenous group, they may in fact be these agents identify a specifically useful effect quite diverse agentsN all of which have a certain utility produced by that agent, this would de facto when used judiciously in manic depressive states. produce a rationale for continuing treatment with that agent in that particular person. Trials could U conceivably compare outcomes in patient groups Psychotropic utility and psychotropic efficacy who could identify beneficial functional effects Recently two further conceptual issues have been compared with those who could not do so. The raised in the domain of mood disorder therapeutics. ultimate benefits of such an approach however will 5 Harris et al. depend critically on practitioners identifying useful 12. 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6 Mood-stabilizers: the archeology of the concept

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Dear Author, During the copy-editing of your paper, the following queries arose. Please respond to these by marking up your proofs with the necessary changes/additions. Please write your answers on the query sheet if there is insufficient space on the page proofs. Please write clearly and follow the conventions shown on the attached corrections sheet. If returning the proof by fax do not write too close to the paper’s edge. Please remember that illegible mark-ups may delay publication.

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Query Query Remarks reference Q1Au: Please provide Fax number if applicable. Q2 Au: Please supply upto six keywords for indexing. MARKED PROOF ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Please correct and return this set ÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐÐ Please use the proof correction marks shown below for all alterations and corrections. If you wish to return your proof by fax you should ensure that all amendments are written clearly in dark ink and are made well within the page margins.

Instruction to printer Textual mark Marginal mark Leave unchanged under matter to remain Stet Insert in text the matter New matter followed by indicated in the margin Delete through matter to be deleted Delete and close up through matter to be deleted Substitute character or through letter or through New letter or new word substitute part of one or word more word(s) Change to italics under matter to be changed Change to capitals under matter to be changed Change to small capitals under matter to be changed Change to bold type under matter to be changed Change to bold italic under matter to be changed Change to lower case Encircle matter to be changed Change italic to upright type (As above) Insert `superior' character through character or where under character required e.g. Insert `inferior' character (As above) over character e.g. Insert full stop (As above) Insert comma (As above) Insert single quotation marks (As above) and/or Insert double quotation (As above) and/or marks Insert hyphen (As above) Start new paragraph No new paragraph Transpose Close up linking letters Insert space between letters between letters affected Insert space between words between words affected Reduce space between letters between letters affected Reduce space between words between words affected