Bipolar Disorder is a psychiatric illness which results in mood shifts from depression to elation which cycles throughout a person's lifetime. In recent years there has been the development of therapies called "Mood Stabilizers" which can dampen or prevent these mood swings. Lithium and valproic acid are two common mood stabilizers which have shown efficacy in reducing bipolar mood swings. Of particular interest is another, an anticonvulsant mood stabilizer used primarily in epilepsy but also in Bipolar Disorder, called Lamotrigine (Lamictal). Lamotrigine is especially active in the prevention of the depressive state in Bipolar Disorder. Lamotrigine is interesting to me because it is the only medication I know of that has shown efficacy in improving the fatigue, muscle cramps, and pain resulting from neuronal damage in the Post-Polio Syndrome (PPS). In addition, it has been shown to decrease emotional upset due to the stress of the Post-Polio Syndrome.
Lamotrigine works by blocking sodium channels in the pre-synaptic neuron which consequently decreases the release of glutamate into the nerve synapse. Glutamate is a neurotransmitter that has been implicated in "excitotoxicity" which contributes to morbidity in several neurological diseases and has been suggested as a mechanism causing pathological changes in post-polio syndrome, as well as in depression, although it's exact mechanism in depression remains unknown.
Figure 1 A neuron. The nerve impulse begins at the dendrites and is passed to the next nerve through the axon terminals. Later you will see a large illustration of the axon terminals (end fibers).
Excitotoxicity means that a neuron "over-fires" due to excessive glutamate release, in glutaminergic neurons. After glutamate is released by the pre-synaptic neuron (lamotrigine inhibits this) it travels across the synaptic gap and enters the post-synaptic neuron through the n-methyl-d-aspartate (NMDA) receptor on the post-synaptic terminal. NMDA is an amino acid that activates the NMDA receptor on the surface of these nerve cell synapses but glutamate passes through these receptors as well, initiating the next nerve to fire.
Ketamine, a veterinary anesthetic, turns off glutamate neuro-transmission by another mechanism. It blocks the NMDA receptor, blocking glutamate entry and neuron firing. Ketamine can relieve treatment resistant depression in 2 hours and the effect can last for a week or more. It's action on this receptor blocks glutamate entry and dampens the stimulus for neurons to fire. Glutamate diffuses across the synapse between two neurons and can sometimes cause damage to the neurons that it stimulates. In alcohol withdrawal, for instance, NMDA is over-activated causing agitation and sometimes epileptic like seizures. And, as mentioned above, glutamate is sometimes over released causing an epileptic seizure. Lamotrigine is used to prevent these epileptic seizures by blocking sodium channels, which lowers the voltage in the pre-synaptic neuron thereby lowering glutamate release. But let's get back to lamotrigine and PPS.
Figure 2 illustrates how the nerve impulse is propagated between two neurons. The end fiber (axon terminal) of the first neuron (the presynaptic neuron) is polarized, with positive sodium ions which have passed into the cell along the inner membrane. The outside of the membrane has an abundance of negative ions. Lamotrigine blocks the sodium from getting into the cell so polarity is lessened. The nerve may not reach the threshold of voltage and will not fire. So glutamate is not released. This has a calming effect on glutaminergic nerve transmission. As will be seen in the Table below, this result relieves pain, fatigue, and other symptoms of PPS
The following Table illustrates the affect of lamotrigine on the symptoms of PPS. In this experiment 30 people with PPS who had their lower limbs affected, were broken into two groups: 15 receiving 100 mg of lamotrigine and the other 15 receiving a placebo. Every symptom used to describe PPS showed statistically significant improvement after 4 weeks. This table was taken from "Effects of lamotrigine on the symptoms and life qualities of patients with post polio syndrome: A randomized controlled study" Neurorehabilitation 20 (2005) 240-251, On et al. Note that after 4 weeks of treatment with lamotrigine every measure of PPS symptoms is significantly better in the lamotrigine group, and, the improvement can be readily seen when comparing symptoms in the first week compared to the fourth week in the test group
Table from: "Effects of lamotrigine on the symptoms and
life qualities of patients with post polio syndrome: A randomized controlled study" Neurorehabilitation 20 (2005) 240-251, On et al
Years ago I gave a talk for Polio Outreach of Connecticut group at Gaylord Hospital in Wallingford, Connecticut. I mentioned a drug named Riluzole, which is used to lengthen the lives of those with ALS by a couple of months. Riluzole also works through inhibition of the glutamate system. Back then it was only used in ALS. Now Riluzole is being used in neuro-psychiatric disorders, like obsessive compulsive disorder and depression, off label. This is not a coincidence. In my view other glutaminergic nerve inhibitors, including Riluzole, should be tried for post-polio syndrome. Lamotrigine has been the only successful drug tested and I haven't seen more on this other than in the study above.
For those of you who want to work with lamotrigine with your physician you have to be careful to slowly titrate your dose up to 100 mg/day. The tapering up usually goes 25mg for two weeks, 50 mg for the next two weeks, then 100 mg on the fifth week. This has been shown to decrease the likelihood of a very serious adverse event called Stevens-Johnson Syndrome which is a rash that can be fatal, usually in about 1 out of 50,000 people. But it can occur in up to 5% of people on lamotrigine, whereupon the drug must be stopped, either for good, or for a second try after the rash clears.
People with post-polio syndrome may derive benefit from the research that is now ongoing for depression drugs using the glutamate model. This research is accelerating. It is possible that many of these drugs may be valuable in reducing symptoms of PPS if only more studies can be done with on PPS with these promising inhibitors of the glutamate system.
- 1. "Effects of lamotrigine on the symptoms and life qualities of patients with post polio syndrome: A randomized controlled study" Neurorehabilitation 20 (2005) 240-251, On et al [ABSTRACT]
- 2. http://en.wikipedia.org/wiki/N-Methyl-D-aspartic_acid
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