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., F.R.C.P.C., M.R.C.Psych(UK);
`and Raymond W. Lam, M.D., F.R.C.P.C.
`
`©
`
`0.
`
`Background: ypfihantipsychotics are commonly
`used in combination wi
`'od stabilizers for acute
`
`Received December 14, 2000; accepted May 3, 2001. From the
`Department of Psychiatry, University of British Columbia, Vancouver,
`British Columbia. Canada.
`In the spirit of fitll disclosure and in compliance with all ACCME
`Essential Areas and Policies, the faculty for this CME activity were asked
`to complete a fidl disclosure statement. The information received is as
`follows: Dr. Yatham has received research grant support from Glaxo,
`Janssen, Lilly, Pfizer, and Astrazeneca; and is a member of the speakers/
`advisory board for Glaxo, Janssen, Lilly, Astraleneca, Lundbeck,
`SmithKline, and Abbott. Dr. Lam has received research grant supportfrom
`Astrazeneca and Janssen; and is a member ofthe speakers/advisory board
`for Lilly. Dr. Miller has no significant commercial relationships to disclose
`relative to the presentation.
`Reprint requests to: Lakshmi N. Yatham, M.B.B.S., Department of
`Psychiatry, University of British Columbia, 2255 Wesbrook Mall,
`Vancouver, BC V6T 2A1 (e-mail: yatham@intert‘lzange.ubc.ca).
`
`otics are effective,
`mania. Although typical
`vp such as induction of
`they have undesirable sid
`depressive symptoms and tardi fly '
`‘
`'
`
`antipsychotics have more favorablt%}si
`-
`and recent evidence shows their effi
`pared risperidone with typical neurol@icsd -on
`therapy to mood stabilizers, no studies
`date n__:
`‘G 1
`directly compared atypical antipsychoticbfivth '
`'
`'liz ‘P
`antipsychotics as add-on therapy to mood
`in a clinically relevant, naturalistic setting.
`Method: This study is a chart review of all pa
`tstg’
`with DSM-IV~—defined bipolar disorder, current epi
`la‘ \ Q)‘
`mania (N = 204), admitted to the University of British 0
`/‘
`Columbia Hospital during a 30-month period. Patients
`afite \
`were separated into 3 groups according to the medica—
`J»
`tions used: (1) mood stabilizer and typical antipsy-
`Qacu
`chotic, (2) mood stabilizer and atypical antipsychotic,
`ffigiia
`lZ
`and (3) combination: mood stabilizer plus a typical
`antipsychotic, then switched to mood stabilizer plus
`are ll
`risperidone or olanzapine within 1 week. The atypical
`group was further subdivided into risperidone and
`olanzapine subgroups. Outcome was measured
`using Clinical Global lmpressions—Severity of Illness
`(CGI-S) and -Improvement (CGI-I) ratings generated
`by review of clinical information in the chart.
`Results: Patients treated with typical antipsychotics
`were more severely ill at admission and at
`discharge than those treated with atypical antipsy-
`chotics. Patients in the atypical (p < .005) and combi—
`nation (p < .05) groups showed significantly greater
`clinical improvement at discharge than patients treated
`with typical antipsychotics. This difference was also
`significant in the subset of patients with psychotic fea-
`tures (p < .03). Risperidone and olanzapine were asso-
`ciated with fewer extrapyramidal side effects than were
`typical antipsychotics (risperidone vs. typical antipsy-
`chotics, xi = 8.72, p < .01; olanzapine vs. typical
`antipsychotics, X3 : 16.9, p < .001).
`Conclusion: Due to their superior effectiveness
`and side effect profile when compared with typical
`antipsychotics, atypical antipsychotics are an excellent
`choice as add—on therapy to mood stabilizers for the
`treatment of patients with mania.
`(J Clin Psychiatry 2001 ,'62:975—980)
`
`ood stabilizers such as lithium or valproic acid
`are used as first—line therapy for treatment of
`ania.” However, surveys of treatment practices for
`ma suggest that up to 90% of patients with acute
`reated with a combination of both mood stabi-
`anlslé ' sychotics.3‘5 Often, typical antipsychotics
`
`‘vantages of using typical antipsychotics
`e
`
`provena icQgaertiesfiand areavailableinanintra-
`in the tr
`' e tC§f mania include the fact that they have
`muscular injeétable
`for behavioral control when
`
`cy setting. However, typical
`le ' eeffects, such as induc-
`
`needed in the acute em
`antipsychotics have undesi
`tion of depressive symptoms, e
`apyramidal side effects
`(EPS), and a long-term risk of tafiizfidyskinesia (TD).7'8
`The risk of TD is particularly impo»
`‘t\,’[O consider when
`treating mania, since studies suggesd at t
`prevalence
`ofTD is higher in patients with bipolar dis
`compared
`with those with schizophrenia.9'“
`Atypical antipsychotics, such as risperidone*and olan-
`zapine, may be better alternatives. Unlike the typical anti-
`psychotics, they have a more favorable side effect profile
`with fewer EPS and less long-term risk of TD.”"5 In addi-
`tion, recent open studies and case series indicate that atypi-
`cal antipsychotics not only do not induce depressive symp-
`toms but in fact may be useful
`in treating depressive
`symptoms in bipolar patients.‘6"7 Furthermore,
`recent
`double-blind, controlled studieslml have shown risperi-
`done (in combination with mood stabilizers) and olanza-
`pine (both alone and in combination with mood stabilizers)
`
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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 CGl—l scores at week 1, week 2, and discharge was
`
`Miller et al.
`
`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
`commonly seen in clinical practice, and such patients are
`often excllxpfde
`from these trials. The result is that formal
`ascertain f efficacy ofmedications is conducted in
`a very speci 1c ,
`’T)“'r‘gation, and this poses problems in gen-
`eralizing the daa. 9 11 patients seen in clinical practice.
`The purpose o W
`7
`study, therefore, was to compare
`
`the efficacy of atyprcaffilfirti sychotics with that of typical
`antipsychotics as ad -on derapy to mood stabilizers
`for treatment of mania in gisgde l‘—world” population. To
`achieve this objective, we rév’ d the charts of all pa-
`tients who were treated for a manic 3% ode at a univer-
`sity teaching hospital during a 30—rn
`’od.
`
`,,
`
`_
`
`‘K
`
`
`
` METHOD
`
`if?
`
`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 confinement to
`a seclusion room were rated as 6 (severely ill), 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,
`A retrospective chart review was defi 3 s= Bgjng
`patients who were symptom free received a score of 1 (not
`7.
`charts of patients admitted to the Universitffgfa
`mentally ill), those who had a few residual symptoms
`received a score of 2 (borderline mentally ill), and those
`Columbia (UBC) Hospital with a DSM—lV—defi
`’ jdla {W}
`who had several ongoing symptoms received a score of
`nosis of bipolar disorder, current episode mania, ‘dirfing
`(mildly ill) or4(moderately ill). The CGI—I ratings were
`a 30-month period (Nov. 1, 1997, to April 30, 20(l”Q§j,;,
`d ne i comparison to the patients’ own baseline severity
`Since the focus of this study was to compare typical witfidgi
`atypical antipsychotics as add—on therapy to mood stabif efigqf s.
`rptoms, ranging from scores of 1 (very much im-
`9 five
`1 7(very much worse).
`lizers, patients not treated with these medications were
`excluded.
`L
`lifie pf
`flee or absence of EPS was also recorded. EPS
`vvereésic
`e£l2;§§t_§ither present (any mention of stiffness/
`rigidit onr£p‘arkinsonism in either nursing notes or
`physician ndtgs) ofgaffent in all charts reviewed. Since we
`found it diffic'€1.l9t'*to£§,_
`tain the presence or absence of
`
`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
`
`976
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`J Clin Psychiatry 62:12, December 2001
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`The information contained in the UBC Hospital charts
`was quite detailed, since most patients were followed by
`psychiatry residents and/or senior medical students. A
`form was developed to summarize the pertinent informa-
`tion from each chart, including demographic data (age,
`gender), length of illness prior to admission, number of
`previous episodes, presence or absence of psychotic fea-
`tures, development of EPS, length of stay in hospital, and
`medications used at 3 points during treatment: week 1,
`week 2, and discharge. Data that were equivocal or un-
`available were excluded on a case-by—case basis. Medi-
`cation decisions were made independently by the treating
`psychiatrists. Patients were divided into 3 groups ac-
`cording to the medications used: (1) mood stabilizer plus
`typical antipsychotic, (2) mood stabilizer plus atypical
`antipsychotic (this group was further divided into 2
`subgroups, mood stabilizer plus risperidone and mood sta-
`bilizer plus olanzapine), and (3) mood stabilizer plus a
`combination of typical and atypical antipsychotics. The
`combination group was composed of patients treated ini-
`tially with a mood stabilizer plus a typical antipsychotic,
`then changed to a mood stabilizer plus risperidone or olan—
`zapine within the first 7 days of treatment.
`
`,
`
`akathisia from chart no
`our definition of EPS.
`
`e did not include akathisia in
`
`\
`if 1’
`Data Analysis
`Statistical analysis was conductéifsjng the Statistical
`Package for the Social Sciences (SP;;,S0)'§r \V1ndows.
`Analysis of variance, the Friedman test (f T
`K
`i'J~§hin—subject
`CGI—I comparisons), the Kruskal-Wallis test (Jfg:r2between—
`group CGI—S and CGI-I comparisons), and the ehi—square
`test were used for data analysis. Where significant results
`were obtained, appropriate post hoc tests such as t tests or
`Mann—Whitney U tests with Bonferroni corrections were
`used for comparing subgroups.
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`Typical vs. Atypical Antipsychotics for Acute Mania
`
`
`
`Table 1. Demographics and Axis I and Il Comorbidity
`Comparisons Between Groups“
`MS + Atypical MS + Typical
`MS +
`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
`Duration of illness
`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 = mood stabilizer.
`bPatients treated with a typical antipsychotic, then switched to an
`atypical antipsychotic within 1 week of admission. For 1 patient
`receiving MS + combination therapy, it was not possible to establish
`with confidence whether Axis I or 11 comorbidity was present.
`
`Of the 155 pat" nts included in the study, 69 (45%)
`were treated with
`.7” od stabilizer plus a typical anti-
`psychotic, 69 (45% yyfietreated with a mood stabilizer
`plus an atypical antipsych§“e*(44 [28%] with risperidone,
`25 [16%] with olanzapine. , % H7 (11%) were treated
`with a mood stabilizer plus a c" net ination of antipsychotic
`medication (typical antipsychotic initijafl ,, then changed to
`atypical antipsychotic).
`K‘
`Demographic Data
`Q
`There were no significant differéi es ‘
`.
`"
`(x2 = 0.866, df = 3, p =. 83), presence of a.r°€§p1o~
`I diagnosis (x2 = 6.57, df= 3, p = .09), or piéjsenee {eggs
`(Mann-Whitney U: 1401,
`, antipsychotics
`comorbid Axis II diagnosis ()6: 3.34, df= 3i,:)‘=.”3él}~«,
`is.
`between the groups. There was no significant diffhgaéfnce %»
`p < .001). When the subgroups were examined, there was
`significant difference between the risperidone, olanza—
`in patient age (F = 0.181, p = .909) or number of previbiirs
`1
`episodes (F = 0.471, p = .703). A significant differencééij,
`pfie, nd combination groups. However, patients treated
`£s¥eridone were found to be significantly less ill at
`was found when the duration of illness prior to admission
`sfipvit
`‘tl}§,chaféé§,than those treated with typical antipsychotics
`was compared (F=2.726, p<.05). Post hoc analysis
`(Mafia
`‘racy U = 719,2 = 4.35, p < .005).
`showed that the patients treated with risperidone had a
`Sihjcipfi
`were significant differences in CGI—S
`longer duration of illness prior to admission than those
`treated with typical antipsychotics (ps .05). No other
`scores a A
`1p§beveen patients who received typical
`antipsycho _
`' a .
`,
`.ose who received atypical anti-
`significant differences were found. Table 1 shows further
`
`details.
`psychotics, weféalso ‘$9 uted changes in CGI—S scores
`from baseline to endpo r_
`. r each group. When changes
`in CGI—S scores were compar mong the 3 groups, no
`significant differences were
`ted (X2 = 0.33, df = 2,
`p = 0.84).
`‘ §
`‘fr
`Comparison of Improvement Betweleg Gr ups
`As shown in Table 2, all groups irnprev‘
`during the
`course of the hospitalization. The difference {:rhimprove—
`ment (measured by the CGI—I) between groups were
`significant at week 1
`(x2 = 6.53, df = 2, p <. 05) and
`at discharge (x2 = 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
`showed no significant difference between patients treated
`with risperidone or olanzapine. Patients treated with ris-
`
`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 complex to fit into one of the 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 number of subjects
`treated with these drugs (N = 5). Two patients were treated
`with electro
`nvulsive therapy and were excluded, and 2
`patients w re, ansferred to another facility within 2 days
`of admission.
`,
`
`
`
`21 (30.43)
`48 (69.57)
`
`30 (44)
`39 (56)
`
`21 (30)
`48 (70)
`
`8 (50)
`8 (50)
`
`5 (31)
`ll (69)
`
`= -3.84,
`
`
`
`Comparison of Severity of Illness Between Groups
`All groups of patients were less severely ill at discharge
`than at admission. The differences between groups in
`CGI—S score at admission and at discharge were signifi-
`cant (x2 = 23.17, df = 2, p < .001 and X2: 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 other significant differences were found.
`When the subgroups were compared, no significant differ-
`ence was found between the risperidone and olanzapine
`groups.
`When differences in CGI—S score at discharge were
`compared, patients treated with atypical antipsychotics
`were significantly less ill than those treated with typical
`
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`
`Table 2. Clinical Global Impressions-Improvement
`and -Severity of Illness and Extrapyramidal Side Effects
`(EPS) Comparison Between Groups“
`MS +
`MS + Atypical MS + Typical
`Antipsyehotic Antipsychotic Combination“
`(N = 69)“
`(N = 69)
`(N = 17)
`
`4.70 (0.65)‘l
`1.79 (0.79)"
`
`5.36 (0.89)
`2.55 (1.34)
`
`5.29 (0.59)
`2.59 (2.37)
`
`Side Effects
`
`Patients treated with typical antipsychotics developed
`more EPS than those treated with either risperidone
`(58.0% vs. 29.5%; X2 = 8.72, df = 1, p <. 01) or olanzapine
`(58.0% vs. 8.7%; X2 = 16.9, df = 1, p < .001). Patients
`treated with olanzapine had fewer EPS than those treated
`with risperidone (8.7% vs. 29.5%; X2 = 3.78, df = 1,
`p = .052). Patients who received a combination of typical
`and atypical antipsychotics were not included in the analy-
`sis, since it would be difficult to determine which medica-
`tion caused the EPS.
`
`.
`
`2.73 (0.70)
`2.23 (0.60)
`1.56 (0.63)‘
`
`DISCUSSION
`
`This chart—review study compared the efficacy of atypi-
`cal antipsychotics with that of typical antipsychotics as add-
`on therapy to mood stabilizers for the treatment of mania
`in a naturalistic environment. The strengths of this study
`are as follows: (1) it reports on a large number of patients,
`(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—
`
`139
`
`5-3:ea
`
`Value
`Clinical Global Impressions-
`Severity of Illness score,
`mean (SD)
`Admission
`Discharge
`Clinical Globaléé ressions-
`Improveme %e,
`mean (SD)
`~«
`3.59 (3.79)
`2.75 (0.90)
`Week 1
`2.79 (1.16)
`2.39 (0.96)
`Week 2
`2.04 (0.73)
`6} 1.59 (0.58)
`Discharge
`.
`V
`Developed EPS, N (%)g
`40 (58)
`&}i~:;~,2,i.z4)
`Yes
`29 (42)
`5 (@36)
`No
`1
`“Abbreviation: MS = mood stabi
`s unclear from the chart
`“In 2 of 25 olanzapine-treated paltlentsé ‘
`review whether they had EPS.
`9%
`“Patients treated initially with a typical anti sfaiotic, then switched to
`an atypical antipsychotic within 1 week of
`EPS data are
`not presented, because it would not be possible.
`rmine if
`e
`presence of EPS in this group is related to typical o
`t
`ical
`antipsychotics.
`gap
`“The MS + atypical group was significantly l sggil th n th
`MS +typical and MS+ combination groups (p @Dl an 05,
`fig}!
`.
`_
`_
`_
`.
`respectively).
`::The MS + atypical group was significantly less ill 6 J}
`MS + typical group (p < .001).
`~(i.“>
`dents, and (5) the improvement scores were obtained from
`{The MS + atypical and MS + combination groups were
`'cai3/itigyw
`a single rater. The limitations are as follows: (1) the study
`more improved than the MS + typical group (p < .005 and p
`£35,
`respectively).
`in was retrospective; (2) the rater was not blind to the medi-
`<6’
`‘=’The MS + atypical group experienced significantly fewer EPS thafil
`{X
`..§/ations given; (3) the estimation of improvement was
`the MS + typical group (p < .001).
`sgiiitey hat crude, using global clinical impressions rather
`\,
`r;:,tha —
`igdspective, objective outcome measures; (4) benze-
`t“ ;a,zep®€pse
`in treatment was not monitored; (5) the
`Ehoifie ofiiapadication was determined by the individual psy-
`chiatifpybsg matic selection bias cannot be excluded;
`(6) di eréiij rn
`st bilizers were used; and (7) the study
`lacked a stri‘i,," tir
`rview to confirm diagnoses.
`Given theséilim »_ ens, the study yields interesting
`results. First,
`the pati%§( treated with typical antipsy-
`chotics were more severel
`7-] t a those treated with atypi-
`cal antipsychotics, both at ad iss n and at discharge. This
`makes intuitive sense, since sexierqgiiill patients often need
`intramuscular medications for behavi
`r‘ lcontrol, and there
`was no intramuscular atypical antipsiyfiglioti available in
`Canada at the time of the study. Given taitégtr the patients
`treated with typical antipsychotics were mo)%everely ill
`than those treated with atypical antipsychotics, the fact that
`they were also more ill at discharge is difficult to interpret
`in a meaningful way. However, the clinical improvement
`(measured by the CGI—I) 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. Among patients
`with psychosis, the risperidone and combination groups
`were associated with significantly greater clinical improve-
`ment at discharge than the typical anti psychotic group. This
`suggests that using atypical antipsychotics, or using a typi-
`
`
`
`peridone showed significantly 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 was not 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 improvement at the time of discharge between groups
`(x2 = 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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`J Clin Psychiatry 62:12, December 2001
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`4of6
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`Alkermes, Ex. 1024
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`4 of 6
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`Alkermes, Ex. 1024
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`

`
`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 mood stabilizers 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 improvement at the
`time of discharge if they are switched to an atypical anti-is
`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 mood stabilizers for the treat-
`ment of patients with mania.
`
`Drug names: olanzapine (Zyprexa), quetiapine (Seroquel), risperidone
`(Risperdal), valproic
`acid
`(Depakene
`and others),
`ziprasidone
`(Geodon).
`
`Disclosure of 0fi‘—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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`cal antipsychotic for 1 week and then switching to an atypi-
`cal antipsychotic, may be superior to using typical antipsy-
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`treatment of moderately to markedly ill patients with ma-
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`is consiste
`ith a previous study that reported a higher
`
`response r -
`’ patients receiving a combination of risper—
`idone and a offitgbilizer compared with those receiving
`a typical neur le i
`and mood stabilizer combination
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`“ 'mprovement at discharge for pa-
`tients treated with o%a_r§a,ine was greater than the im-
`provement in patients tregédfiwith typical antipsychotics,
`although this difference xvaxsfgb
`ignificant. It is possible
`
`that this difference represente
`rue difference in out-
`come that may not have been si
`nt due to type 11
`error related to the small sample s '
`V
`the olanzapine
`group (N = 25). Also, there was no si nifiié vt difference
`in improvement between the risperfiééie figd‘ 0, nzapine
`
`groups. Again, the implications of thisrfifesult
`‘
`as type 11 error may be involved in this coifipgriséfi
`When side effects were compared, this 2:’-isgéi gd.
`that risperidone and olanzapine have a lower 1'IIl;$ld6l§%6"}
`of EPS than typical antipsychotics, and other sttiiiii "M"
`have demonstrated a lower risk of TD with these drugs flan
`with typical antipsychotics. Furthermore, recent data su§f?g..
`gest that atypical antipsychotics may improve depression,
`whereas typical antipsychotics can worsen depressioi1.”"9’2°
`Thus, the atypical antipsychotics may be a better choice
`than the typical antipsychotics
`in the treatment of
`moderate—to-marked mania, with or without psychotic fea-
`tures, due to their superior effectiveness and better side ef-
`fect profile compared with the typical antipsychotics.
`Given this information, how should patients with
`severe illness who refuse oral medication (thus requiring
`intramuscular medication) be treated? Currently, intramus-
`cular typical antipsychotics are the only option for treating
`such patients. The data above suggest that patients who
`require typical antipsychotics during the first week of hos-
`pitalization may have a better outcome (with greater im-
`provement at time of discharge) if switched to an atypical
`antipsychotic for the remainder of their hospital stay.
`In addition, since injectable forms of the atypical antipsy-
`chotics are being developed, clinicians may soon have the
`opportunity to use these medications in acute settings with
`severely ill patients.
`In the future, prospective trials should be done compar-
`ing patients treated with intramuscular forms of typical ver-
`sus atypical antipsychotics as add—on therapy to mood sta-
`bilizers in the treatment of mania. Also, the newer atypical
`antipsychotics, such as ziprasidone and quetiapine, should
`be compared in similar trials or chart reviews.
`
`J Clin Psychiatry 62:12, December 2001
`
`979
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`f " For the CME Posttest for this article, see pages 998-999.
`
`980
`
`J Clin Psychiatry 62:12, December 2001
`
`6of6
`
`Alkermes, Ex. 1024
`
`6 of 6
`
`Alkermes, Ex. 1024