Lamotrigine in the Treatment of Bipolar DIsorder
Christian Jonathan Haverkampf, M.D.
Lamotrigine is an effective medication in the treatment of bipolar disorder and bipolar depression. However, as bipolar disorder is not a homogenous condition but possesses distinctly different phenomenologies and subtypes, which can have an impact on the effectiveness and range of adverse effects of a mood stabilizer, it is crucial to elucidate the characteristics which help in matching the right drug to the individual patient.
Keywords: lamotrigine, bipolar disorder, depression, medication, treatment, psychiatry
Table of Contents
Lamotrigine is an anti-epileptic, which is also frequently used to treat the mood instability inherent in bipolar disorder. It is generally well tolerated, with the best evidence for the maintenance treatment of bipolar disorder, particularly in prevention of depressive episodes. (Reid, Gitlin, & Altshuler, 2013) However, in acute bipolar depression, meta-analyses suggest only a modest benefit, especially for more severely depressed subjects, with switch rates similar to placebo. (Reid et al., 2013)
Common brand names of Lamotrigine include Lamictal®, Lamictal XR®, Lamictal CD®, Lamictal ODT®, Subvenite® and others.
Mood stabilizers form a cornerstone in the long-term treatment of bipolar disorder. The first representative of their family was lithium, still considered a prototype drug for the prevention of manic and depressive recurrences in bipolar disorder. Along with carbamazepine and valproates, lithium belongs to the first generation of mood stabilizers, which appeared in psychiatric treatment in the 1960s. Atypical antipsychotics with mood-stabilizing properties and lamotrigine, which were introduced in the mid-1990s, form the second generation of such drugs.
Overall, advances in drug treatment remain quite modest. Among the mood stabilizers, Lithium has the strongest evidence for long-term relapse prevention. The evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics. (Geddes & Miklowitz, 2013) Antipsychotic drugs are effective in the acute treatment of mania, while their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. In a systematic review of new treatment guidelines for bipolar depression in 2011, a trend to the gradual acceptance of the use of quetiapine as monotherapy as first-line treatment was observed. Antidepressant monotherapy was discouraged in most of them, although some support the use of antidepressants in combination with antimanic agents for a limited period of time. Lamotrigine had become a highly controversial option. (Nivoli et al., 2011) However, the initial sharp gap between efficacy and effectiveness judgments seemed to narrow over time. Parker and McCraw suggested that the early trials evaluating lamotrigine for acute bipolar disorder depression focused on a suboptimal clinical target, and in so doing, ensured less lamotrigine efficacy compared with trials of bipolar disorder preventative treatment. Moreover, a number of additional methodological limitations compromised analyses. (Parker & McCraw, 2015)
Bowden and Singh reviewed publications of randomized clinical trials of lamotrigine, emphasizing studies in bipolar disorder, for a study published in 2012. The low burden of adverse effects with lamotrigine has been confirmed in these studies. Its lack of benefit in acute mania is established. Despite modest benefits for a subset of depressive episodes in bipolar disorder, it was not superior to placebo in well-designed studies. As monotherapy, in randomized, blinded trials in rapid cycling bipolar disorder it was not superior to placebo. Its role in maintenance treatment is relatively well established as one component of combination therapy, with evidence for benefits when combined with lithium or valproate. Combination regimens including lamotrigine appear to be superior to monotherapy. Monotherapy utilization of lamotrigine for maintenance treatment is not supported by these studies. (Charles L Bowden & Singh, 2012)
It has been suggested that responders to carbamazepine or lamotrigine may differ clinically from responders to lithium. The vast majority of data on genetic influences on the response to mood stabilizers has been gathered in relation to lithium. The genes studied for their association with lithium response have been those connected with the neurotransmitters serotonin, dopamine and glutamate, second messengers (phosphatidyl inositol, cAMP and protein kinase C pathways), substances involved in neuroprotection (brain-derived neurotrophic factor and glycogen synthase kinase 3-β) and a number of other miscellaneous genes. The glutamatergic receptor AMPA gene and the sodium bicarbonate transporter gene may also play a role, as well as the amiloride-sensitive cation channel 1 neuronal gene in long-term lithium response. (Rybakowski, 2013)
Lamotrigine like other mood stabilizers blocks NMDA-mediated signalling involving the arachidonic acid cascade, which may also be responsible for its effectiveness. An up-regulated brain arachidonic acid cascade and a hyperglutamatergic state characterize bipolar disorder, as has been found in post-mortem brain tissue. Lamotrigine is reported to interfere with glutamatergic neurotransmission involving NMDA receptors, which allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 to release arachidonic acid from membrane phospholipid. (Ramadan et al., 2012)
The best use of lamotrigine in the treatment of bipolar disorder, and its overall use for the condition, is still being debated. However, findings have illustrated the importance of lamotrigine in alleviating the depressive symptoms of bipolar disorder, without causing mood destabilization or precipitating mania. Lamotrigine stabilizes mood from “below baseline”, preventing switches to mania or episode acceleration in bipolar I and bipolar II disorder. (Prabhavalkar, Poovanpallil, & Bhatt, 2015) In bipolar disorder as compared with its use in treatment for epilepsy, lower lamotrigine serum concentrations seem to lead to therapeutic benefit. (Unholzer & Haen, 2015)
Currently, no mood stabilizers are available having equal efficacy in the treatment of both mania and depression, two of which forms the extreme sides of the bipolar disorder (Prabhavalkar, Poovanpallil, & Bhatt, 2015). A recent study, however, suggested that lamotrigine may be more suitable for maintenance treatment in bipolar II than in bipolar I. (Terao, Ishida, Kimura, Yarita, & Hara, 2017) In a wider literature search (Amann, Born, Crespo, Pomarol-Clotet, & McKenna, 2011), which also included unpublished data, lamotrigine showed efficacy in the prophylaxis of bipolar disorder, more so in depressive than manic episodes. There was no evidence of effectiveness in the acute treatment of mania, mixed episodes, unipolar depression or rapid-cycling bipolar I disorder. Its effect in the acute treatment of bipolar depression was at most small. (Amann, Born, Crespo, Pomarol-Clotet, & McKenna, 2011) In another study, adjunctive lamotrigine led to sustained improvement of bipolar II depression and was generally well-tolerated. The number of prior hospitalizations for depression affected response to lamotrigine. Suicide attempters with bipolar II depression show poor response to lamotrigine (Chang, Moon, Cha, & Ha, 2010)
In a systematic literature review and random-effects meta-analysis of depression ratings, response, remission, and adverse effects on randomized controlled trials comparing lamotrigine to placebo or other agents with antidepressant activity in unipolar or bipolar depression, lamotrigine was superior to placebo in improving unipolar and bipolar depressive symptoms, without causing more frequent adverse effects or discontinuations. Lamotrigine did not differ from lithium and the combination olanzapine and fluoxetine. (Solmi et al., 2016) However, in a randomized, placebo‐controlled maintenance study of treatment for bipolar depression the combination of lamotrigine and divalproex generally provided greater maintenance efficacy than Lamotrigine alone for depressive indices in recently depressed bipolar patients. (C. L. Bowden et al., 2012)
Open‐label lamotrigine treatment appears to be beneficial in the treatment of bipolar disorder and associated conditions in children. (Biederman et al., 2010) In another study on a paediatric population, there seemed to be significant improvement in cognitive abilities in patients with bipolar patients treated with lamotrigine that was most prominent in the areas of working memory and verbal memory and that occurs along with mood stabilization. A study comparing the efficacy of adding on lamotrigine versus placebo in 10- to 17-year-olds with bipolar I disorder who were receiving conventional bipolar disorder treatment failed to detect a benefit of adding on lamotrigine, while the investigators speculated that it may be of benefit in a subgroup of older adolescents. (Findling et al., 2015)
In an uncontrolled trial with bipolar depressed elders, lamotrigine was associated with improvement in depression, psychopathology, and functional status. Although there was a moderate number of adverse events, particularly falls, a link with the medication could not be clearly determined dues to the nature of the uncontrolled trial. (Sajatovic et al., 2011)
About one-third of lithium-treated patients are excellent responders, showing total prevention of the episodes, and these patients are clinically characterized by an episodic clinical course, complete remission, a bipolar family history, low psychiatric co-morbidity and a hyperthymic temperament. (Rybakowski, 2013)
To compare the levels of effectiveness between lithium and lamotrigine, adult bipolar I patients with at least two episodes within the preceding five years and an index episode requiring treatment were randomized to lithium (serum levels of 0.5–1.0 mmol/L) or to lamotrigine (up‐titrated to 400 mg/day) as maintenance treatments. No difference in effectiveness could be demonstrated, while lamotrigine was better tolerated than lithium. (Licht, Nielsen, Gram, Vestergaard, & Bendz, 2010) In another study, Kessing and colleagues identified 730 patients who received lamotrigine and 3518 patients received lithium subsequent to a diagnosis of bipolar disorder in psychiatric hospital settings during a period from 1995 to 2006. The overall rate of switching to or adding on another psychotropic was increased for lamotrigine compared with lithium, regardless of whether the index episode was depressive, manic, mixed or remission. In addition, the overall rate of psychiatric hospitalization was increased for lamotrigine compared with lithium, as were the rates for patients with a depressive and patients with a manic index episode. (Kessing, Hellmund, & Andersen, 2012) Looking at the somewhat contradictory data, it may be that certain characteristics of the condition or the patient could have a larger than assumed influence on the effectiveness of the mood stabilizer.
Lamotrigine has also been added to lithium. In one study, 124 bipolar depressed patients receiving lithium were randomly assigned to one group taking the combination and another only taking lithium. In patients with bipolar depression, addition of lamotrigine revealed a continued benefit compared to placebo throughout the entire study. (van der Loos et al., 2011) In a pilot study on adding lamotrigine to lithium and divalproex in patients with rapid-cycling bipolar disorder and a recent substance use disorder, lamotrigine adjunctive therapy was well tolerated in patients previously non-responsive to initial treatment of lithium plus divalproex. However, further investigations are needed (Wang et al., 2010).
While the second-generation antipsychotics risperidone, olanzapine, aripiprazole, and quetiapine have been increasingly used in the treatment of adults and adolescents with bipolar disorder, these treatments have also been associated with substantial adverse effects especially weight gain, prolactinaemia, glycaemic dyscontrol, and dyslipidaemia.
Goodwin and colleagues have argued that if one defines a mood stabilizer as a drug that prevents new episodes of mania and depression in monotherapy, then studies on the use of antipsychotics in bipolar conditions do not show that atypical neuroleptics are mood stabilizers. Patients are pre-selected to respond to the study drug for an acute mood episode (mania) and when they relapse, they do so into an episode of the same polarity (i.e. mania). (Goodwin, Whitham, & Ghaemi, 2011) As new episodes typically are of the opposite polarity, this does not represent protection from anew mood episode.
Lamotrigine has been added to antipsychotics. In a double-blind randomised controlled multicentre study with bipolar disorder I or II patients, the addition of lamotrigine to quetiapine treatment improved outcomes. (Geddes et al., 2016) Interestingly, in this study, folic acid seemed to nullify this effect. In another randomized, multicenter, double‐blind study, aripiprazole and lamotrigine delayed the time to manic/mixed relapse but did not reach statistical significance. (Carlson et al., 2012)
There are several potential side effects, some of them severe and even potentially lethal, which can be found in the relevant literature. Lamotrigine may, for example, cause a severe life-threatening skin rash. The risk may be higher in children and in people who take a very high starting dose, or those who also take valproic acid or divalproex, but it can occur in any patient.
If a skin rash or any other potentially serious side effect develops, the medication usually needs to be stopped, and the procedures to be followed can be found in the literature. Inaba and colleagues, however, review twelve patients with bipolar disorder who underwent lamotrigine rechallenge following lamotrigine discontinuation due to various adverse reactions, including skin rash, although none of the patients showed Stevens-Johnson syndrome. They report that with very slow titration of lamotrigine, rechallenge was successful with no recurrence of the rash. In three out of twelve cases, lamotrigine was discontinued owing to movement disorders, such as oral dyskinesia and action tremor, and liver dysfunction. (Inaba et al., 2018)
Disclosure: The authors report no conflicts of interest in this work.
Dr Jonathan Haverkampf, M.D. MLA (Harvard) LL.M. trained in medicine, psychiatry and psychotherapy, law and economics. He works in private practice for psychotherapy, counselling and psychiatric medication in Dublin, Ireland. Jonathan is the author of over two hundred articles and several books. He can be reached by email at jo****************@gm***.com or on the websites www.jonathanhaverkampf.com and www.jonathanhaverkampf.ie.
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