Many different types of channels are located in the membrane , acting like guards at an exclusive community, only letting certain molecules in and out.
Some of these channels open or close depending on what the membrane voltage is. One of these voltage -gated channels is the sodium channel, and it opens when the inside of the membrane becomes more electrically positive than usual. When the channel opens, sodium ions are free to enter the cell and continue the messaging cascade that ultimately leads to the release of neurotransmitters such as glutamate.
After the sodium channel lets enough sodium into the cell so that it reaches a maximum voltage , the channel temporarily becomes inactivated. An inactivated channel means that not only can no more sodium get through to relay the current message, but also the channel cannot be immediately reset, and thus will let no new messages be relayed.
This intermediate stage between open and closed is called the refractory period. The sodium channel returns to the closed position only after the membrane voltage returns to a normal level restoring the normal voltage involves the exit and entry of different ions. Once the channel is back in the closed position it can be opened again when the voltage rises enough.
See figure L-5 for a representation of the different sodium channel positions. Studies have shown that lamotrigine may inhibit the release of glutamate. While lamotrigine may act in several different ways, it is primarily thought to act as an anti-glutamate drug by interfering with sodium channels. These channels are a necessary step in the nerve impulse and for normal release of glutamate by a nerve cell.
For more information on riluzole click here. Lamotrigine exerts its effects during the refractory period by binding to sodium channels. In overactive nerve cells such as in people with seizure disorders or HD, it takes longer for sodium channels to transition from the open period to the inactivated refractory period. An extended open period is what allows so much glutamate to be released in overactive cells.
Lamotrigine targets these overactive cells that are slow to inactivate, leaving normal areas of the brain unaffected. Lamotrigine acts by prolonging the inactive refractory period so that sodium channels cannot return to the closed position. Since the channel must first be closed before it can be re-opened, prolonging the inactive period decreases the time of the open period, thus decreasing glutamate release.
It is important to follow up with your doctor routinely and to contact your doctor immediately if you notice any skin rash or changes in mood or behavior. It is very important to tell your doctor how you feel things are going during the first few weeks after you start taking lamotrigine. It will probably take several weeks to see big enough changes in your symptoms to decide if lamotrigine is the right medication for you.
Mood stabilizer treatment is generally needed lifelong for persons with bipolar disorder. Your doctor can best discuss the duration of treatment you need based on your symptoms and illness. Serious and sometimes fatal skin reactions have been reported with lamotrigine use.
Since it is not always possible to predict which rashes will prove to be serious or life threatening, it is important to talk to your doctor at the first sign of a rash while taking lamotrigine. Last Updated: January This information is being provided as a community outreach effort of the College of Psychiatric and Neurologic Pharmacists. This information is for educational and informational purposes only and is not medical advice. This information contains a summary of important points and is not an exhaustive review of information about the medication.
Always seek the advice of a physician or other qualified medical professional with any questions you may have regarding medications or medical conditions. Never delay seeking professional medical advice or disregard medical professional advice as a result of any information provided herein. The College of Psychiatric and Neurologic Pharmacists disclaims any and all liability alleged as a result of the information provided herein.
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Your Journey Frontline Professionals. Get Involved Become a Fundraiser. Get Involved Awareness Events. Get Involved Share Your Story. In the four other studies subjects diagnosed with bipolar I disorder Calabrese et al. However, CGI-Improvement score was significantly greater with lamotrigine treated group in two studies Calabrese et al. Amann et al. Many prior studies have been focused on the efficacy of lamotrigine monotherapy in preventing the depressive relapse in bipolar I disorder and rapid-cycling disorder.
Bipolar II disorder is characterized by one or more episodes of major depression which is often accompanied by atleast one hypomania episode. In contrast to this, bipolar II depression is associated with either one or more maniac or depressive episodes mixed episodes which may alternate from depressive episode lasting for several weeks or months to intense maniac symptoms lasting for about the same duration. In patients with bipolar II disorder, the clinical data for the long term use of lamotrigine is very limited Bowden et al.
Patients suffering from the depressive phase of the bipolar disorder were suggested with adjunctive lamotrigine treatment, the usage of which was considered to be safe and well tolerated. Lamotrigine therapy showed significant response in comparison to placebo in severely ill patients in a recent meta-analysis conducted Geddes et al. It was found that antidepressant augmentation with lamotrigine was reported to show higher rates of recovery in treatment-resistant bipolar I or II disorder.
Results that were obtained from related studies conducted earlier gave sufficient evidence for the long-term effectiveness of lamotrigine adjunctive therapy in the management of treatment-resistant bipolar II depression Sharma et al.
In comparison with bipolar I disorder, higher suicidal tendency and psychosocial impairment was observed in bipolar II disorder. The longitudinal course of bipolar II disorder is dominated by recurrent depressive episodes and residual symptoms of depression, which has a potential to exert strong influence on the psychosocial functioning levels.
Owing to this, the clinical output of bipolar II disorder can be improved by the proper long-term management of the depressive symptoms Endicott et al. With this respect, a naturalistic week follow-up study was conducted for evaluating the long-term effectiveness of lamotrigine adjunctive therapy for bipolar II depression, in the absence of treatment-related mania or hypomania.
The results of which showed that the severity of depression was significantly reduced throughout weeks in bipolar II disorder. During the initial week treatment, the rate of response was found to be Depression was improved during the initial treatment phase and maintained for about 1 year Chang et al.
Management of acute phase of bipolar depression was found to be ineffective by lamotrigine monotherapy as per the results obtained from the five randomized trials whereas, addition of lamotrigine to lithium in treating patients with acute bipolar depression was found to effective on the basis of the results of a recently conducted randomized trial Calabrese et al.
Augmentation of atypical antipsychotics or mood stabilizers with lamotrigine is expected to produce additive or synergistic effects through modulation of sodium channel or serotonergic regulation Bourin et al. The results obtained from an animal study using sodium channel opener, lamotrigine showed antidepressant effects due to two different mechanisms such as inactivation of sodium channels and monoaminergic neurotransmission suggesting different mode of antidepressant activity Prica et al.
Adjunctive use of lamotrigine may be more beneficial in terms of safety and tolerance as compared to lamotrigine monotherapy, since patients already receiving mood stabilizers could easily avail a slower titration of lamotrigine Joe et al. In various clinical trials lamotrigine use as an augmentation agent was explored for bipolar disorder with depressive episodes not responsive to typical mood stabilizers.
In a randomized, double-blind, 7-week pilot trial, lamotrigine augmentation was compared with citalopram augmentation for bipolar I and II depression Schaffer et al.
Nierenberg et al. Although no significant difference was found between groups for primary outcome, subjects in lamotrigine group remained in the randomized phase significantly longer compared to other groups. This study evaluated efficacy of lithium plus lamotrigine for the treatment of acute bipolar depression. MADRS score change was significantly different between groups. Further, subjects were more responsive in lithium plus lamotrigine treated group compared to placebo.
In a recent study, Kagawa et al. The antidepressant drug lamotrigine is found to be therapeutically more effective in the treatment of depressive phase of the bipolar disorder than in treating hypomania or mania Bourin et al. The use of lamotrigine as an augmentation drug was suggested from the evidence of the efficacy of the drug in the treatment of major depressive disorders, which also includes refractory unipolar depression Frye et al.
The onset of antidepressant action accelerated when administered in combination with other classical antidepressants Normann et al. In a study, various in vivo evaluations in various regions of the brain were conducted to understand the effect of lamotrigine on serotonin 5-hydroxytryptamine, 5-HT 1A -receptor-mediated adenyl cyclase responses in various brain areas in the mice.
The results, which were obtained thereafter, suggested a new pathway which reflected the therapeutic efficacy of various classes of mood stabilizers. Thus showing significant role of 5-HT in the physiopathology of maniac depressive disorder Vinod and Subhash, For quantifying 5-HT 1A , 5-HT 1B , and 5-HT 2A m-RNA levels in the hippocampus and dorsal prefrontal cortex, the technique of in situ hybridization was used, as a part of a recent study of subjects with a history of bipolar disorder.
The result of the same indicated that these subjects showed highly altered 5-HT receptor m-RNA expression giving more evidence to support the involvement of 5-HT receptors in the mechanism of action of lamotrigine in bipolar disorders Lopez-Figueroa et al. Shim et al. They concluded that 5-HT firing in the DRN is decreased but 5-HT transmission in the forebrain is enhanced by sustained carisbamate and lamotrigine administration.
One of the biggest challenges faced in the studies and evaluation of mood stabilizers was the development of a valid and satisfactory animal model for bipolar disorder as it comprised of complex interplay of episodes of mania, depression, euthymia and mixed states. The animal models that have been proposed was found only to be partially matching the bipolar illness and in such case modeling of either depression or maniac behavior could be achieved, but not both Machado-Vieira et al.
The FST, as compared to all the other models was found to be a simpler model Porsolt et al. All the data obtained from the study showed significant decrease in the immobility time of lamotrigine when used in combination with the various 5-HT ligands indicating the involvement of postsynaptic 5-HT receptors in activity of lamotrigine.
The antidepressant-like effect of lamotrigine was also known to be produced by the neurotransmitters regulated by postsynaptic 5-HT receptors Bourin et al. Another study on the effect of 5HT transmission on lamotrigine reported carbamazepine and lamotrigine to be the only anticonvulsant drugs to result in elevated extracellular 5-HT concentrations by inhibiting both in vitro and in vivo 5-HT uptake Clifford et al.
Cortical 5-HT 1A receptors mediated downregulation of responses also suggests another possible mechanism of action of lamotrigine Vinod and Subhash, It was found that when higher dose this inhibitor was given in combination with lamotrigine, it produced sedative effect, which was considered to be responsible for the reversal of the antidepressant-like effect of lamotrigine.
Lamotrigine was also reported to inhibit the synaptosomal uptake of serotonin, noradrenaline, and dopamine in the rat brain which could be an indication that lamotrigine indirectly affects the noradrenergic system, by the release of noradrenaline, which could further result in interaction with the receptors Southam et al.
When mice were pretreated with prazosin and yohimbine, it reversed the decrease in the immobility time evoked by lamotrigine suggesting the underlying actions of these receptor subtypes in the forced swimming test. A strong reduction in the locomotor activity which was produced by the administration of adrenergic drugs phenylephrine and clonidine was already reported in the earlier study.
However, the more recent study conducted on the involvement of noradrenergic system in the antidepressant-like action of lamotrigine reported that inspite of these adrenergic drugs showing sedative effects Sukul et al. A better understanding of the mechanisms of action of mood-stabilizing agents forms a basis of the mechanisms underlying the pathology of bipolar disorder. For the better understanding of the efficacy of lamotrigine, assessment of neural activity in different areas of the brain was undertaken in healthy human volunteers to study the effects of the drug by activating specific neural circuits using transcranial magnetic stimulation TMS which was used in combination with functional magnetic resonance imaging fMRI for monitoring the response.
This is a significant non-invasive method for the assessment of motor cortex excitability which also helps in the stimulation of the cerebral cortex. This method is also found to be useful in the pharmacological examination of neuroactive drugs on specific brain circuits Li et al. It was observed from the previous studies which used TMS Manganotti et al.
TMS-induced motor cortical circuits activation was observed beneath the stimulator coil in the presence of the drug. Lamotrigine was also found to show facilitatory effect on the blood-oxygen-level-dependant BOLD response to TMS of the prefrontal cortex.
Application of TMS to the motor cortex showed that with the reduction in the excitability of the motor cortex, reduction of the BOLD response was consistent, which was in line with the sodium channel blocker effects Paulus et al. TMS was applied to the prefrontal cortex in the second part of the study that elicited BOLD response in the corticolimbic brain areas such as hippocampus and orbital frontal gyrus thereby showing increased excitability of prefrontal cortex.
The detailed investigations in the study showed that anticonvulsant activity of the antiepileptic drugs such as lamotrigine and valproic acid is conferred to the inhibition of the brain activation caused by the reduced excitability of the motor cortex induced by TMS stimulation.
However, lamotrigine exerts a different action in the prefrontal corticolimbic system on TMS stimulation which shows that lamotrigine differs from valproic acid in molecular mechanisms of action as increased TMS-induced BOLD response was observed in corticolimbic circuits when TMS was applied over the dorsolateral prefrontal cortex Li et al. Thus, lamotrigine, anticonvulsant drug, was found to exert a positive effect on the activity of the corticolimbic circuits in patients with bipolar disorder.
Further studies for highlighting the facilitatory effects of lamotrigine on the activity of the corticolimbic system was done to investigate the in vitro activity of the hippocampus in response to the drug Large et al.
It was very much necessary to study the effects of the drug on the brain neural network, rather than on the individual neurons Xie et al. For this purpose, the CA3 region of the hippocampus was chosen for studying the effects of lamotrigine on oscillatory field potentials, manifested at low concentrations of kainic acid resulted in network oscillations Fisahn, , which was believed to be able of mimicking the physiological neural network activity, responsible for the encoding and retrieval of memory in the hippocampus Mann and Paulsen, The results obtained from the neuronal network studies provided sufficient evidence of the facilitatory effects of lamotrigine in healthy volunteers and in patients with bipolar disorder Large et al.
Thus, along with the activity of the corticolimbic circuits lamotrigine also exerts a positive effect on the neural network activity. Based on this, a hypothesis was drawn that neuroplasticity dysfunction and cellular resilience formed an important component of the bipolar disorder. With use of clinically effective mood stabilizers such as lithium and valproic acid this approach was utilized Bachmann et al. There are several cellular and molecular actions of lamotrigine that may contribute to its action in bipolar disorder Xie and Hagan, The main mechanism by which lamotrigine emerged as a well-established anticonvulsant is due to the inhibition of neuronal hyperexcitability and modification of synaptic plasticity via voltage-dependant inhibition of neuronal voltage-activated Sodium channels and possible high voltage-activated Calcium channels, as a result of which excessive neurotransmitter release in the brain is reduced Xie et al.
However, the reason for this mechanism of lamotrigine to exert its efficacy against depressive phase of the bipolar disorder is quite unclear. In , GSK3 pathway was first linked to bipolar disorder from the finding that lithium is a direct inhibitor of GSK3 and it directly as well as indirectly inhibited GSK3 by increasing the phosphorylation of Akt, which inturn is responsible for the phosphorylation of Ser 9 Phiel and Klein, ; De Sarno et al.
However, lamotrigine indirectly acts by attenuation of staurosporine and heat-shock-induced caspase 3 activity in a cell line responsible for over expression of GSK3 Bijur et al. Bipolar disorder is characterized by hyperglutamatergic neurotransmission and by upregulated arachidonic acid cascade, which forms a new profound therapeutic target in the treatment of the disorder Michael et al.
These receptors allow the extracellular flow of calcium into the cell, which causes the membrane phospholipid to selectively release arachidonic acid, via the activation of cPLA 2 type IV calcium-dependant cytosolic phospholipase A 2 -IV; Epolia et al.
Studies show that in bipolar disorder, associated with the above mechanisms, lamotrigine was found to cause interference with the glutamatergic neurotransmission that involved the NMDA receptors. Lamotrigine reduces the presynaptic neuronal depolarization by acting on the voltage-gated sodium and calcium channels thereby reducing the release at the excitatory synapse Xie and Hagan, ; Cunningham and Jones, ; Sitges et al.
However, lamotrigine does not produce any effect on the resting membrane potential, excitatory neuronal transmission of low-frequency or neuronal excitability Xie and Hagan, , even the release of glutamate in the hippocampal region of the freely moving rats Ahmad et al. Thus lamotrigine, like many other approved mood-stabilizers causes inhibition of the arachidonic acid signaling mediated by the NMDA receptors thereby bringing about down-regulation of brain metabolic arachidonic acid cascade in the rat brain, initiated by NMDA Rapoport and Bosetti, ; Rapoport et al.
Moreover, the post mortem BD rat brain showed consistent glutamatergic state with up-regulated arachidonic acid cascade and NMDA receptor signaling markers which includes COX-2 cyclooxygenase , PLA 2 , and PG E synthase prostaglandin E synthase responsible for the conversion of arachidonic acid to pro-inflammatory Prostaglandin E 2 , greater expression of vesicular glutamate transporter I, as well as elevated levels of protein and m RNA in the rat frontal cortex Hashimoto et al.
Lamotrigine was also found to suppress ketamine induced perceptual abnormalities in healthy human volunteers Anand et al. Besides its efficacy in treating bipolar disorder by inhibition of the metabolic arachidonic cascade, lamotrigine has also been reported for its neuroprotective effects with respect to bipolar disorder arising out from its potential to increase the levels of mRNA and proteins of brain-derived neurotropic factor BDNF as well as by increasing the levels of anti-apoptotic factor B-cell lymphoma 2 Bcl-2; Chang et al.
Lamotrigine was also used successfully in the experimental models of cerebral ischemia as well as in excitotoxicity induced by glutamate Bacher and Zornow, ; Maj et al. Lamictal lamotrigine is an anticonvulsant by GlaxoSmithKline approved by the U. Food and Drug Administration for the treatment of partial-onset seizures , generalized tonic-clonic seizures , and seizures associated with Lennox-Gastaut syndrome, in patients ages 2 and older.
Lamictal can also be used to treat seizures in Batten disease , usually in combination with another anticonvulsant such as valproate. Batten disease, also called neuronal ceroid lipofuscinosis , is a disorder caused by defects in the processing of cellular waste.
This leads to a buildup of these wastes, a mixture of fat and protein called lipofuscin , inside cells causing their death. Nerve cells are particularly vulnerable to lipofuscin accumulation so a major symptom of Batten disease is brain damage and seizures. Lamictal is chemically unrelated to other anti-epileptic treatments.
In nerve cells, it binds to a sodium channel, preventing it from opening as it normally would when a nerve signal is sent.
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