The Role of
`Novel Antipsychotics
`in Bipolar Disorders
`
`Lakshmi N. Yatham, M.B.B.S., F.R.C.P.C., M.R.C.Psych.
`
`Patients with bipolar disorder frequently receive antipsychotic agents during both the acute
`a‘nd maintenance phases of treatment. Conventional antipsychotics are effective against mania. but
`the}? HI:
`induce depressive symptoms and expose patients with bipolar disorder to increased risks of
`tardi c
`_'.itlt_inesia. Recent studies have shown risperidone to be effective for acute mania, both as
`nionotltfapf
`d in combination with mood stabilizers; this agent has also shown efficacy as add-on
`maintenance 3
`'n open-label studies as it exhibited both antimanic and antidepressant effects.
`Olanzapine,
`novel antipsychotic, is also effective against both manic and depressive symp-
`toms and in the ma
`mace treatment as indicated by an open-label study. Data on other novel agents
`are more limited.
`.
`(J Clin Psychiatry 2002;63[suppI 31:10-14)
`
`.
`
`A ntipsychotic medications have a loIag}31,istdi:y't)fuse
`in bipolar disorders, considerably predtfi]
`«fig gse.
`of lithium. Chlorpromazine. for example, has b ‘
`,usei:l:=far
`control agitation and psychotic symptoms almost sifide its
`introduction in the early 1950s.‘ Increasingly, resear
`'
`focusing on the potential uses of the novel antipsyehotic@
`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% of patients 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`chotic (L.N.Y., unpublished observation, 1999).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
`./anssen, Eli Lilly, Glaxosmithlfline, and AstraZeneca and
`receives grant and research support from ./anssen, Eli Lilly,
`and GlaxoSmithKline.
`Reprint requests to: Lakshmi N. Yatham, M.B.B.S.,
`F.‘R.C.P.C., M.R.C.Psych., Division ofMood Disorders, University
`ofBritish Columbia, 2255 WesbrookMalI, Vancouver; BC,
`Canada V6‘T 2.4] (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-
`ment phase into the maintenance phase.’
`’Gi en this high degree of antipsychotic use, which
`anti
`hotic agents are preferable to use in the setting of
`Bipolar §l;1ess? Conventional antipsychotics are effective
`nolzfinly/~lij‘l]1e treatment of the symptoms of acute ma-
`t1ia,“’@but._a1§:65[iay have some usefulness in the preven-
`tion of'#a‘g“,ic eRi‘§.bdes.3'” However, the incidence of tar-
`dive dyskirrésia a"
`;ated with these agents is of concern.
`and there is sofiié eviiifne that the risk of tardive dyskine-
`sia is higher in patients 'wifB,bipolar disorders than in those
`with schizophrenia.” Furtlierm , conventional antipsy-
`chotic medications do not appeal‘-gig help patients with de-
`pressive episodes—in fact, they't@ _even induce depres-
`sion.'° Therefore, conventional antipsyqhotics are unlikely
`to be the optimal choices for treating pfitientsswith bipolar
`disorder who require antipsychotic medicflinn.
`The remainder of this article will review etfie current
`
`evidence for treating 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 of ris-
`
`peridone in 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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`Figure 1. Mean Young Mania Rating Scale (YMRS) Change
`Scores With Risperidone, Lithium, or Haloperidol‘
`
`Haloperidol
`(N=15)
`—— .
`’ "'
`E
`‘
`l_
`'
`
`
`
`_
`-14.6-/.
`
`Rispendone
`(N=15)
`0% —
`
`Lithium
`(N=15)
`.
`
`._
`ii 5-».
`a E - -=
`2 9
`o 3 -10%
`as
`2 m
`>. 00
`§ E 45%
`E
`
`1
`
`-20%
`
`'_l
`-
`
`l
`l
`'
`—12.7%
`
`- ‘i 4"
`1.,‘ I
`
`"Data from Segal et al."
`
`W’
`K
`
`.E3.1»
`
`Novel Antipsychotics in Bipolar Disorders
`
`Figure 3. Patients With Improvement on Clinical Global
`lmpcfessions-Improvement (CGI-l) Scale in 2 Double-Blind
`Stu ies“
`El “-3 Very much improved
`°’a Much improved
`
`US Study”
`
`International Study‘:
`
`PatientsWithCGI
`
`
`
`ImprovementsatEndpoint(%)
`
`"Abbreviation: MS = mood stabilizer.
`"U.S. study. Data from Sachs."
`"lntemational study. Data from Yatham.
`*p < .01 risperidone vs. placebo.
`'l'p < .05.
`
`'
`
`v
`
`-'3
`
`cordingly. 2 similarly designed double-blind combina-
`tion studies in acute mania examined the addition of ris-
`
`9
`
`‘$6 ‘,9
`.«
`60
`0
`Q“
`
`Q
`..
`\3
`00
`X
`(b
`o
`Q0‘
`°é.°
`15”
`<2"-“’
`<2"’
`
`4..51,.t,O
`
`I=1
`
`z
`
`-14
`
`-16"
`
`'N=5o
`
`1-
`
`N=54
`
`Figure 2. Young Mania Rating Scale ( ange Scores
`1‘ i_’lacebo or
`From Baseline to Endpoint With Risperigl
`Haloperidol Add-On to Mood Stabilizers i;IL2 Flgubli,-,l3lind
`Studies“
`a-4%
`, c 1?
`f5’
`$25.
`6-
`0
`.4'“_.r
`~
`s .r g
`_.-
`,‘
`06
`,‘
`J." Q .
`-
`.90 QP
`(6
`.90
`0‘
`dz.
`g....' 0.’
`dz.
`-’ peridone or placebo to a mood stabilizer.'2*"‘ One study
`Q‘-"3
`9"” Q53 " ' -
`9""
`'
`R
`"was an international trial” that enrolled 150 patients and
`iifiludgd lithium, valproate, or carbamazepine as the
`finioatlkdtabilizers. The other was a U.S. trial” that in-
`’<e},ude.;rai__
`_
`additional haloperidol treatment arm, but in
`ihitgfstudy ia‘itl_y lithium or valproate were permitted as
`moo
`Both studies were double blind and
`were ogl°)§ee‘lQ‘_',‘d_uration followed by a 10-week open-
`label extensigq péiidé In the U.S. study, both risperidone
`and haloperi 6l’fedLhz€dYMRS scores by approximately
`6 points compared witfipll ‘ bo; this difference was both
`statistically and clinicallfig ‘ "cant (Figure 2). In the
`international study,” initial aria
`is of data showed a dif-
`ference of about 4.5 points on
`scores between the
`risperidone plus mood stabilizer artcifilacebo plus mood
`stabilizer groups, which was clinically butsnot statisti-
`cally significant. However, patients in thifsntfiy who re-
`ceived both risperidone and carbamazepine lfqtfinean se-
`rum risperidone concentrations 1.7 times lower than
`those who received risperidone with valproic acid or lith-
`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-
`
`
`
`
`
`
`
`MeanYMRSChangeScores
`
`"Abbreviation: MS = mood stabilizer.
`"US. study. Data from Sachs."
`‘International study. Data from Yatham."
`“lntemational revised sample excluding carbamazepine.
`*p < .01.
`ip = .089.
`;1;p < .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 points for the haloperidol group, and
`12.7 points for the lithium group (Figure 1).
`This study was suggestive of the efficacy of risperi-
`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-
`
`] Clin Psychiatry 2002;63 lsuppl 3)
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`Lakshmi N. Yatham
`
`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‘
`
`I Mania
`0 Schtzoaffecttve disorder
`
`A Bipolar ll
`0 Mixed
`D Depression
`
`Mean
`Baseline Score:
`0
`-2
`
`"‘
`
`-4
`
`Study 1”
`3 Weeks
`28 7
`27.7
`
`Study 2°
`4 Weeks
`28 8
`29 4
`
`A. Young Mania Rating Scale (YMRS)
`30
`
`25
`
`M0
`
`on85.‘
`
`
`
`
`
`MeanTotalYMRSScore
`
`
`
`
`arm 9 -6
`E to :7
`2 n: .2
`.5
`0 5 8
`E ?— U -10
`as N '3
`-- u:
`E ,9 O _12
`
`'
`
`-10.3
`I Olanzapine
`
`El Placebo
`
`_14 5
`
`“Abbreviation: LOCF = last observation carried forward.
`“Data from Tohen et al."
`"Data from Tohen et al."'
`
`OLANZAPINE
`
`Two double-blind tria1s'5"‘ 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
`YMRS score compared with placebo (Figure 5). Olanza-
`upjne was effective in treating manic symptoms in both psy-
`Bttbtic
`d nonpsychotic mania as well as in those with
`nix
`_isodes. Of the 139 patients in the 3-week double-
`-bglgittd sti.I_§y.‘5 113 entered a 49-week, open-label extension
`p
`Foflfqne percent of patients received olanzapine
`mondthggatgduring this phase. The YMRS scores de-
`creased 'l’$rfpol'rgt§') and 88% of patients experienced re-
`mission of magic symptoms: 25% subsequently relapsed.
`HAM-D scoreffiflso *dE,qrpased by a mean of 5.77 points
`(p < .001), which sugge
`t olanzapine does not induce
`depressive symptoms and that jfinay be effective in pre-
`venting both depressive and r|’£ar‘t;s,episodes.” No cases of
`tardive dyskinesia were seen.
`Olanzapine monotherapy has als‘i5hc£n found to be at
`least as effective as lithium” or divalp.roe.'
`'odium“" for
`treating patients with acute mania. In a 6-
`I5 augmenta-
`tion study.“ 334 patients with mania who toolfdfibod stabi-
`lizers (lithium or valproic acid) received olarrzapine or
`placebo add-on therapy. The YMRS scores 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).
`Among the 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? Wk2 Wk4 Wk6 M03 M06
`Visit
`
`B. Hamilton Rating Scale for Déprgssion (HAM-D)
`.4
`35
`I Mania
`Q Schizoaffectlve disorder
`30
`A
`ar ll
`
`
`
`25
`
`20
`
`15
`
`10
`
`
`
`
`
`MeanTotalHAM-DScore
`
` ?"
`
`'
`
`Baseline Wk 1
`
`Wk 2
`
`Wk 6
`
`Mo 3
`
`Wk 4
`Visit
`
`"Data trom Vieta et :11." There was a highly statistically significant
`trend toward reduction in YMRS scores and HAM-D scores across all
`groups (p < .0001).
`
`done-treated patients was seen within the first week. This
`improvement in manic symptoms was evident in patients
`both with and without psychosis, suggesting that risperi-
`done is not simply an antipsychotic agent but also an ef-
`fective antimanic agent.
`A 6-month open-maintenance trial" involving 541
`patients found that risperidone. used as an add-on therapy,
`was effective in treating both manic (as measured by
`YMRS scores) 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% of the 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~ltem Hamilton Rating Scale for Depression
`(I-LAM-D—21) Total Scores in Patients With Moderate-to-
`Severe Depressive Symptoms“
`
`Mean
`Baseline Score:
`
`25.41
`
`24.71
`
`°
`_2
`
`_4
`_6
`
`_ E
`53 8
`,9 '0
`5 iii
`an 2 f_‘
`C” o
`C 9
`5 8 3.- _
`0 '
`.
`I
`.
`E '0 3
`. as
`$ '
`2 E
`33
`
`
`
`'10’
`
`1E_
`
`Olanzapine cotherapy. N =51
`El Uthium or valproic acid
`monolherapy. N = 21
`
`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 own right.
`
`Drug nanre.i-: carbamaiepine (Tegretol and others), chlorpromazine
`tThorazine and others). clozapine (Clozaril and others),
`tlivalproex
`sodium (Depakote), haloperidol
`tHaldol
`and others). olanzapine
`(Zyprexa), quetiapine (Seroquel). risperidone (Risperdal), valproic acid
`(Depakene and others), /.iprasidone (Geodon).
`
`“Data from Tohen et al.”:
`diagnosis and HAM-D-2l tciiiil
`
`definition of DSM-IV mixed episode
`_ re 2 20 at baseline.
`
`REFERENCES
`
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`'*p<.O0l.
`
`v#
`
`_
`
`
`Figure 7. Mania Rating Scale (MRS) Scale Qfiaiiges in
`Ziprasidone and Placebo Groups“
`
`Days
`
`I
`
`
`
`I Placebo (N= 66)
`El Zlprasidone (N = 131)
`
`1. 3
`’r
`
`MeanChangeinMRSFromBaseline 1.1.NO
`
`I
`
`.4 A
`
`"Data from Keck and Ice.“
`*p < .01.
`ip < .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 about the utility of ziprasidone as
`an add-on therapy are likely to be available in the near
`future. Two published uncontrolled open trials of quetia-
`pineal” suggest that it is antimanic and may be mood sta-
`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.3‘M5 but it is not considered a first-line treatment be-
`
`J Clin Psychiatry 2002;63 lsuppl 3)
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`Lakshmi N. Yatham
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`20.
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`25.
`
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