Lamotrigine: Pharmacology, Clinical Utility, and New Safety Concerns

Lamotrigine was originally developed as an antiseizure drug because of its ability to reduce folate levels (1). At the time of the drug's development, it was thought that folate depletion would treat epileptic activity. Although this is now known to be incorrect, the drug did serendipitously treat seizures effectively (1). Currently, pharmacologists understand that lamotrigine reduces neuronal activity via a variety of mechanisms. The most commonly accepted mechanisms of action are enhancement of sodium channel inactivation and possible inhibition of synaptic glutamate release (2). In early studies, patients with epilepsy who were taking lamotrigine reported increases in a subjective sense of well-being, and this led to its exploration as a psychotropic drug (3). From a neuropsychiatric standpoint, lamotrigine appears to inhibit uptake of serotonin, dopamine, and noradrenaline (4).

Lamotrigine is absorbed continuously along the entire length of the gastrointestinal tract and is metabolized primarily by glucuronidation (2, 5). Both the immediate-release and extended-release formulations have half-lives of approximately 24–30 hours, but the enteric-coated extended-release form is absorbed more slowly (5). The extended-release formulation was created for the purpose of once-daily dosing for seizure disorders. When lamotrigine is used concurrently with carbamazepine, phenytoin, or phenobarbital, its plasma levels decrease by one-half (1, 2). When it is used with valproic acid, the valproic acid levels are reduced by about 25%, and the lamotrigine levels double (1, 2). The mechanisms of these drug interactions are not completely understood but thought to be due to competition for hepatic glucuronide metabolism (6).

The most common side effects of lamotrigine are dizziness, visual disturbances, ataxia, nausea or vomiting, and nonserious rash. The drug's manufacturer states that when used as monotherapy, the most common adverse reactions with the extended-release and immediate-release formulations are similar (7). Additionally, the rate of serious rash is usually not different between the two formulations (7). Serious rash (Stevens-Johnson syndrome), toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms are more common in pediatric populations compared with adult patients (0.3% in adults and 1% in children) (8). It is noteworthy that the distinction between the above serious conditions can be unclear and likely represents a spectrum of disease states. The vast majority of rashes that occur as a result of lamotrigine use are mild (8). Nonserious rashes can present as morbilliform, erythema multiforme, or urticaria (8). Unfortunately, simple morbilliform or urticarial rash can represent the initial stage of Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug reaction with eosinophilia and systemic symptoms (8). Consequently, when a rash occurs, patients must be referred for medical evaluation within 24 hours with possible referral to dermatology (8). Unless it is clear that the rash is not a result of lamotrigine use, lamotrigine should be discontinued immediately (6). The greatest risk of rash occurs within the first 6 weeks of treatment, although eruptions occurring beyond this time frame have been reported (6). Factors thought to increase the risk of rash are as follows: exceeding the maximum recommended dosage, titrating upward more rapidly than recommended in the guidelines, and coadministration of valproate (6). However, a rash can occur when none of these features are present (6).

There is an association between lamotrigine and aseptic meningitis as well as possible oral cleft abnormalities in newborns exposed to the drug in utero (2). The Food and Drug Administration (FDA) issued a controversial safety alert reporting an increase in suicidal thinking or behavior with all antiseizure medications, including lamotrigine; however, concerns have been raised regarding the methodology used in identifying this risk (9).

Lamotrigine is rated as a class C drug in pregnancy, and it is found in plasma levels of up to 50% in nursing infants (8). Dose reductions may be effective for patients with chronic kidney disease as a result of the prolongation of half-life, and caution is advised for patients with severe renal failure because of the paucity of studies (8). Reductions in dosage are also recommended for patients with moderate to severe hepatic insufficiency (8).

Efficacy in Bipolar Disorder

Lamotrigine has the strongest evidence for the maintenance treatment of bipolar disorder and is well established for this indication (10). Its primary benefit is increasing the time between the relapse of mood episodes, up to double that of placebo (11, 12). The drug appears to be most beneficial in delaying the onset of new depressive episodes (11, 12). There is modest evidence that the drug is effective in the treatment of bipolar depression, although some meta-analyses have found marginal to no benefit in the acute treatment of depressive symptoms (13–15). One randomized double-blind placebo-controlled trial demonstrated that lamotrigine as an augmentation agent to lithium significantly reduced depressive symptoms compared with placebo augmentation (16). The Texas implementation of medication algorithms update for bipolar I disorder recommends lamotrigine with or without an antimanic (depending on the presence of recurrent or severe mania) as a first-line option for maintenance treatment if the most recent episode is depressed (17). The same medication guidelines are recommended as level-1 treatment for acute depression in bipolar I disorder (17). Lamotrigine does not have proven efficacy in the treatment of acute mania (3).

Lamotrigine is an attractive option for the treatment of bipolar disorder because it is weight neutral, unlike many psychotropic drugs, and does not induce mania (3). When initiating treatment, a slow titration is recommended, since this may decrease the risk of rash development. When using lamotrigine immediate release without enzyme-inducing agents or valproate, the manufacturer recommends starting with a dosage of 25 mg once daily for weeks 1–2, 50 mg daily for weeks 3–4, 100 mg for week 5, and 200 mg daily thereafter (6). When using lamotrigine with valproate, the manufacturer recommends 25 mg once every other day for weeks 1–2, 25 mg once daily for weeks 3–4, 50 mg once daily for week 5, and 100 mg daily thereafter (6). There are additional titration schedules if an enzyme-inducing agent is concurrently prescribed. If discontinuing lamotrigine for a nonsafety reason, a stepwise titration downward over 2 weeks is recommended (6).

The Newest FDA Alert

On April 25, 2018, the FDA released a safety alert that lamotrigine use carries a risk of the immune system disorder hemophagocytic lymphohistiocytosis. This warning was based on eight cases globally of confirmed or suspected hemophagocytic lymphohistiocytosis that have been reported since the drug's initial approval in 1994 (18). The FDA determined that there was reasonable suspicion that lamotrigine was the causal agent for the development of hemophagocytic lymphohistiocytosis given the time course and temporal association with the initiation of the drug. All patients required hospitalization, and one died. Of the eight cases identified by the FDA, five met the five criteria necessary for diagnosis of the disease, and three met four criteria (categorized as suspected cases). All patients developed the illness within 24 days of initiating lamotrigine, and the doses ranged from 25 mg every other day to 250 mg daily (18).

Hemophagocytic lymphohistiocytosis is a rare and potentially devastating disorder of immune system overactivation. The underlying pathophysiology is abnormal T cell activation leading to exuberant cytokine production and life-threatening inflammation (19). The disease exists as a primary familial form that presents in infancy and childhood and a secondary form that presents in older children and adults in the absence of genetic mutations. The secondary form of the condition is triggered most commonly by rheumatologic disease, malignancy, and Epstein-Barr virus infection, although there is a wide range of known triggers (19). Treatment typically includes a combination of cytotoxic chemotherapy and immunosuppressants (19).

Hemophagocytic lymphohistiocytosis is a syndromic disease in that the diagnosis is made on the basis of a constellation of findings, and diagnosis is often delayed due to the nonspecific nature of the diagnostic criteria. In the absence of several known molecular mutations present in the familial form, hemophagocytic lymphohistiocytosis is diagnosed by the presence of five of the following eight criteria (20): a fever >38.5°C; splenomegaly; cytopenias affecting two out of three lineages; hypertriglyceridemia or hypofibrinogenemia; hemophagocytosis (the engulfment of erythrocytes by macrophages) in the bone marrow, spleen, lymph nodes, or liver; low or absent natural killer cell activity; a ferritin level >500 ng/ml; and an elevated soluble CD25 level. Organ dysfunction is common and can include hepatitis (or acute liver failure), neurologic symptoms (seizures and altered level of consciousness), lymphadenopathy, and coagulopathy (19). Acute respiratory failure can lead to rapid admission to the intensive care unit (19). A nonspecific rash can occur in hemophagocytic lymphohistiocytosis but is less commonly seen in the syndrome (19). However, because a rash can occur with hemophagocytic lymphohistiocytosis, it must be added to the differential diagnosis of serious conditions possible when an eruption presents in the setting of lamotrigine use. Therefore, the FDA recommends that lamotrigine be discontinued and medical evaluation be conducted if the patient develops a fever or rash (18).

Conclusions

Bipolar disorder is a serious mental illness that can cause significant impairments in psychosocial functioning, and patients with bipolar disorder have one of the highest rates of death by suicide among patients with psychiatric illness (10). Lamotrigine is an important pharmacologic option for the management of bipolar disorder, most significantly for its role in the prophylaxis of mood episodes. Psychiatrists prescribing lamotrigine must be aware of the idiosyncratic safety concerns associated with the drug and should counsel patients thoroughly before initiation.

Key Points/Clinical Pearls