In the hippocampus, it was observed that the power of the gamma oscillations induced by kainic acid was enhanced significantly by lamotrigine at concentrations consistent with the therapeutic range (310 M), in contrast to valproic acid which had no effect at its therapeutic concentration of 100 M. (2007). Besag FM, Ng GY, Pool F. Successful re-introduction of lamotrigine after initial rash. PMC 2021 Jan 21;21(1):50. doi: 10.1186/s12888-021-03053-0. Behavioural models in mice implication of the alpha noradrenergic system, Increased levels of glutamate in brains from patients with mood disorders, New ways to classify bipolar disorders: going from categorical groups to symptom clusters or dimensions. These are sequentially discussed below. Of interest, out of the three daily lamotrigine doses studied (50 mg, 200 mg and 400 mg), only patients on 200 mg showed significant advantage over placebo in time to intervention for both overall mood episodes and depressive episodes. Consideration of bipolar subtype and index polarity in acute episodes may be helpful, as it may provide evidence-based guidance on the selection of the maintenance agent. Despite many methodological weaknesses, this study demonstrated positive findings in a literature-poor area, and observed that possibly greater benefits could be associated with the higher plasma lamotrigine levels (above 5 mg/L) that were recommended in epileptology. Safety and tolerability of lamotrigine for bipolar disorder. Antidepressant effect of repetitive transcranial magnetic stimulation is not impaired by intake of lithium or antiepileptic drugs. One such report stemmed from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) (Nierenberg et al 2006). Seizures are bursts of electrical activity in the brain that temporarily affect how it works. Harm avoidance moderates the influence of serotonin transporter gene variants on treatment outcome in bipolar patients. Thus showing significant role of 5-HT in the physiopathology of maniac depressive disorder (Vinod and Subhash, 2002). Antidepressant-like behavioral effects in 5-hydroxytryptamine. Lamotrigine oral tablet is a prescription drug used to treat certain types of seizures in people with epilepsy. Cortical excitability in patients after loading doses of lamotrigine: a study with magnetic brain stimulation, Mechanisms underlying gamma (40 Hz) network oscillations in the hippocampus: a mini-review. It can also help prevent low mood (depression) in adults with bipolar disorder. Lithium therapy: limitations and alternatives in the treatment of bipolar disorders. The utilization of slow titration methods has proven a useful mechanism for avoiding serious side effects but may impede the acute efficacy of the drug. Sinz MW, Remmel RP. It is approved for the treatment of bipolar disorder (also known as manic depression) and certain types of seizure disorders. 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. However, it was found that lamotrigine differs markedly from valproic acid and lithium in treating bipolar disorder as none of the targets for bipolar disorder seemed to be modulated by lamotrigine, showing greater efficacy for the prevention/amelioration of episodes of depression rather than mania (Large et al., 2009). 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. Specifically, there was a trend towards fewer major malformations for pregnancies exposed only to lamotrigine than to valproate, and a significant dose-dependent relationship was found for lamotrigine, with major malformation rates of 1.3% for daily doses under 100 mg, 1.9% for 100200 mg and 5.4% for doses exceedingly 200 mg. 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., 2005). Using the CGI for bipolar illness as primary outcome measure, 52% of the lamotrigine group had a rating of much improved or very much improved, compared with 26% of the gabapentin and 23% of the placebo groups (p = 0.031). It remains that few medications have an adequate evidence base for the treatment and prevention of bipolar depression, despite its phenotypic dominance in bipolar disorder. Table Randomized controlled trials of lamotrigine for MDD. sharing sensitive information, make sure youre on a federal However, recent findings have also illustrated the importance of lamotrigine in alleviating the depressive symptoms of bipolar disorder, without causing mood destabilization or precipitating mania. There is an urgent need of the depression mood stabilizers for the treatment of bipolar depression as the conventional antidepressants that are used commonly for the acute treatment of bipolar depression fails the requirements of the definition of depression mood stabilizers mainly because of their tendency to cause mood destabilization by inducing switches to mania or episode acceleration (Post et al., 1997; Henry et al., 2001; Ketter and Calabrese, 2002; Sienaert et al., 2013). Segal J, Berk M, Brooks S. Risperidone compared with both lithium and haloperidol in mania: a double-blind randomized controlled trial. Valproate and carbamazepine are options in the treatment of mania, mixed states and those with rapid cycling illness and comorbid substance abuse (Greil 1998; Bowden and Singh 2005), but lack full support in prophylaxis and the treatment of bipolar depression. Lamotrigine [3,5-diamino-6 (2,3-dichlorophenyl-1,2,4-triazine)] is an established anticonvulsant drug. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. 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. Interaction of the antiepileptic drug lamotrigine with recombinant rat brain type IIA Na. Zarate C. A., Jr., Du J., Quiroz J, Gray N. A., Denicoff K. D., Singh J., et al. Lamotrigine therapy showed significant response in comparison to placebo in severely ill patients in a recent meta-analysis conducted (Geddes et al., 2009). The Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. Yatham L. N., Kusumakar V., Parikh S. V., Haslam D. R. S., Matte R., Sharma V., et al. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Lamotrigine blocks NMDA receptor-initiated arachidonic acid signalling in rat brain: implications for its efficacy in bipolar disorder. 2022 Oct 19;12(10):1645. doi: 10.3390/life12101645. FST is also one such sensitive model to the compounds acting on the 5-HT system (Redrobe et al., 1996; Redrobe and Bourin, 1997), which was of great help in the association studies that involved lamotrigine along with the most specific brain-penetrating ligands for 5-HT1A and 5-HT1B receptors currently available to study the possible interaction between the two and also to investigate the potential antidepressant-like action of lamotrigine (Redrobe and Bourin, 1999b, Tatarczynska et al., 2004). Latest maintenance data on lamotrigine in bipolar disorder. These results must be interpreted with caution, given the many methodological limitations of this preliminary study, such as its treatment-refractory and heterogeneous population with regards to both bipolar type and phase, open-label non-randomized design, and lack of control for concurrent psychotropic use. The current understanding of lamotrigine as a mood stabilizer. In a recent study, Kagawa et al. It undergoes minimal first-pass metabolism, and has a bioavailability of 98% (Peck 1991; Keck and McElroy 2002; Hahn et al 2004). Chronic NMDA administration to rats up-regulates frontal cortex cytosolic phospholipase A2 and its transcription factor, activator protein-2. (2001). Li X., Teneback C. C., Nahas Z., Kozel F. A., Large C., Cohn J., et al. Treatment of bipolar II depression with adjunctive lamotrigine may also be associated with a history of suicide-attempts and a number of depression-related prior hospitalization in case of poor response to the adjunctive lamotrigine therapy, as per the data from the 52-week follow-up study. Dose adjustments are required in both of these situations. 19.79. 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. There have been a number of published studies of higher-order design for lamotrigine in bipolar disorder. Yuan P. X., Huang L. D., Jiang Y. M., Gutkind J. S., Manji H. K., Chen G. (2001). It was also demonstrated that in mice, -methyl-p-tyrosine without affecting the levels of serotonin, reduced levels of dopamine and noradrenaline (57 and 53% respectively; Mayorga et al., 2001). Ketter T. A., Brooks J. O., Hoblyn J. C., Champion L. M., Nam J. Y., Culver J. L., et al. Lamotrigine has not been shown to be effective when people experience the actual episodes of depression or mania, so other medications must be used to help people recover from these episodes. Sabers A, Buchholt JM, Uldall P, et al. The mechanism of NMDA receptor-mediated arachidonic acid signaling which is responsible for triggering a bipolar disorder is through glutamatergic neurotransmission, which involves N-methyl-D-aspartate receptors (NMDARs). This case demonstrates that lamotrigine may be effective for treating patients with antidepressant resistant PDD and suggests that it may be a promising alternative to combination therapy of antidepressants and benzodiazepines in the treatment of PDD. Lamotrigines tolerability, especially in comparison with lithium and other mood stabilizers, is a factor conducive to adherence, which is a confronting issue in bipolar disorder with an estimated 51% of patients unable to adhere to prescribed medications in a 1-year follow-up study (Keck et al 1997). Ginsberg LD. In a double-blind, randomized crossover study comparing patient preference of lamotrigine and topiramate using healthy subjects, the majority (70%) preferred lamotrigine (Werz et al 2006), which lends support for its acceptability to patients. The therapeutic daily dose range appears to lie between 200 to 400 mg, with the majority of studies demonstrating efficacy at the lower end of this range. Lamotrigine, a phenyltriazine derivative, has been demonstrated to possess multiple mechanisms of action, a summary of which has been detailed elsewhere (Ketter et al 2003; Hahn et al 2004). the contents by NLM or the National Institutes of Health. This paper aims to review the evidence for the efficacy of lamotrigine in bipolar disorder, and to provide some practical recommendations in the clinical setting. Shim et al. Dean RL, Hurducas C, Hawton K, Spyridi S, Cowen PJ, Hollingsworth S, Marquardt T, Barnes A, Smith R, McShane R, Turner EH, Cipriani A. Cochrane Database Syst Rev. Kagawa S., Mihara K., Nakamura A., Nemoto K., Suzuki T., Nagai G., et al. Lamotrigine was also reported to show negative results in acute mania as per the results obtained from two double-blinded placebo-controlled studies (Vieta, 2004). What is lamotrigine? Xie X., Lancaster B., Peakman T., Garthwaite J. These syndromes are understood to be fundamentally the same drug-induced cutaneous reaction characterized by blistering and epidermal detachment resulting from keratinocytic apoptosis, but denote differing severity with SJS defined as <10% body surface area epidermal detachment, SJS/TEN 10% to 30% detachment and TEN >30% detachment. Using the Clinical Global Impression-Improvement (CGI-I) scale as outcome measure, 59.5% of patients were rated as either very much improved or much improved on lamotrigine, and a further 20.4% were deemed to have minimally improved. The specificity of platelet glutamate receptor supersensitivity in psychotic disorders. Dual monoamine modulation for the antidepressant-like effect of lamotrigine in the modified forced swimming test, The anticonvulsant, lamotrigine decreases spontaneous glutamate release but increases spontaneous GABA release in the rat entorhinal cortex. Paykel ES, Abbott R, Morriss R, et al. Data on file, Lamictal, RM2004/00533/00, Study Synopsis of SCA100223, 2006. National Library of Medicine Three randomized trials (total n >900 patients) that compared lamotrigine (200 mg per day) with placebo for . Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update. (1995). 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., 2008). 2023 Feb;37(2):119-134. doi: 10.1177/02698811221140005. Decreased neural activity was seen with higher concentrations of lamotrigine (100 M). The diagnostic distribution of these patients was 6 unipolar illness, 11 bipolar I and 14 bipolar II disorder, the majority of the bipolar group (23 out of 25) had a rapid cycling course. No use, distribution or reproduction is permitted which does not comply with these terms. J Clin Psychiatry. The most worrying adverse effect of lamotrigine is the rare but potentially lethal Stevens-Johnson syndrome (SJS) or toxic epidermal necrosis (TEN). Hahn CG, Gyulai L, Baldassano CF, et al. Efficacy of lamotrigine was evaluated in subjects with bipolar I depression in a double-blind, parallel-group, multicenter trial (Calabrese et al., 1999a). 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. Further, in a recent review Parker and McCraw (2015) explored disconnect between the clinical efficacy and quantified efficacy in controlled trials. sharing sensitive information, make sure youre on a federal Paulus W., Classen J., Cohen L. G., Large C. H., Di Lazzaro V., Nitsche M., et al. Perspectives for the development of animal models of bipolar disorder. Clinical pharmacology of lamotrigine. Bowden CL, Asnis GM, Ginsberg LD, et al. 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., 2004). Immediate-release lamotrigine can be used in children as young as 2 years old when it is given as part of a combination of seizure medications. HHS Vulnerability Disclosure, Help Bachmann R. F., Schloesser R. J., Gould T. D., Manji H. K. (2005). Despite obvious methodological limitations, this study had the benefit of a large sample size. Successful rechallenge with slowly titrated lamotrigine after rash. Newer anticonvulsants in the treatment of bipolar disorder. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. However, the two groups statistically diverged in their survival in study figures in favor of lamotrigine, a difference that retained statistical significance in the bipolar II population when the subtypes were analyzed. Patients were randomized, with stratification by diagnostic classification, to receive sequential 6-week trials of each of the 3 treatment arms. Predictors of response to pharmacological treatments in bipolar disorder. Data on file, Lamictal, RM2002/00129/00, Clinical Study Report for SCA40910, 2002 p 24, 5859. Another trial studied the adjunctive use of lamotrigine in treatment-resistant depression, including a subset with bipolar II depression (N = 8) although the majority had unipolar depression (N = 15) (Barbosa et al 2003) (Table 3). Lamotrigine is also shown to possess some limitation, encountered during the course of the treatment though infrequent. There are also small studies comparing lamotrigine to venlafaxine (McIntyre et al 2004) and to citalopram (Schaffer et al 2006) for bipolar depression, neither showing any advantage with lamotrigine. Effectiveness of lamotrigine in bipolar disorder in a clinical setting, Stabilization of mood from below versus above baseline in bipolar disorder: a new nomenclature. Effects of carbamazepine, phenytoin, valproic acid, oxcarbazepine, lamotrigine, topiramate and vinpocetine on the presynaptic Ca. Michael N., Erfurth A., Ohrmann P., Gossling M., Gssling M., Arolt V., et al. Lamotrigine is in a class of medications called anticonvulsants. Disclaimer. When time to intervention was examined according to the polarity of the emergent mood episode, lamotrigine but not lithium was superior to placebo for depression, whereas the reverse held true for manic, hypomanic and mixed episodes. After 7 weeks of treatment, primary measures were not significantly different secondary measures, had a significantly superior response rate on mean SD observed scores on 17-item HDRS, CGI-Severity of Illness, and CGI-Improvement in lamotrigine 200 mg/d group. Calabrese JR, Bowden CL, Sachs GS, et al. 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., 2006). 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