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Bipolar disorder, today, can be defined as a brain disorder that causes changes in a persons mood and energy that cause significant impairment in daily functioning. It can be categorized into three different conditions: bipolar I, bipolar II, and cyclothymic disorder. Symptoms-wise, patients with bipolar disorder experience mood episodes in which they experience extreme and intense emotional states. These mood episodes can further be categorized as manic, hypomanic, or depressive. Patients with bipolar disorders also generally have periods of normal mood in between the manic, hypomanic, or depressive states. Today, as a result of many significant contributions from various influential people, bipolar disorder can be treated, and patients can generally lead full and productive lives. Treatment is individualized to meet each individual patients needs, and it most commonly includes mood stabilizers and antidepressants, depending on the specific symptoms. If depression symptoms are severe and the patient does not respond to medication, ECT can also be considered. [1] However, this current understanding of bipolar disorder symptomatology and treatment has a remarkable and elaborate background.

Bipolar disorder is perhaps one of the oldest known mental illnesses. The origins of bipolar disorder can be traced back to humoral medicine. Starting with the classical Greek physician, Hippocrates (430-377 BC), and disseminating even wider by Roman Galen (129-216 AD), the basic idea of balance behind humorism was developed. It was the understanding that balance was needed between the four humors found in the human body: black bile, yellow bile, blood, and phlegm. Each of these humors represented different qualities. For example, back bile was cold and dry, yellow bile was hot and dry, blood was hot and wet, and phlegm was cold and wet. With these combinations of different qualities, the four humors also matched the four seasons, the four elements, and four different emotional characteristics. Specifically, they represented different temperaments: black bile was melancholic, yellow bile was choleric, blood was sanguine and phlegm was phlegmatic. Melancholic people were described as despondent and gloomy. Choleric people were described as bad-tempered. Sanguine people were courageous, hopeful, and amorous. And phlegmatic people were calm, cool, and unemotional. [2]

The classical practice of medicine at that time focused on balancing these humors by changing everyday life things, such as diet, lifestyle, occupation, and climate, or by administering medication. The focus on balance was also believed to be key to maintaining emotional well-being, as melancholic people were believed to have excess black bile, and manic people were believed to have excess blood or yellow bile causing the problem. [2] Although nowadays we still consider balancing an integral part of treatment, with the continual discovery of pharmacology, the treatment of bipolar disorder has made leaps and strides moving from balancing humor to treat mania to considering the implication of genetics on this disorder and the use of psychopharmacology with the discovery of lithium and later more modern options such as lamotrigine.

The journey of shifting from mania to bipolar disorder continued throughout the 19th century when the terms mania with delirious and non-delirious states were established by Philippe Pinel. He also hypothesized that mania was closely linked to psychosis. Then, halfway through the 19th century, with the rise of a new mentality, the anatomoclinic mentality, semanticist movements began to emerge in the field of psychiatry. Following with these new movements, Jacques-Joseph Moreau de Tours and Wilhelm Griesinger suggested a structural alteration of the brain as an etiological basis of madness. Finally, during this same anatomoclinical period, Emil Kraepelin, at the end of the 19th century devised the concept of manic-depressive psychosis and separated this disorder from the dementia praecox or schizophrenia. Later, in the 1950s, Karl Leonhard was the first to introduce the concept of polarity in the understanding of affective disorders and this concept was later included in the DSM diagnostic criteria. [3]

Despite this elaborate history, bipolar disorder did not always receive the properly deserved scientific and social recognition it enjoys today. This can potentially be attributed to scientific negligence at the time when compared to other psychiatric disorders such as major depression or schizophrenia, the lack of knowledge about its etiology or pathogenesis, the underestimation of its prevalence, and the general underdevelopment of treatments that had not been amended until about 2 decades ago. As a matter of fact, until the mid-1990s, before valproic acids anti-manic effects were demonstrated, the only medication available for treating bipolar patients was lithium. In parallel to valproic acid, carbamazepine (another anti-epileptic medication), was also developed for the treatment of patients with bipolar disorder. Finally, since 2000, different atypical antipsychotics have been approved by the FDA to use for antigenic or antidepressant indications. Lamotrigine, a modern anti-epileptic medication was authorized in 2003 for the prevention of depressive episodes in bipolar disorder. [3]

However, obtaining the approval to use lamotrigine for bipolar disorder was not an easy task. The development of lamotrigine for bipolar disorder provides an interesting story of chance, clinical observation, and a willingness to take on major financial risks despite the limited but convincing clinical experiences. Like many things in medicine, chance is often the driving force in new discoveries. Many of the medications used to treat psychiatric conditions such as iproniazide and imipramine were first developed to treat other conditions. And similarly, Cades discovery of lithiums mood-stabilizing properties was originally driven by observations of its CNS effects on animals. Even the anticonvulsant properties of valproic acid were accidentally discovered when it was being used as a solvent for other agents being tested in animals. Overall, the lack of well-established animal models for mood bipolarity has not permitted the more systematic pattern of medication development that has been seen in other disorders such as major depression. As a result, treatment discovery for bipolar disorder has almost exclusively been driven by clinical observations of potential mood-stabilizing properties that existing medication can offer. These discoveries are often made by physicians who are looking for treatment alternatives for their patients. This was the case in the development and licensing of lamotrigine as a treatment option for bipolar disorder.

Lamotrigine was first synthesized in the early 1980s after no medication for the treatment of epilepsy had been developed for over thirty years. Lamotrigine first entered human phase I studies in the early 1980s, where it was demonstrated to be rapidly absorbed, have high bioavailability with oral dosing, linear pharmacokinetics, no active metabolites, and a half-life of approximately 1 day. An extensive series of clinical trials followed these phase I studies which led to the approval of lamotrigine for use in epilepsy in 1990 in Ireland, followed by worldwide regulatory approvals for epilepsy over the next several years. In 1994, in the United States, the FDA approved it for adjunctive use in epilepsy.

The first recorded use of lamotrigine in the treatment of bipolar disorder was presented at the 1994 annual meeting of the American Psychiatric Association. Dr. Weisler can be credited for first identifying lamotrigines usefulness in bipolar disorder treatment back in 1993. He was the first to present his successful treatment using lamotrigine with two of his severely treatment-resistant patients. Dr. Weislers clinical observations and theory about lamotrigines positive impact on depressive symptoms and mood cycling helped propel further research that led to lamotrigine being approved in 2003 by the FDA as the first new medication for the maintenance treatment of bipolar in 30 years. [5] More in-depth, this story provides an interesting example of serendipity and clinical observation in medication development.

Dr. Weisler had first heard of lamotrigine in the late 1980s while he was conducting clinical trials with bupropion. At that time, he was then treating two of his long-term private patients with bipolar disorder who had failed to respond to any of several licensed and experimental treatments available at that time in the United States. Based on previous work of Ballenger, Post, and others, Dr. Weisler then speculated that lamotrigines potent anti-epileptic effects, its sodium channel blockade effects, and anti-glutamatergic activity might be helpful for the treatment of bipolar disorder. Unfortunately, lamotrigine was not currently approved for the treatment of bipolar disorder in the United States, and it would not be available in the U.S. for at least an additional year.

Nonetheless, Dr. Weisler shared the information about the anticipated date of FDA approval with one of his most treatment-resistant patients. This patient was a 43-year-old white male with Bipolar II disorder who had experienced many years of depression followed by several years of rapid cycling (about 8 cycles/year) between hypomanic and depressive episodes. He had tried several prior treatments including lithium, carbamazepine, ECT, clonazepam, valproate, 11 different antidepressants, buspirone, levothyroxine, verapamil, and phototherapy. Although he did show some response to several of these treatments, he continued to cycle and tolerated most medications poorly. When the patient heard about lamotrigine, he gave informed consent to undergo experimental treatment and was able to import it from Europe under an FDA compassionate use exemption. This new medication was added to his treatment regimen of lithium, bupropion, and levothyroxine. The dosing of lamotrigine was started at 25 mg every morning and 50 mg at night. The patient noted that the addition of lamotrigine produced immediate improvement in his mood and energy. Given his positive response to the treatment, over the next 4 months, the dose of lamotrigine was titrated to 400 mg every day and bupropion was discontinued. He tolerated lamotrigine well and exhibited no evidence of cycling while on it. Seven months after he initiated treatment with lamotrigine, unfortunately, the patient experienced a depressive relapse when he ran out of the medication, but about one week after resuming lamotrigine at his old dose, the patient reported an improvement in his symptoms and returned to his normal energy level. He continued to notice significant benefits from lamotrigine over a period of more than ten years. This remarkable clinical story not only highlighted the value of lamotrigine in the treatment of bipolar disorder but also shed light on potentially helping other treatment-resistance patients in the future.

Following this encouraging result, Dr. Weisler discussed the possible use of lamotrigine with another of his treatment-resistant patients. This second patient was a 77-year-old female with a 50-year history of Bipolar I mood disorder, with predominant major depressive episodes, several serious suicide attempts and psychiatry hospitalizations, and a few manic episodes dating beginning in the 1960s. She had also tried several previous treatments including ECT, lithium, carbamazepine, valproic acid, and a variety of antidepressants. She had shown some improvement with carbamazepine but experienced sedation as a side effect. Since treatment options available at the time had been exhausted, Dr. Weisler obtained informed consent to use lamotrigine, and again it was imported from Europe under an FDA compassionate use exemption. Treatment was initiated at 50 mg twice a day and then one week later it was increased to 100 mg twice a day. Lamotrigine was an adjunct to her current medication regimen which included only a stable dose of levothyroxine. Over the next several weeks after the initiation of the treatment the patient demonstrated steady clinical improvement. She was able to maintain a high level of functioning and was able to participate in and enjoy normal activities. At the time of the 1994 APA presentation where lamotrigine was presented as a potential treatment for bipolar disorder, she had evidenced no further manic or psychotic symptoms and was experiencing her longest period of stability in the past 45 years.

Considering that clinical data was only available from these two patients at the time, the decision to commit substantial resources to a clinical trial was risky but ultimately successful. During the time that an open-label study was being organized and conducted, other investigators also began conducting a series of open-label trials with lamotrigine in various phases of bipolar disorder. These began to appear in the scientific literature in 1996, beginning with the description (Calabrese et al., 1996) of the response of a treatment-refractory rapid cycling patient, and followed by other descriptions (e.g., Walden et al., 1996, Sporn and Sachs, 1997, Kusumakar and Yatham, 1997a) of responses to lamotrigine treatment in a variety of refractory patients, usually characterized by prominent depressive symptoms and/or rapid cycling. Lamotrigine was also shown to be successful as a monotherapy in a series of newly diagnosed rapid cycling bipolar patients by Kusumakar and Yatham (1997b). However, as with its anti-epileptic use, the development of a skin rash with lamotrigine was a concern. Therefore, slow titration at treatment initiation was done and in a few cases, the treatment was discontinued when patients experienced a rash. The favorable results from these open case reports provided a supportive ground and help build positive expectations for conducting subsequent clinical studies, some of which did not produce positive results.

From January of 1995 through mid-1996, the sponsor (originally Burroughs Wellcome, and then GlaxoWellcome) conducted a large (n = 75), 12-month open-label study of lamotrigine used as both an add-on or monotherapy at 5 international study sites (Calabrese et al., 1999a). The results, although uncontrolled, suggested a potential efficacy against both mania/hypomania (81% marked response rate, 74% decrease in Mania Rating Scale scores) and depression (48% marked response rate, 42% decrease in Hamilton depression scores). Secondary analyses further suggested benefits in rapid cycling as well as non-rapid cycling patients and a more prominent benefit was noted in the depressive aspects of bipolar disorder (Bowden et al., 1999). Lamotrigine was generally well-tolerated with the most common side effect being dizziness, tremor, somnolence, headache, nausea, and sometimes a rash. Based on these promising results, the sponsor embarked on a full development program for lamotrigine in bipolar disorder, with the hope that the medication would prove to help both the mania and depressive symptoms.

Between 1996 and 2001 the sponsor (eventually GlaxoSmithKline) initiated and completed one of the largest Phase III development programs ever undertaken in bipolar disorder. The program originally consisted of 10 double-blind, controlled trials, including 2 studies of the acute treatment of bipolar depression (later expanded to 5), 2 studies of the acute treatment of mania, and 4 prophylaxis studies (1 each in recently stabilized manic and depressed patients, and 2 in rapid cycling patients) that enrolled a total of more than 2400 patients across 4 continents. Because previous bipolar disorder drug development programs (e.g., for lithium, valproic acid) were conducted entirely in North America, the lamotrigine program became the first major bipolar development to be conducted internationally. However, neither of the mania studies demonstrated efficacy, and the depression studies provided mixed results.

The first study to complete (Calabrese et al., 1999b) did not reach statistical significance (p = 0.08) on the primary endpoint (Hamilton 17-item depression scale) but did separate significantly on a number of other key measures including MADRS, Hamilton depressed mood item (item 1) and CGI severity and improvement. Despite these encouraging results, the 4 studies that followed, which included both separate and mixed populations of bipolar I and II patients, failed to provide clear efficacy signals in the acute treatment of depression, although a recent meta-analysis of all the studies suggests a small but significant treatment effect (Geddes et al., 2007). Because of the need to titrate lamotrigine slowly (i.e. over a 6-week period to avoid rash) than originally used by Dr. Weisler, it is possible that lamotrigine’s failure in most of these studies (which were a maximum of 10 weeks in duration) was due to delay in reaching therapeutic levels. These secondary analyses also indicate that lamotrigine had no or minimal benefits on insomnia and reduced appetite. More recently, lamotrigine has demonstrated efficacy as an add-on therapy to lithium in the acute treatment of bipolar depression (van der Loos and Nolen, 2007).

The prophylaxis studies produced clearer results, especially in non-rapid cycling patients. The latter consisted of paired studies (Bowden et al., 2003, Calabrese et al., 2003, respectively enrolling manic and depressed patients) that allowed open stabilization on any combination of drugs including lamotrigine, followed by randomization to parallel groups receiving monotherapy with either lamotrigine, lithium or placebo. Patients were then followed for up to 18 months, with the primary endpoint being time for the next mood episode. The studies showed that both lithium and lamotrigine delayed time to intervention for any mood episode in both recently depressed and manic patients, with differing and potentially complementary spectra of action (lithium more efficacious for mania prophylaxis, lamotrigine more efficacious for depression prophylaxis). These studies remain two of the largest and longest bipolar maintenance studies ever conducted (over 1300 patients were initially enrolled), and provide some of the most compelling evidence of maintenance efficacy for lithium uncontaminated by potential treatment discontinuation artifacts. Largely based on these 2 studies, lamotrigine has been granted a license for the maintenance treatment of bipolar disorder in over 50 countries worldwide. These remain the only large-scale studies to date to account for the polarity of the acute presenting episode (i.e., depressed or manic) on the spectrum of performance of treatment for bipolar disorder in the maintenance phase. [4]

Overall, this journey that resulted in the use of lamotrigine for the maintenance treatment of bipolar disorder can serve as an example to show how the concept of balance still remains central in the treatment of psychiatric disorders. This serves as an example of how balancing the risks and benefits of trying a new medication can lead to a new discovery that will help patients’ symptoms be better controlled and live a more balanced life.

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