The Effect of Dermatologic Precautions on the Incidence of Rash With Addition of Lamotrigine in the Treatment of Bipolar I Disorder

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Calif, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.5). 04/2006; 67(3):400-6. DOI: 10.4088/JCP.v67n0310
Source: PubMed


Prescribing recommendations specify that lamotrigine should ordinarily be discontinued at the first sign of rash, regardless of its type and severity, unless the rash is clearly not drug related. This practice helps to ensure that lamotrigine is discontinued in instances of serious rash (an event occurring in up to 0.13% of cases in bipolar clinical trials) but may lead to unnecessary discontinuation of lamotrigine for cases of nonserious rash arising from nondrug causes. Measures aimed at reducing overall occurrence of dermatologic reactions might reduce the incidence of nonserious rash leading to premature lamotrigine discontinuation. This study assessed the impact of specific instructions designed to decrease risk of dermatologic reactions, including nonserious rash, during initiation of and early treatment with lamotrigine in patients with bipolar I disorder.
Outpatients with DSM-IV-diagnosed bipolar I disorder >/= 13 years of age at 188 sites were randomly assigned to receive Usual Care Precautions (UCP; precautions from the patient instructions in the prescribing information for reducing risk of rash including nonserious rash) or Dermatologic Precautions (DP; precautions as above [UCP] plus additional precautions intended to decrease risk of any dermatologic reaction including nonserious rash) during 12 weeks of adding open-label lamotrigine to concomitant medications. Patients with comorbid medical and psychiatric problems were not excluded unless, in the opinion of the investigators, these problems were sufficiently severe to preclude participation. Investigators and patients were blinded to which precaution group patients were randomly assigned. The primary outcome measure was the rate of rash during the treatment period. Secondary outcome measures included clinical response to lamotrigine, assessed with the investigator- and self-rated Clinical Global Impressions-Bipolar version (CGI-BP) and the Clinical Global Impressions-Efficacy Index (CGI-EI). Data were collected from August 2003 to August 2004.
867 (74%) of 1175 patients completed the study. Only 182 (15%) of 1175 patients had an adverse event leading to discontinuation of study medication or withdrawal, including 62 (5.3%) of 1175 due to non-serious rash. No serious rashes were reported during the study in either group. The incidence of nonserious rash was similarly low in patients with UCP and DP (8.8% and 8.6%, respectively). CGI-BP-Severity and -Improvement scores indicated mood improvement when lamotrigine was added to existing therapy, and CGI-EI scores at weeks 5 and 12 reflected a favorable balance between control of mood symptoms and tolerability. At both weeks 5 and 12, investigators reported that therapeutic effects of additional lamotrigine outweighed side effects in 74% of subjects.
UCP and DP yielded low, similar non-serious rash rates, which were marginally lower than nonserious rash rates in prior clinical trials that did not utilize DP but marginally higher than that in a prior open case series using DP. Nevertheless, the results are encouraging: in this large study reflecting real-world use, lamotrigine was well tolerated with no serious rash and low incidences of nonserious rash and discontinuation due to rash, and lamotrigine therapy was associated with clinical improvement in a heterogeneous cohort of patients with bipolar I disorder.

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    • "Severe side effects were reported only in a small number of patients. Mostly mild side effects occurred and included headache, nausea, or dizziness.5,6,41 No metabolic side effects or weight gain were reported during LTG therapy, and no evidence of inducing shifts into mania was found.5,42 "
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    ABSTRACT: The anticonvulsant drug lamotrigine (LTG), a sodium channel blocker and inhibitor of glutamate release, has been found to have antidepressant effects in the treatment of bipolar disorder. It is recommended by certain therapy guidelines as a first-line agent for acute and maintenance therapy in bipolar depression, but there have been only some promising results of placebo-controlled trials on its acute antidepressant effects, and the recommendation in therapy guidelines has been reconsidered. On the contrary, positive results for maintenance therapy could be confirmed, and LTG is still a well-tolerated option, especially in patients with predominant depressive episodes. Antimanic effects are not shown in the literature, and its use is not advised in any guidelines that were examined. In conclusion, the findings of the present review article on treatment guidelines for bipolar disorder question the role of LTG in acute depressive states, and critically discusses its use, particularly in acute depressive states.
    Neuropsychiatric Disease and Treatment 01/2013; 9(1):101-11. DOI:10.2147/NDT.S37126 · 1.74 Impact Factor
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    • "In BD clinical trials conducted in the 1990s and 2000s, the rate of serious rash in adult patients receiving LTG monotherapy was 0.08 % (1/1233) (Calabrese et al., 2002) compared to 0.3 % (11/3348) of adult patients in the clinical trials of LTG in treatment of epilepsy mentioned above. In the BD clinical trials where LTG was used as an adjunctive therapy, the rate of serious rash was 0.13 % (2/1538) (Ketter et al., 2006). No fatalities occurred among these individuals. "
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    ABSTRACT: The major burden of illness in bipolar disorder (BD) is in the depressive pole. Lamotrigine has been shown to be useful in the long-term prophylaxis of depressive episodes in BD. Current guidelines recommend discontinuing lamotrigine in patients who develop rash. Our objective in this paper is to review literature to identify possible predictors of serious vs. benign rash that might help guide clinical decision-making and recommend titration strategy for re-introduction of lamotrigine, if indicated. We performed a search of the literature between 1966 and July 2008 to investigate the phenomenon of lamotrigine-induced rash and rechallenge procedures. The search identified six reports, and we were able to identify another case series from reviewing the bibliography of all of the above papers. We reviewed all the papers of lamotrigine rash rechallenge that resulted from the literature search. These papers describe 44 cases of lamotrigine rechallenge. Currently, there are 39 reported cases in the literature of successful lamotrigine rechallenge after a rash and five cases with rash recurrence. There are some characteristics of the rash that can help identify serious cases from benign ones. In addition, very slow titration of lamotrigine is crucial to the reduction of rash recurrence rate. Several cases that develop benign rash on lamotrigine can be rechallenged without adverse consequences. We believe that lamotrigine rechallenge in bipolar depression is an under-utilized option in our clinical armamentarium, and further studies are needed to guide us in this area.
    The International Journal of Neuropsychopharmacology 11/2008; 12(2):257-65. DOI:10.1017/S1461145708009504 · 4.01 Impact Factor
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    ABSTRACT: Approximately half of all patients with diagnosed bipolar disorder are prescribed 2 or more psychotropic medications. Lamotrigine was approved in 2003 for the maintenance treatment of bipolar I disorder. This study examined comparative effects of lamotrigine with and without concomitant medications. A post hoc analysis of data from a prospective, open-label study of lamotrigine in 1175 patients with bipolar I disorder evaluated the clinical response to and quality-of-life and weight effects of lamotrigine as monotherapy and in patients receiving concomitant valproate, lithium, antipsychotics, or antidepressants. The study was originally designed to assess the rate of rash among patients instructed to use specific dermatologic precautions compared with those receiving usual care. Lamotrigine was administered for 12 weeks, including a 5-week titration, with target dose of 200 mg/d, adjusted as necessary for concomitant medication(s). Evaluations at baseline and week 12 included the severity component of the Clinical Global Impression-Bipolar Version scale, the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form, and weight and body mass index (BMI). Efficacy data were available for 1139 patients. Symptoms and quality-of-life mean scores improved following treatment in all patient groups. Quality-of-life scores improved significantly more in patients not receiving than in those receiving concomitant antipsychotics. There were no changes in weight or BMI after lamotrigine monotherapy or adjuvant therapy. Most patients were satisfied with lamotrigine treatment. Lamotrigine was effective and well tolerated and appeared to have no effect on body weight when given as monotherapy or as adjunctive therapy with valproate, antipsychotics, lithium, or antidepressants to outpatients with bipolar I disorder in a 12-week open-label study.
    MedGenMed: Medscape general medicine 02/2007; 9(2):41.
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