What is/are Lamotrigine?
Lamotrigine, marketed in the US and most of Europe as Lamictal /ləˈmɪktəl/ by GlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used off-label as an adjunct in treating depression. For epilepsy, it is used to treat focal seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Like many other anticonvulsant medications, Lamotrigine also seems to act as an effective mood stabilizer, and has been the first U.S. Food and Drug Administration (FDA)-approved drug for this purpose since lithium, a drug approved almost 30 years earlier. It is approved for the maintenance treatment of bipolar type I. Chemically unrelated to other anticonvulsants (due to lamotrigine's being a phenyltriazine), lamotrigine has many possible side-effects. Lamotrigine is generally accepted to be a member of the sodium channel blocking class of antiepileptic drugs, but it could have additional actions since it has a broader spectrum of action than other sodium channel antiepileptic drugs such as phenytoin and carbamazepine and is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel blocking antiepileptic drugs are not. In addition, lamotrigine shares few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties. Lamotrigine is inactivated by hepatic glucuronidation.
Epilepsy and seizures
Lamotrigine is approved in the US for the treatment of partial seizures. Lamotrigine is one of a small number of FDA-approved therapies for seizures associated with Lennox-Gastaut syndrome, a severe form of epilepsy. Typically developing before four years of age, LGS is associated with developmental delays. There is no cure, treatment is often complicated, and complete recovery is rare. Symptoms include the atonic seizure (also known as a "drop attack"), during which brief loss of muscle tone and consciousness cause abrupt falls. Lamotrigine significantly reduces the frequency of LGS seizures, and is one of two medications known to decrease the severity of drop attacks. Combination with valproate is common, but this increases the risk of lamotrigine-induced rash, and necessitates reduced dosing due to the interaction of these drugs.
Lamotrigine is approved in the US for maintenance treatment of Bipolar I disorder. While traditional anticonvulsant drugs are predominantly antimanics, lamotrigine is most effective for preventing the recurrent depressive episodes of bipolar disorder. The drug seems ineffective in the maintenance of current rapid-cycling, mania, or depression bipolar disorder; however, it is effective at prophylaxis or delaying the mania, depressive, or rapid cycle. According to studies in 2007, lamotrigine may treat bipolar depression without triggering mania, hypomania, mixed states, or rapid-cycling.
There is less evidence of therapeutic benefit when lamotrigine is used to treat a current mood episode. It has not demonstrated effectiveness in treating acute mania, and there is controversy regarding the drug’s effectiveness in treating acute bipolar depression. While the 2002 American Psychiatric Association (APA) guidelines recommend lamotrigine as a first-line treatment for acute depression in Bipolar II disorder, the APA’s website notes that the guidelines, being more than five years old, “can no longer be assumed to be current." A paper written in 2008 by Nasser et al. reviewed evidence from trials that were unpublished and not referenced in the 2002 APA guidelines, and it concludes that lamotrigine has "very limited, if any, efficacy in the treatment of acute bipolar depression." A 2008 paper by Calabrese et al. examined much of the same data, and found that in five placebo controlled studies, lamotrigine did not significantly differ from placebo in the treatment of bipolar depression. However, in a meta-analysis of these studies conducted in 2008, Calabrese found that lamotrigine was effective in individuals with bipolar depression, with a number needed to treat (NNT) of 11, or 7 in severe depression.
Off-label uses include the treatment of peripheral neuropathy, trigeminal neuralgia, cluster headaches, migraines, and reducing neuropathic pain. Off-label psychiatric usage includes the treatment of depersonalization disorder, schizoaffective disorder, borderline personality disorder, and post-traumatic stress disorder. Lamotrigine has been studied as an adjunctive therapy for treatment of refractory unipolar depression, attaining efficacy on the secondary metric for treatment outcomes (Clinical Global Impressions), but not the primary metrics (Montgomery-Åsberg Depression Rating Scale and Hamilton Rating Scale for Depression).
Lamotrigine prescribing information has a black box warning about life-threatening skin reactions, including Stevens–Johnson syndrome, DRESS syndrome and toxic epidermal necrolysis. The manufacturer states that nearly all cases appear in the first 2 to 8 weeks of therapy and if medication is suddenly stopped then resumed at the normal dosage. Patients should seek medical attention for any unexpected skin rash, as its presence is an indication of a possible serious or even deadly side-effect of the drug. Not all rashes that occur while taking lamotrigine progress to SJS or TEN. Between 5 to 10% of patients will develop a rash, but only one in a thousand patients will develop a serious rash. It is thought that one in 50,000 exposed patients may die from the rash. Rash and other skin reactions are more common in children, so this medication is often reserved for adults.
There is also an increased incidence of these eruptions in patients who are currently on, or recently discontinued a valproate-type anticonvulsant drug, as these medications interact in such a way that the clearance of both is decreased and the effective dose of lamotrigine is increased. As of December 2010, lamotrigine carries an FDA black box warning for aseptic meningitis. Side-effects such as rash, fever, and fatigue are very serious, as they may indicate incipient Stevens–Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome or aseptic meningitis.
Other side-effects include loss of balance or coordination, double vision, crossed eyes, pupil constriction, blurred vision, dizziness and lack of coordination, drowsiness, insomnia, anxiety, vivid dreams or nightmares, dry mouth, mouth ulcers, memory and cognitive problems, mood changes, runny nose, cough, nausea, indigestion, abdominal pain, weight loss, missed or painful menstrual periods, and vaginitis. The side-effect profile is different for different patient populations.
Lamotrigine has been associated with a decrease in white blood cell count (leukopenia).Lamotrigine does not prolong QT/QTc in TQT studies in healthy subjects
Effects in women
In clinical trials women were more likely than men to have side-effects. This is the opposite of most other anticonvulsants.
There is evidence showing interactions between lamotrigine and female hormones, which can be of particular concern for women on estrogen-containing hormonal contraceptives. Ethinyl estradiol, the ingredient of such contraceptives, has been shown to decrease serum levels of lamotrigine. Women starting an estrogen-containing oral contraceptive may need to increase the dosage of lamotrigine to maintain its level of efficacy. Likewise, women may experience an increase in lamotrigine side-effects upon discontinuation of the pill. This may include the "pill free" week where lamotrigine serum levels have been shown to increase twofold. Another study showed a significant increase in follicle stimulating hormone (FSH) and luteinizing hormone (LH) in women taking lamotrigine with oral contraceptive compared to women taking oral contraceptives alone. However, these increases were not in conjunction with increased progesterone, indicating that oral contraceptives maintained suppression of ovulation.
Pregnancy and breastfeeding
Lamotrigine is rated Pregnancy Category Risk C. Use during pregnancy is recommended only if benefits outweigh potential risks. In September 2006, the FDA issued a warning stating that taking lamotrigine during the first trimester of pregnancy may increase the risk for cleft lip and palate malformation in newborns. Since then, review studies have found that overall rates of congenital malformations in infants exposed to lamotrigine in utero are relatively low (1-4%). This compares to a typical 3% rate in the untreated population. A prospective study on cognition in children (mean age = 4.2 years) exposed to lamotrigine in utero did not indicate any adverse effects.
Lamotrigine is found in breast milk; the manufacturer does not recommend breastfeeding during treatment. In "Medications and Mothers' Milk," a frequently updated review of scientific literature, lamotrigine is rated as L3: moderately safe.
Other types of effects Lamotrigine binds to melanin-containing tissues such as the iris of the eye. The long-term consequences of this are unknown.
Some patients have reported experiencing a loss of concentration, even with very small doses. Lamotrigine has been implicated in the apoptotic neurodegeneration of the developing brain. On the other hand, others have actually reported an increase in alertness and concentration. GlaxoSmithKline investigated lamotrigine for the treatment of ADHD. The results were inconclusive. No detrimental effects on cognitive function were observed; however, the only statistical improvement in core ADHD symptoms was an improvement on a test, PASAT (Paced Auditory Serial Addition Test), that measures auditory processing speed and calculation ability.
Lamotrigine is known to affect sleep. Studies with small numbers (10-15) of patients reported that lamotrigine increases sleep stability (increases the duration of REM sleep, decreases the number of phase shifts, and decreases the duration of slow-wave sleep), and that there was no effect on vigilance, and daytime somnolence and cognitive function. However, a retrospective study of 109 patients' medical records found that 6.7% of patients experienced an 'alerting effect' resulting in intolerable insomnia, for which the treatment had to be discontinued.
Lamotrigine can induce a type of seizure known as a myoclonic jerk, which tends to happen soon after the use of the medication. When used in the treatment of myoclonic epilepsies such as juvenile myoclonic epilepsy, lower doses (and lower plasma levels) are usually needed, as even moderate doses of this drug can lead to induction of seizures, including tonic-clonic seizures, which can develop into status epilepticus, which is a medical emergency. It can also cause myoclonic status epilepticus. In overdose, lamotrigine can cause uncontrolled seizures in most people.
This article uses material from the Wikipedia article Lamotrigine, which is released under the Creative Commons Attribution-Share-Alike License 3.0.