Introduction
Lamotrigine (LTG), with the brand name Lamictal, is a mood stabilizer medication that is approved for the treatment of bipolar disorder and certain types of seizures disorders (CITATION). Lamotrigine was originally developed for the treatment of seizure disorders, then began to be used as an “off-label” treatment for bipolar disorder. Bipolar disorder is a mental illness that is defined by episodes of depression and mania. LTG is administered orally in pill form up to 200mg doses, and has both standard and extended release formulations.
As previously stated, LTG is a mood stabilizer that acts on use- and voltage-gated sodium channels in the brain (Ketter et al., 2003). LTG provides a blockade of voltage-gated sodium channels, which contributes to its mood stabilizing effects. LTG also inhibits cortical and striatal voltage-activated calcium currents, as well as, reduces calcium conductance involved in neurotransmitter release. Lastly, LTG also has antiglutaminergic properties within the brain.
Typical antidepressants are effective in decreasing the common symptoms of depression, but in patients with bipolar disorder, antidepressants destabilize mood and push bipolar patients into a manic state. LTG does not destabilize mood and is particularly effective at preventing depressive episodes, making it a much more efficacious drug choice for patients with bipolar disorder (Watanabe & Hongo, 2017).
LTG has been seen to be effective in treating acute depressive symptoms, bipolar depressive episodes, maintenance therapy for patients with bipolar I disorder, and as maintenance therapy for patients with rapid-cycling bipolar II disorder. In a study of 445 outpatients with bipolar I disorder, bipolar II disorder and bipolar disorder – not otherwise specified, LTG treatment efficacy was seen in week 4 of treatment, with improved Hamilton Depression Scale Scores sustained through week 52 for all types of bipolar disorder.
127 our experts are availableright now
LTG is a safe drug option for bipolar patients, as a meta-analysis of retrospective studies revealed an overall incidence of adverse events to be 7.2%, with the most common adverse event being skin rash. LTG use also does not elicit sedation, fatigue, cognitive impairment or weight gain (Ketter et al., 2003). Overall, LTG is a safe, efficacious and well-tolerated drug for bipolar disorder.
Mechanism of Action
Numerous pathological conditions produce the disease state of bipolar disorder. The “Unified Field Theory” sees bipolar disorder as a suite of related neurodevelopmental conditions with interconnected functional abnormalities that often appear early in life and worsen as time progresses (Maletic & Raison, 2014). Twin studies have found the concordance rate for bipolar disorder to be 40-70% with heritability values found as high as 90%, displaying the strong genetic basis for bipolar disorder.
Bipolar is a highly heterogeneous condition, but two major genes that are implicated in the manifestation of the disorder are: (1) CACNA1C: the gene that codes for L-type voltage-gated calcium channels, and (2) ANK3: the gene involved in the localization of sodium channels. Genome-wide association studies (GWAS) have found evidence that bipolar disorder affects, but is not limited to the following pathways: CRF hormone signaling, beta-adrenergic signaling, and glutamate receptor signaling.
Along with the genetic nature of bipolar disorder, the mental illness also has physical and physiological effects on the brain. Imaging studies have found that patients with bipolar disorder have larger lateral ventricles than healthy controls, and ventricle size is directly correlated to the number of manic episodes experienced by the patient. This shows that bipolar disease may be progressive and deleterious, leading to brain degradation with recurrent episodes (Maletic & Raison, 2014).
Another supporting finding of bipolar disorder leading to brain degradation is imaging studies have also show that bipolar patients experience a loss in hippocampal volume. These brain losses could be due to a polymorphism of the genes that regulate brain-derived neurotropic factor (BDNF), but mood stabilizers, such as lithium and LTG, have been shown to increase hippocampal volume.
Bipolar patients also display hyperactivity of the ventromedial prefrontal cortex (vmPFC) and amygdala, which is involved in emotion regulation, and hypoactivity of the dorsolateral prefrontal cortex, which plays a role in cognitive and executive function.
The “anatomic bridge” between the dorsal and ventral parts of the brain is the subgenual ACC, which has been found to be hyperactive during mania and hypoactive during depression. The neurobiology of bipolar disorder is complex, and drugs used to treat the disorder should be able to combat the numerous mechanisms behind the disorder.
Since the neural mechanisms of bipolar disorder are complex, the underlying therapeutic effects of LTG are still relatively unexplored. LTG is known to be a sodium channel blocker that also inhibits glutamate release and voltage-gated ion channel activity (Bauer et al., 2018). The antidepressant efficacy of LTG is shown through the antiglutaminergic and sodium channel blocking properties. However, LTG effects on brain volumes wanted to be investigated.
One imaging study used 12 bipolar II patients and 12 healthy controls to see LTG’s mechanism of action for increasing brain volumes and decreasing symptoms associated with bipolar disorder over a 12-week period of taking the drug. The results demonstrated that remitted bipolar patients displayed a decrease in volume of the amygdala, cerebellum, hippocampus and nucleus accumbens (all areas associated with mood and emotion regulation).
This study provides evidence that one mechanism of LTG in bipolar disorder is to decrease amygdala and cerebellum volumes to combat the hyperactivity of these brain regions associated with bipolar disorder, which results in mood improvement.
Another mechanism of LTG involved in the neuroprotective properties of the drug is LTG blocks NMDA receptor-mediated arachidonic acid (AA) signaling in the brain (Ramadan et al., 2012).
NMDA receptors allow extracellular calcium into the neuron, stimulating the release of AA from membrane phospholipids. Bipolar disorder is characterized by an upregulated AA cascade and a hyperglutaminergic state. Prostaglandin is a metabolite of AA that is pro-inflammatory within the brain. Inflammation of the brain is another problematic characteristic of bipolar disorder.
This mechanism has been modeled in rats who have been treated with clinically relevant doses of LTG for a minimum of 6 weeks then injected with NMDA in order to measure AA and AA cascade markers using autoradiography. LTG treatment results in reduced concentrations of AA and its metabolites. Therefore, LTG works to block NMDA-initiated activation of the AA cascade and formation of prostaglandin, which demonstrates LTG’s neuroprotective properties.
Tying together the neurobiology of bipolar disorder with the mechanisms of action for LTG is difficult, since bipolar disorder is a disease that has such a complex network of physiological symptomatology. LTG has antidepressant and anti-manic efficacy through its blockade of voltage-gated sodium and calcium channels to inhibit further action potentials from being generated.
But, LTG also affects the volumes of certain brain regions like the amygdala and cerebellum to decrease brain volumes that are hyperactive in a bipolar state. Also, LTG could affect brain volumes through a possible stimulation of the BDNF cascade and a blockade of the AA cascade that results in less inflammation. LTG’s mechanisms of action result in decreasing both the depressive and manic symptoms associated with bipolar disorder.
Preclinical Research
Animal models are used to depict the human condition, so the predictive validity of drugs can be shown before human testing. However, bipolar disorder is a condition defined with two distinct components. Therefore, when investigating the effects of drugs for bipolar disorder, it must be tested for both depression and manic animals models.
The LTG antidepressant-like effect was assessed using mice in the forced swim test (FST) in order to investigate the involvement of NMDA receptor signaling and NO pathway (Ostadhadi et al., 2016). NMDA receptors have been found to be reduced in patients with depression, and NMDA receptors mediate antidepressant-like actions. The investigators put mice through the FST and open field test (OFT) in order to measure immobility time and locomotor activity, respectively through both tests.
The mice were injected with LTG alone, and LTG with a combination of other drugs, like NOS inhibitors, an NO precursor, NMDA receptor antagonists, and an NMDA agonist. These combinations were used to investigate the effects LTG has on NMDA receptors and the NO pathway that appear to be involved in LTG’s antidepressant effects.
The results demonstrated that LTG alone led to significantly less immobility time in the FST, and high dose LTG mirrored the results seen with the antidepressant gold standard of fluoxetine. Immobility time was also significantly decreased when LTG was administered in conjunction with NMDA antagonists and NOS inhibitors, but no effect on immobility time was seen when LTG was injected with NMDA agonists or NO precursors. These results conclude that LTG exerts antidepressant effects, but the exact mechanism of how (whether through NMDA effects or NO pathway effects) still needs to be directly identified.
In order to be an effective treatment for bipolar disorder, LTG must also demonstrate efficacy in mania animal models. The most common model for mania is kindling, which is also a model for seizures. Kindling is the repeated stimulation of a brain region that leads to intensifying seizures, and mania is characterized similarly to seizures where neurons fire at a high rate (Stratton et al., 2003).
A study was performed to determine whether LTG, in addition to its anticonvulsant profile, demonstrates antiepileptic-like activity in the kindling model. A stimulation/recording electrode was placed into the basolateral amygdala in rats. Prior to stimulation, rats were injected with clinically relevant doses of LTG, and the main dependent variables being measured were seizure severity and amygdala afterdischarge duration.
The results demonstrated that LTG reduced seizure severity (from class 5.0 to class 3.3) and amygdala afterdischarge duration. These results demonstrated that LTG is effective in lessening seizure-like effects in the brain, and stabilizing neuronal seizure activity in the amygdala, which is central to the pathophysiology of bipolar disorder.
Preclinical research has demonstrated that LTG has antidepressant efficacy by acting on NMDA receptors and the NO pathway, and is effective in lessening and/or preventing neuronal seizure-like activity similar to what is expressed during episodes of mania.
Clinical Research
Clinical research has displayed the predictive validity from preclinical animal studies. Previous research showed that LTG had no effect on depressive symptoms in patients with bipolar II disorder, so one study aimed to determine if splitting a sample of bipolar II patients into melancholic and non-melancholic depression subgroups would reveal a significant treatment effect with LTG (Peters et al., 2018). Prior to treatment with LTG, patients filled out the HAMD-17 and MADRS depression scales to determine baseline depression scores. Out of a total of 150 outpatients, 90 were placed into the melancholic group, while the other 60 were placed into the non-melancholic group.
The study lasted for a total of 8 weeks, with LTG dosage increasing over the period. LTG dose was 25mg/day for weeks 1-2, 50mg/day for weeks 3-4, 100mg/day for week 5, and 200mg/day for weeks 6-8. The study found that LTG had a significant effect on HAMD-17 scores, and a marginally significant effect on MADRS scores in the melancholic group, while LTG had no significant effects on the scale scores in the non-melancholic group. The conclusion can then be made that LTG is effective in decreasing depressive symptoms in bipolar II patients that display severely melancholic symptoms of depression.
Bipolar disorder has several different subtypes. The most debilitating of which is rapid-cycling bipolar disorder. Patients with this subtype of bipolar disorder are often treatment resistant due to constant episodic changes in mood.
Another clinical trial aimed to determine the safety and efficacy of LTG as monotherapy for long-term prophylaxis of mood episodes in rapid-cycling bipolar patients (Calabrese et al., 2000). The preliminary phase of the study was a 6-week titration of LTG with doses ranging from 100-300mg/day. This process was accompanied by a tapering of other medications that were previously being taken. During this phase, subjects also filled out numerous questionnaires, such as the HAMD, MADRS, SADS, CGI-S and GAS, so researchers could determine baseline symptomatology. The next phase of the trial lasted 26 weeks, and was a randomization of remaining participants into either LTG or placebo groups.
During this phase, LTG dosages ranged from 100-500mg/day. At the conclusion of this phase, all questionnaires were filled out again. The results demonstrated that a significantly higher percentage of patients in the LTG group remained clinically stable for 6 months compared to placebo. Also, it was found that LTG led to a longer median time to additional needed pharmacotherapy than did placebo (18 weeks vs. 12 weeks). HAMD scores were also significantly decreased in the LTG group than placebo, again displaying LTG’s antidepressant efficacy. It was concluded that LTG is a well-tolerated and effective mood stabilizer with prophylactic properties when used a s monotherapy for patients with rapid-cycling bipolar disorder.
References
- Bauer, I. E., Suchting, R., Cazala, F., Alpak, G., Sanches, M., Nery, F. G., Zunta-Soares, G. B., & Soares, J. C. (2018). Changes in amygdala, cerebellum, and nucleus accumbens volumes in bipolar patients treated with lamotrigine. Psychiatry Research: Neuroimaging 278, 13-20.
- Calabrese, J. R., Suppes, T., Bowden, C. L., Sachs, G. S., Swann, A. C., McElroy, S. L., Kusumakar, V., Ascher, J. A., Earl, N. L., Greene, P. L., & Monaghan, E. T. (2000). A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. J Clin Psychiatry 61, 841-850.
- Ketter, T. A., Manji, H. K., & Post, R. M. (2003). Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. Journal of Clinical Psychopharmacology 23(5), 484-495.
- Maletic, V., & Raison, C. (2014). Integrated neurobiology of bipolar disorder. Front Psychiatry 5(98), 1-24.
- NAMI: National Alliance on Mental Illness. (2019). Lamotrigine (Lamictal). Retrieved from: https://www.nami.org/Learn-More/Treatment/Mental-Health-Medications/Types-of-Medication/Lamotrigine-(Lamictal)
- Ostadhadi, S., Ahangari, M., Nikoui, V., Norouz-Javidan, A., Zolfaghari, S., Jazaeri, F., Chamanara, M., Akbarian, R., & Dehpour, A. R. (2016). Pharmacological evidence for the involvement of the NMDA receptor and nitric oxide pathway in the antidepressant-like effect of lamotrigine in the mouse forced swimming test. Biomedicine & Pharmacotherapy 82, 713-721.
- Peters, E. M., Bowen, R., & Balbuena, L. (2018). Melancholic symptoms in bipolar II depression and responsiveness to lamotrigine in an exploratory pilot study. Journal of Clinical Psychopharmacology 38(5), 509-512.
- Ramadan, E., Basselin, M., Rao, J. S., Change, L., Chen, M., Ma, K., & Rapoport, S. I. (2012). Lamotrigine blocks NMDA receptor-initiated arachidonic acid signaling in rat brain: Implications for its efficacy in bipolar disorder. Int J Neuropsychopharmacol 15(7), 931-943.
- Stratton, S. C., Large, C. H., Cox, B., Davies, G., & Hagan, R. M. (2003). Effects of lamotrigine and levetiracetam on seizure development in a rat amygdala kindling model. Epilepsy Research 53, 95-106.
- Watanabe, Y., & Hongo, S. (2017). Long-term efficacy and safety of lamotrigine for all types of bipolar disorder. Neuropsychiatr Dis Treat 13, 843-854.
