A Placebo-Controlled 18-Month Trial of Lamotrigine and Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I Disorder

Calabrese, Joseph R.; Bowden, Charles L.; Sachs, Gary S.; Yatham, Lakshmi N.; Behnke, Kirsten; Mehtonen, O.-P.; Montgomery, Paul; Ascher, John; Paska, W.; Earl, N.; DeVeaugh-Geiss, Joseph

doi:10.4088/jcp.v64n0906

Cited by 576 publications

(509 citation statements)

References 21 publications

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“…Two recent maintenance studies have reported that lithium was not superior to placebo in delaying a new depressive episode, whereas lamotrigine was superior to placebo, with similar results in a combined analysis (Bowden et al, 2003a;Calabrese et al, 2003;Goodwin et al, 2004). An earlier maintenance study of lithium indicated an increased rate of depressive episodes in both rapid cycling and nonrapid cycling patients compared with placebo (Dunner et al, 1976), and a crossover study indicated little long-term benefit on depressive symptoms in bipolar disorder (Denicoff et al, 1994).…”

Section: Discussionmentioning

confidence: 82%

“…Recent randomized, placebo-controlled trials in patients with bipolar I disorder have demonstrated the significant but limited prophylactic efficacy of lithium, divalproex, lamotrigine and olanzapine (Bowden et al, 2000(Bowden et al, , 2003aCalabrese et al, 2003;Tohen et al, 2003). However, little data exist to aid psychiatrists in selecting the treatment most likely to be well tolerated and efficacious during maintenance therapy for a given patient.…”

Section: Introductionmentioning

confidence: 99%

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Relationship of Mania Symptomatology to Maintenance Treatment Response with Divalproex, Lithium, or Placebo

Bowden

Collins

McElroy

et al. 2005

Neuropsychopharmacol

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Euphoric and mixed (dysphoric) manic symptoms have different response patterns to divalproex and lithium in acute mania treatment, but have not been studied in relationship to maintenance treatment outcomes. We examined the impact of initial euphoric or dysphoric manic symptomatology on maintenance outcome. Randomized maintenance treatment with divalproex, lithium, or placebo was provided for 372 bipolar I patients, who met improvement criteria during open phase treatment for an index manic episode. The current analysis grouped patients according to the index manic episode subtype (euphoric or dysphoric), and evaluated the impact on maintenance treatment outcome. The rate of early discontinuation due to intolerance during maintenance treatment was higher for initially dysphoric patients (N ¼ 249) than euphoric patients (N ¼ 123; 15.7 vs 7.3%, respectively; p ¼ 0.032). Both lithium (23.2%) and divalproex (17.1%) were associated with more premature discontinuations due to intolerance than placebo (4.8%; p ¼ 0.003 and 0.02, respectively) in the initially dysphoric patients. Among initially euphoric patients, treatment with lithium was associated with significantly more premature discontinuations due to intolerance compared to placebo (18.2 vs 0%; p ¼ 0.03), and divalproex was significantly (p ¼ 0.05) more effective than lithium, but not placebo in delaying time to a depressive episode. Initial euphoric mania appeared to predispose to better outcomes on indices of depression and overall function with divalproex maintenance than with either placebo or lithium. Dysphoric mania appeared to predispose patients to more side effects when treated with either divalproex or lithium during maintenance therapy.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Relationship of Mania Symptomatology to Maintenance Treatment Response with Divalproex, Lithium, or Placebo

Bowden

Collins

McElroy

et al. 2005

Neuropsychopharmacol

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“…Lamotrigine is an FDA-approved agent for the maintenance phase of bipolar I disorder Calabrese et al, 2003). There are additional controlled data demonstrating acute efficacy in bipolar depression (Frye et al, 2000;Obrocea et al, 2002;Calabrese et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

Frye

Watzl

Banakar

et al. 2007

Neuropsychopharmacol

202

127

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Proton magnetic resonance spectroscopy ( 1 HMRS) is an in vivo brain imaging method that can be used to investigate psychotropic drug mechanism of action. This study evaluated baseline 1 HMRS spectra of bipolar depressed patients and whether the level of cerebral metabolites changed after an open trial of lamotrigine, an anti-glutamatergic mood stabilizer. Twenty-three bipolar depressed and 12 control subjects underwent a MRS scan of the anterior cingulate/medial prefrontal cortex. The scan was performed on a GE whole-body 1.5 T MRI scanner using single-voxel PRESS (TE/TR ¼ 30/3000 ms, 3 Â 3 Â 3 cm 3 and post-processed offline with LCModel. Baseline CSF-corrected absolute concentrations of glutamate + glutamine ([Glx]), glutamate ([Glu]), and creatine + phosphocreatine ([Cr]) were significantly higher in bipolar depressed subjects vs healthy controls. The non-melancholic subtype had significantly higher baseline [Glx] and [Glu] levels than the melancholic subtype. Remission with lamotrigine was associated with significantly lower post-treatment glutamine ([Gln]) in comparison to non-remission. These data suggest that non-melancholic bipolar depression is characterized by increased glutamate coupled with increased energy expenditure. Lamotrigine appears to reduce glutamine levels associated with treatment remission. Further study is encouraged to determine if these MR spectroscopic markers can delineate drug mechanism of action and subsequent treatment response.

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“…19,20 Since the design for these two studies is identical, with the exception of the pole of the most recent episode (recently manic/hypomanic 19 vs depressed 20 ), the results of these two studies were combined and the data reanalyzed. 13 In this analysis, lamotrigine effectively prolonged the time to intervention for both manias and depressions independently compared to placebo (P = 0.034 and 0.009, respectively).…”

Section: Recently Validated Treatment Options In Bipolar Disordermentioning

confidence: 99%

Treatment-resistant bipolar disorder

2006

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Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder. With the first report of lithium's efficacy in 1949 by Cade, bipolar disorder has the longest record of treatment efficacy among the major Axis I disorders. Furthermore, after more than half a century of clinical research, multiple agents from many different pharmacological classes have shown at least some efficacy, while many other agents (albeit without a consistent database demonstrating their utility) are prescribed regularly by clinicians. Yet, despite this plethora of choices, treatment of bipolar disorder remains suboptimal from the points of view of clinicians and patients alike. Whether measured by recovery time from manic or depressive episodes or preventive efficacy of maintenance treatments, bipolar disorder is characterized by sluggish responses, inadequate responses, poor compliance and recurrences in controlled cli...

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A Placebo-Controlled 18-Month Trial of Lamotrigine and Lithium Maintenance Treatment in Recently Depressed Patients With Bipolar I Disorder

Cited by 576 publications

References 21 publications

Relationship of Mania Symptomatology to Maintenance Treatment Response with Divalproex, Lithium, or Placebo

Relationship of Mania Symptomatology to Maintenance Treatment Response with Divalproex, Lithium, or Placebo

Increased Anterior Cingulate/Medial Prefrontal Cortical Glutamate and Creatine in Bipolar Depression

Treatment-resistant bipolar disorder

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