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Proposed Mechanisms of Action of Lamotrigine

Posted by Cam W. on October 19, 2001, at 19:08:33

I believe it was Collette that had asked me to explain the mechanisms of action of Lamictal™ (lamotrigine). Although the mechanisms of action of Lamictal as an augmenting agent in bipolar disorder (esp. bipolar
depressiom), unipolar depression, and anxiety disorders are not fully understood, I will see if can talk my way through possible mechanisms, as I type.

Lamictal is related to antifolate compounds. It's positive benefits on mood were noted very early on, during clinical epilepsy trials in the early to mid-90s. As a matter of fact, in one clinical trial, conducted in 1993, 66% of those receiving Lamictal continued taking the drug after the trial was over, but only 18% of participants had improved seizure control.

Lamictal is known to block sodium channels similar to valproate (Epival™/Depakote™ - divalproex & Tegretol™ carbamazepine). The reason that this is beneficial
relates to the way that an electrical signal travels down the length of an axon (the long part of the neuron). The inside of a nerve cell is slightly negatively charged, relative to the outside of a nerve cell. This electrical gradient is maintained by sodium ion pumps (pumping the positively charged sodium out of the cell) and chloride ion pumps (pumping negatively charged chloride ions into the cell) that are located within the nerve cell wall. Positively charged calcium ions and positively charged potassium ions are also involved in modifying the conduction of an electrical signal (called an action potential).

During the firing of a nerve cell, the outside and inside of the cell temporarily reverses polarity (outside of the cell becomes negatively charged and inside of the cell positively charged). This change in polarity occurs because the electrical signal causes the the sodium ion channels and the chloride ion channels to open up. Because an osmotic gradient is set up by the ion pumps, the sodiums ions flow into the cell and the chloride ions flow out of the cell. The ion pumps almost immediately begin to pump their respective ions in (chloride) and out (sodium) of the cell. This flip-flop of polarity causes the movement (propagation) of the electrical signal (action potential) down the nerve cell toward the nerve terminus (where the action potential cause the release of the neurotransmitters into the synaptic gap and these neurotransmitters carry the electrical signal across the gap and stimulate post synaptic receptors and causes an action potential to propagate along the next neuron's axon).

By blocking sodium ion channels, by Lamictal, stops (or at least slows) the action potential from propagating down the axon as readily. This is because when the action potential causes the sodium and calcium ion channels to open, the chloride can flow freely, but the sodium channel is blocked by the Lamictal. Thus, a hypersensitive, or overactive nerve cell (perhaps caused by hypersecretion of cortisone from the adrenals, etc., that occurs in depression).

Lamictal also blocks calcium channels. As mentioned above calcium also modulates the propagation of an action potential. Also calcium plays a major role in the release of neurotransmitters, and is involved in other synaptic processs,in energy metabolism, in neuronal plasicity, heart function, etc. (Hence the advertising is correct: "Milk IS good for every body). Without going into the detail that I did above, blocking calcium ion channels, also slow down hyperactive nerve cells, or essentially helps to normalize the electrical flow within the nerves of the brain.

This normalization of an overexcited nervous system in depression (possibly partly die to the uncoupling of the HPA axis) by Lamictal is also helped to be accomplished by another of Lamictal's actions: the inhibition of glutamate release. Glutamate is the primary excitiatory neurotransmitter in the brain, and mainly causes it's excitatory action via stimulation of the NMDA receptor complex. Blocking glutamate release essntially slows excitatory neurotransmission and inihibitory transmitters (like GABA) are able to calm the nervous system more efficiently.

It has been also noted that Lamictal also weakly blocks the serotonin reuptake mechanism (like the SSRIs) and may have anti-kindling action (like valproate and carbamazepine).

I hope that this explains some of the actions of Lamictal. This drug basically slows overactive nerves, and allows antidepressants to help to recouple the body's stress defense, the HPA axis. Since Lamictal only calms neurons and doesn't "fix" the HPA axis, it would not make a good antidepressant by itself, but it does help antidepressants work better by calming down overactive neurons. This should also possibly explain why Lamictal augments other mood stabilizers in bipolar depression, as well.

If you have anymore questions, don't hesitate to ask. I may not be able to answer them, but I will try. - Cam




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