Quetiapine Fumarate: Package Insert and Label Information (Page 8 of 9)

14.2 Bipolar Disorder

Bipolar I Disorder , Manic or Mixed Episodes

Adults:

The efficacy of quetiapine in the acute treatment of manic episodes was established in 3 placebo-controlled trials in patients who met DSM-IV criteria for bipolar I disorder with manic episodes. These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes. Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex. Key outcomes in these trials were change from baseline in the Young Mania Rating Scale (YMRS) score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy. Adjunct therapy is defined as the simultaneous initiation or subsequent administration of quetiapine with lithium or divalproex.

The primary rating instrument used for assessing manic symptoms in these trials was YMRS, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score).

The results of the trials follow:

Monotherapy

The efficacy of quetiapine in the acute treatment of bipolar mania was established in 2 placebo-controlled trials. In two 12-week trials (n=300, n=299) comparing quetiapine to placebo, quetiapine was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking quetiapine were dosed in a range between 400 mg/day and 800 mg per day (studies 1 and 2 in Table 20).

Adjunct Therapy

In this 3-week placebo-controlled trial, 170 patients with bipolar mania (YMRS ≥20) were randomized to receive quetiapine or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. Quetiapine was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score (study 3 in Table 20).

The majority of patients in this trial taking quetiapine were dosed in a range between 400 mg/day and 800 mg per day. In a similarly designed trial (n=200), quetiapine was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect.

The primary efficacy results of these studies in the treatment of mania in adults is presented in Table 20.

Children and Adolescents (Ages 10 to 17):

The efficacy of quetiapine in the acute treatment of manic episodes associated with bipolar I disorder in children and adolescents (10 to 17 years of age) was demonstrated in a 3-week, double-blind, placebo-controlled, multicenter trial (study 4 in Table 20). Patients who met DSM-IV diagnostic criteria for a manic episode were randomized into one of three treatment groups: quetiapine 400 mg/day (n=95), quetiapine 600 mg/day (n=98), or placebo (n=91). Study medication was initiated at 50 mg/day and on day 2 increased to 100 mg/day (divided doses given two or three times daily). Subsequently, the dose was titrated to a target dose of 400 mg/day or 600 mg/day using increments of 100 mg/day, given in divided doses two or three times daily. The primary efficacy variable was the mean change from baseline in total YMRS score.

Quetiapine 400 mg/day and 600 mg/day were superior to placebo in the reduction of YMRS total score (Table 20).

Table 20: Mania Trials

Mood stabilizer: lithium or divalproex; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

*
Adult data mean baseline score is based on patients included in the primary analysis; pediatric mean baseline score is based on all patients in the ITT population.
Difference (drug minus placebo) in least-squares mean change from baseline.
Doses that are statistically significantly superior to placebo.
§
Included in the trial as an active comparator.
Study Number Treatment Group Primary Efficacy Measure : YMRS Total
Mean Baseline Score ( SD ) * LS Mean Change from Baseline ( SE ) Placebo - Subtracted Difference ( 95 % CI )
Quetiapine (200 to 800 mg/day) §34.0 (6.1) -12.3 (1.3) -4.0 (-7.0, -1.0)
Study 1 Haloperidol §32.3 (6.0) -15.7 (1.3) -7.4 (-10.4, -4.4)
Placebo 33.1 (6.6) -8.3 (1.3)
Quetiapine (200 to 800 mg/day) 32.7 (6.5) -14.6 (1.5) -7.9 (-10.9, -5.0)
Study 2 Lithium §33.3 (7.1) -15.2 (1.6) -8.5 (-11.5, -5.5)
Placebo 34.0 (6.9) -6.7 (1.6)
Study 3 Quetiapine (200 to 800 mg/day) + mood stabilizer 31.5 (5.8) -13.8 (1.6) -3.8 (-7.1, -0.6)
Placebo + mood stabilizer 31.1 (5.5) -10 (1.5)
Quetiapine (400 mg/day) 29.4 (5.9) -14.3 (0.96) -5.2 (-8.1, -2.3)
Study 4 Quetiapine (600 mg/day) 29.6 (6.4) -15.6 (0.97) -6.6 (-9.5, -3.7)
Placebo 30.7 (5.9) -9.0 (1.1)

Bipolar Disorder , Depressive Episodes

Adults:

The efficacy of quetiapine for the acute treatment of depressive episodes associated with bipolar disorder was established in 2 identically designed 8-week, randomized, double-blind, placebo-controlled studies (N=1045) (studies 5 and 6 in Table 21). These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course. Patients randomized to quetiapine were administered fixed doses of either 300 mg or 600 mg once daily.

The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-rated scale with scores ranging from 0 to 60. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, quetiapine was superior to placebo in reduction of MADRS score. Improvement in symptoms, as measured by change in MADRS score relative to placebo, was seen in both studies at Day 8 (week 1) and onwards. In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF).

The primary efficacy results of these studies in the acute treatment of depressive episodes associated with bipolar disorder in adults is presented in Table 21.

Table 21: Depressive Episodes Associated with Bipolar Disorder

SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval.

*
Difference (drug minus placebo) in least-squares mean change from baseline.
Doses that are statistically significantly superior to placebo.
Study Number Treatment Group Primary Efficacy Measure : MADRS Total
Mean Baseline Score ( SD ) LS Mean Change from Baseline ( SE ) Placebo - subtracted Difference *( 95 % CI )
Quetiapine (300 mg/day) 30.3 (5.0) -16.4 (0.9) -6.1 (-8.3, -3.9)
Study 5 Quetiapine (600 mg/day) 30.3 (5.3) -16.7 (0.9) -6.5 (-8.7, -4.3)
Placebo 30.6 (5.3) -10.3 (0.9)
Quetiapine (300 mg/day) 31.1 (5.7) -16.9 (1.0) -5.0 (-7.3, -2.7)
Study 6 Quetiapine (600 mg/day) 29.9 (5.6) -16.0 (1.0) -4.1 (-6.4, -1.8)
Placebo 29.6 (5.4) -11.9 (1.0)

Maintenance Treatment as an Adjunct to Lithium or Divalproex

The efficacy of quetiapine in the maintenance treatment of bipolar I disorder was established in 2 placebo-controlled trials in patients (n=1326) who met DSM-IV criteria for bipolar I disorder (studies 7 and 8 in Figures 1 and 2). The trials included patients whose most recent episode was manic, depressed, or mixed, with or without psychotic features. In the open-label phase, patients were required to be stable on quetiapine plus lithium or divalproex for at least 12 weeks in order to be randomized. On average, patients were stabilized for 15 weeks. In the randomization phase, patients continued treatment with lithium or divalproex and were randomized to receive either quetiapine (administered twice daily totaling 400 mg/day to 800 mg/day) or placebo. Approximately 50% of the patients had discontinued from the quetiapine group by day 280 and 50% of the placebo group had discontinued by day 117 of double-blind treatment. The primary endpoint in these studies was time to recurrence of a mood event (manic, mixed, or depressed episode). A mood event was defined as medication initiation or hospitalization for a mood episode; YMRS score ≥20 or MADRS score ≥20 at 2 consecutive assessments; or study discontinuation due to a mood event (Figure 1 and Figure 2).

In both studies, quetiapine was superior to placebo in increasing the time to recurrence of any mood event. The treatment effect was present for increasing time to recurrence of both manic and depressed episodes. The effect of quetiapine was independent of any specific subgroup (assigned mood stabilizer, sex, age, race, most recent bipolar episode, or rapid cycling course).

Figure 1: Kaplan-Meier Curves of Time to Recurrence of a Mood Event (Study 7)

Figure 1
(click image for full-size original)

Figure 2: Kaplan-Meier Curves of Time to Recurrence of a Mood Event (Study 8)

Figure 2
(click image for full-size original)

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