The Role of
`Novel Antipsychotics
`in Bipolar Disorders
`
`Lakshmi N. Yatham, M.B.B.S., FR.C.P.C., M.R.C.Psych.
`
`Patients with bipolar disorder frequently receive antipsychotic agents during both the acute
`and jngintenance phases of treatment. Conventional antipsychotics are effective against mania, but
`they’ #ig’,induce depressive symptoms and exposepatients with bipolar disorderto increased risks of
`tardi¥ve-dyékinesia. Recent studies have shown risperidone to be effective for acute mania, both as
`
`monnae in combination with moodstabilizers; this agent has also shownefficacy as add-on
`maintenanceRoe n open-label studies as it exhibited both antimanic and antidepressant effects.
`
`t
`Olanzapine, ¢
`toms and in the m
`are morelimited.
`
`Hi
`
`novel antipsychotic, is also effective against both manic and depressive symp-
`naryce treatment as indicated by an open-label study. Data on other novel agents
`=
`(J Clin Psychiatry 2002;63[suppl 3]:10-14)
`
`A ntipsychotic medications have a lopf/hijstényofuse
`in bipolar disorders, considerably predétj
`+hE ase.
`of lithium. Chlorpromazine. for example, has bee} used
`controlagitation and psychotic symptomsalmost sige its:
`introduction in the early 1950s.' Increasingly, researchyig
`focusing on the potential uses of the novel antipsychoti
`in bipolar disorders. This article reviews some of the most
`recent results obtained with these agents.
`Studies examining prescription rates have suggested
`that up to 90% of patients with bipolar disorders receive
`antipsychotic medications at some time during the ill-
`ness.” A survey at a university teaching hospital, whose
`prevailing philosophy was to discourage the use of un-
`necessary medications, found that 82% ofpatients with
`mania admitted to a hospital were receiving an antipsy-
`chotic (L.N.Y., unpublished observation, 1999). The most
`common reasons for their use included rapid control of
`
`From the University ofBritish Columbia, Vancouver,
`Canada,
`Based on proceedings ofa special symposium ofthe
`Canadian Network for Mood and Anxiety Treatments
`(CANMAT), which was held at the 50th annual meeting ofthe
`Canadian Psychiatric Association, October 2000, in Victoria,
`British Columbia. The symposium was supported by an
`unrestricted educational grant from Janssen-Ortho Inc.
`Financial disclosure: Dr. Yatham is a consultant for
`Janssen, Eli Lilly, GlaxoSmithKline, and AstraZeneca and
`receives grant and research support from Janssen,Eli Lilly,
`and GlaxoSmithKline.
`Reprint requests to: Lakshmi N. Yatham, M.B.B.S.,
`FER.C.PC., M.R.C.Psych., Division ofMood Disorders, University
`ofBritish Columbia, 2255 Wesbrook Mail, Vancouver, BC,
`Canada V6T 2A1 (e-mail: yatham@interchange.ubc.ca).
`
`psychotic symptoms, agitation or overactivity, violent
`behavior, and refractoriness to treatment with a mood
`stabilizer alone. Moreover,
`the use of antipsychotic
`medications often extended well beyond the acute treat-
`‘mentphase into the maintenancephase.’
`Giyen this high degree of antipsychotic use, which
`anti
`hotic agents are preferable to use in the setting of
`‘Bjpolaf ness? Conventionalantipsychoticsare effective
`notnlyinthe treatment of the symptoms of acute ma-
`nia,"
`but atsé;may have some usefulness in the preven-
`tion ofifGnjic @pigedes.?”* However, the incidenceoftar-
`dive dyskinesia as&otyated with these agents is of concern,
`and there is sofgé evidénee that the risk of tardive dyskine-
`sia is higherin patients Wsth-bipolar disorders than in those
`with schizophrenia.’ Furthermore, conventional antipsy-
`chotic medications do not appealjtp help patients with de-
`pressive episodes—infact, they fay even induce depres-
`sion.'° Therefore, conventional antipsy¢holics are unlikely
`to be the optimal choicesfortreating pagients.with bipolar
`disorder who require antipsychotic medication.
`The remainderofthis article will review fie current
`evidencefortreating bipolar disorder patients with novel
`antipsychotics. Risperidone and olanzapine are the 2
`novel antipsychotics for which the most evidence has ac-
`cumulated.
`
`RISPERIDONE
`
`There are robust double-blind data on the use ofris-
`peridonein acute mania. One small 4-week monotherapy
`study'! compared risperidone, 6 mg/day; haloperidol, 10
`mg/day: and lithium, 800 to 1200 mg/day, in 45 patients
`
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`Novel Antipsychotics in Bipolar Disorders
`
`Figure 1. Mean Young Mania Rating Scale (YMRS) Change
`Scores With Risperidone, Lithium, or Haloperidol*
`
`Risperidone
`(N= 15)
`0%7—
`
`nan
`ge
`
`a2
`5 2 -10%
`ao
`“
`en
`i}
`=o
`LS
`S
`a
`§ 6 -15%
`*
`
`-20%
`
`o
`A
`
`Haloperidol
`Lithium
`(N=15)
`(N= 15)
`i i 7
`
`
`
`14.8%
`
`:
`|
`z
`9,
`12.7%
`
`“Data from Segaletal."
`a 3
`Figure2.YoungMania RatingScale witiahe ange Scores
`
`¥ Placebo or
`From Baseline to Endpoint With Risperig
`Haloperidol Add-On to MoodStabilizers ip 2 Apuidle,Blind
`¢
`ve
`Studies
`7
`)
`
`A)
`
`Re]
`
`.
`
`>
`4 i
`
`3
`-
`
`x)
`
`0 & fod,
`0 w we
`w an
`S
`wv
`e
`.*
`s
`a tS
`se w
`x
`x
`oe
`& eS
`Lf
`LS
`Sh e &
`fg
`
`a ee L
`eo
`oe €
`g 2o
`a +
`ae
`-6
`=Go
`A-8
`2 N=47
`=
`§ -12
`= -14
`-16-
`
`N=7
`
`N=62
`
`JN=50
`
`7
`
`7
`bi
`
`N=68
`t
`
`Ley
`N=54
`
`“Abbreviation: MS = moodstabilizer.
`"U.S. study. Data from Sachs."
`“International study. Data from Yatham."
`“International revised sample excluding carbamazepine.
`*p<.0l.
`+p = .089.
`tp < .047.
`
`with acute mania. Risperidone was found to be as effec-
`tive as the other 2 agents—the mean Young Mania Rating
`Scale (YMRS)scores decreased by 16.2 points for the ris-
`peridone group, 14.6 pointsfor the haloperidol group, and
`12.7 points for the lithium group (Figure 1).
`This study was suggestive of the efficacy ofrisperi-
`done monotherapy in acute mania, However, in clinical
`practice, the combination of an antipsychotic medication
`with a mood-stabilizing agent is far more common. Ac-
`
`Figure 3. Patients With Improvement on Clinical Global
`impressions-Improvement (CGI-I) Scale in 2 Double-Blind
`
`Studies*
`
`C) % Very much improved
`% Much improved
`
`PatientsWithCGI
`
`US Study
`
`International Study
`
`(%)
`ImprovementsatEndpoint
`
`“Abbreviation: MS = moodstabilizer.
`°ULS. study. Data from Sachs."*
`‘International study. Data from Yatham.'’
`*p < OL risperidone vs. placebo.
`tp <.05.
`
`cordingly, 2 similarly designed double-blind combina-
`tion studies in acute mania examined the addition ofris-
`, peridone or placebo to a moodstabilizer.'** One study
`‘was an internationaltrial’? that enrolled 150 patients and
`irfeluded lithium, valproate, or carbamazepine as the
`‘> mogthstabilizers. The other was a U.S.
`trial!? that in-
`‘eludedgn_additional haloperidol treatment arm, but in
`thisstudy shly lithium or valproate were permitted as
`mood"
`bit{zees. Both studies were double blind and
`were FBpocheduration followed by a 10-week open-
`label extenperiod In the U.S.study, both risperidone
`and haloperi SviediieedYMRSscores by approximately
`6 points compared witht sebo; this difference was both
`statistically and clinicallystp ificant (Figure 2). In the
`international study,’ initial arfal¥sis of data showeda dif-
`ference ofabout 4.5 points on YMRS scores between the
`risperidone plus moodstabilizer ardpiacebo plus mood
`stabilizer groups, which was clinicalfy bub.not statisti-
`cally significant. However, patients in thi¢'sfady whore-
`ceived both risperidone and carbamazepine Hat?'mean se-
`tum risperidone concentrations 1.7 times lower than
`those whoreceived risperidone with valproic acid orlith-
`ium. The lower serum concentrations were most likely
`caused by the induction of risperidone metabolism by
`carbamazepine. Exclusion of the patients taking carba-
`mazepine yielded a statistically significant difference
`(p < .05; Figure 2) between the 2 groups. Moreover, in
`both studies, the proportion of patients who were “much
`improved” or “very much improved” was significantly
`greater in the risperidone group than in the placebo group
`(Figure 3). In addition, the improvement in the risperi-
`
`J Clin Psychiatry 2002;63 (suppl 3)
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`Lakshmi N. Yatham
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`
`Figure 4. Scores of 541 Bipolar Patients According to Subtype
`Treated With Add-On Risperidone in an Open-Label Study*
`
`Figure 5. Olanzapine Versus Placebo in Acute Mania*
`
`A. Young Mania Rating Scale (YMRS)
`30
`
`
`
`@ Mania
`© Schizoaffective disorder
`A Bipolar i!
`Mixed
`O Depression
`
`
`
`
`
`Baseline Wk. Wk2 Wk4
` Wk6E
`Mo 3
`Mo 6
`Visit
`
`25
`
`20
`
`15
`
`10
`
`5 0
`
`
`
`
`
`MeanTotalYMRSScore
`
`B. Hamilton Rating Scale for Dépression (HAM-D)
`,
`35
`:
`i Mania
`& Schizoaffective disorder
`30
`&
`jar il
`
`25
`
`20
`
`15
`
`10
`
`5 0
`
`Study 15
`3 Weeks
`287
`277
`
`Study 2¢
`4 Weeks
`288
`294
`
`Mean
`Baseline Score:
`0
`
`
`MeanChangeinTotalYMRS
`
`
`ScoretoEndpoint(LOCF)
`
`do i Olanzapine
`
`© Placebo
`
`~148
`
`"Abbreviation: LOCF = last observation carried forward.
`*Data from Tohenet al.'*
`“Data from Tohenet al.’*
`
`OLANZAPINE
`
`
`
`
`
`MeanTotalHAM-DScore
`
`Two double-blindtrials'*'® lasting 3 and 4 weeks, re-
`spectively, compared olanzapine monotherapy with pla-
`cebo in the treatment of acute mania. In both studies, olan-
`zapine produced at least a 5-point improvement on the
`YMRSscore compared with placebo (Figure 5). Olanza-
`spine was effective in treating manic symptomsin both psy-
`
`éhbtic
`and nonpsychotic mania as well as in those with
`Visit
`mix
`pisodes. Of the 139 patients in the 3-week double-
`bind sfiigy.'* 113 entered a 49-week, open-label extension
`p asd Fériy2one percent of patients received olanzapine
`monotherap ‘during this phase. The YMRS scores de-
`creased ¥8-polnesy and 88% of patients experienced re-
`mission ofrizanic Syzhptoms; 25% subsequently relapsed.
`HAM-D scoregAiso ‘d€creased by a mean of 5.77 points
`(p < .001), which suggedis’that olanzapine does not induce
`depressive symptoms and that jay beeffective in pre-
`venting both depressive and tifarify,episodes.” Nocases of
`tardive dyskinesia were seen.
`Olanzapine monotherapy has alsoheen found to be at
`least as effective as lithium!® or divalfroex;sodium" for
`lreating patients with acute mania. In a 6-week augmenta-
`tion study,”° 334 patients with mania whotookgiivodstabi-
`lizers (lithium or valproic acid) received olanzapine or
`placebo add-on therapy. The YMRSscores decreased by
`a mean of 13.11 in the olanzapine group and 9.10 in the
`placebo group (p= .003). Moreover, significantly more
`patients receiving olanzapine achieved at least a 50% de-
`crease in YMRS scores (67.7% vs. 44.7%; p= .023).
`Amongthe 72 patients in this study who also had substan-
`tial depressive symptoms, scores on the 21-item HAM-D
`scale decreased by 10.31 with olanzapine vs. 1.57 with
`placebo (p< .001), again consistent with the hypothesis
`that olanzapine has antidepressant properties (Figure 6).
`
`Baseline Wk 1 Wk2 Wk4=Wké6 Mo 3 eb
`
`
`
`“Data trom Vieta et al.'* There was a highly statistically significant
`trend toward reduction in YMRS scores and HAM-Dscoresacrossall
`groups (p < .0001).
`
`done-treated patients was seen within the first week. This
`improvement in manic symptoms was evidentin patients
`both with and without psychosis, suggesting that risperi-
`done is not simply an antipsychotic agent but also an ef-
`fective antimanic agent.
`yt
`involving 541
`A 6-month open-maintenance trial
`patients found that risperidone, used as an add-on therapy,
`was effective in treating both manic (as measured by
`YMRSscores) and depressive symptoms (as measured
`by the Hamilton Rating Scale for Depression [HAM-D)]),
`and maintaining the improvement throughout the study
`period (Figure 4, A and B). Only 7% ofthe patients subse-
`quently relapsed. None of the patients developed tardive
`dyskinesia during the 6-month study period; if these pa-
`tients had been taking haloperidol, 15 to 20 new cases of
`tardive dyskinesia would have been expected to emerge.
`Open data such as these will require confirmation with
`double-blind studies, but the results of this study suggest
`that risperidone does not
`induce depressive symptoms,
`and it may be useful in preventing both depressive and
`manic episodes.
`
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`Figure 6, 21-Item Hamilton Rating Scale for Depression
`(HAM-D-21) Total Scores in Patients With Moderate-to-
`Severe Depressive Symptoms*
`
`Mean
`Baseline Score:
`ek
`ge
`2
`es
`eul
`4
`oot250
`ae
`BSg
`7 aaa ie
`Fy
`o<
`2 3
`~103
`=
`42-
`
`-~6
`
`
`
`25.41
`
`24.71
`
`Olanzapine cotherapy, N=51
`B Lithum or valproic acid
`monotherapy. N= 21
`
`ae
`*Data from Tohenetal.“prinri definition of DSM-IV mixed episode
`diagnosis and HAM-D-2{ tauitesore = 20 at baseline.
`
`:
`*p< 001.
`=a Figure7. ManiaRatingScale (MRS) Scoreoii-in
`
`Ziprasidone and Placebo Groups*
`
`.
`
`J
`
`Days
`
`
`MeanChangeinMRSFromBaseline 12
`
`i Placebo (N=66)
`G Ziprasidone (N= 131)
`
`t
`
`-116
`t
`
`"Data from Keck andIce.7!
`4p < 01.
`tp <.001.
`
`OTHER NOVEL
`ANTIPSYCHOTICS
`
`The available data on the efficacy of other novel anti-
`psychotics in bipolar disorders are more limited. A 3-week
`double-blind, placebo-controlled study” of ziprasidone
`monotherapy in 195 acutely manic patients found that
`ziprasidone significantly improved Mania Rating Scale
`scores (Figure 7); data aboutthe utility of ziprasidone as
`an add-on therapy are likely to be available in the near
`future. Two published uncontrolled open trials of quetia-
`pine”suggestthatit is antimanic and may be moodsta-
`bilizing, but these data await confirmation with double-
`blind studies. Finally, clozapine has also shown promise
`in open trials as an antimanic drug and mood stabi-
`lizer,""**> butit is not considereda first-line treatment be-
`
`Novel Antipsychotics in Bipolar Disorders
`
`cause of concerns about agranulocytosis, sedation, sei-
`zures, and other side effects.
`In summary, a variety of novel antipsychotics have
`been used for treating patients with bipolar disorder.
`Mounting evidence supports their efficacy, their low in-
`cidence of extrapyramidal side effects and tardive dys-
`kinesia, and the suggestion that they may also have mood-
`stabilizing properties in their ownright.
`
`Drug names: carbamazepine (Tegretol and others), chlorpromazine
`(Thorazine and others), clozapine (Clozaril and others), divalproex
`sodium (Depakote), haloperidol
`(Haldol
`and others), olanzapine
`(Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), valproic acid
`(Depakeneandothers), ziprasidone (Geodon).
`
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