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).