Lamotrigine: A Safe and Effective Mood Stabilizer for Bipolar Disorder in Reproductive-Age Adults

Introduction

Lamotrigine, as an anticonvulsant drug, was introduced in 1994 in the United States, when it was approved for the treatment of primary generalized tonic-clonic seizures and in seizures caused by Lennon-Gastaut syndrome [1]. Over time, its great potential was noticed in the treatment of affective diseases, such as bipolar disorder type 1 with predominance of depressive episodes, in maintenance treatment, and in rapid-cycling bipolar depression in adults [1]. Moreover, the results of several studies do not exclude the effectiveness of lamotrigine in the treatment of an acute depressive episode in the course of bipolar disorder [2]. The problem remains the need to gradually increase the dose to reach an effective level (200–300 mg/day), when a quick reaction is necessary in the acute phase of the disease [2,3]. In 2019, the proposed bipolar disorder treatment algorithm published by Giakoumatos and Osser in a Harvard study lists lamotrigine as one of the five treatment options for an acute episode of depression [2]. The authors reported that the decision belongs to the specialist and depends on the individual approach to the patient’s profile, especially regarding the reaction to adverse effects and the risk of turning into mania [2]. Numerous studies have shown the effectiveness and safety of lamotrigine in bipolar disorder, also in a pediatric population [4].

Epidemiology, Diagnosis, and Course of Illness of Bipolar Disorder

Bipolar disorder is a chronic and disabling mental illness that affects approximately 1% of the general population worldwide [5]. This is confirmed by bipolar disorder taking 46th place on the list of the most common causes of disability-adjusted life years worldwide [3]. In the ICD-10 criteria, the following conditions must be met for the final diagnosis of bipolar disorder. The current episode meets the criteria for hypomania, mania, a depressive episode. There has been at least one affective episode in the past (hypomanic, manic, depressive, mixed). At least one of these affective episodes was other than depressive episode, and the episodes were not caused by the use of psychoactive substances or organic disorders. The average age of onset is usually 15 to 25 years of age [6].

This is a special group of patients, including people who are of reproductive age, are able to start a family, and are experiencing the most important period of life in terms of professional and spiritual development [7]. It is crucial to provide appropriate and safe treatment options that do not have a teratogenic effect and or pose a significant burden on the metabolism, a description that best fits the mode of action of lamotrigine [7]. The onset of bipolar disorder is most often initiated by symptoms of depression, accounting for up to 75% of the symptoms presented during the development of the disease [6]. Between depressive episodes, patients experience recurrent episodes of mania or hypomania. Confirmed risk factors for the development of bipolar disorder include experiencing the first depressive episode at a young age (before the age of 25 years), having a diagnosis of many depressive episodes (5 or more) throughout life, and having a positive family history of bipolar disorder [8]. To detect the disease at an earlier stage in people with many risk factors, screening tools are used, including the Mood Disorders Questionnaire and the Hypomanic Symptoms Questionnaire [8]. In more than half of patients with bipolar disorder, there is co-occurrence with another psychiatric disease, including personality disorder, panic disorder, social phobia, and drug disorder [8]. Rapid cycling bipolar disorder (RCBD) is diagnosed with a minimum of 4 mood episodes meeting the criteria for depression, mania, or hypomania in the last 12 months [9]. According to the DSM-5, affective episodes must be separated by at least a 2-month period of complete or partial remission or a change to an episode of the opposite polarity [10]. It is estimated that RCBD affects up to 20% of people with bipolar disorder [9]. Treatment of patients in this group is more likely to be associated with a lower response to therapy with traditional mood stabilizers, a worse prognosis, and an increased risk of suicide [9]. Current guidelines for the treatment of bipolar disorder do not specify the specific treatment of RCBD [9]. Studies show promising effects of the use of lamotrigine as monotherapy in bipolar disorder type II with rapid phase change [11,12]. Increasingly, clinicians are observing the benefits of treating RCBD using polytherapy, with lamotrigine and lithium in more severe cases [9,12].

Indications for the Use of Lamotrigine

Lamotrigine, being a mood stabilizer, works by preventing the so-called “lows” [13]; therefore, in bipolar disorder type I it serves to prevent the recurrence of depressive episodes. On the other hand, lithium protects against the occurrence of excessive “highs” [13]. Numerous high-quality studies have reported fewer days of hospitalization during lamotrigine treatment than with other common methods of treating bipolar disorder [14]. The mood-balancing effect of lamotrigine was not observed to lead to euthymia, and consequently caused mood inversion and transformed into mania [13]. However, during the initial stages of lamotrigine treatment, the occurrence of symptoms of increased mood that did not yet meet the criteria for mania was associated with reduced effectiveness of the treatment in the future [13]. The latest Cochrane review extends the effect of lamotrigine, proving its bidirectional effect in also preventing mania in bipolar disorder, achieving a 33% lower probability of mania in a placebo trial, with a confidence interval of 0.51–0.87 [13]. This is undoubtedly an important topic to explore in the future.

Special Indication of Lamotrigine Treatment of Bipolar Disorder in Women of Reproductive Age

The treatment of bipolar disorder in women of reproductive age is a challenge for clinicians due to the teratogenic properties and adverse effects, including weight gain (especially with antipsychotics and valproate), of drug groups used in this disease [7]. This is a significant medical problem because of the fact that up to 50% of pregnancies in women with bipolar disorder are unplanned [7]. Studies confirm an increased risk of disease recurrence in women discontinuing treatment during pregnancy compared with in women continuing maintenance treatment [7]. The use of valproate during pregnancy is associated with the highest risk of congenital anomalies in the fetus [7]. Statistics describe the occurrence of serious congenital defects in 10% of fetuses, and up to 40% of children born have neurodevelopmental disorders [7]. For this reason, the use of valproate in the group of women of reproductive age with a bipolar disorder diagnosis should be limited to only women using concurrent contraception with proven high effectiveness [7]. Despite the common nature of these facts, in some places in the world there is still a higher percentage of use of valproate than of the safer lamotrigine in this group of patients [7]. The use of antipsychotic drugs is inextricably linked to metabolic dysfunction, causing weight gain [7]. This adverse effect is associated with discontinuation of treatment in young patients due to the deterioration of well-being and reduced attractiveness, which is so important in this age group [7]. Lamotrigine, compared with other mood stabilizers, is characterized by a higher safety profile in terms of teratogenicity and safety during breastfeeding [7]. Additionally, there was no negative effect found on the metabolic profile of patients, and it may even reduce body weight [2,7]. Finally, an important aspect is the predominance of depressive symptoms in women in this age group, compared with manic/hypomanic symptoms in the course of bipolar disorder, which lamotrigine can prevent to the greatest extent [7].

Adverse Effects of Lamotrigine

The most common adverse effects of lamotrigine include nausea and vomiting, dizziness, visual disturbances, and minor rash [15]. In the context of the safe use of lamotrigine, it is worth mentioning its weak inhibitory effect on dihydrofolate reductase [1], which can disturb the metabolism of folates necessary for the development of the embryo, especially in the first trimester. One of the most well-known and documented serious adverse effects of lamotrigine is the dermatological and mucous membrane necrosis known as Stevens-Johnson syndrome (SJS), manifesting as a skin rash.

SJS is a serious adverse effect, as the mortality rate is up to 10% [15]. The risk of occurrence of SJS is highest in the first weeks of treatment, and available statistics estimate the probability of its occurrence of 0.3% to 0.8% in children and 0.03% to 0.08% in adults [1]. Studies show a greater likelihood of experiencing a life-threatening rash when doses are increased too rapidly [3] and in cases of polytherapy with valproate [2]. However, most rashes occurring after the use of lamotrigine are mild [2]. Discontinuation of drug use, which is crucial in this clinical situation, does not guarantee the interruption of the toxic effect of the drug and the avoidance of serious complications [2]. Therefore, it is necessary to constantly monitor the evolution of changes occurring on the skin and mucous membranes and report this fact to a specialist [2]. The Food and Drug Administration (FDA) draws attention to the increased risk of serious arrhythmias when using lamotrigine [16]. Lamotrigine can have class Ib antiarrhythmic effects at specific therapeutic concentrations [16], which is related to the drug’s blocking of sodium channels [16]. This risk increases with concomitant heart disease and the use of drugs that affect cardiac conduction [17]. However, the latest FDA announcement from 2021, which was issued after the re-assessment of the safety profile of lamotrigine, withdrew the recommendation to avoid it in the presence of certain heart diseases and arrhythmias and emphasizes the significant consequences of its discontinuation [16]. The article devoted to this phenomenon focuses on lamotrigine as a drug with mainly antiepileptic properties; hence, it is necessary to conduct further research on lamotrigine as a drug used in bipolar disorder in the context of cardiac safety [16]. It is worth mentioning that the use of oral contraceptives is associated with an increase in drug clearance and reduced effectiveness [15].

Immunological Complications of Lamotrigine Use

We want to increase readers’ awareness of the occurrence of immune system disorders during therapy with lamotrigine. Hemophagocytic lymphohistiocytosis (HLH) is a set of symptoms resulting from immunological imbalance due to the excessive stimulation of lymphocytes and macrophages [18]. The occurrence of HLH is predisposed to genetic factors (HLH families) and sporadic factors, including viral infection, cancer, rheumatological diseases, and some medications [18]. Its final stage is multi-organ failure, resulting in a mortality rate of up to 75% [18]. The pathomechanism explaining the correlation between lamotrigine and the dysregulation of the immune system is not yet known [18]. The literature describes 8 cases of HLH occurring after the use of lamotrigine [18]. Discontinuation of lamotrigine and the use of glucocorticoids together with other immunosuppressive drugs in the initial stage of HLH allowed for clinical improvement [18]. HLH is a rare adverse effect, but it causes great diagnostic difficulties and a very unfavorable prognosis [18].

Another possible immune-related adverse effect of lamotrigine is drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome [19], which is a life-threatening hypersensitivity syndrome in response to various drugs, including lamotrigine [19]. The most dangerous complication is fulminant liver failure, the incidence of which is around 10% [19]. It is estimated that DRESS syndrome is experienced by as many as 1 in 1000 to 10 000 patients starting antiepileptic drug therapy [19]. The main symptoms include rash, swelling, and characteristic inflammation of the organs, including the liver, heart, and kidneys [19]. The mainstay of treatment is systemic glucocorticosteroids and discontinuation of lamotrigine [19].

Contraindications of Lamotrigine Use

The contraindication to the use of lamotrigine is the occurrence of rash with accompanying systemic symptoms, including gastrointestinal symptoms, fever, and headache [15]. The presence of a history of SJS associated with the use of lamotrigine is not an absolute contraindication to repeated use of the drug [15]. Studies have presented a patient profile supporting the decision to restart lamotrigine treatment: a mild rash in the initial stage and a break of at least 4 weeks after the onset of the syndrome [15].

Additionally, an increased susceptibility to SJS was found in patients with the phenotype HLAB*15: 02 coming from Asia [15]. Therefore, the FDA issued a warning that genetic testing should be performed to exclude or confirm an increased risk [15].

Future Directions

It is necessary to expand research on the possibilities of lamotrigine therapy during acute depressive episodes in the course of bipolar disorder. The effect of lamotrigine on the prevention of manic episodes should be further explored, especially in patients who tolerate lamotrigine well, to avoid the need to switch to drugs with a lower safety profile, such as lithum, a mood stabilizer with a low therapeutic index. There are no studies describing the effect of lamotrigine on patients with a diagnosis of bipolar II disorder. Bipolar disorder with rapid phase changes is a significant therapeutic challenge. A satisfactory effect of simultaneous therapy with lithium and lamotrigine has been demonstrated to minimize the number of cycles. More high-quality research supporting this thesis is needed. The results of studies on the effect of lamotrigine on the occurrence of arrhythmias and the severity of existing heart defects are not clear; therefore, it seems justified to conduct further studies confirming the direction of action of lamotrigine in this topic.

Conclusions

We wanted to emphasize the key position of lamotrigine, in comparison with other mood-stabilizing drugs, in the treatment of bipolar disorder. For this purpose, the indications, contraindications, and adverse effects of lamotrigine have been presented. By preventing depressive episodes that dominate the typical picture of bipolar disorder, lamotrigine allows the effective achievement of a longer period of disease remission. The high safety profile of lamotrigine is not without significance, which translates so significantly into the use of this drug in the most frequently diagnosed age group, young adults. The negligible effect on the developing fetus and the maintenance of a stable metabolic rate make lamotrigine more frequently chosen by specialists for the treatment of bipolar disorder. However, we must not forget that lamotrigine is not indifferent to the immune system and in extreme cases it causes SJS, HLH, and DRESS syndrome. Physicians must be aware of the possibility of such systemic hypersensitivity reactions and that it is most important to react rapidly with immunosuppressive treatment. Reactions of HLH and DRESS syndrome will permanently eliminate the possibility of using lamotrigine, and SJS will do so in most cases.