Search

Objective: To assess the relationship between depressive relapse and change in thyroid function in an exploratory post hoc analysis from a controlled maintenance evaluation of bipolar I disorder., Method: Mean thyroid-stimulating hormone (TSH) and outcome data were pooled from two 18-month, double-blind, placebo-controlled, maintenance studies of lamotrigine and lithium monotherapy. A post hoc analysis of 109 subjects (n = 55 lamotrigine, n = 32 lithium, n = 22 placebo) with serum TSH values at screening and either week 52 (+/-14 days) or study drop-out was conducted., Results: Lithium-treated subjects who required an intervention for a depressive episode had a significantly higher adjusted mean TSH level (4.4 microIU/ml) compared with lithium-treated subjects who did not require intervention for a depressive episode (2.4 microIU/ml)., Conclusion: Lithium-related changes in thyroid function are clinically relevant and should be carefully monitored in the maintenance phase of bipolar disorder to maximize mood stability and minimize the risk of subsyndromal or syndromal depressive relapse.

Objective: To review the clinical trials literature on the use of antiepileptic drugs (AED) as mood stabilizers and to suggest an evidence-based approach when utilizing these agents in bipolar disorder., Method: The literature is reviewed and subdivided into the following sections: carbamazepine and oxcarbazepine, valproate, lamotrigine, gabapentin and other AED, and discussion., Results: Data exist to support the use of carbamazepine and valproate - and to a lesser extent, oxcarbazepine - in the management of acute manic episodes associated with bipolar I disorder. Lamotrigine, gabapentin, and other AED have not demonstrated consistent anti-manic effects. Clinical trials data favor lamotrigine over all other AED in the treatment of acute bipolar I depression and in rapid cycling bipolar disorder (particularly type II), although the absence of an active comparator in these lamotrigine trials must be noted. Lamotrigine, carbamazepine, and valproate all have evidence supporting their roles as potential long-term mood stabilizers to prevent bipolar relapse, with lamotrigine having a stronger effect in the prevention of depression., Conclusion: The AED are a heterogeneous group of medications with differential spectrum of efficacy in the treatment of bipolar disorder.

The phenomenon of frequent cycling in bipolar disorder was first recognized by Emil Kraepelin in 1913. More recently, rapid cycling has been reported to be a predictor of nonresponse to treatment. At the time of presentation, most patients with DSM-IV-defined rapid cycling appear to be in the depressed phase of their illness. Frequent and more severe episodes of depression appear to be the hallmark of rapid cycling. Reported in this article are recent preliminary data suggesting that the combination of lithium and divalproex sodium administered continuously over 6 months appears to result in marked acute and continuation antimanic efficacy in 85% of patients and marked antidepressant efficacy in 60%. However, only one half of patients experienced bimodal stabilization. Comorbid alcohol, cannabis, and/or cocaine abuse and/or dependence did not appear to directly affect the spectrum of efficacy of lithium and divalproex or response rates in compliant patients. Comorbidity appeared to alter prognosis by increasing the prevalence of poor compliance. The majority of patients receiving lithium and divalproex who required additional treatment were depressed, suggesting that the frequent recurrence of depression is the primary unmet need in patients with rapid cycling. The use of antidepressants in this population has been discouraged because of concerns about the possibility of cycle acceleration. There exists a need for a pharmacotherapy that not only possesses marked acute antidepressant properties, but that does so without inducing switching or cycle acceleration. A double-blind, placebo-controlled trial of lamotrigine monotherapy in bipolar I depression has demonstrated efficacy without causing switching at a rate exceeding placebo; however, this initial study excluded patients with rapid cycling. To explore the efficacy of lamotrigine in rapid cycling, a recent multicenter study has examined lamotrigine as a maintenance therapy for this population. The results indicate that lamotrigine may be a useful treatment for patients with rapid-cycling bipolar II disorder and that this drug has begun to address this unmet need.

The rapid-cycling variant of bipolar disorder (RCBD) has been variably defined, with episode frequencies ranging from several per day to a minimum of four per year. It is diagnosed disproportionately in women with bipolar II disorder. Its time of onset may be in childhood, adolescence, or adulthood. It appears to be treatment refractory, but controlled trials are lacking. Concurrent treatment with lithium and an antiepileptic drug is considered the current mainstay of treatment, and antidepressants are discouraged. Controlled trials in homogeneous cohorts of RCBD patients are needed. Preliminary data suggest that two or more mood stabilizers are required for adequate control.

Objective: New mood stabilizers are needed that possess efficacy for all phases of bipolar disorder. This study was designed to provide preliminary evidence for the safety and efficacy of a new anticonvulsant, lamotrigine, in adult patients with bipolar disorder who had been inadequately responsive to or intolerant of prior pharmacotherapy., Method: A 48-week, open-label, prospective trial was conducted in 75 patients with bipolar I or bipolar II disorder. Lamotrigine was used as adjunctive therapy (N = 60) or monotherapy (N = 15) in patients presenting in depressed, hypomanic, manic, or mixed states., Results: Of the 40 depressed patients included in the efficacy analysis, 48% exhibited a marked response and 20% a moderate response as measured by reductions in 17-item Hamilton Depression Rating Scale scores. Of the 31 with a hypomanic, manic, or mixed state, 81% displayed a marked response and 3% a moderate response on the Mania Rating Scale. From baseline to endpoint, the depressed patients exhibited a 42% decrease in Hamilton depression scale scores, and the patients presenting with hypomania, mania, or a mixed state exhibited a 74% decrease in Mania Rating Scale scores. The most common drug-related adverse events were dizziness, tremor, somnolence, headache, nausea, and rash. Rash was the most common adverse event resulting in drug discontinuation (9% of patients); one patient developed a serious rash and required hospitalization., Conclusions: These open-label data provide preliminary evidence that lamotrigine may be an effective treatment option for patients with refractory bipolar disorder; however, potential benefits must be weighed against potential side effects, including rash.

Background: More treatment options for bipolar depression are needed. Currently available antidepressants may increase the risk of mania and rapid cycling, and mood stabilizers appear to be less effective in treating depression than mania. Preliminary data suggest that lamotrigine, an established antiepileptic drug, may be effective for both the depression and mania associated with bipolar disorder. This is the first controlled multicenter study evaluating lamotrigine monotherapy in the treatment of bipolar I depression., Methods: Outpatients with bipolar I disorder experiencing a major depressive episode (DSM-IV, N = 195) received lamotrigine (50 or 200 mg/day) or placebo as monotherapy for 7 weeks. Psychiatric evaluations, including the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), Mania Rating Scale, and the Clinical Global Impressions scale for Severity (CGI-S) and Improvement (CGI-I) were completed at each weekly visit., Results: Lamotrigine 200 mg/day demonstrated significant antidepressant efficacy on the 17-item HAM-D, HAM-D Item 1, MADRS, CGI-S, and CGI-I compared with placebo. Improvements were seen as early as week 3. Lamotrigine 50 mg/day also demonstrated efficacy compared with placebo on several measures. The proportions of patients exhibiting a response on CGI-I were 51%, 41%, and 26% for lamotrigine 200 mg/day, lamotrigine 50 mg/day, and placebo groups, respectively. Adverse events and other safety results were similar across treatment groups, except for a higher rate of headache in the lamotrigine groups., Conclusion: Lamotrigine monotherapy is an effective and well-tolerated treatment for bipolar depression.

The designs employed in bipolar maintenance studies have evolved greatly over the last 28 years. Consequently, there has been minimal consensus set for methods used to demonstrate the ability of any new putative mood stabilizers to prevent relapse and recurrence in bipolar disorder. The methods that have evolved the most include enrollment procedures, randomization schemes, use of outcome measures, statistical analyses, and country-specific commercial and regulatory issues. This article contrasts the various methods employed in first- and second-generation placebo-controlled bipolar I maintenance studies. This article also explores the advantages and disadvantages associated with various designs.

Background: We evaluated the antidepressant and mood-stabilizing effects of lamotrigine, a novel anticonvulsant, in a group of rapid-cycling bipolar patients. Most were already nonresponders or poor partial responders to other conventional mood-stabilizing agents., Methods: This open, naturalistic, and prospective study was conducted with five rapid-cycling bipolar patients (DSM-IV). Each received lamotrigine titrated to a minimum dose of 150 mg/day as monotherapy or in combination with other psychotropic agents. Patients were assessed with the Global Assessment Scale (GAS), Beck Depression Inventory (BDI), and Young Mania Rating Scale (YMRS) for evidence of cycling mood., Results: Lamotrigine was used at a mean +/- SD dose of 185.0 +/- 33.5 mg/day for 225.8 +/- 28.0 days. Random regression modeling of data showed significant dose- and time-dependent improvements in depressive symptoms and social function of patients taking lamotrigine (Dose: z = 2.17, p < .03 for BDI, z = 4.44, p < .001 for GAS; Time: z = -3.79, p < .001 for BDI, z = 2.16, p < .03 for GAS). Further random regression modeling analysis of change over time in symptoms prior to lamotrigine compared with symptoms during lamotrigine treatment showed a significant treatment by time effect for GAS (z = 2.40, p < .016) and a trend for BDI scores (z = -1.79, p < .073). No significant time or dosage effect or time by treatment effect was observed for YMRS. Finally, t statistics showed a significant reduction in mean BDI scores following treatment with lamotrigine (t = -5.26, p < .006). Lamotrigine was well tolerated by all patients; only one patient experienced several side effects, which were probably due to interaction between several psychotropic medications., Conclusion: Lamotrigine augmentation therapy and monotherapy appeared to have mood-stabilizing and antidepressant efficacy in the treatment of five rapid-cycling bipolar patients. The effect persisted for an average of 7.5 months.

Although lithium remains the treatment of choice for manic depression, it is now well recognized that 20%-40% of patients either do not tolerate the drug or their disease does not respond to it. This subgroup of patients accounts for a substantial majority of the morbidity that accompanies this illness. For this reason, alternatives to lithium therapy will have a significant clinical impact. In a great majority of cases, the rapid-cycling variant of this disorder accounts for the resistance to lithium treatment. Recently, a growing body of literature has suggested that several medications routinely used in the management of seizure disorders, particularly carbamazepine and valproate, have therapeutic mood-altering properties. These drugs have been evaluated in numerous drug trials using open, double-blinded, longitudinal, and (in the case of carbamazepine) randomized designs. The authors comment on the phenomenology of manic depression and review the literature on use of anticonvulsants in the management of lithium-resistant manic depression.