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My pdoc just added Gabapentin to my Depakote and Lamotrigine.

Has anyone ever been on 3 different anticonvulsants at the same time?

The Lamotrigine is 100mg 2x per day. Depakote is 250mg 2x per day. Gabapentin is at 300mg 3x per day.

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I was on 3 when I was titrating Lamictal down while being on clonazepam and titrating Keppra up.

The important thing is that they work and complament each other, not the number.

Edited by notloki
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On 6/5/2020 at 4:26 PM, bpjett said:

Does anyone know the mechanism of action for these meds? Do they all work in different ways in the brain?


It is mainly sodium channel blocking and/or fooling with GABA. Amticonvulsives tend to make the tissue less electrically conductive. All of this came from wikipedia https://en.wikipedia.org/wiki/Main_Page :

Lamotrigine is a member of the sodium channel blocking class of antiepileptic drugs.  

Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).

Oxcarbazepine is a prodrug, which is largely metabolised to its pharmacologically active 10-monohydroxy derivative licarbazepine (sometimes abbreviated MHD).[ Oxcarbazepine and MHD exert their action by blocking voltage-sensitive sodium channels, thus leading to the stabilization of hyper-excited neural membranes, suppression of repetitive neuronal firing and diminishment propagation of synaptic impulses. Furthermore, anticonvulsant effects of these compounds could be attributed to enhanced potassium conductance and modulation of high-voltage activated calcium channels.


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As notloki said, the three you mentioned all act differently. So there's no competing mechanism of action(s) going on. I take Depakote and Lamictal, but have never taken more unless you count Klonopin, which I am taking scheduled twice a day right now. I'm not having any issues, if thats what you're curious about.

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On 6/5/2020 at 5:26 PM, bpjett said:

Does anyone know the mechanism of action for these meds? Do they all work in different ways in the brain?

The ultra-detailed answer to your question:

Lamotrigine (Lamictal)

Mechanism of action

Lamotrigine is a member of the sodium channel blocking class of antiepileptic drugs. This may suppress the release of glutamate and aspartate, two of the dominant excitatory neurotransmitters in the CNS. It 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 is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel-blocking antiepileptic drugs are not, possibly on account of its sigma receptor activity. In addition, lamotrigine shares few side effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties.

It is a triazine derivate that inhibits voltage-sensitive sodium channels, leading to stabilization of neuronal membranes. It also blocks L-, N-, and P-type calcium channels and weakly inhibits the serotonin 5-HT3 receptor. These actions are thought to inhibit release of glutamate at cortical projections in the ventral striatum limbic areas, and its neuroprotective and antiglutamatergic effects have been pointed out as promising contributors to its mood stabilizing activity. Observations that lamotrigine reduced γ-aminobutyric acid (GABA)-A receptor-mediated neurotransmission in rat amygdala suggest that a GABAergic mechanism may also be involved. It appears that lamotrigine does not increase GABA blood levels in humans.

Lamotrigine does not have pronounced effects on any of the usual neurotransmitter receptors that anticonvulsants affect (adrenergic, dopamine D1 and D2, muscarinic, GABA, histaminergic G1, serotonin 5-HT2A/2C, and NMDA). Inhibitory effects on monoamine transporters (SERT, NET, and DAT) are weak. Lamotrigine is a weak inhibitor of dihydrofolate reductase, but whether this effect is sufficient to contribute to a mechanism of action or increases risk to the fetus during pregnancy is not known (it's generally advisable to supplement with sufficient doses of L-methylfolate or folonic acid AKA "leucovorin," both of which are reduced forms of folic acid and bypass the necessity of the dihydrofolate reductase enzyme for proper metabolism, if taking lamotrigine to avoid a functional folate deficiency, especially if taking high doses or taking for a long time; this is from my and my mother's experience, but we both also have MTHFR genetic mutations that interfere with folate metabolism...). Early studies of lamotrigine's mechanism of action examined its effects on the release of endogenous amino acids from rat cerebral cortex slices in vitro. As is the case for antiepileptic drugs that act on voltage-dependent sodium channels, lamotrigine thereby inhibits  the release of glutamate and aspartate, which is evoked by the sodium-channel activator veratrine, and was less effective in the inhibition of acetylcholine or GABA release. At high concentrations, it had no effect on spontaneous or potassium-evoked amino acid release.

These studies suggested that lamotrigine acts presynaptically on voltage-gated sodium channels to decrease glutamate release. 

It antagonizes the 5-HT3 and sigma (σ) receptors weakly.


Gabapentin (Neurontin)


Gabapentin is a gabapentinoid, or a ligand of the auxiliary α2δ subunit site of certain voltage-dependent calcium channels (VDCCs), and thereby acts as an inhibitor of α2δ subunit-containing VDCCs. There are two drug-binding α2δ subunits. α2δ-1 and α2δ-2, and gabapentin shows similar affinity for (and hence lack of selectivity between) these two sites. Gabapentin is selective in its binding to the α2δ VDCC subunit. Despite the fact that gabapentin is a GABA analogue, and in spite of its name, it does not bind to the GABA receptors, does not convert into GABA or another GABA receptor agonist in vivo, and does not modulate GABA transport or metabolism. There is currently no evidence that the effects of gabapentin are mediated by any mechanism other than inhibition of α2δ-containing VDCCs. In accordance, inhibition of α2δ-1-containing VDCCs by gabapentin appears to be responsible for its anticonvulsant, analgesic, and anxiolytic effects.

The endogenous α-amino acids L-leucine and L-isoleucine, which closely resemble gabapentin and the other gabapentinoids in chemical structure, are apparent ligands of the α2δ VDCC subunit with similar affinity as the gabapentinoids (e.g., IC50 = 71 nM for L-isoleucine), and are present in human cerebrospinal fluid at micromolar concentrations (e.g., 12.9 µM for L-leucine, 4.8 µM for L-isoleucine). It has been theorized that they may be the endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoiods. In accordance, while gabapentinoids like gabapentin and pregabalin (Lyrica) have nanomolar affinities for the α2δ subunit, their potencies in vivo are in the low micromolar range, and competition for binding by endogenous L-amino acids has been said to likely be responsible for this discrepancy.


Divalproex sodium (Depakote) AKA "valproate/valproic acid"


Although the mechanism of action of valproate is not fully understood, traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of γ-aminobutyric acid (GABA). The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate. In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase (SSADH), and by inhibiting the reuptake of GABA by neuronal cells.

Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism. Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-triphosphate (PIP3) as a potential therapeutic mechanism.

It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.

Endocrine actions

Valproic acid has been found to be an antagonist of the androgen and progesterone receptors, and hence as a nonsteroidal antiandrogen and antiprogestogen, at concentrations much lower than therapeutic serum levels. In addition, the drug has been identified as a potent aromatase inhibitor, and suppresses estrogen concentrations. These actions are likely to be involved in the reproductive endocrine disturbances seen with valproic acid treatment.

Valproic acid has been found to directly stimulate androgen biosynthesis in the gonads via inhibition of histone deacetylases and has been associated with hyperandrogenism in women and increased 4-androstenedione levels in men. High rates of polycystic ovary syndrome and menstrual disorders have also been observed in women treated with valproic acid.


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