Lamotrigine augmentation for the treatment-resistant mood disorder

Abstract

Purpose: A number of depressed patients do not respond adequately to standard antidepressant treatments, and some of them subsequently suffer from treatment-resistant mood disorder (TRMD). Lamotrigine (LTG) is the only mood stabilizer that is effective for preventing depressive episodes of bipolar disorders. This study aimed to evaluate the efficacy of LTG augmentation in Japanese patients with TRMD. Methods: The subjects were 30 patients with refractory depression who had already shown insufficient response to multiple pharmacotherapy including antidepressants, mood stabilizers and atypical antipsychotics. The diagnoses were major depressive disorder (n=16), bipolar disorder (n=10) and dysthymic disorder (n=4). All patients gave written informed consent to receive LTG as an off-label indication in Japan after explanation for possible risks of unwanted skin reactions. The daily dose of LTG was titrated by the clinician's decision (88.0±61.9 mg/day). Treatment response was assessed by Montgomery-Åsberg Depression Rating Scale (MADRS) and Global Assessments of Functioning (GAF) before and after the 8-week LTG augmentation. Results: Significant improvements were observed in the scores of MADRS (25.3±10.1 → 14.7±10.5) and GAF (49.2±12.3 → 64.1±11.7) after the 8-week LTG augmentation (p=0.0010). Greater number of the past mood episodes and shorter duration of the present depressive episode are associated with better response to LTG. Mild adverse skin reactions developed in 10 patients although 8 out of them were treatment responders. Discussion: LTG augmentation may be effective for the treatment of TRMD, especially with shorter duration of unremitted depression and more recurrent episodes. However, attention should be paid to the development of adverse skin reactions in LTG responders.

A Partial Response at Week 4 Can Predict Subsequent Outcome during Lamotrigine Augmentation Therapy in Treatment-Resistant Depressive Disorder: A Preliminary Study

“…In addition, post hoc analyses of a large double-blind placebo-controlled trial suggested a greater response to lamotrigine in the more severely depressed and more treatment-resistant patients than that seen with placebo [5]. This finding together with previous studies [3, 4] implies that lamotrigine augmentation may be one of the options available for some treatment-resistant depressed patients.…”

“…The present study originally included 56 Japanese depressed inpatients. The inclusion criteria were: (a) major depressive disorder, bipolar I disorder or bipolar II disorder according to the DSM-IV-TR criteria [13]; (b) insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers or atypical antipsychotics despite sufficient therapeutic doses and at least 4 weeks of treatment [4, 6, 7]; (c) a Montgomery-Åsberg Depression Rating Scale (MADRS) [14] score of 21 or more [4, 6, 7]; and (d) no treatment with lamotrigine. They were physically healthy without any history of substance abuse including alcoholism, neurological disorder, delirium or dementia and without any clinically significant findings, including clinical laboratory examinations, electrocardiography, and electroencephalography.…”

“…Ivković et al [3] have shown that lamotrigine is a useful augmentation of antidepressants for treatment-resistant unipolar depression. Kagawa et al [4] have also shown that lamotrigine augmentation may be effective for the treatment of treatment-resistant depressive disorder. In addition, post hoc analyses of a large double-blind placebo-controlled trial suggested a greater response to lamotrigine in the more severely depressed and more treatment-resistant patients than that seen with placebo [5].…”

“…Kagawa et al [4] have reported that patients with treatment-resistant depressive disorder with a greater number of mood episodes in the past and a shorter duration of the present episodes may benefit from lamotrigine augmentation irrespective of diagnosis for mood disorders. Also, Kagawa et al [6] have demonstrated that an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentration and that a plasma concentration of 12.7 μmol/L may be a threshold for a good therapeutic response in treatment resistant depressive disorder.…”

How can we classify “mood stabilizers” with different properties?

“…Although it had once been expected that LTG might be effective for rapid cycling based on the results of earlier studies [44,59,60], the current thinking on LTG holds that it has no practical usefulness for rapid cycling [61]. However, our latest study has demonstrated that LTG augmentation may be sufficiently effective for the treatment of any treatment-resistant mood disorders, especially those with unremitted depression of shorter duration and more recurrent depressive episodes [62]. Therefore, the potential efficacy of LTG for refractory pathophysiology associated with frequent recurrence of mood episodes, including rapid cycling, needs to be reexamined.…”