What Makes It So Special? A Review of the Mechanisms of Action of Lamotrigine, Carbamazepine, and Valproic Acid and How They Differ From Other Antiepileptics

It’s a normal day in your office when your patient, Ms. Q, comes in. Ms. Q is an established patient in your practice and is taking lamotrigine for bipolar I disorder. She tells you that her husband, Mr. Q, has focal epilepsy and has been stable on levetiracetam. However, her husband often feels angry and is easily frustrated. “Why is lamotrigine special? Why isn’t levetiracetam a mood stabilizer too?” You sit... and you think....

Why do some antiepileptics act as mood stabilizers while others can worsen depression and even lead to rage or psychosis? What are the qualities of mood stabilizing antiepileptics compared to others? Why can’t we rely on all antiepileptics to improve mood?

Current mood stabilizing antiepileptics include valproic acid, carbamazepine (and by extension oxcarbazepine), and lamotrigine.¹ Over time, these therapeutics have been approved by the US Food and Drug Administration (FDA) in the United States as mood stabilizers with indications for acute mania (valproic acid and carbamazepine) and long-term stabilization (valproic acid, carbamazepine and lamotrigine).¹

Valproic Acid

Valproic acid was initially discovered in 1882 and was used as an inert solvent until 1962, when its antiepileptic properties were discovered by means of the Khellin derivative trial.² In 1966 it was trialed as a mood stabilizer with great success and was eventually approved by the FDA in 1994 when it was compared to lithium for the treatment of bipolar disorder.²

Valproic acid’s main antiepileptic mechanism of action is T-calcium channel blockade, as well as some mild sodium channel blockade.⁸ In addition, its antiepileptic properties stem from gamma-aminobutyric acid (GABA) transmission stimulation and N-methyl-D-aspartate (NMDA) receptor antagonism.⁸ In fact, GABA transmission is so pronounced that valproic acid has been shown to block GABA transaminase and succinate semi-aldehyde dehydrogenase, virtually blocking the conversion of GABA into glutamate.⁷ Further, it blocks glutamate reception on the 3alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor.⁷ Lastly, valproic acid also blocks histone deacetylase 1 which prevents the acetylation of genes associated with inflammatory transcription.¹² Valproic acid is considered a first line treatment for bipolar disorder and acute mania and is comparable to lithium.¹² Valproic acid has also been used off label to address impulsivity and agitation post traumatic brain injury.

Carbamazepine

Carbamazepine was initially created and developed in 1953 to treat trigeminal neuralgia and, eventually, seizure activity.³ It was approved as a mood stabilizer in 2004 and has also been shown to be beneficial for psychosis in Alzheimer dementia.^3,4

Carbamazepine acts primarily as an antiepileptic by blocking voltage gated sodium channels and L-type calcium channels.⁸ It also demonstrates antagonism of the anti-NMDA receptor (like valproic acid) but to a lesser extent.⁸

Thought to have mood stabilization properties because of its close structural relationship to imipramine, carbamazepine has been comparable to lithium and haloperidol for mood stabilization in several large trials.¹⁰ The literature also has shown carbamazepine’s utilization for acute agitation.¹⁰

Lamotrigine

Lamotrigine was first synthesized in 1980 following a 30-year drought of new antiepileptic treatments.⁵ It was then studied from 1995 to 1996 in large clinical trials of patients struggling with bipolar I and bipolar II disorder, with positive results.⁵ Lamotrigine was found to be effective at stabilizing rapid cycling and served as an effective treatment for bipolar depression; this eventually led to its approval by the FDA in 2003.⁶

Lamotrigine works by inhibiting voltage gated sodium channels and shares a common sodium receptor with carbamazepine and phenytoin.⁶ In animal studies, this inhibition has been shown to increase release of dopamine, glutamate, and GABA.⁶ Lamotrigine has also been associated with voltage gated calcium channels antagonism on multiple channels (R, N, Q, and T), which in some animal models has been associated with neuroprotective properties of the medication.⁶

Lamotrigine is effective for the maintenance of mood stabilization in bipolar disorder and appropriate for both depersonalization and aggression in borderline personality disorder.¹¹ There are other indications in the literature for its use, including a double blind, randomized, placebo-controlled trial that showed augmentation of a selective serotonin reuptake inhibitor with lamotrigine improved obsessive compulsive symptoms.¹¹

Bipolar Pathophysiology

In order to review the unique properties of these 3 antiepileptics in terms of their efficacy in mood stabilization, it is prudent to discuss several pathophysiological theories of bipolar disorder. Bipolar disorder is considered to be a combination of neurotransmitter imbalance, neuronal excitation leading to potential apoptosis, and neuronal inflammation. Several studies have also indicated decrease in neuroplasticity as evidenced by changes in brain derived neurotrophic factor, nerve growth factor, and neurotrophine.⁹ Further, imaging has shown notable changes in neuronal activity and interconnectivity second to inflammatory processes.⁹ Monoamine changes (particularly dopamine and serotonin) have also been associated with bipolar disorder.⁹ The extent of any one of these mechanisms is unclear; the disease is thought to instead be a combination of multiple pathways.⁹

Pharmacological Mechanisms of Actions

Clearly, the mood stabilizing benefits evident in valproic acid, carbamazepine, and lamotrigine are not limited to their pharmacologic mechanism of actions. In fact, many other antiepileptics share these properties without acting as mood stabilizers. Felbamate, zonisamide and topiramate all have sodium channel inhibition, but they do not have the mood stabilizing properties of lamotrigine or carbamazepine.⁷ Barbiturates, which are associated with GABA neurotransmitter enhancement, have been associated with increased rates of depression and even suicidal ideation.⁸ Levetiracetam has GABA-A agonism, is a calcium voltage gate blockade, and has been associated with causing psychotic symptoms. So, what makes carbamazepine, lamotrigine, and valproic acid so special?

While many antiepileptics share similar pharmacokinetic pathways, there are some key differences. Mood control in antiepileptics appears to be related to possible rebalance of the GABA and Glutamate.⁸ Medications that increase transmission GABA, particularly GABA -A, have been associated with increased fatigue and cognitive slowing.⁸ We can also see this with medications such as topiramate, felbamate and the benzodiazepines.⁸ Medications with limited or negligible diffuse GABA enhancement (valproic acid, lamotrigine, carbamazepine) appear to have less overall patient complaints of cognitive slowing, although there may be reports of fatigue.⁸

Activating antiepileptics appears to modulate glutamic acid and limited overexcitation through NMDA receptor pathways.⁸ This receptor antagonism appears to reduce overall neuronal inflammation and has been associated with antidepressant properties, as evidenced by felbamate and oxcarbazepine.⁸ Contrarily, medications that appear to inhibit AMPA receptors have been associated with worsened mood. AMPA receptors have been shown in animal models to increase BDNF and improve neuroplasticity, leading to reductions in depression.¹² Medications that inhibit this, such as levetiracetam and topiramate, have been associated with increases in depressive symptomatology.⁸ While lamotrigine acts as both an antagonist on NMDA and AMPA, it appears to have stronger antagonism to NMDA.

It would be erroneous not to address the differences in calcium channel blockade. L-type calcium channels in the cellular membrane have been associated with the release of vesicular monoamine transporters (VMAT), leading to reuptake of monoamines such as dopamine, serotonin, and norepinephrine.¹³ The blockade of the L-type calcium channel mimics behavior of other VMAT inhibitors such as reserpine and tetrabenazine and therefore increases intercellular concentrations of monoamine.¹³ This mechanism likely explains some of the mood stabilizing properties of carbamazepine.¹³ Further, calcium itself has been shown to activate monoamine oxidase and its blockade from cellular absorption appears to increase concentrations of monoamine intercellular.¹⁵ Contrarily, valproic acid and lamotrigine act as T-calcium channel blockers, which may inhibit monoamine release. However, some scientists theorize this blockade reduces inflammatory pathways related to the release of free radicals.¹⁴ 

N-type calcium channels have been associated with the release of monoamines, including serotonin, norepinephrine, and dopamine, and have been associated with both neuronal growth and neuroplasticity.¹ Multiple antiepileptics, including levetiracetam and zonisamide, have high blockade of this limiting release of potential neurotransmitters and diminishing neuroplasticity.^5,8 P/Q channels are also associated with release of monoamine.¹⁶

Concluding Thoughts

It is likely that multiple pathways influence the mood stabilization effects of carbamazepine, lamotrigine, and valproic acid. While these medications share pharmacokinetics with other antiepileptics, it is the combination of mechanisms that lead to mood stabilization.

Further, patients are not always clearly defined the way literature indicates. Our patients struggle with combinations of factors that influence their moods and likely influence how medications affect their pathophysiology. Many patients are on multiple antiepileptics and the drug-drug interactions affect psychopathology and overall neuroplasticity. It is important to recognize that our patients’ experiences also influence their overall tolerance of medications and how these, in turn, affect their mood and health.

And…you are back in your office. You turn to your patient and say “Well…not every medication in epilepsy does the same thing”

References

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2. Bowden CL. Valproate. Bipolar Disord. 2003;5(3):189-202.

3. Schwarz A, Strakos C, Weihrich R. A brief review on carbamazepine: history, pharmacological properties and environmental impact. Ins Chem Biochem. 2021.

4. Weisler RH. Carbamazepine extended-release capsules in bipolar disorder. Neuropsychiatr Dis Treat. 2006;2(1):3-11.

5. Weisler RH, Calabrese JR, Bowden CL, et al. Discovery and development of lamotrigine for bipolar disorder: a story of serendipity, clinical observations, risk taking, and persistence. J Affect Disord. 2008;108(1-2):1-9.

6. Ketter TA, Manji HK, Post RM. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. J Clin Psychopharm. 2003;23(5):484-495.

7. El Hage M, Baverel G, Martin G. Effects of valproate on glutamate metabolism in rat brain slices: a (13)C NMR study.Epilepsy Res. 2012; 99:94-100.

8. Mula M, Sander JW. Negative effects of antiepileptic drugs on mood in patients with epilepsy. Drug Safety. 2007;30(7):555-567.

9. Jain A, Mitra P. Bipolar Disorder. StatPearls Publishing; 2025.

10. Grunze A, Amann BL, Grunze H. Efficacy of carbamazepine and its derivatives in the treatment of bipolar disorder. Medicina (Kaunas). 2021;57(5):433.

11. Naguy A, Al-Enezi N. Lamotrigine uses in psychiatric practice. Am J Ther. 2019;26(1):e96-e102.

12. Alt A, Nisenbaum ES, Bleakman D, et al. A role for AMPA receptors in mood disorders. Biochem Pharmacol. 2006;71(9):1273-1288.

13. Mahata M, Mahata SK, Parmer RJ, et al. Vesicular monoamine transport inhibitors. Novel action at calcium channels to prevent catecholamine secretion. Hypertension. 1996;28(3):414-420.

14. Cao X, Li XM, Mousseau DD. Calcium alters monoamine oxidase-A parameters in human cerebellar and rat glial C6 cell extracts: possible influence by distinct signalling pathways. Life Sci. 2009;85(5-6):262-268.

15. Weiss N. The N-type voltage-gated calcium channel: when a neuron reads a map. Journal Neurosci. 2008;28(22): 5621–5622.

16. Stahl SM. Stahl's Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. Cambridge University Press; 2021.