Article
`
`Combination of a Mood Stabilizer With Risperidone
`or Haloperidol for Treatment of Acute Mania:
`A Double-Blind, Placebo-Controlled Comparison
`of Efficacy and Safety
`
`Gary S. Sachs, M.D.
`
`Fred Grossman, D.O.
`
`S. Nassir Ghaemi, M.D.
`
`Akiko Okamoto, Sc.D.
`
`Charles L. Bowden, M.D.
`
`Objective: The study assessed the effi-
`cacy and safety of risperidone as an ad-
`junctive agent to mood stabilizers in the
`treatment of acute mania.
`
`Method: This 3-week randomized, dou-
`ble-blind, placebo-controlled study in-
`cluded 156 bipolar disorder patients with
`a current manic or mixed episode who re-
`ceived a mood stabilizer (lithium or dival-
`proex) and placebo, risperidone, or halo-
`peridol. The primary efficacy measure
`was the Young Mania Rating Scale. Other
`assessments used the Brief Psychiatric
`Rating Scale, the Clinical Global Impres-
`sion scale, and safety measures.
`
`Results: The trial was discontinued by 25
`(49%) of the 51 placebo group patients, 18
`(35%) of the 52 risperidone group patients,
`and 28 (53%) of the 53 haloperidol group
`patients. Mean modal doses were 3.8 mg/
`day (SD=1.8) of risperidone and 6.2 mg/
`day (SD=2.9) of haloperidol. Significantly
`
`greater reductions in Young Mania Rating
`Scale scores at endpoint and over time
`were seen in the risperidone group and in
`the haloperidol group, compared with the
`placebo group. Young Mania Rating Scale
`total scores improved with risperidone
`and with haloperidol both in patients with
`psychotic features and in those without
`psychotic features at baseline. Extrapyra-
`midal Symptom Rating Scale total scores at
`endpoint were significantly higher in the
`haloperidol patients than in the placebo
`patients. Antiparkinsonian medications
`were received by 8%, 17%, and 38% of pa-
`tients in the placebo, risperidone, and ha-
`loperidol groups, respectively.
`
`Conclusions: Risperidone plus a mood
`stabilizer was more efficacious than a
`mood stabilizer alone, and as efficacious
`as haloperidol plus a mood stabilizer, for
`the rapid control of manic symptoms and
`was well tolerated.
`
`(Am J Psychiatry 2002; 159:1146–1154)
`
`A cute manic episodes can have devastating conse-
`
`quences (1; DSM-IV). Management of acute mania is di-
`rected at rapidly controlling the irritability, agitation, im-
`pulsivity, aggression, and psychotic symptoms that
`characterize the hyperaroused state in manic and mixed
`episodes. The primary goal of treatment for mania is to re-
`store behavioral control as quickly as possible so as to
`minimize dangerousness to self and others and limit the
`high economic, social, and personal costs of manic epi-
`sodes. Although many experts agree that combination
`therapy may offer an advantage over monotherapy (2), few
`controlled studies offering evidence for the advantages of
`this approach have been performed.
`In the United States, mood stabilizers, principally lith-
`ium and divalproex, are standard treatment choices for
`the management of bipolar disorder (2–4). Double-blind
`studies have demonstrated the superior efficacy of these
`agents compared with placebo as monotherapy for mania
`(5). However, these studies have also indicated that many
`patients treated for up to 3 weeks with lithium or dival-
`proex retain clinically significant manic symptoms.
`
`Higher serum levels of the mood stabilizers have been as-
`sociated with greater efficacy but are complicated by more
`adverse effects and secondary noncompliance (5, 6).
`Conventional antipsychotics have been used alone to
`achieve rapid control of acute manic symptoms (7), but
`their efficacy appears to be modest (8, 9). In addition, con-
`ventional antipsychotics are often poorly tolerated. Al-
`though atypical antipsychotics are generally better toler-
`ated than the conventional agents (10), we are aware of
`only three controlled trials assessing the effects of atypical
`antipsychotics in patients with bipolar disorder. Risperi-
`done, haloperidol, and lithium were equivalent in efficacy
`in a 28-day double-blind study involving 45 inpatients
`with mania (11). In a 3-week double-blind study, olanza-
`pine was superior to placebo for treatment of symptoms
`of acute mania in 139 patients for whom treatment with
`mood stabilizers had failed (12). A 4-week replication
`study again found olanzapine monotherapy superior to
`placebo in 115 patients hospitalized for acute mania (13).
`These reports are encouraging and suggest that the effi-
`cacy of treatment with atypical antipsychotics as mono-
`
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`

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`therapy appears to be of the same magnitude as that for
`mood stabilizer monotherapy.
`Because rapid control of acute mania is desired, adjunc-
`tive agents, including combinations of two mood stabiliz-
`ers or of a mood stabilizer with an antipsychotic agent, are
`widely used (14). Although this approach has been recom-
`mended in published treatment guidelines (2, 3), few well-
`controlled studies of combination therapies have been
`conducted. For patients with bipolar I disorder who were
`receiving lithium, adjunctive treatment with gabapentin
`was equivalent to placebo for treatment acute mania or
`hypomania (15). The combination of a mood stabilizer
`plus an antipsychotic agent has been widely used for rapid
`control of acute manic episodes (14, 16). Muller-Oerling-
`hausen et al. (17) reported that adjunctive valproate plus a
`conventional antipsychotic provided greater symptom re-
`duction than placebo and at a lower mean dose of the an-
`tipsychotic agent. Concern about possible additive ad-
`verse effects (particularly extrapyramidal symptoms and
`tardive dyskinesia) with combination therapy has limited
`the use of conventional antipsychotics for patients with
`bipolar disorder (18).
`Evidence from several small trials (19–22) and a survey
`of a hospital database (23) have suggested that risperidone
`may be useful in patients with bipolar and affective disor-
`ders. In a 3-week double-blind, placebo-controlled study
`involving manic patients, we evaluated the effects of ris-
`peridone and haloperidol in combination with a mood
`stabilizer. To our knowledge, this study also provides the
`first controlled comparison of a typical and atypical anti-
`psychotic in the treatment of mania.
`
`Method
`
`Subjects
`
`Subjects were patients aged 18–65 years with a history of bipo-
`lar disorder and at least one prior manic episode who were hospi-
`talized for treatment of a manic episode in one of 20 centers. In-
`clusion criteria included a minimum score of 20 on the Young
`Mania Rating Scale (24) and a DSM-IV diagnosis of bipolar disor-
`der, with the most recent episode manic or mixed (296.4x, 296.6x).
`Patients had to be medically stable according to a pretrial physi-
`cal examination, medical history, and electrocardiography. After
`complete description of the study to the subjects, written in-
`formed consent was obtained.
`Exclusion criteria included another DSM-IV axis I diagnosis
`that required psychopharmacologic treatment; use of disallowed
`concomitant therapy; history of drug or alcohol abuse or depen-
`dence within 1 month before study entry; seizure disorder requir-
`ing medication; participation in an investigational drug trial
`within 30 days before the start of the trial; known sensitivity to ris-
`peridone, lithium, divalproex, or carbamazepine; use of cloza-
`pine within 1 month before study entry; use of depot neuroleptics
`within one cycle before study entry; and laboratory values outside
`the normal range. Women of childbearing potential who were
`without adequate contraception were also excluded.
`
`Procedure
`
`Patients were randomly assigned to receive placebo, risperi-
`done, or haloperidol under double-blind conditions in addition
`
`SACHS, GROSSMAN, GHAEMI, ET AL.
`
`to a mood stabilizer (lithium or divalproex) for up to 3 weeks.
`Random assignment was stratified by mood stabilizer (lithium or
`divalproex) and was preceded by a washout period of up to 3 days
`for patients who had received any disallowed concomitant medi-
`cations such as antipsychotics other than risperidone or halo-
`peridol or mood stabilizers other than lithium or divalproex.
`Patients who had completed either the 3-week double-blind
`study or at least 7 days of double-blind treatment but who termi-
`nated because of lack of efficacy or an adverse event were eligible
`to enter a 10-week open-label extension study. Data from the 10-
`week study will be reported elsewhere.
`
`Assessments
`All patients received a psychiatric evaluation to establish the
`diagnosis of bipolar disorder. During the double-blind phase, the
`Young Mania Rating Scale was completed at baseline screening
`and days 1, 8, 15, and 22. The Clinical Global Impression (CGI)
`scale (25) was completed on days 1, 8, 15, and 22. Severity of ex-
`trapyramidal symptoms was rated with the Extrapyramidal
`Symptom Rating Scale (26) on days 1, 8, 15, and 22. Information
`on adverse events was obtained on days 1, 3, 8, 15, and 22. Elec-
`trocardiography and standard laboratory tests were performed at
`screening and day 22. Vital signs were measured at screening and
`days 1, 8, 15, and 22. Serum levels of the mood stabilizer were
`measured at screening and days 1 and 22. Patients received a
`physical examination at screening and on day 22 and were
`weighed on days 1 and 22.
`
`Dosing Schedule
`The study employed a flexible dosing schedule for risperidone,
`haloperidol, and the mood stabilizers. In addition to receiving lith-
`ium or divalproex, on days 1 and 2 of the double-blind phase, pa-
`tients received 2 mg/day of risperidone (2 tablets), 4 mg/day of ha-
`loperidol (2 tablets), or 2 tablets of placebo. On days 3 and 4, the
`doses could be maintained, reduced to 1 tablet, or increased to 4
`mg/day of risperidone, 8 mg/day of haloperidol, or 4 tablets of
`placebo. On days 5 to 21, the doses could be increased to 6 mg/day
`of risperidone, 12 mg/day of haloperidol, or 6 tablets of placebo.
`If a patient was not receiving lithium or divalproex at study en-
`try, treatment with one or the other was started immediately after
`consent was provided. Mood stabilizers could not be switched for
`lack of efficacy. If a patient experienced an adverse event attrib-
`uted to the mood stabilizer, the dose could be reduced. If the ad-
`verse event persisted, the mood stabilizer could be switched. For
`the data analyses, three patients who switched mood stabilizers
`remained in their original mood stabilizer group (mood stabilizer
`groups were used as strata).
`Investigators were instructed to adjust doses of the mood stabi-
`lizers to obtain serum concentrations in the usual therapeutic
`range: for divalproex, 50–120 µg/ml (trough); for lithium, 0.6–1.4
`meq/liter (12 hours after last dose).
`
`Concomitant Medications
`The following were not permitted during the trial: antipsy-
`chotics other than risperidone or haloperidol; mood stabilizers
`other than lithium or divalproex; benzodiazepines other than
`temazepam, oxazepam, or flurazepam for sleep; lorazepam for
`agitation after day 7 (however, up to 4 mg/day was permitted
`during days 1 to 7 for sleep); antiparkinsonian medication at
`baseline; and antidepressants at entry into the double-blind
`phase.
`
`Efficacy Measures
`Severity of the illness and psychopathology were measured
`with the Young Mania Rating Scale (range=0–60), the CGI severity
`scale (from 0, “not ill,” to 7, “extremely severe”), and the CGI
`change scale (from 1, “very much better,” to 7, “very much
`
`Am J Psychiatry 159:7, July 2002
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`RISPERIDONE PLUS MOOD STABILIZER
`
`TABLE 1. Characteristics of Patients in a 3-Week Randomized, Double-Blind, Placebo-Controlled Study of Combination
`Therapy With a Mood Stabilizer and an Adjunctive Agent for Treatment of Acute Mania
`Patients Receiving Placebo
`Patients Receiving
`Plus a Mood Stabilizer
`Risperidone Plus a
`(N=51)a
`Mood Stabilizer (N=52)a
`Median
`Median
`Range
`
`Patients Receiving
`Haloperidol Plus a
`Mood Stabilizer (N=53)a
`Median
`Range
`
`Characteristic
`
`Range
`
`Age (years)
`
`43
`
`N
`
`18–64
`
`%
`
`24
`27
`
`Male
`Female
`Severity of current manic episode
`Mild
`Moderate
`Severe, with psychosis
`Severe, without psychosis
`Episode type
`40
`Manic
`11
`Mixed
`Receiving psychotropic medicationb at baseline
`31
`a Patients received either lithium or divalproex as a mood stabilizer.
`b Other than lorazepam.
`
`0
`22
`22
`7
`
`47
`53
`
`0
`43
`43
`14
`
`78
`22
`61
`
`41
`
`N
`
`26
`26
`
`1
`22
`21
`8
`
`42
`10
`27
`
`18–61
`
`%
`
`50
`50
`
`2
`42
`40
`15
`
`81
`19
`52
`
`44
`
`N
`
`30
`23
`
`3
`23
`18
`9
`
`41
`12
`30
`
`20–66
`
`%
`
`57
`43
`
`6
`43
`34
`17
`
`77
`23
`57
`
`worse”). The primary measure of efficacy was the change in the
`mean Young Mania Rating Scale total score from baseline to end-
`point. Endpoint was the last available postbaseline assessment.
`Secondary measures included changes from baseline in severity
`of illness as reflected in CGI change scale scores.
`
`Statistical Analysis
`All patients who were randomly assigned to treatment groups
`and had at least one postbaseline assessment were included in
`the efficacy analysis. All patients who were randomly assigned to
`treatment groups were included in the safety analysis. The pri-
`mary time point was the endpoint of the double-blind phase (i.e.,
`the last available observation for each patient during the double-
`blind phase), and the primary comparison was between risperi-
`done and placebo. Haloperidol was included as an active com-
`parator to assess the sensitivity of the trial. An analysis of covari-
`ance model was used to test differences between treatments at
`endpoint. The model included factors for treatment, investigator,
`and type of mood stabilizer and baseline score on the Young Ma-
`nia Rating Scale as a covariate. Young Mania Rating Scale total
`scores at all time points in the double-blind treatment phase were
`analyzed jointly by means of a repeated-measures model. Investi-
`gator, type of mood stabilizer, and treatment over time were used
`as factors in the model, with an assumption that observations of
`each subject were correlated with an autoregression variance and
`covariance structure. Gehan’s generalized Wilcoxon test (27) was
`used to evaluate differences in time to discontinuation, and the
`Van Elteren test (28) (controlling for investigator) was used to
`evaluate differences in CGI change scores.
`
`Results
`
`Characteristics of the patients in the three treatment
`groups are summarized in Table 1. The groups included
`equivalent proportions of men and women, all of whom
`received a DSM-IV diagnosis of bipolar disorder, manic or
`mixed episode. The severity specifier for the diagnosis was
`moderate or severe for most patients, and psychotic fea-
`tures were present in more than one-third of the patients.
`Differences in demographic and clinical characteristics
`between the groups at baseline were not significant.
`
`Of the 180 patients who were recruited, 158 were ran-
`domly assigned to a treatment group; 156 of these received
`at least one dose of study medication. The trial was dis-
`continued by 25 (49%) of the 51 patients in the placebo
`plus mood stabilizer group, 18 (35%) of the 52 patients in
`the risperidone plus mood stabilizer group, and 28 (53%)
`of the 53 patients in the haloperidol plus mood stabilizer
`group (Figure 1). Reasons for early discontinuation are
`shown in Table 2. Time to premature discontinuation was
`significantly shorter for the patients who received placebo
`plus a mood stabilizer (25% had discontinued by day 9)
`than for the patients who received risperidone plus a
`mood stabilizer (25% had discontinued by day 15) (χ2=
`4.35, df=1, p<0.04; Wilcoxon test).
`
`Medications
`During the double-blind phase, the mean modal doses
`of medication were 3.8 mg/day (SD=1.8) of risperidone
`and 6.2 mg/day (SD=2.9) of haloperidol. The mean dura-
`tion of exposure to medication was 17.1 days (SD=6.5) for
`the patients who received risperidone plus a mood stabi-
`lizer and 16.2 days (SD=6.6) for the patients who received
`haloperidol plus a mood stabilizer.
`Before entering the trial, 63% of the patients (N=99 of
`156) were receiving a mood stabilizer. At the start of the
`double-blind phase, 71% of the patients (N=111 of 156) re-
`ceived divalproex, and 29% (N=45 of 156) received lithium
`(Table 3). Blood levels of the medications at week 3 were
`within the targeted therapeutic range for all groups.
`Lorazepam was received by 59% (N=30 of 51) of the pa-
`tients in the placebo plus mood stabilizer group, 67% (N=
`35 of 52) in the risperidone plus mood stabilizer group,
`and 64% (N=34 of 53) in the haloperidol plus mood stabi-
`lizer group. Antiparkinsonian medications were received
`by four (8%) patients in the placebo plus mood stabilizer
`group, nine (17%) patients in the risperidone plus mood
`
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`

`
`FIGURE 1. Time to Study Discontinuation in a 3-Week Randomized, Double-Blind, Placebo-Controlled Study of Combina-
`tion Therapy With a Mood Stabilizer and an Adjunctive Agent for Treatment of Acute Maniaa
`
`SACHS, GROSSMAN, GHAEMI, ET AL.
`
`Placebo + mood stabilizer
`46
`49
`49
`50
`51
`
`44
`
`43
`
`43
`
`40
`
`37
`
`35
`
`35
`
`33
`
`31
`
`30
`
`28
`
`26
`
`26
`
`24
`
`23
`
`22
`
`19
`
`Risperidone + mood stabilizer
`48
`48
`49
`51
`52
`
`48
`
`Haloperidol + mood stabilizer
`49
`49
`52
`53
`53
`
`47
`
`46
`
`46
`
`44
`
`44
`
`44
`
`42
`
`42
`
`40
`
`40
`
`37
`
`36
`
`36
`
`34
`
`34
`
`31
`
`26
`
`47
`
`46
`
`43
`
`42
`
`41
`
`38
`
`36
`
`35
`
`35
`
`35
`
`33
`
`33
`
`33
`
`32
`
`27
`
`21
`
`Remaining
`
`Number of
`
`Subjects
`
`9
`
`10
`
`11
`Time in Trial (days)
`
`12
`
`13
`
`14
`
`15
`
`16
`
`17
`
`18
`
`19
`
`20
`
`21
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Percentage of Subjects Who
`
`Discontinued the Study
`
`a For patients who discontinued the double-blind study to enter the open-label study, discontinuation was the first date of open-label enroll-
`ment. For patients who discontinued and did not enter the open-label study, discontinuation was the last date medication was administered
`in the double-blind study. Patients who completed 19 days or more of the double-blind study were considered completers.
`
`stabilizer group, and 20 (38%) patients in the haloperidol
`plus mood stabilizer group. The only significant between-
`group difference was in the use of antiparkinsonian medi-
`cations between the placebo plus mood stabilizer group
`and the haloperidol plus mood stabilizer group (Cochran-
`Mantel-Haenszel χ2=12.96, df=1, p<0.001).
`
`Efficacy
`
`The mean total scores on the Young Mania Rating Scale
`for the three groups at baseline were comparable (Table 4).
`Significantly greater improvement in the mean total score
`on the Young Mania Rating Scale was seen in the risperi-
`done plus mood stabilizer group than in the placebo plus
`mood stabilizer group at endpoint (–14.3 versus –8.2) (Ta-
`ble 4, Figure 2). In the haloperidol plus mood stabilizer
`group also, improvement in the mean total score on the
`Young Mania Rating Scale was significantly greater than in
`the placebo plus mood stabilizer group at endpoint (–13.4
`versus –8.2). Significantly greater improvements in Young
`Mania Rating Scale total scores over time were seen in the
`risperidone plus mood stabilizer group and in the halo-
`peridol plus mood stabilizer group than in the placebo
`plus mood stabilizer group (Figure 2).
`An additional analysis compared treatment effects in
`the 99 patients (63%) who were receiving mood stabilizers
`when they entered the trial (patients with a “breakthrough
`episode”) and the 57 patients (37%) who started treatment
`with mood stabilizers on entering the trial. Among pa-
`tients who were receiving mood stabilizers at the start of
`the trial (“breakthrough” patients), the mean total score
`on the Young Mania Rating Scale (higher scores indicate
`more severe symptoms) decreased by 7.4 (SD=10.8) in
`
`TABLE 2. Reasons for Early Discontinuation From a 3-Week
`Randomized, Double-Blind, Placebo-Controlled Study of
`Combination Therapy With a Mood Stabilizer and an Ad-
`junctive Agent for Treatment of Acute Mania
`Patients
`Patients
`Receiving
`Receiving
`Placebo
`Risperidone
`Plus a Mood
`Plus a Mood
`Stabilizer
`Stabilizer
`(N=51)a
`(N=52)a
`
`Patients
`Receiving
`Haloperidol
`Plus a Mood
`Stabilizer
`(N=53)a
`
`Reason for
`%
`N
`%
`N
`%
`N
`Discontinuation
`28
`15
`17
`9
`20
`10
`Withdrew consent
`6
`3
`6
`3
`10
`5
`Insufficient response
`2
`1
`6
`3
`2
`1
`Noncompliance
`6
`3
`2
`1
`4
`2
`Ineligible
`9
`5
`0
`0
`6
`3
`Lost to follow-up
`2
`1
`4
`2
`4
`2
`Adverse event
`Otherb
`0
`0
`0
`0
`4
`2
`53
`28
`35
`18
`49
`25
`All reasons
`a Patients received either lithium or divalproex as a mood stabilizer.
`b Including moved to a distant location, subject felt well.
`
`those who received placebo plus a mood stabilizer (N=28),
`15.7 (SD=10.6) in those who received risperidone plus a
`mood stabilizer (N=34), and 14.9 (SD=9.5) in those who re-
`ceived haloperidol plus a mood stabilizer (N=33). Among
`patients who did not receive mood stabilizers until the
`start of the trial, the mean total score on the Young Mania
`Rating Scale decreased by 9.4 (SD=10.1) in the patients
`who received placebo plus a mood stabilizer (N=19), 11.3
`(SD=6.9) in the patients who received risperidone plus a
`mood stabilizer (N=17), and 10.1 (SD=10.4) in the patients
`who received haloperidol plus a mood stabilizer (N=17).
`A comparison was also made of patients with and with-
`out psychotic features at baseline. Of the 156 patients re-
`
`Am J Psychiatry 159:7, July 2002
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`4 of 9
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`Alkermes, Ex. 1075
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`

`
`RISPERIDONE PLUS MOOD STABILIZER
`
`Mood Stabilizer and Characteristic
`Divalproex
`Dose at start of double-blind phase
`(mg/day)
`Serum level (µg/ml) at week 3 of double-
`blind phase
`Lithium
`Dose at start of double-blind phase
`(mg/day)
`Serum level (meq/liter) at week 3 of
`double-blind phase
`
`TABLE 3. Doses and Serum Levels of Mood Stabilizers in a 3-Week Randomized, Double-Blind, Placebo-Controlled Study of
`Combination Therapy With a Mood Stabilizer and an Adjunctive Agent for Treatment of Acute Mania
`Patients Receiving Placebo
`Patients Receiving Risperidone
`Patients Receiving Haloperidol
`Plus a Mood Stabilizer
`Plus a Mood Stabilizer
`Plus a Mood Stabilizer
`N at Baseline Mean
`SD
`N at Baseline Mean
`SD
`N at Baseline Mean
`SD
`37
`38
`36
`
`1312
`
`410
`
`77.3
`
`27.3
`
`1418
`
`433
`
`65.4
`
`27.1
`
`14
`
`17
`
`1436
`
`686
`
`76.2
`
`25.6
`
`14
`
`1077
`
`285
`
`1052
`
`431
`
`1041
`
`337
`
`0.8
`
`0.3
`
`0.7
`
`0.3
`
`0.7
`
`0.2
`
`TABLE 4. Scores on the Young Mania Rating Scale at Baseline and Change in Scores From Baseline in a 3-Week Random-
`ized, Double-Blind, Placebo-Controlled Study of Combination Therapy With a Mood Stabilizer and an Adjunctive Agent for
`Treatment of Acute Mania
`
`Patients Receiving Placebo
`Plus a Mood Stabilizera
`N
`Mean
`SD
`50
`28.0
`6.1
`
`Patients Receiving Risperidone
`Plus a Mood Stabilizera
`N
`Mean
`SD
`52
`28.0
`5.5
`
`Patients Receiving Haloperidol
`Plus a Mood Stabilizera
`N
`Mean
`SD
`53
`27.3
`6.1
`
`Young Mania Rating Scale Variable
`Baseline score
`Change in score from baseline
`8.6
`–6.1
`46
`Week 1
`9.8
`–8.4
`36
`Week 2
`8.7
`–13.4
`25
`Week 3
`Endpointb
`10.4
`–8.2
`47
`a Patients received either lithium or divalproex as a mood stabilizer.
`b Significant differences between the risperidone plus mood stabilizer and the placebo plus mood stabilizer groups (t=2.65, df=128, p=0.009)
`and between the haloperidol plus mood stabilizer and the placebo plus mood stabilizer groups (t=2.34, df=128, p<0.03) but not between
`the risperidone plus mood stabilizer and the haloperidol plus mood stabilizer groups (t=0.31, df=128, p=0.76) in analyses of covariance with
`treatment, baseline score, type of mood stabilizer, and investigator as factors.
`
`49
`43
`38
`51
`
`–9.7
`–13.7
`–16.6
`–14.3
`
`7.8
`8.5
`7.9
`9.7
`
`47
`39
`33
`50
`
`–9.4
`–11.5
`–15.4
`–13.4
`
`7.2
`10.2
`8.9
`10.0
`
`ceiving at least one dose of study medication, 61 had psy-
`chotic features at baseline and 95 did not. The mean total
`score on the Young Mania Rating Scale had improved at
`endpoint with risperidone plus a mood stabilizer and with
`haloperidol plus a mood stabilizer both in patients with
`psychotic features (mean change=–15.4, SD=11.2, N=20;
`and mean change=–16.8, SD=10.1, N=18, respectively) and
`in patients without psychotic features (mean change=–13.5,
`SD=8.7, N=31; and mean change=–11.3, SD=9.5, N=32). For
`the patients who received placebo plus a mood stabilizer,
`the mean changes in score were –9.3 (SD=11.5) and –7.5
`(SD=9.7) in patients with (N=20) and without (N=27) psy-
`chotic features, respectively.
`The results were also analyzed in subgroups of patients
`with a manic or a mixed episode. In patients with pure ma-
`nia, the improvement in the mean total score on the Young
`Mania Rating Scale was greater with risperidone plus a
`mood stabilizer (mean change=–14.4, SD=9.4, N=42) or
`haloperidol plus a mood stabilizer (mean change=–13.7,
`SD=10.9, N=38) than with placebo plus a mood stabilizer
`(mean change=–6.6, SD=10.2, N=37). Patients with a
`mixed episode showed similar improvements with risperi-
`done plus a mood stabilizer (mean change=–13.6, SD=
`11.3, N=9), haloperidol plus a mood stabilizer (mean
`change=–12.1, SD=6.3, N=12), and placebo plus a mood
`stabilizer (mean change=–14.2, SD=9.5, N=10).
`
`CGI severity scores were similar in the treatment groups
`at baseline, with severity of manic symptoms being rated
`as marked to moderate in most patients. At endpoint, sig-
`nificant between-group differences were noted on the CGI
`change scale: ratings of much or very much improved
`were reported in 30% (N=14 of 47) of the patients who re-
`ceived placebo plus a mood stabilizer, 53% (N=27 of 51) of
`those who received risperidone plus a mood stabilizer,
`and 50% (N=25 of 50) of those who received haloperidol
`plus a mood stabilizer (risperidone plus mood stabilizer
`versus placebo plus mood stabilizer: Cochran-Mantel-
`Haenszel χ2=9.7, df=1, p=0.002; and haloperidol plus
`mood stabilizer versus placebo plus mood stabilizer: Co-
`chran-Mantel-Haenszel χ2=8.9, df=1, p=0.003). An end-
`point rating of very much improved was achieved by none
`of the patients who received placebo plus a mood stabi-
`lizer, 25% of the patients who received risperidone plus a
`mood stabilizer, and 16% of the patients who received ha-
`loperidol plus a mood stabilizer.
`A comparison of results for patients receiving lithium
`versus divalproex showed that improvements in the mean
`total scores on the Young Mania Rating Scale at endpoint
`were similar in the risperidone plus mood stabilizer group
`and the haloperidol plus mood stabilizer group (range of
`mean changes in score: –11.9, SD=9.6, to –14.4, SD=9.9).
`However, improvement was greater in patients who re-
`ceived placebo plus lithium (mean change=–12.5, SD=
`
`1150
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`Am J Psychiatry 159:7, July 2002
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`
`Alkermes, Ex. 1075
`
`

`
`FIGURE 2. Mean Percentage Improvement in the Young
`Mania Rating Scale Total Score in a 3-Week Randomized,
`Double-Blind, Placebo-Controlled Study of Combination
`Therapy With a Mood Stabilizer and an Adjunctive Agent
`for Treatment of Acute Mania
`
`FIGURE 3. Mean Change in Extrapyramidal Symptom Rat-
`ing Scale Total Score in a 3-Week Randomized, Double-
`Blind, Placebo-Controlled Study of Combination Therapy
`With a Mood Stabilizer and an Adjunctive Agent for Treat-
`ment of Acute Mania
`
`SACHS, GROSSMAN, GHAEMI, ET AL.
`
`Placebo + mood stabilizer (N=46)
`Risperidone + mood stabilizer (N=49)
`Haloperidol + mood stabilizer (N=47)
`
`a
`
`a
`
`6 5 4 3 2 1 0
`
`–1
`
`Change in Score
`
`Placebo + mood stabilizer
`N=36
`N=46
`
`Risperidone + mood stabilizer
`N=43
`N=49
`
`Haloperidol + mood stabilizer
`N=39
`N=47
`
`N=25
`
`N=47
`
`N=38
`
`N=51
`
`N=33
`
`N=50
`
`ab
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Percentage Improvement
`
`Week 1
`
`Week 2
`
`Week 3
`
`Endpoint
`
`a Significant difference between the risperidone plus mood stabilizer
`and the placebo plus mood stabilizer groups (t=–2.64, df=353,
`p<0.009, repeated-measures analysis).
`b Significant difference between the haloperidol plus mood stabilizer
`and the placebo plus mood stabilizer groups (t=–2.16, df=353,
`p<0.04, repeated-measures analysis).
`
`10.4) than in those who received placebo plus divalproex
`(mean change=–6.6, SD=10.1). These differences may not
`be related to the difference in mood stabilizers because
`the subjects were stratified in assignment to mood stabi-
`lizer group rather than randomly assigned and thus the
`characteristics of the patients in the two groups may not
`be comparable.
`
`Adverse Events and Safety
`Severity of extrapyramidal symptoms (the mean total
`score on the Extrapyramidal Symptom Rating Scale) was
`similar in the placebo plus mood stabilizer group and in
`the risperidone plus mood stabilizer group at endpoint
`(Figure 3). Among patients who received haloperidol plus
`a mood stabilizer, however, the mean change in the Ex-
`trapyramidal Symptom Rating Scale total score from base-
`line to endpoint and the mean changes to the maximum
`score were significantly greater than in patients who re-
`ceived placebo plus a mood stabilizer.
`Adverse events were reported by 84% (N=43 of 51), 81%
`(N=42 of 52), and 92% (N=49 of 53) of patients in the pla-
`cebo plus mood stabilizer, risperidone plus mood stabi-
`lizer, and haloperidol plus mood stabilizer groups, respec-
`tively. The most commonly reported adverse events are
`listed in Table 5. The class of adverse events most com-
`monly reported was related to the central and peripheral
`nervous systems and included headache, extrapyramidal
`
`Change at Endpoint
`Change to Maximum
`a Significant difference between the haloperidol plus mood stabilizer
`and the placebo plus mood stabilizer groups (χ2=4.60, df=1,
`p<0.05, Van Elteren test controlling for investigator and mood
`stabilizer).
`
`disorder, and tremor. These adverse events were more fre-
`quent in patients who received haloperidol plus a mood
`stabilizer (N=35; 66%) than in those who received placebo
`plus a mood stabilizer (N=21; 41%) or risperidone plus a
`mood stabilizer (N=22; 42%). The greatest between-treat-
`ment difference was in extrapyramidal disorder (28%,
`13%, and 4% of the patients in the haloperidol plus mood
`stabilizer, risperidone plus mood stabilizer, and placebo
`plus mood stabilizer groups, respectively, experienced this
`adverse event). Antiparkinsonian medications were re-
`ceived by twice as many patients in the haloperidol plus
`mood stabilizer group (38%) than in the risperidone plus
`mood stabilizer group (17%). A manic reaction was re-
`ported in three patients who received placebo plus a
`mood stabilizer (6%), three patients who received halo-
`peridol plus a mood stabilizer (6%), and none of the pa-
`tients who received risperidone plus a mood stabilizer.
`The mean weight of patients at baseline was 182.2,
`191.9, and 196.9 lb in the placebo plus mood stabilizer, ris-
`peridone plus mood stabilizer, and haloperidol plus mood
`stabilizer groups, respectively. The mean weight change in
`the three groups at endpoint was 1.1 lb (SD=4.8), 5.3 lb
`(SD=7.0), and 0.3 lb (SD=5.4), respectively. The weight gain
`in the risperidone plus mood stabilizer group was signifi-
`cantly greater than in the placebo group (t=2.95, df=105,
`p<0.004).
`No clinically significant changes in vital signs or labora-
`tory values were noted in any group at endpoint. Among
`the 119 patients (76%) for whom baseline and endpoint
`ECG data were available, no clinically significant changes
`were observed in any patient. QTc prolongation (450–500
`msec in men and 470–500 msec in women) at endpoint
`was reported in three patients who received placebo plus a
`mood stabilizer, three who received risperidone plus a
`
`Am J Psychiatry 159:7, July 2002
`
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`

`
`RISPERIDONE PLUS MOOD STABILIZER
`
`TABLE 5. Adverse Events Reported in a 3-Week Random-
`ized, Double-Blind, Placebo-Controlled Study of Combina-
`tion Therapy With a Mood Stabilizer and an Adjunctive
`Agent for Treatment of Acute Mania
`Patients
`Patients
`Patients
`Receiving
`Receiving
`Receiving
`Placebo
`Haloperidol
`Risperidone
`Plus a Mood
`Plus a Mood
`Plus a Mood
`Stabilizer
`Stabilizer
`Stabilizer
`(N=53)b
`(N=52)b
`(N=51)b
`Adverse Eventa
`N
`%
`N
`%
`N
`%
`16
`30
`13
`25
`6
`12
`Somnolence
`8
`15
`11
`21
`12
`24
`Headache
`9
`17
`9
`17
`9
`18
`Dyspepsia
`15
`28
`7
`13
`2
`4
`Extrapyramidal disorder
`4
`8
`7
`13
`1
`2
`Dizziness
`6
`11
`3
`6
`2
`4
`Constipation
`6
`11
`2
`4
`2
`4
`Tremor
`a Events reported by at least 10% of patients in any of the three treat-
`ment groups.
`b Patients received either lithium or divalproex as a mood stabilizer.
`
`mood stabilizer, and four who received haloperidol plus a
`mood stabilizer.
`
`Discussion
`
`The addition of risperidone to a mood stabilizer was a
`safe therapy and was more effective than a mood stabilizer
`alone in the treatment of acute bipolar mania. Reduction
`in the severity of mania (Young Mania Rating Scale total
`score) at endpoint was significantly greater in patients re-
`ceiving risperidone and a mood stabilizer than in patients
`receiving a mood stabilizer alone (placebo plus a mood
`stabilizer). Patients receiving haloperidol plus a mood sta-
`bilizer also showed clinical improvement on most efficacy
`measures, but haloperidol was associated with substan-
`tially more extrapyramidal symptoms than risperidone.
`The overall results are consistent with those from several
`prior small studies and case reports that suggested