Doi:10.1016/j.jad.2007.09.012

Journal of Affective Disorders 108 (2008) 1 – 9 Discovery and development of lamotrigine for bipolar disorder: A story of serendipity, clinical observations, risk taking, and persistence Richard H. Weisler a,⁎, Joseph R. Calabrese b, Charles L. Bowden c, John A. Ascher d, a University of North Carolina at Chapel Hill and Duke University Medical Center, United States b Case Western Reserve University/University Hospitals Case Medical Center, United States c University of Texas Health Science Center, San Antonio, Texas, United States d GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina, United States e Duke University Medical Center and the University of North Carolina at Chapel Hill, United States Received 27 June 2007; received in revised form 7 September 2007; accepted 26 September 2007 This paper briefly reviews and comments on the development of lamotrigine as a treatment for bipolar disorder. The events described include astute clinical observations by epileptologists, serendipitous coupling of the drug's clinical profile to unmet needof two refractory bipolar patients by a practicing psychiatrist, risk taking on the part of an industry sponsor, and persistence on thepart of a few key internal and external advocates to see development through to its conclusion, taking place against a backdrop of adisease area which, at the time of the earliest events described here, had not seen the development of any new pharmacologictreatments for decades. Fortunately for patients, since that time there has been a veritable explosion of research into treatments forbipolar disorder, both old and new, so that now patients and physicians have multiple evidence-based options for the treatment ofthis devastating illness. The development of lamotrigine provides one example of the importance of prescience, patience andpersistence in bringing a novel idea to clinical fruition.
2008 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder; Lamotrigine; Lithium; Carbamazepine Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Discovery and early development of lamotrigine for epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
First treatment experiences in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Convincing the sponsor to study lamotrigine for bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The first clinical trial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Subsequent development of lamotrigine in bipolar disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
0165-0327/$ - see front matter 2008 Elsevier B.V. All rights reserved.
doi: R.H. Weisler et al. / Journal of Affective Disorders 108 (2008) 1–9 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Role of the funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 Conflicts of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6Appendix A. Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 to an unmet need for antiepileptic drug (AED) treatmentswith improved safety profiles and wider therapeutic There are three principal means of acquiring knowl- indices At the time it was first synthesized edge available to us: observation of nature, reflection, in the early 1980s, no new drugs had been successfully and experimentation. Observation collects facts; developed for the treatment of epilepsy for over thirty reflection combines them; experimentation verifies years. Based on evidence dating from the mid-1960s that the result of that combination. — Denis Diderot, On folate was proconvulsant and the suggestion that many the Interpretation of Nature — 1753.
AEDs in use at the time were folic acid antagonistsa rational drug discovery Serendipity has often been the engine of drug program was initiated with pyrimethamine, a drug development, especially in psychopharmacology. Many previously developed for the treatment of malaria.
of the first drugs used to treat psychiatric illnesses (e.g.
Among the series of compounds developed, lamotrigine iproniazid, imipramine) were originally developed to was found to have considerable anticonvulsant activity in treat other illnesses ). In these cases, clinical animal models, although it ultimately proved to be only a observations in patients suffering from other disorders weak inhibitor of dihydrofolate reductase.
provided the impetus for testing and development of Lamotrigine first entered human phase I studies in drugs as treatments for their ultimate therapeutic targets.
the early 1980s, and was demonstrated to be rapidly Similarly, Cade's discovery of the mood stabilizing absorbed with high bioavailability after oral dosing, and properties of lithium was originally driven by general to have linear pharmacokinetics, no active metabolites, observation of its CNS effects in animals ), and a half-life of approximately one day whereas the anticonvulsant properties of valproate were An extensive series of clinical trials culminated in its accidentally discovered when it was used as a solvent for first approval for use in epilepsy in 1990 in Ireland, followed by worldwide regulatory approvals for epi- ). Overall, the absence of well-established lepsy over the next several years. In 1994 the FDA animal models for mood bipolarity has not permitted the approved lamotrigine for adjunctive use in epilepsy in more systematic pattern of drug development that has the US. The early epilepsy clinical trials also provided a been the recent model for some of the other psychiatric signal of potential clinical utility outside of epilepsy, in disorders such as major depression. As a result, drug the form of improved mood and communicativeness of discovery in bipolar disorder has almost exclusively been patients receiving lamotrigine treatment driven by clinical observation of the potential mood ). This was reminiscent of earlier observations with stabilizing properties of existing medications made by other anticonvulsants, especially valproate and carba- clinicians desperately in pursuit of treatment alternatives mazepine, which had originally led to the suggestion for their patients. This has been the case regarding the use that AEDs might be useful in the treatment of bipolar of antiepileptic drugs in bipolar disorder (although it is now clear that not all drugs of this class are effective in Robert Post and colleagues at the National Institute of Mental Health (NIMH) hypothesized that an overactive this description of events leading to the development and limbic system was implicated in mood swings, leading licensing of lamotrigine for the treatment of bipolar to the search for, and testing of therapeutic agents like carbamazepine that were effective in animal models oflimbic epilepsy 2. Discovery and early development of lamotriginefor epilepsy 3. First treatment experiences in bipolar disorder The phenyltriazine lamotrigine was originally synthe- The first recorded use of lamotrigine in bipolar sized by scientists at Wellcome Laboratories in response disorder, presented at the 1994 annual meeting of the R.H. Weisler et al. / Journal of Affective Disorders 108 (2008) 1–9 tolerated and the patient exhibited no evidence of provides an interesting example of serendipity cycling. Seven months after lamotrigine treatment was and clinical observation in drug development. Weisler initiated, the patient experienced a depressive relapse had first heard of lamotrigine in the late 1980's while when he ran out of the drug because of delays in its conducting clinical trials with another investigational clearing US Customs. He took half of his normal dose drug (bupropion). He also had occasion to attend an for 3 days and then was off medication for 4 full days.
international meeting in Japan in 1990 where, because At that time, the patient reported a marked increase in of EEG and evoked potential research he was sleep and appetite disturbances, anxiety, and psycho- conducting, he had the opportunity to interact with motor retardation, as well as feelings of fatigue, European epileptologists who had early clinical sadness and guilt despite continuing his lithium experiences using lamotrigine in epilepsy. Weisler therapy at the same dose. His 31-item Hamilton was then treating two long-term private patients with Depression Rating Scale (HAM-D) total score was 34.
bipolar disorder who had failed to respond to any of About one week after resuming lamotrigine treatment several licensed and experimental treatments available at his old dose, the patient reported an alleviation of at the time. Based on the previous work of vegetative symptoms and a return to his normal energy level, with a decrease in HAM-D total score to lamotrigine's potent anti-kindling effects and its 2. The patient continued to derive significant benefit sodium channel blockade and resultant anti-glutama- from lamotrigine over a period of more than ten years, tergic activity might be helpful for the treatment of although he still occasionally experienced affective bipolar disorder. Weisler recalls discussing these cases in 1993 with one of the authors (JAA) who was on Following this encouraging result, Weisler discussed the medical staff of the sponsor, only to learn that the possible use of lamotrigine with another refractory lamotrigine would not be available in the U.S. for at patient and her family. This second patient was a 77 year-old female who had also been a long-term Shortly after this conversation and before hearing private patient with a 50-year history of a Bipolar I about any other responses of bipolar patients to mood disorder, characterized by a predominance of lamotrigine, Weisler shared the information about the major depressive episodes (but also including manic anticipated date of FDA approval with one of his episodes dating from the 1960s) and several serious most refractory patients, a 43 year-old white male suicide attempts and psychiatric hospitalizations. Pre- with Bipolar II disorder who had experienced many vious treatments had included maintenance ECT, years of depression followed by several years of rapid lithium, carbamazepine, valproate and a variety of cycling (averaging 8 cycles/year) of hypomanic and antidepressants. She had shown some response to depressive episodes. Previous treatments had included carbamazepine but complained of sedation, which led lithium, carbamazepine, ECT, clonazepam, valproate, to non-compliance. In August of 1993 she was 11 different antidepressants (including some that were hospitalized again for a severe psychotic depression only available in Europe at the time), buspirone, and was practically catatonic — not speaking, eating or levothyroxine, verapamil and phototherapy. Although ambulating unassisted. Since treatment options avail- the patient showed some response to several treat- able at the time had been exhausted, Weisler obtained ments, he continued to cycle and tended to tolerate informed consent from the patient and family, and again most medications poorly. The patient gave informed lamotrigine was imported from Europe under an FDA consent to undergo experimental treatment with compassionate use exemption. Treatment was initiated lamotrigine and was able to import it from Europe at 50 mg bid (higher than the currently recommended under an FDA compassionate use exemption. Treat- starting dose) and then increased to 100 mg bid 1 week ment was initiated at 25 mg q.a.m. and 50 mg q.h.s.
later in addition to her only other medication at the time, as was customary at the time (higher than the a stable dose of levothyroxine. The patient demonstrated currently recommended starting dose) and added to steady clinical improvement over the next few weeks a treatment regimen of lithium carbonate, bupropion, and began to interact with staff and her family on her and levothyroxine. The patient noted that addition of own initiative. After discharge, she maintained a high lamotrigine produced immediate improvement in level of functioning and was able to participate in and mood and energy. Over the next 4 months the enjoy normal activities. At the time of the 1994 APA lamotrigine dose was escalated to 400 mg/day and presentation, she had evidenced no further manic or bupropion was discontinued. Lamotrigine was well psychotic symptoms and according to self and family R.H. Weisler et al. / Journal of Affective Disorders 108 (2008) 1–9 report, had experienced her longest period of stability of lamotrigine with a relatively large (n = 75) and in the past 4–5 years. The patient remained much lengthy (6 months, later amended to 12 months) improved to very much improved for many years on the open-label study of patients in all active phases of combination of lamotrigine and levothyroxine.
In the discussion section of their 1994 poster, Considering that clinical data were only available Weisler, et al commented that while carbamazepine from two patients at the time, the decision to commit and valproic acid were efficacious in bipolar disorder substantial resources to a clinical trial was a risky, they were more effective for controlling mania than although ultimately successful, strategy on the part of depression, especially in rapid cycling patients. They the sponsor. However, during the time that the open- wrote, “ It is interesting to note that via clinical label study was being organized and conducted, other impressions and patient self-reports, these patients' investigators began conducting series of open-label depressive symptomatology has been markedly trials with lamotrigine in various phases of bipolar reduced.” They also referenced a personal communica- disorder. These began to appear in the scientific tion from Professor Nicol Ferrier, MD in the UK that literature in 1996, beginning with the description several of his patients had demonstrated a favorable response when treated with lamotrigine.
refractory rapid cycling patient, and followed by otherdescriptions (e.g., 4. Convincing the sponsor to study lamotrigine for responses to lamotrigine treatment in a variety ofrefractory patients, usually characterized by promi- Following the initial case presentations and the nent depressive symptomatology and/or rapid cycling.
interest that they generated, a series of meetings took place between the sponsor (including one of success with lamotrigine monotherapy in a series of the authors [JAA], as well as Charles Lineberry, newly diagnosed rapid cycling patients. As with who was instrumental in initially championing epilepsy patients, development of skin rash on development in bipolar disorder) and a number of lamotrigine was a concern, necessitating slow titration external consultants (Gary Sachs, Sue McElroy, at treatment initiation and, in a few cases, need to David Dunner, William Potter as well as including discontinue patients when rash occurred. The favor- authors RHW, JRC and CLB, the latter two of able results from these open case reports provided a whom played key roles in subsequent develop- supportive context and positive expectations for the ment). This was followed in 1994 by a meeting of conduct of subsequent clinical studies, some of which an international panel of bipolar experts at Well- come's Beckenham research facility in England(participants included authors JRC and CLB) to propose priority objectives for possible developmentof lamotrigine in psychiatric disorders and the most From January of 1995 through mid-1996 the sponsor promising research designs to employ. One outcome (originally Burroughs Wellcome, then GlaxoWellcome) from these meetings was the company's recognition conducted a large (n = 75), 12 month open-label study of of a need for new bipolar treatment options, lamotrigine (add-on or monotherapy) at 5 international especially those aimed at decreasing depressive symptoms and overall cycling as seen in Weisler's bipolar I and II patients in any phase of the disorder and initial two cases. The group surmised that if was designed to provide a preliminary assessment of the progress was going to be made in the medical spectrum of efficacy of lamotrigine against a variety of management of bipolar disorder, it would not have presentations, including mania, hypomania, depression, the luxury of being informed by animal models.
mixed states and rapid cycling. Patients were eligible Accordingly, an open study was conceptualized to whether or not they were currently receiving other drug evaluate the spectrum of efficacy of lamotrigine in treatments for their illness. Systematic assessments bipolar disorder. After reviewing the substantial allowed characterization of the behavioral profile of unmet need (at that time lithium was the only lamotrigine and assessment of both acute and continua- treatment licensed in most countries for the tion effects. As such, the study efficiently achieved treatment of bipolar disorder), the sponsor made what had been accomplished ad hoc in off label use the decision to commit to exploratory development of two other antiepileptic drugs, valproate and R.H. Weisler et al. / Journal of Affective Disorders 108 (2008) 1–9 carbamazepine, over more than two decades of use by numeric but not statistical separation from placebo on psychiatrists prior to initiation of well-controlled symptoms of mania. A 6-week add-on study enrolling studies. The results, although uncontrolled, suggested 229 patients showed no signal of efficacy for potential efficacy against both mania/hypomania (81% lamotrigine vs. placebo, while demonstrating clear marked response rate, 74% decrease in Mania Rating assay sensitivity as evidenced by significant separation Scale scores) and depression (48% marked response from placebo of a fully powered lithium arm. The rate, 42% decrease in Hamilton depression scores).
depression studies provided mixed results. The first Secondary analyses suggested benefits in rapid cycling as well as non-rapid cycling patients and more reach statistical significance (p = 0.08) on the primary prominent benefits on depressive aspects of the illness endpoint (Hamilton 17-item depression scale), but did separate significantly on a number of other key The drug was generally well-tolerated with the most measures including MADRS, Hamilton depressed common drug-related adverse events being dizziness, mood item (item 1) and CGI severity and improvement.
tremor, somnolence, headache, nausea, and rash. Based To the authors' knowledge, this study was the first on these results, the sponsor embarked on a full large-scale, placebo-controlled, parallel-group mono- development program for lamotrigine in bipolar dis- therapy study ever to be conducted in a pure population order, with the hope that the medication would prove to of bipolar depressed patients. Despite these encoura- be a genuinely bimodal mood stabilizer, i.e. effective ging results, the 4 studies that followed, which included both separate and mixed populations of bipolar I and IIpatients, failed to provide clear efficacy signals in the 6. Subsequent development of lamotrigine in bipolar acute treatment of depression, although a recent meta- analysis of all the studies suggests a small butsignificant treatment effect Between 1996 and 2001 the sponsor (eventually Because of the need to titrate lamotrigine far more GlaxoSmithKline) initiated and completed one of the slowly (i.e. over a 6 week period to avoid rash) than largest and most ambitious Phase III development originally used by Weisler or epileptologists prior to programs ever undertaken in bipolar disorder, under 1994, it is possible that lamotrigine's failure in most of the direction of one of the authors (JD-G). The program these studies (which were a maximum of 10 weeks in originally consisted of 10 double-blind, controlled duration) was due to delay in reaching therapeutic trials, including 2 studies of the acute treatment of levels. The designs employed in these acute studies bipolar depression (later expanded to 5), 2 studies of utilized change on either the Hamilton or MADRS the acute treatment of mania, and 4 prophylaxis studies rating scale total scores as the primary measure of (1 each in recently stabilized manic and depressed efficacy. Analyses of change on components of patients, and 2 in rapid cycling patients) that enrolled a depressive symptomatology, both based on individual total of more than 2400 patients across 4 continents.
items and a factor analysis of Hamilton scores from Because previous bipolar disorder drug development acute studies, provided more positive evidence of programs (e.g., for lithium, valproate) were conducted specific acute benefits on depressive cognitions and entirely in North America, the lamotrigine program became the first major bipolar development to be analyses also indicate that lamotrigine had no or conducted internationally, a practice followed for minimal benefits on some items of these scales, e.g., subsequent industry programs (e.g. atypical antipsy- insomnia and reduced appetite. More recently, lamo- chotics). Full results of all of these studies have been trigine has also demonstrated efficacy as add-on therapy to lithium in the acute treatment of bipolar depression available on the sponsor's public clinical trial register The prophylaxis studies produced clearer results, The hope for acute bimodal efficacy was not borne especially in non-rapid cycling patients. The latter out by the placebo-controlled trials. Neither of the mania studies demonstrated efficacy. A 3-week mono- therapy study enrolling a total of 215 acutely manic and depressed patients at study entry) that allowed patients showed no differences (better or worse) from open stabilization on any combination of drugs placebo for lamotrigine 50 mg, whereas an under- including lamotrigine, followed by randomization to powered active control arm (lithium, n = 36) exhibited parallel groups receiving monotherapy with either R.H. Weisler et al. / Journal of Affective Disorders 108 (2008) 1–9 lamotrigine, lithium or placebo. Patients were then ges in management, issues with slow enrollment, followed for up to 18 months, with the primary reporting of several negative studies and limited patent endpoint being time to the next mood episode life, the program owes a great debt to a few strong (operationalized as the need to intervene with addi- internal and external advocates who argued persua- tional treatment) assessed by survival analytic meth- sively against multiple attempts to curtail or terminate ods. The studies showed that both lithium and it, allowing it to survive to its eventual outcome.
lamotrigine delayed time to intervention for any Unfortunately, such conflicting priorities and unex- mood episode in both recently depressed and (some- pected complications are not uncommon in psycho- what surprisingly for lamotrigine, given the acute pharmaceutical drug development, as exemplified by mania results) manic patients, with differing and the difficult development pathway for lithium, which potentially complementary spectra of action (lithium took more than 20 years to achieve licensing after more efficacious for mania prophylaxis, lamotrigine Cade's initial observations in the 1940s. Similarly, more efficacious for depression prophylaxis). These carbamazepine was only approved for bipolar disorder studies remain two of the largest and longest bipolar maintenance studies ever conducted (over 1300 26 years after Ballenger and Post's article appeared patients were initially enrolled), and provide some of and 32 years after Okuma's original astute observa- the most compelling evidence of maintenance efficacy tions were reported. Although the latter programs for lithium uncontaminated by potential treatment faced different fundamental problems (the develop- discontinuation artifacts. Largely based on these 2 ment of a therapy with little perceived prospect for studies, lamotrigine has been granted a license for the financial return on investment in the cases of lithium maintenance treatment of bipolar disorder in over 50 and carbamazepine), in all of these cases, because of countries worldwide. These remain the only large- the ingenuity of a few clinicians, the willingness of a scale studies to date to account for the polarity of the pharmaceutical sponsor to listen to their experiences, acute presenting episode (i.e., depressed or manic) on and the persistence of individuals both inside and the spectrum of performance of a treatment for bipolar outside of industry to see the development through, novel treatments for bipolar disorder were carefully The lamotrigine development program was also the studied and found to be of benefit. Today millions of first to enroll pure populations of rapid cycling patients have benefited from the addition of these and patients into placebo-controlled clinical trials. These other novel approaches to the treatment armamentar- studies did not provide clearcut evidence of efficacy, although one of them showed supporting evidence ofefficacy (prolonged overall survival in study, which was not the primary endpoint) and a positive signal in Most of the studies described in this paper were sponsored by the subset of bipolar II patients enrolled ( GlaxoSmithKline or its predecessor companies (Glaxo Wellcome, Glaxo). No funding was provided by the sponsor for the writing of thispaper other than the fact that Drs. Ascher and Evoniuk are fulltimeemployees of GSK.
The development of lamotrigine for bipolar dis- In the past three years, Dr. DeVeaugh-Geiss has been a consultant order provides an interesting story of serendipity, to Voyager Pharmaceutical Corporation, and served as Voyager's clinical observation, and a willingness to take on a interim Chief Medical Officer from January 2006 to May 2007. He major financial risk on the basis of very limited, but was a member of the Board of Directors for Vela Pharmaceuticals, and ultimately convincing clinical experience. Given the has been a consultant to Pozen Pharmaceuticals, Schwarz Biosciences, increasing costs of conducting clinical research, it is Jazz Pharmaceuticals, JDS Pharmaceuticals, GlaxoSmithKline, andNeurotherapeutics.
doubtful that most sponsors today would consider Dr. DeVeaugh-Geiss is a shareholder in GlaxoSmithKline, Pozen investment in a one-year trial based on anecdotal Pharmaceuticals, and Voyager Pharmaceutical Corporation.
evidence from two patients, let alone embark on a Dr. DeVeaugh-Geiss is a former employee of GlaxoSmithKline, 2000 patient development plan, based entirely on Glaxo Wellcome, and Glaxo. He was directly involved with the open-label experience. Moreover, given the challenges development program for lamotrigine in Bipolar Disorder and epilepsy that jeopardized the conduct of the program (two Drs. Ascher and Evoniuk are both full time employees of corporate mergers of large international research GlaxoSmithKline and former employees of Glaxo Wellcome and pharmaceutical companies) with corresponding chan- Glaxo. Both own stock in GlaxoSmithKline.
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