For many years, lithium was considered to be the standard treatment for bipolar depression. Improvement rates of 80% have been reported in nine placebo-controlled studies, conducted mostly in the 1970s. Response rates for lithium were equivalent to those for tricyclic antidepressants (tricyclic antidepressants). A recent study of outpatients with bipolar depression compared the efficacy of lithium monotherapy with combined lithium and paroxetine and combined lithium and imipramine. Overall, the combination therapies were not superior to lithium monotherapy. However, at blood levels of lithium < 0.8 mEq/L, both the paroxetine and impramine combinations were superior to lithium monotherapy. The disadvantages of lithium in the acute treatment of bipolar depression are its slow onset of action (usually between 1 and 2 months) and the side-effect profile, such as weight gain, tremor, gastrointestinal disturbances, and lethargy.
Recent studies have also demonstrated the effectiveness of lithium as maintenance treatment in reducing depressive morbidity in both bipolar I and II.
There have been two monotherapy placebo-controlled, double-blind trials.
In the first, bipolar I patients with a major depressive episode received fixed doses of lamotrigine 50 mg or 200 mg per day versus placebo for 7 weeks. The titration schedule started with 25 mg of lamotrigine for the first 2 weeks, 50 mg in the third week, and then increases in the 200-mg arm to 100 mg in the fourth week and 200 mg in the fifth week. There was a non-significant trend (p = 0,084) at end point for the lamotrigine 200-mg group on the change from baseline on the 17-item Hamilton-D (HAM-D), the primary efficacy variable. However, there was a significant drug/placebo difference for the 200-mg dose. There were no significant differences on these measures for the lamotrigine 50-mg group. Lamotrigine separated from placebo on the Montgomery-Asberg Depression Rating Scale (MADRS) at week 3 and throughout the rest of the study. The only side effect with significantly higher rates than placebo was headache. There were no differences among the three groups on rash. Treatment-emergent manic and hypomanic episodes were low and did not differ between the active groups and the placebo.
Another study examined bipolar I or II patients with a depressed episode. This 10-week placebo-controlled study allowed flexible dosing between 100 mg and 400 mg of lamotrigine. The bipolar I subjects in this study separated from placebo on theMontgomery-Asberg Depression Rating Scale total score. The bipolar II subjects did not separate because of lower baselineMontgomery-Asberg Depression Rating Scale score in the bipolar II lamotrigine arm vs. the Bipolar II placebo arm (26.4 vs. 28.3)
Taken together, these studies suggest that lamotrigine has an important role in the acute treatment of bipolar depression. Results suggest efficacy for bipolar I depression, beginning at week 3 with a favorable, benign tolerability profile for monotherapy. A slow titration is essential to reduce risk of serious rash.
Divalproex and Sodium Valproate
A pilot placebo-controlled double-blind study was conducted to evaluate the efficacy of divalproex vs. placebo in the treatment of bipolar depression. Patients with bipolar I or II disorder with depression were treated in this flexible dose study beginning at 250 mg qhs with a mean maximum daily dose of divalproex of 1391 mg per day. Forty-three percentage (9/21) of the divalproex-treated patients met criteria for recovery, whereas 27% (6/22) of the placebo patients met these criteria (p <0,4). The endpoint HAM-D total score did not differ between placebo and divalproex. However, there were significant differences in favor of divalproex at several points during the study. The study was not powered to test adequately the utility of divalproex in the treatment of bipolar depression, but these results certainly would support further research on the utility of divalproex monotherapy in the treatment of bipolar depression.
Olanzapine and Olanzapine/Fluoxetine Combination
The utility of olanzapine, either as monotherapy or in combination with fluoxetine, was evaluated in a very large placebo-controlled clinical trial. The study involved bipolar I depressed patients with an MADRS score of at least 20. Patients were randomized to olanzapine monotherapy, olanzapine/fluoxetine combination (OFC), or placebo for 8 weeks. The mean modal dose of olanzapine in the monotherapy arm was 9.7 mg per day. In the olanzapine/fluoxetine combination, the olanzapine dose was 7.4 mg per day and fluoxetine 39.3 mg per day. Both olanzapine monotherapy and olanzapine/fluoxetine combination separated from placebo at week 1 and both continued to demonstrate significance throughout the study. Remission rate for olanzapine/fluoxetine combination was 49%, 33% for olanzapine monotherapy, and 25% for placebo.O lanzapine/fluoxetine combination remission rates were significantly higher than both placebo and monotherapy, and monotherapy was significantly higher than placebo.
An analysis of the baseline to endpoint change in the individual MADRS items revealed eight out of the 10 differences were different for olanzapine/fluoxetine combination versus placebo (concentration difficulties and suicidal thoughts were the two exceptions). However, for olanzapine monotherapy, only three out of the 10 items separated from placebo — inner tension, reduced sleep, and reduced appetite. Changes in these symptoms may be attributed to the sedating and appetite-stimulating side effects of olanzapine. Therefore, the antidepressant qualities of olanzapine monotherapy are not as clearly demonstrated or evident as they are for olanzapine/fluoxetine combination.
Treatment-emergent mania was low in all groups with no significant differences between placebo and the active agents. In general, the side effect profile was similar for olanzapine and olanzapine/fluoxetine combination and included somnolence, weight gain, increased appetite, and asphenia.
Patients completing the 8-week acute treatment phase entered a 6-month open-label extension with either olanzapine or olanzapine/fluoxetine combination. Of the patients who were in remission upon entering the open-label phase, 62% remained free of relapse over the 6 months of the trial. Of the patients to relapse, median time to relapse was 194 days.
The efficacy of quetiapine in the treatment of depression in bipolar I or II patients was tested in an 8-week, 3-arm (quetiapine 600 mg per day, quetiapine 300 mg per day, and placebo) study. Of the 542 patients who were randomized, approximately two-thirds were bipolar I and one-third bipolar II. Approximately 20% were rapid cycling and the rest non-rapid cycling. Titration was rapid with target doses of 300 mg per day, by day 4 or 600 mg per day by week 1.
Both doses of quetiapine separated from placebo by week 1 and continued throughout the 8 weeks of the study. The effect size was 0.75 for the 600 mg dose and 0.64 for the 300 mg dose (mixed-model analysis). Remission rates (MADRS ≤12) were > 50% for both doses and 37% for placebo (p < 0.001). An analysis of the 10 individual MADRS items revealed separation from placebo on eight of the 10 items for both groups (with the exception of reduced appetite and lassitude). Both doses were effective in both rapid cycling and non-rapid cycling patients.
Treatment-emergent mania was low in all groups without significant differences. Sedation, somnolence, and dizziness were the major side effects.
This study strongly supports the efficacy of quetiapine monotherapy in the treatment of both bipolar I and bipolar II depression. Concerns about sedation and somnolence might lead the clinician to consider a slower titration or lower maximum dose.
Benzodiazepines may be useful adjunctively in the treatment of patients with bipolar depression but should not be used as first-line agents. For example, benzodiazepines are useful in treating patients with significant anxiety symptoms or syndromes. Benzodiazepines’ augmentation may also be useful for managing aggression and impulsivity.