Comparative Efficacy of Typical and
`Atypical Antipsychotics as Add-On Therapy
`to Mood Stabilizers in the Treatment of Acute Mania
`
`Debra S. Miller, M.D.; Lakshmi N. Yatham, M.B.B.S., FR.C.P.C., M.R.C.Psych(UK);
`and Raymond W. Lam, M.D., FR.C.P.C.
`
`
`
`therapy to moodstabilizers, no studiest
`
`date hav
`
`needed in the acute
`antipsychotics have undesi
`
`for behavioral contro! when
`cy setting. However, typical
`e effects, such as induc-
`
`975
`
`Received December 14, 2000; accepted May 3, 2001. From the
`OI.
`Department of Psychiatry, University of British Columbia, Vancouver,
`British Columbia, Canada.
`Background: ¥pigh)-antipsychoties are commonly
`In the spirit of full disclosure and in compliance with all ACCME
`used in combination Wi
`Sod stabilizers for acute
`Essential Areas and Policies, the faculty for this CME activity were asked
`theyhaveundesirablesid oeioasinductionof
`to complete a full disclosure statement. The information received is as
`mania. Although typical Ne otics are effective,
`follows: Dr. Yatham has received research grant support from Glaxo,
`depressive symptoms and tarditefh
`inesi
`i
`Janssen, Lilly, Pfizer, and AstraZeneca; and is a member of the speakers!
`antipsychotics have more favorable.sidge
`
`advisory board for Glaxo, Janssen, Lilly, AstraZeneca, Lundbeck,
`ect profiles,
`SmithKline, and Abbott. Dr. Lam has received research grant supportfrom
`fp
`and recent evidence showstheir efficaty
`AstraZeneca and Janssen; and is a memberofthe speakers/advisory board
`
`mania. Apart from a previous small studythéyat.pom-
`paredrisperidonewithtypicalacs,-on
`JorLilly. Dr. Miller has no significant commercial relationshipsto disclose
`relative to the présentation,
`Reprint requests to: Lakshmi N. Yatham, M.B.B.S., Depariment of
`directly compared atypical “nghatebte
`antipsychoticsasadd-ontherapytomoodeee,
`Psychiatry, University of British Columbia, 2255 Wesbrook Mall,
`Vancouver, BC V6T 2A] (e-mail: yatham@ interchange.ubc.ca).
`Fi.
`inaclinically relevant, naturalistic setting, ‘“>
`
`with DSM-IV—defined bipolardisorder, current fiass
`ipOy"
`Method: This study is a chart review ofall pa
`mania (N = 204), admitted to the University of Buti’-
`ood stabilizers such as lithium or valproic acid
`~, :
`20, GGe mania.'?However,surveys oftreatmentpracticesfor
`are used asfirst-line therapy for treatment of
`Columbia Hospital during a 30-month period. Patients
`ypesuggestthatup to 90% ofpatients with acute
`were separated into 3 groups according to the medica-
`“ee reatedwithacombinationofbothmoodstabi-
`tions used: (1) moodstabilizer and typical antipsy-
`chotic, (2) moodstabilizer and atypical antipsychotic,
`1Z Sor sychotics.>> Often, typical antipsychotics
`and (3) combination: mood stabilizer plus a typical
`
`antipsychotic, then switched to moodstabilizer plus
`
` are uSe vantages of using typical antipsychotics
`risperidone or olanzapine within | week. The atypical
`in the tr
`oer include the fact that they have
`group wasfurther subdivided into risperidone and
`proven antl
`Fibperties and are available in an intra-
`muscular meadeMe
`olanzapine subgroups. Outcome was measured
`using Clinical Global Impressions-Severity of Illness
`tionofdepressivesichsideeffects
`(CGI-S) and -Improvement (CGI-Dratings generated
`by review of clinical information in the chart.
`Results: Patients treated with typical antipsychotics
`were more severely ill at admission and at
`(EPS), and a long-term risk of engdyskinesia (TD).”*
`treating mania, since studies inporisn prevalence
`discharge than those treated with atypical antipsy-
`chotics. Patients in the atypical (p < .005) and combi-
`nation (p< .05) groups showedsignificantly greater
`clinical improvementat discharge than patients treated
`ofTD is higher in patients with bipolar disdzeey compared
`with typical antipsychotics. This difference was also
`with those with schizophrenia.?”
`significant in the subset of patients with psychotic fea-
`Atypical antipsychotics, such as risperidonesand olan-
`tures (p < .03). Risperidone and olanzapine were asso-
`ciated with fewer extrapyramidal side effects than were
`zapine, may bebetter alternatives. Unlike the typical anti-
`typical antipsychotics (risperidone vs. typical antipsy-
`psychotics, they have a more favorable side effect profile
`chotics, x? = 8.72, p< .01; olanzapine vs. typical
`with fewer EPS andless long-term risk of TD.'**In addi-
`antipsychotics, y? = 16.9, p< .001).
`tion, recent open studies and case series indicate thatatypi-
`Conclusion: Due to their superior effectiveness
`cal antipsychotics not only do not induce depressive symp-
`and side effect profile when compared with typical
`antipsychotics, atypical antipsychotics are an excellent
`toms but in fact may be useful
`in treating depressive
`choice as add-on therapy to moodstabilizers for the
`symptoms in bipolar patients.’*!” Furthermore,
`recent
`treatment of patients with mania.
`double-blind, controlled studies'*' have shownrisperi-
`(J Clin Psychiatry 2001 ;62:975-980)
`done (in combination with mood stabilizers) and olanza-
`
`pine (both alone and in combination with moodstabilizers)
`
`Therisk of TD is particularly impoftaytto consider when
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`Outcome Measures
`Patients were compared in terms of length of stay, de-
`velopment of EPS, Clinical Global Impressions-Severity
`of Illness (CGI-S)* score at admission and at discharge,
`and Clinical Global Impressions-Improvement (CGI-I)”
`score at week 1, week 2, and discharge. A subset analysis
`of CGI-I scores at week 1, week 2, and discharge was
`done using patients who had mania with psychotic fea-
`tures. Patients were considered to have psychotic features
`if it was noted in the clinical chart that they experienced
`delusion(s), hallucination(s), or both.
`The CGI scores were obtained by reviewing the psy-
`chiatrists’, residents’, medical students’, and nurses’ notes.
`All ratings were done by a single investigator (D.S.M.). In
`rating the CGI-S scores, some objective measures were
`used. Patients who were admitted to the hospital voluntar-
`ily were given a rating of 4 (moderately ill) or less. Pa-
`tients committed involuntarily were rated as 5 (markedly
`ill). Patients who required several days of confinementto
`a seclusion room wererated as 6 (severelyill), and patients
`referred to the tertiary psychiatric hospital intensive care
`unit (at Riverview Hospital, Coquitlan, British Columbia)
`received scores of 7 (most severely ill). At discharge,
`patients who were symptom free received a score of | (not
`mentally ill), those who had a few residual symptoms
`received a score of 2 (borderline mentally ill), and those
`who had several ongoing symptoms received a score of
`
`.
`
`don
`
`foundit diffictlt to
`
`in the presence or absence of
`
` Miller et al.
`
`976
`
`to be effective in the treatment of acute mania. However,
`as with all double-blind, randomized trials, these data may
`be subject to selection bias (volunteer bias, severity bias)
`and limitations due to exclusion criteria. For example,
`patients with severe illness are routinely excluded from
`double-blind clinical trials due to their inability to give
`informed consent. Also, patients with comorbid medical
`and psychiatric conditions, including substance abuse, are
`common'y seen in clinical practice, and such patients are
`ascertain,naefficacy ofmedications is conducted in
`often ae? from these trials. The result is that formal
`Thepurposeofsastudy,therefore, wastocompare
`a very specific
`Spal,ation, and this poses problemsin gen-
`eralizing the data.tg-all patients seen in clinical practice.
`theefficacyofayiath sychoticswiththatoftypical
`antipsychotics as ae-on therapy to mood stabilizers
`for treatment of mania in te t-world” population. To
`achieve this objective, we reviewed the charts ofall pa-
`tients who were treated for a manic epi ode at a univer-
`sity teaching hospital during a 30-m
`
`METHOD (©)
`
`es
`A retrospective chart review was defi,
`hweying
`charts of patients admitted to the Universit¥.3eaish «
`Columbia (UBC) Hospital with a DSM-IV—defi diag,
`nosis of bipolar disorder, current episode mania, tingve
`dy, SUunityill) or4(moderately ill).The CGL-Iratings were
`a 30-month period (Noy. 1, 1997, to April 30, 2000);
`Since the focus of this study was to compare typical witty,
`comparison to the patients’ own baseline severity
`ofof 8}
`ptoms, ranging from scores of 1 (very much im-
`atypical antipsychotics as add-on therapy to moodstabi-
`7 (very much worse).
`ve
`lizers, patients not treated with these medications were
`~ Pheof eyorabsenceofEPS wasalsorecorded. EPS
`excluded.
`eeeBp Pens ineithernursing notesor
`were's
`‘aSpeither present (any mention of stiffness/
`The information contained in the UBC Hospital charts
`physicianncyhabeentinallchartsreviewed. Sincewe
`was quite detailed, since most patients were followed by
`akathisiafromchartta edidnotincludeakathisiain
`psychiatry residents and/or senior medical students. A
`form was developed to summarize the pertinent informa-
`tion from each chart, including demographic data (age,
`our definition of EPS.
`gender), length of illness prior to admission, number of
`previous episodes, presence or absence of psychotic fea-
`Data Analysis
`“
`tures, development of EPS, length of stay in hospital, and
`Statistical analysis was conductédising the Statistical
`medications used at 3 points during treatment: week 1,
`Package for the Social Sciences (SPS S)
`Windows.
`week 2, and discharge. Data that were equivocal or un-
`Analysis of variance, the Friedmantest (for within-subject
`available were excluded on a case-by-case basis. Medi-
`CGI-I comparisons), the Kruskal-Wallis test €prbetween-
`cation decisions were made independently by the treating
`group CGI-S and CGI-I comparisons), and the chi-square
`psychiatrists. Patients were divided into 3 groups ac-
`test were used for data analysis. Where significant results
`cording to the medications used: (1) moodstabilizer plus
`were obtained, appropriate post hoc tests such ast tests or
`typical antipsychotic, (2) mood stabilizer plus atypical
`Mann-Whitney U tests with Bonferroni corrections were
`antipsychotic (this group was further divided into 2
`used for comparing subgroups.
`subgroups, moodstabilizer plus risperidone and moodsta-
`bilizer plus olanzapine), and (3) mood stabilizer plus a
`combination of typical and atypical antipsychotics. The
`combination group was composedofpatients treated ini-
`tially with a moodstabilizer plus a typical antipsychotic,
`then changed to a moodstabilizer plus risperidoneor olan-
`zapine within the first 7 days of treatment.
`
`RESULTS
`
`Between November 1, 1997, and April 30, 2000, 204
`patients were admitted to the hospital with a diagnosis
`of bipolar disorder, current episode mania. Of these, 155
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`patients were included in the study. Patients treated with
`mood stabilizers alone (N = 17), benzodiazepines alone
`(N = 3), or antipsychotics alone (N=5) were excluded
`from the study, as were patients whose medication regimen
`was too complexto fit into one ofthe categories described
`below (N = 15). Patients treated with new or experimental
`atypical antipsychotics (ziprasidone and quetiapine) were
`excluded as well, due to the very small numberof subjects
`treated with these drugs (N = 5). Two patients were treated
`with electrocanvulsive therapy and were excluded, and 2
`patients wéfe transferred to anotherfacility within 2 days
`of admission.
`Of the 155 patients included in the study, 69 (45%)
`were treated with
`‘a“iigod stabilizer plus a typical anti-
`
`Typical vs. Atypical Antipsychotics for Acute Mania
`
`Table 1. Demographics and Axis | and II Comorbidity
`Comparisons Between Groups"
`MS +
`MS + Atypical MS + Typical
`Antipsychotic Antipsychotic Combination”
`(N = 69)
`(N = 69)
`(N = 17)
`39.72 (14.50)
`40.86 (16.11)
`41.06 (18.08)
`5,39 (5.65)
`3.49 (3.07)
`3.43 (2.71)
`
`2.72 (2.80)
`
`3.13 (1.51)
`
`3.00 (1.46)
`
`27 (18)
`
`31 (24)
`
`29 (15)
`
`37 (53.62)
`32 (46.38)
`
`32 (46.38)
`37 (53,62)
`
`9 (52.94)
`8 (47.06)
`
`Variable
`Age, mean (SD), y
`Durationofillness
`prior to admission,
`mean (SD), wk
`No. of previous
`episodes, mean (SD)
`Duration of hospital
`stay, wk
`Gender, N (%)
`Female
`Male
`Comorbid Axis I
`diagnosis, N (%)
`Present
`Absent
`Comorbid Axis II
`diagnosis, N (%)
`13 (18.84)
`Present
`56 (81.16)
`Absent
`*Abbreviation: MS = moodstabilizer.
`>Patients treated with a typical antipsychotic, then switchedto an
`atypical antipsychotic within 1 week of admission. For 1 patient
`receiving MS + combinationtherapy, it was not possible to establish
`with confidence whether Axis I or I] comorbidity was present.
`
`psychotic, 69 (45% Wolotreated with a mood stabilizer
`plus an atypical antipsych6ththe(44 [28%] with risperidone,
`25 [16%] with olanzapine)s Ghd 17 (11%) were treated
`with a moodstabilizer plus a Consbination of antipsychotic
`medication (typical antipsychotic initially,
`then changed to
`
`atypical antipsychotic).
`~
`Demographic Data
`O f
`
`There were no significant diffeénces:
`(x? = 0.866,df = 3, p =. 83), presence of atmo ‘bi
` Axis
`I diagnosis (? = 6.57, df = 3, p= .09), or présenee fsa-
`(Mann-Whitney U= 1401,
`3645, =a . antipsychotics
`comorbid Axis II diagnosis (x? = 3.34, df = 3;
`Ds oe.rpp<.001).Whenthesubgroupswereexamined,therewas
`between the groups. There wasno significantdiffe’ nce
`in patientage(F= 0.181, p = .909) ornumberofPree,
`‘ieridone were found to be significantly less ill at
`Peignificant difference between the risperidone, olanza-
`episodes (F = 0.471, p= .703). A significant differencé
`combination groups. However, patients treated
`was found whenthe duration of illness prior to admission”
`“ehischafgs1than those treated with typical antipsychotics
`MaseWie U=719,Z=—4.35, p<.005).
`was compared (F = 2.726, p<.05). Post hoc analysis
`showed that the patients treated with risperidone had a
`Si ce, there,iaor significant differences in CGI-S
`contad/those who received atypical anti-
`longer duration of illness prior to admission than those
`scores a
`pebetween patients who received typical
`treated with typical antipsychotics (ps .05). No other
`
`significant differences were found. Table | shows further
`psychotics, also! 1 uted changes in CGI-S scores
`
`details.
`
`
`from baseline to endpoint’for each group. When changes
`in CGI-S scores were comparegsamong the 3 groups, no
`significant differences were detected (x = 0.33, df = 2,
`
`p=0.84).
`.
`
`21 (30.43)
`48 (69.57)
`
`30 (44)
`39 (56)
`
`21 (30)
`48 (70)
`
`8 (50)
`8 (50)
`
`5 (31)
`11 (69)
`
`Z= 3.84,
`
`Comparison of Severity of IlIness Between Groups
`All groupsof patients were less severelyill at discharge
`than at admission. The differences between groups in
`CGLS score at admission and at discharge were signifi-
`cant (x? = 23.17, df=2, p<.001 and y?= 14.42, df = 2,
`p <.001, respectively). Post hoc testing revealed that the
`patients treated with atypical antipsychotics were signifi-
`cantly less ill at admission than those treated with typical
`antipsychotics or a combination of typical and atypical
`antipsychotics
`(Mann-Whitney U= 1439, Z=-—4.43,
`p <.001 and Mann-Whitney U = 321, Z =—3.25, p < .005,
`respectively). No othersignificant differences were found.
`When the subgroups were compared, no significant differ-
`ence was found between the risperidone and olanzapine
`groups.
`Whendifferences in CGI-S score at discharge were
`compared, patients treated with atypical antipsychotics
`were significantly less ill than those treated with typical
`
`Comparison of Improvement Between Groups
`As shown in Table 2, all groups impréved
`during the
`course of the hospitalization. The difference {iimprove-
`ment (measured by the CGI-I) between groups were
`significant at week 1 (y’=6.53, df=2, p<.05) and
`at discharge (y” = 16.47, df = 2, p<. 001). At discharge,
`patients treated with atypical antipsychotics (Mann-
`Whitney U = 1423, Z =—3.82, p < .005) or a combination
`of typical and atypical antipsychotics (Mann-Whitney
`U = 345, Z = -2.53, p <.05) showed significantly more
`improvement
`than those treated with typical antipsy-
`chotics. Analysis of the atypical antipsychotic subgroups
`showednosignificant difference between patients treated
`with risperidone or olanzapine. Patients treated with ris-
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`Table 2. Clinical Global Impressions-Improvement
`and -Severity of Illness and Extrapyramidal Side Effects
`(EPS) Comparison Between Groups*
`MS + Atypical MS + Typical
`MS +
`Antipsychotic Antipsychotic Combination®
`
`(N= 69)"
`(N =69)
`(N= 17)
`
`Value
`Clinical Global Impressions-
`Severity of Hlness score,
`mean (SD)
`Admission
`Discharge
`
`Clinical vem npressions-
`Improveme: ste,
`mean (SD) e
`
`4.70 (0.65)!
`1,79 (0,79)
`
`5.36 (0.89)
`2.55 (1.34)
`
`5.29 (0.59)
`2.59 (2.37)
`
`2.73 (0.70)
`2.23 (0.60)
`1.56 (0.63)
`
`3.59 (3.79)
`2.79 (1.16)
`2.04 (0.73)
`40(58)
`
`‘
`
`«
`
` Miller et al.
`
`Side Effects
`Patients treated with typical antipsychotics developed
`more EPS than those treated with either risperidone
`(58.0% vs. 29.5%; x° = 8.72, df = 1, p<. 01) or olanzapine
`(58.0% vs. 8.7%; 72= 16.9, df=1, p<.001). Patients
`treated with olanzapine had fewer EPS than those treated
`with risperidone (8.7% vs. 29.5%; y?=3.78, df=1,
`p = .052). Patients who received a combination of typical
`and atypical antipsychotics were not includedin the analy-
`sis, since it would be difficult to determine which medica-
`tion caused the EPS.
`
`DISCUSSION
`
`This chart-review study comparedthe efficacy of atypi-
`cal antipsychotics with that of typical antipsychotics as add-
`on therapy to moodstabilizers for the treatment of mania
`in a naturalistic environment. The strengths of this study
`are as follows: (1) it reports on a large number ofpatients,
`(2) medications were used in a naturalistic setting with
`treatment decisions made by treating clinicians, (3) the
`study included patients seen routinely in clinical practice,
`(4) the information obtained from the charts was quite de-
`tailed due to the contributions of residents and medical] stu-
`dents, and (5) the improvementscores were obtained from
`a single rater. The limitations are as follows: (1) the study
`was retrospective; (2) the rater was not blind to the medi-
`
`Canada at the time of the study. Given thatthe patients
`treated with typical antipsychotics were moreSeverely ill
`than those treated with atypical antipsychotics,the fact that
`they were also more il] at discharge is difficult to interpret
`in a meaningful way. However, the clinical improvement
`(measured by the CGI-D in patients treated with atypical
`antipsychotics or a combination of typical and atypical
`antipsychotics was significantly greater than that of those
`treated with typical antipsychotics alone. Amongpatients
`with psychosis, the risperidone and combination groups
`were associated with significantly greater clinical improve-
`ment at discharge than the typical antipsychotic group. This
`suggests that using atypical antipsychotics, or using a typi-
`
`2.75 (0.90)
`Week 1
`2.39 (0.96)
`Week 2
`7
`© 1,59 (0.58)
`Discharge
`Developed EPS, N (%)8 > .
`Yes
`Asai
`
`No
`52°(78:36)
`29 (42)
`2Abbreviation: MS = mood sabia ;
`"In 2 of 25 olanzapine-treated patieritg’ iPwas unclear from the chart
`review whether they had EPS.
`?
`syghotic, then switched to
`“Patients treated initially with a typical anti
`#Ssion. EPS data are
`an atypical antipsychotic within 1 week of
`étgrmine if
`not presented, because it would not be possiblé.
`presence ofEPSin this groupis related totypicalto Ca
`antipsychotics.
`C2
`“The MS + atypical group wassignificantly les§ll than th
`MS+ typical and MS + combination groups (p
`<"001 ané 2,
`respectively).
`o> cb
`*The MS + atypical group wassignificantly less ill
`MS+ typical group (p < .001).
`‘The MS +atypical and MS + combination groups were sigiBiicably
`more improved than the MS + typical group (p < .005 and p &;
`fw,
`respectively).
`if
`“éfeations given; (3) the estimation of improvement was
`®The MS + atypical group experiencedsignificantly fewer EPS thai?
`ie,
`
`the MS + typical group (p < .001).
`©
`ap.
`sdmevwhat crude, using global clinical impressions rather
`a than respective, objective outcome measures; (4) benzo-
`diazepihgcpse in treatment was not monitored; (5) the
`Choiée ofsmedication was determined by the individual psy-
`chia sodys matic selection bias cannot be excluded;
`
`a
`ergami
`
`(6) di
`stabilizers were used; and (7) the study
`
`lacked a stridture
`rview to confirm diagnoses.
`Given theséAfimitafiens, the study yields interesting
`results. First,
`the patien®. treated with typical antipsy-
`chotics were more severely than those treated with atypi-
`cal antipsychotics, both at adriiisSien and at discharge. This
`makesintuitive sense, since severelyill patients often need
`intramuscular medications for behavior: , control, and there
`was no intramuscular atypical antipsyehotipavailabe in
`
`peridone showedsignificantly greater improvement than
`those treated with typical antipsychotics (Mann-Whitney
`U=778, Z=—4.29, p< .005). Although the olanzapine
`group had numerically greater improvement compared
`with those treated with typical antipsychotics, this differ-
`ence wasnot significant.
`
`Other Comparisons
`There was no significant difference between groups in
`length of hospital stay. A comparison of outcome in the
`subset of patients with psychosis (28/44 patients treated
`with risperidone, 21/25 patients treated with olanzapine,
`51/69 patients treated with typical antipsychotics, and
`14/17 patients treated with a combination of typical and
`atypical antipsychotics had psychotic features associated
`with mania) demonstrated a significant difference in clini-
`cal improvementatthe time of discharge between groups
`6? = 11.8, df =2, p<.005). Post hoc analysis revealed
`that both the atypical group (Mann-Whitney U = 836,
`Z=~-2.86, p< .01) and the combination group (Mann-
`Whitney U = 187, Z=—-2.738, p<.03) showed signi-
`ficantly more improvement at discharge when compared
`with the group treated with typical antipsychotics. When
`the subgroups of the atypical antipsychotics were com-
`pared, no significant difference was found.
`
`978
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`cal antipsychotic for 1 week and then switching to an atypi-
`cal antipsychotic, may be superior to using typical antipsy-
`chotics alone as add-on therapy to moodstabilizers in the
`treatment of moderately to markedly ill patients with ma-
`nia, with or without psychotic features, in a real-world
`clinical population.
`Whenthe atypical antipsychotics were compared sepa-
`rately, the risperidone subgroup showed greater improve-
`ment than the typical antipsychotic group. This finding
`is consistentsvith a previous study that reported a higher
`
`responserafe.
`fii patients receiving a combination of risper-
`idone anda mogetspbilizer compared with those receiving
`and mood stabilizer combination
`a typical neurdleptic
`(90% vs. 43%).¥
`Fhésimprovementat discharge for pa-
`tients treated with“olanzapine was greater than the im-
`
`Typical vs. Atypical Antipsychotics for Acute Mania
`
`In summary,this chart review demonstrates that atypi-
`cal antipsychotics may be more effective than typical
`antipsychotics when used with moodstabilizers to treat
`manic episodes. Risperidone in particular may be more
`effective than the typical antipsychotics. If patients require
`initial treatment with typical antipsychotics, they may have
`better short-term outcome with greater improvementat the
`time of discharge if they are switched to an atypical anti-
`psychotic after the first week of hospitalization. Long-term
`outcome may also be better with the atypical antipsy-
`chotics, due to decreased risk of EPS, TD, and possibly
`depression, making atypical antipsychotics an excellent
`choice as add-on therapy to moodstabilizers forthetreat-
`ment of patients with mania.
`
`Drug names: olanzapine (Zyprexa), quetiapine (Seroquel), risperidone
`(Risperdal), valproic
`acid
`(Depakene
`and others),
`ziprasidone
`(Geodon).
`
`Disclosure of off-label usage: The authors of this article have deter-
`mined that, to the best of their knowledge, quetiapine, risperidone, and
`ziprasidone are not approved by the U.S. Food and Drug Administra-
`tion for the treatment of bipolar disorder and acute mania.
`
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