Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jun
29
2010

Lamotrigine

control medium

Drug Summary: Lamotrigine belongs to a group of medications called anticonvulsants, which are used to control seizure disorders. Lamotrigine acts on the central nervous system to control the number and severity of seizures. It is thought to suppress the activity of certain parts of the brain and the abnormal firing of nerve cells that cause seizures. In psychiatry, lamotrigine may be used as a mood stabilizer. In the laboratory, researchers have found that lamotrigine also inhibits release of the neurotransmitter glutamate. This is important because glutamate may play a role in nerve cell degeneration in the brains of people with HD, so reducing the amount of glutamate released makes lamotrigine a potential treatment for HD.

Problem: Glutamate sensitivity^

Many factors contribute to the degeneration and death of nerve cells in people with HD. One aspect of HD is that nerve cells are particularly sensitive to glutamate. Glutamate is a neurotransmitter that is used to pass messages along from one nerve cell to another. (For more information on glutamate and HD click here.) Researchers have observed that because glutamate receptors in some nerve cells of people with HD are more sensitive than in people without HD, they are activated more frequently than normal receptors. This increased activity and sensitivity to glutamate has been associated with nerve cell death.

One way to prevent the overstimulation of a nerve cell by glutamate is to inhibit glutamate release from the nerve cells that communicate with it. In order to understand this kind of treatment, we must first understand the steps involved in the nerve impulse. (For more information on how nerve impulses work, click here.) It is important that we understand the steps of the nerve impulse because different treatments can be used to inhibit glutamate release by interfering at different steps. A nerve impulse involves receiving a message at one end of a cell and transmitting it via an electric signal to the other end of the cell. Neurotransmitters such as glutamate are stored at the end of the cell and are released in the last step. They act as a chemical signal, transmitting the message to a neighboring cell.

An important step in the electrical transmission of the nerve impulse involves sodium (Na+) channels. Most of the time, charged particles called ions line up along the inside and outside of the nerve cell membrane, giving the membrane a small electric voltage. Many different types of channels are located in the membrane, acting like guards at an exclusive community, only letting certain molecules in and out. Some of these channels open or close depending on what the membrane voltage is. One of these voltage-gated channels is the sodium channel, and it opens when the inside of the membrane becomes more electrically positive than usual. When the channel opens, sodium ions are free to enter the cell and continue the messaging cascade that ultimately leads to the release of neurotransmitters such as glutamate.

After the sodium channel lets enough sodium into the cell so that it reaches a maximum voltage, the channel temporarily becomes inactivated. An inactivated channel means that not only can no more sodium get through to relay the current message, but also the channel cannot be immediately reset, and thus will let no new messages be relayed. This intermediate stage between open and closed is called the refractory period. The sodium channel returns to the closed position only after the membrane voltage returns to a normal level (restoring the normal voltage involves the exit and entry of different ions). Once the channel is back in the closed position it can be opened again when the voltage rises enough. (See figure L-5 for a representation of the different sodium channel positions.)

Fig L-5: Sodium Channels

How can lamotrigine reduce glutamate release?^

Studies have shown that lamotrigine may inhibit the release of glutamate. While lamotrigine may act in several different ways, it is primarily thought to act as an anti-glutamate drug by interfering with sodium channels. These channels are a necessary step in the nerve impulse and for normal release of glutamate by a nerve cell. In this way, lamotrigine’s inhibition of glutamate release is similar to that of the drug riluzole. (For more information on riluzole click here.)

Lamotrigine exerts its effects during the refractory period by binding to sodium channels. In overactive nerve cells such as in people with seizure disorders or HD, it takes longer for sodium channels to transition from the open period to the inactivated refractory period. An extended open period is what allows so much glutamate to be released in overactive cells. Lamotrigine targets these overactive cells that are slow to inactivate, leaving normal areas of the brain unaffected. Lamotrigine acts by prolonging the inactive refractory period so that sodium channels cannot return to the closed position. Since the channel must first be closed before it can be re-opened, prolonging the inactive period decreases the time of the open period, thus decreasing glutamate release. To put it another way, during the inactive refractory period, no more sodium can get in, so the membrane’s voltage is stabilized. When sodium is kept out, no more messages can be relayed, and thus no more glutamate is released. Therefore, lamotrigine inhibits glutamate release by interfering with sodium channels.

Research on lamotrigine^

Kremer, et al. (1999) recognized that prolonged exposure to glutamate leads to the gradual decline and death of nerve cells in diseases such as HD. They therefore hypothesized that inhibiting the release of glutamate would prevent or at least slow the progression of HD. Lamotrigine is known to inhibit glutamine release in vitro, and has been successfully applied to protect nerve cells in other experiments using animal models. Building on these results, the researchers ran a clinical trial on humans lasting 30 months to see if lamotrigine would slow the progression of HD in people who had experienced physical symptoms for less than five years.

The researchers studied the effects of lamotrigine on 28 people with HD; they also gave a placebo to 27 people with HD to control for psychological effects of treatment as well as to have a comparison group. This was a double-blind study, meaning neither the researchers nor the patients knew which group received the lamotrigine and which received the placebo. (The purpose of a double-blind study is to remove any experimenter or patient bias in evaluating the treatment.) The efficacy of the drug was primarily measured using the total functional capacity (TFC) scale. Patients were also assessed using a variety of cognitive and physical tests.

Over the course of the 30 months of the study, both groups significantly declined in their TFC scores, without any significant difference between the group receiving lamotrigine treatment and the group receiving a placebo pill. This led the researchers to conclude that lamotrigine is not effective in slowing the progression of HD. However, there was slightly less deterioration in terms of the physical symptoms known as chorea in the group receiving lamotrigine. Also, when asked about their various symptoms (mood, physical, etc.), a larger percentage of patients in the group receiving lamotrigine reported an improvement. Despite this perception, both groups declined in their performance on physical tasks. In addition, not much change was observed in the cognitive tests, although the placebo group performed better than the lamotrigine group on one test due to better learning.

Sixteen (of 28) people receiving lamotrigine treatment reported several side effects, including nausea, skin rash, insomnia, and severe depression. Eight (of 27) people receiving a placebo reported mild side effects.

While the study reported the overall inefficacy of lamotrigine, it is important to consider the relatively small sample size and the fact that deterioration varied widely among participants. This is why the researchers have not fully ruled out lamotrigine’s ability to treat early HD. The positive results of the study (decreased chorea and improved symptoms such as mood) may be a result of what lamotrigine is already used for – as an anticonvulsant and mood elevator. A possible reason why the clinical results on humans were not as favorable as those on animals is because the effective dose in animals is much too high for humans to tolerate. Increasing the dose in people is not an option because of the harmful side effects associated with the drug.

Higgins, et al. (2002) also focused on decreasing the amount of glutamate released in nerve cells. Since lamotrigine is known to inhibit the release of glutamate, this group tested the safety of various doses of the drug and how well it was tolerated in HD patients. They conducted an open-label study, meaning that the patients knew they were receiving an actual drug and not a placebo. Over the course of seven weeks the researchers increased the amount of lamotrigine given and then continued giving the maximum dose up to six months. The effects of the drug were tested using the Unified Huntington’s disease Rating Scale (UHDRS) and cognitive tests.

The researchers studied only twenty people with HD and ended up collecting data from fifteen (two people’s symptoms got worse while three people did not report back). The researchers did not find any changes in the UHDRS (this includes motor, functional, and behavioral aspects of HD). However, significant improvements were seen in two parts of the cognitive tests, Verbal Fluency and Symbol Digit Modalities.

Overall, the researchers found that the patients were able to tolerate the drug well and that it was safe to use. They were not able to reproduce the results seen in a previous study that found lamotrigine could reduce chorea. Researchers will need to follow up on this study with a longer lasting investigation that is not open-label and includes more patients.

For further reading^

  1. Kremer, et al. Influence of lamotrigine on progression of early Huntington’s disease. 1999. Neurology 53(5): 1000. Online.
    This is a research article about a clinical trial of lamotrigine and HD. It describes the study’s methods and results in great detail and is directed toward a scientific audience.
  2. Higgins, et al. Safety and tolerability of lamotrigine in Huntington’s disease. 2002. Movement Disorders 17(S5): S324.
    This is a short description of medium difficulty of a clinical trial using lamotrigine as presented at the 7th international congress of Parkinson’s disease and movement disorders.
  3. Hurley, Stephen C. Lamotrigine update and its use in mood disorders. 2002. The Annals of Pharmacotherapy 36(5): 860-873. Online.
    This article reviews known information about lamotrigine and evaluates its use in treating mood disorders. It is not directly related to HD, but the section on pharmacology on page 861 is helpful in understanding how lamotrigine works on nerve cells.

-K. Taub, 11/21/04