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You may have heard of the drug Lamictal or lamotrigine (generic name) being used to treat various mental health issues, including bipolar. For a little over a decade, lamotrigine has been touted as a “mood stabilizer,” not unlike the medication lithium. However, a true mood stabilizer is a medication that—on its own—prevents episodes of mania or depression. Some clinical trials suggest that lamotrigine can prevent depressive episodes, but nothing like the clinical research showing lithium’s efficacy.
Lamotrigine and lithium are supposed to sustain a window or metaphorical room to contain symptoms and thus prevent mood episodes. It has been understood that lithium acts as a ceiling for preventing manic symptoms. Lamotrigine is the floor of that room, so the person does not fall into a basement-dwelling depression. Is this metaphor remotely accurate? Or are we dealing with a 21st-century version of the direct-to-consumer marketing strategy built around the “chemical imbalance theory”? What is the whole story behind lamotrigine?
Lamotrigine is an atypical anticonvulsant medication. The initial purpose of the drug was the treatment of seizures, and it has since been applied to various mental health issues. Clinical trials began in 1984 using lamotrigine as both a monotherapy and an adjunct treatment for conditions such as epilepsy. It has been understood that lamotrigine binds to receptors in the brain that inhibit “excitatory” neurotransmitters such as glutamate. Lamotrigine acts to calm these neural firings in the brain. According to Leach et al. (1991), lamotrigine does this with fewer neurological side effects related to motor functioning (e.g., ataxia), learning declines, or working memory issues compared with other antiepileptic drugs (e.g., Tegretol, Dilantin). The most common side effect of lamotrigine is headache (about 25%), but others include dizziness, drowsiness, tremor, and nausea.
More importantly, within the first two months of lamotrigine treatment some individuals develop skin rash. Because of the risk of rash development, the medication is titrated up (usually 25 milligrams per day/week) very slowly. The higher the dosage—especially over short periods of time—the more likely a skin rash will break out. Although rare (3% to 5%), these rashes can require hospitalization and immediate discontinuation of the drug. Stopping the medication and then quickly returning to the previous amount can induce these rashes as well. Based on some clinical trials, one out of 300 individuals prescribed lamotrigine develops more serious and perhaps life-threatening rashes such as Stevens-Johnson syndrome.
In 1994, the Food and Drug Administration (FDA) approved lamotrigine for marketing in the United States as an anticonvulsant medication (patented by Glaxo Wellcome). By the end of the 20th century, studies commenced with small sample sizes for the treatment of bipolar via lamotrigine. Specifically, findings were gathered for the treatment of “rapid cycling” moods and the depressive component of bipolar. Frequent recipients were those with “refractory bipolar” or individuals with bipolar who had not responded positively to other medications or were intolerant of previous psychotropic interventions.
The medication began to show slight improvements for individuals with bipolar in terms of preventing depressive episodes. Calabrese et al. (2003) found for individuals who initially presented with manic symptoms, lamotrigine had a clinically significant effect at preventing a depressive episode over a one-year period versus placebo and lithium intervention. There was no significant difference for reducing manic episodes compared to placebo. The methods of these types of trials (i.e., “relapse prevention design”) have been scrutinized by some who suggest true “mood stabilizers” need to be tested over longer periods with consideration given to enrichment, withdrawal, and polarity effects (see Goodwin et al., 2011).
In the Calabrese et al. (2003) study, superiority of lamotrigine over placebo was modest and there was a sobering “financial disclosure.” Head researchers in the study were involved in advisory boards, received funding from, were employed by and consulted for GlaxoSmithKline, Glaxo Wellcome, Janssen, Eli Lilly, and UCB Pharma, Inc., to name a few. Was there an incentive for a positive trial?
The cautionary lamotrigine tale often omitted is that individuals taking the medication have a potential for the onset of seizures. Functionally, lamotrigine is an anti-seizure medication.
In 2003, these unassertive findings were influential to the FDA approval (it requires only two positive trials over placebo) of lamotrigine for the maintenance treatment of bipolar depression. GlaxoSmithKline was granted a patent on lamotrigine (i.e., brand name Lamictal, and in 2009, Lamictal XR). The drug became one of the bestselling pharmaceuticals in the United States ($2 billion annually) and launched a multibillion-dollar company. It is hard to trust a corporation with so much power, money, and influence over the psychiatric milieu.
In June 2012, GlaxoSmithKline agreed to plead guilty to wide-ranging, federal criminal charges and civil allegations. The $3 billion was the largest settlement by a drug company at the time. Two-thirds of the civil settlement was due in order to resolve civil liabilities under the False Claims Act. They were charged with the unlawful promotion of various drugs—including Lamictal—for off-label, noncovered uses, failure to disclose safety data, and paying kickbacks to physicians to prescribe drugs during periods from the late 1990s through 2007.
For example, GlaxoSmithKline marketed Paxil to children as being non-habit-forming and lacking withdrawal symptoms. The government claims that GlaxoSmithKline published and distributed a journal article that falsely concluded that Paxil had positive results with pediatric use.
Lawsuits claimed that the drug has serious side effects, which GlaxoSmithKline allegedly downplayed in patient information. In 2001, the World Health Organization ranked Paxil as the most difficult antidepressant to withdraw from. One can’t help but wonder if a similar case will eventually surface relative to the practices surrounding Lamictal (i.e., lamotrigine). GlaxoSmithKline has since been forced to implement and start maintaining transparency in its research practices and publication policies.
The cautionary lamotrigine tale often omitted is that individuals taking the medication have a potential for the onset of seizures. Functionally, lamotrigine is an anti-seizure medication. What happens over time is the brain becomes sensitized to the medication. While administering the drug, you are telling your brain, Hey, I don’t want you to have a seizure. Over time, the absence of the drug makes the brain sensitive to overstimulation. The overstimulation of the brain combined with a rapid reduction of the medicine (e.g., forgetting to take a dose or stopping the medication abruptly) can result in tonic (loss of consciousness, body arching, difficulty breathing), clonic (muscle spasms, jerking), or tonic-clonic seizures (formerly known as grand mal seizures).
You don’t need an epileptic history to develop these types of seizures. The result can come solely from the use, discontinuation, and/or an increased tolerance to a dosage of lamotrigine. Anecdotally speaking, few people are informed of this potential adverse event when prescribed the medication. In addition, the off-label use of this medication is increasing for various conditions such as migraines and pain management as well as mental health disturbances (e.g., borderline personality, refractory depression, posttraumatic stress, schizoaffective condition, and depersonalization).
Make no mistake about it: lamotrigine is not an antidepressant and it does not stop manic symptoms. It does not directly alter levels of serotonin. Eliminating the medical jargon, it reduces agitation and anxiety to keep one’s mood stable. The drug keeps the excitement levels turned down or, put another way, decreases electrical activity (think analogically to how stress can induce a seizure for someone with epilepsy).
Lamotrigine will not miraculously lift a weighing depression, nor will it bring one down from the heights of mania. Although it has become heralded as a prophylactic medication or preventive form of treatment for bipolar mood episodes (depressive episodes), it is lithium that remains the gold-standard treatment. At best, lamotrigine is birth control to the gestation of depression, not the plan B (morning-after pill) or abortion of depressive symptoms once conceived.
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