A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder.

OBJECTIVE: The authors tested the hypothesis that divalproex would be more effective than lithium in the long-term management of patients with recently stabilized rapid-cycling bipolar disorder. METHOD: A 20-month, double-blind, parallel-group comparison was carried out in recently hypomanic/manic patients who had experienced a persistent bimodal response to combined treatment with lithium and divalproex. Sixty patients were randomly assigned to lithium or divalproex monotherapy in a balanced design after stratification for illness type (bipolar I versus bipolar II disorder). RESULTS: Of the 254 patients enrolled in the open-label acute stabilization phase, 76% discontinued the study prematurely (poor adherence: 28%; nonresponse: 26% [of whom 74% remained depressed and 26% remained in a hypomanic/manic/mixed episode], intolerable side effects: 19%). Of the 60 patients (24%) randomly assigned to double-blind maintenance monotherapy, 53% relapsed (59% into depression and 41% into a hypomanic/manic/mixed episode), 22% completed the study, 10% had intolerable side effects, and 10% were poorly adherent. The rates of relapse into any mood episode for those given lithium versus divalproex were 56% and 50%, respectively; the rates were 34% and 29% for a depressive relapse and 19% and 22% for a hypomania/mania relapse. There were no significant differences in time to relapse. The proportion discontinuing prematurely because of side effects was 16% for lithium and 4% for divalproex. CONCLUSIONS: The hypothesis that divalproex is more effective than lithium in the long-term management of rapid-cycling bipolar disorder is not supported by these data. Preliminary data suggest highly recurrent refractory depression may be the hallmark of rapid-cycling bipolar disorder.

Gender differences in criminality: bipolar disorder with co-occurring substance abuse.

Outpatient interviews to collect criminal history data were conducted with 55 women and 77 men who had the dual diagnosis of rapid-cycling bipolar disorder with co-morbid substance abuse disorders (DD-RCBD), to ascertain gender-related similarities and differences. Fifty-three percent of women and 79 percent of men reported that they had been charged with a crime, and nearly half of those charged had been incarcerated. Men with DD-RCBD were more likely to have committed a felony and had a trend of committing more misdemeanors. Although women with DD-RCBD were less likely to have a criminal history than their male counterparts, they were far more likely to have a criminal history than were women in the general population. Implications from this pilot study include the need for earlier identification of bipolar disorder and for the increased availability of psychiatric and substance abuse services within correctional facilities.

Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the Systematic Treatment Enhancement Program.

OBJECTIVE: This study compared demographic and phenomenological variables between bipolar patients with and without rapid cycling as a function of bipolar I versus bipolar II status. METHOD: The authors examined demographic, historical, and symptomatic features of patients with and without rapid cycling in a cross-sectional study of the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder, a multicenter project funded by the National Institute of Mental Health designed to evaluate the longitudinal outcome of patients with bipolar disorder. RESULTS: Rapid-cycling bipolar disorder occurred in 20% of the study group. Rapid-cycling patients were more likely to be women, although the effect was somewhat more pronounced among bipolar I patients than bipolar II patients. In addition, rapid-cycling bipolar patients experienced onset of their illness at a younger age, were more often depressed at study entry, and had poorer global functioning in the year before study entry than nonrapid-cycling patients. Rapid-cycling patients also experienced a significantly greater number of depressive and hypomanic/manic episodes in the prior year. A lifetime history of psychosis did not distinguish between rapid and nonrapid-cycling patients, although bipolar I patients were more likely to have experienced psychosis than bipolar II patients. CONCLUSIONS: Patients with rapid-cycling bipolar disorder demonstrate a greater severity of illness than nonrapid-cycling patients on a number of clinical measures. This study highlights the need to refine treatments for rapid cycling to reduce the overall morbidity and mortality of patients with this illness course modifier.

Bipolar disorders and the effectiveness of novel anticonvulsants.

The discovery that valproic acid is helpful in the management of patients with rapid-cycling bipolar disorder led to an explosion of research culminating in the third-generation anticonvulsants. Refractory depressive phases are frequent in bipolar disorders. No studies to date have shown that gabapentin is effective in bipolar mania or hypomania. Lamotrigine may have a role in treating bipolar depressive episodes, but it is not a particularly effective antimanic agent. Topiramate has shown encouraging results in both depressed and manic bipolar patients, and it may also promote weight loss. The new anticonvulsants are promising agents for the treatment of bipolar disorders, but they are heterogeneous with regard to their efficacy, target symptoms, and adverse event profiles.

Long-term treatment of bipolar disorder with lamotrigine.

Bipolar depression is as debilitating as mania in bipolar disorder, but the treatment of bipolar depression has historically received less attention. To date, there is no mood stabilizer (liberally defined as a medication that decreases episode severity, duration, or frequency in one phase of bipolar illness without producing a negative effect in other phases) that demonstrates similar efficacy in both the depressive and the manic phases of bipolar disorder. However, bipolar depression--which is prevalent, sometimes chronic, and associated with a low quality of life and a high risk of suicide--must be addressed as energetically as mania. Recent research into the long-term treatment of bipolar disorder has raised several questions about the generalizability of early lithium studies, as a result of these studies' designs. Researchers conducting more recent studies of mood stabilizers in the long-term treatment of bipolar disorder have attempted to clarify their results by, for example, performing survival analyses of the data. Until pharmacotherapy has been found that is equally efficacious in the treatment of both manic and depressive episodes in bipolar disorder, the use of combination therapy to manage bipolar disorder is advised. Lithium and divalproex sodium remain the first-line treatments for mania. Lamotrigine has been found to have acute efficacy in treating episodes of bipolar depression without increasing cycling or provoking a switch into mania, as well as a long-term role in delaying relapse and recurrence of depressive episodes.

Citalopram treatment of fluoxetine-intolerant depressed patients.

BACKGROUND: We assessed the tolerability of and response to citalopram in depressed patients who had discontinued fluoxetine treatment due to adverse events. METHOD: Fifty-five outpatients with DSM-IV major depressive disorder and a confirmed history of intolerance to fluoxetine (mean final dose = 24.6 mg/day) were switched to citalopram (20 mg/day) after a 2- to 4-week single-blind placebo washout period. During a 6-week, open-label treatment protocol, citalopram could be titrated up to 40 mg/day. Safety and tolerability, including reemergence of symptoms that previously had been associated with fluoxetine, were assessed by recording all spontaneously reported or observed adverse events. Efficacy was evaluated using the Hamilton Rating Scale for Depression (HAM-D), the Clinical Global Impressions (CGI) scale, and several other measures. Response was defined as a CGI-Improvement score at endpoint of 1 or 2 (i.e., very much or much improved). RESULTS: Ninety-five percent of patients (N = 52) completed the citalopram trial. The only adverse events reported by more than 5 patients (>or= 10%) were pharyngitis (15%) and constipation (11%), and none of the 3 early terminations were attributed to adverse events. The rate of recurrence of the fluoxetine-associated adverse events was low, with headache (3 [27%] of 11 cases), nausea (2 [22%] of 9 cases), and decreased libido (5 [18%] of 28 cases) being the most common. Significant improvement from baseline HAM-D (p <.001) was observed by the first week of citalopram therapy and continued until study end. The intent-to-treat CGI response rate was 65% (36 of 55 patients) at study endpoint; 69% (36 of 52 patients) of the completers responded. CONCLUSION: These data suggest that fluoxetine-intolerant patients can be treated effectively with citalopram.

Rash in multicenter trials of lamotrigine in mood disorders: clinical relevance and management.

BACKGROUND: The rate of lamotrigine-associated rash in patients with mood disorders has not been well characterized. The objective of this report was to determine rash rates in clinical trials of lamotrigine in DSM-IV unipolar depression or bipolar disorder. METHOD: A retrospective analysis was conducted of rates of lamotrigine-related rash in 12 multicenter studies, including 1 open study, 7 randomized controlled acute trials, and 4 randomized controlled maintenance trials from 1996 to 2001. RESULTS: A total of 1955 patients were treated with lamotrigine in open-label settings (open-label phases preceding or following randomization and 1 stand-alone open-label study); 1198 patients received lamotrigine in controlled settings, and 1056 patients received placebo. In controlled settings, rates of benign rash were 8.3% and 6.4% in lamotrigine- and placebo-treated patients, respectively. Rates of serious rash were 0% with lamotrigine, 0.1% (N = 1) with placebo, and 0% with comparators. In the open-label setting, the overall rate of rash for lamotrigine was 13.1% (N = 257) and of serious rash, 0.1% (N = 2). One mild case of Stevens-Johnson syndrome not requiring hospitalization occurred in a patient treated with lamotrigine. There were no cases of toxic epidermal necrolysis in any setting. CONCLUSION: Serious drug eruptions associated with lamotrigine were rare. Although rash is a potentially life-threatening reaction, the risk of serious rash due to lamotrigine should be weighed against more common risks associated with untreated or undertreated bipolar depression.

Latest maintenance data on lamotrigine in bipolar disorder.

Two 18-month, randomised, double-blind trials have compared lamotrigine, lithium, and placebo as maintenance treatment in a total of 1315 recently manic or depressed patients with bipolar I disorder. Individual and combined analyses of these studies showed that both lamotrigine and lithium significantly prolonged the time to intervention for any mood episode compared with placebo. Lamotrigine was primarily effective against depression and lithium was primarily effective against mania. There was no evidence that lamotrigine induced mania/hypomania/mixed states, caused episode acceleration, or destabilised the overall course of illness. Lamotrigine was well tolerated, with a placebo-like adverse-event profile. In summary, lamotrigine is an effective and well-tolerated maintenance treatment for bipolar I disorder, providing a spectrum of efficacy complementary to that of lithium.