Full text of DOI:10.2165/00003495-200161100-00004

Drugs 2001; 61 (10): 1407-1414
0012-6667/01/0010-1407/$27.50/0
REVIEW ARTICLE
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Adis International Limited. All rights reserved.
Emerging Options in the Treatment of
Bipolar Disorders
Michael Berk, Jose Segal, Leigh Janet and Merryll Vorster
Department of Psychiatry, University of Melbourne, Geelong, Victoria, Australia
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1407
1. Anticonvulsants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1408
1.1 Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1408
1.2 Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1409
1.3 Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1409
1.4 Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1409
2
3
4
. Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1410
2.1 Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1410
2.2 Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411
2.3 Quetiapine and Ziprasidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411
. Novel Therapeutic Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411
3.1 Omega-3 Fatty Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1411
3.2 Electroconvulsive Therapy and Transcranial Magnetic Stimulation . . . . . . . . . . . . . . . 1411
3.3 Others . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412
. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1412
Abstract
Bipolar disorder is a common and severe condition, and has a clinical outcome
that is frequently sub-optimal. Only a small number of therapeutic options are
currently available for the disorder. Agrowing range of novel therapeutic options
for the treatment of bipolar disorder are under investigation. These include the
anticonvulsants, atypical antipsychotics and options such as the omega-3 fatty
acids and transcranial magnetic stimulation. Of the anticonvulsants, lamotrigine
is currently the agent for which the greatest amount of controlled clinical data is
accumulating, particularly in the depressed and rapid cycling phases of the illness.
Olanzapine is currently the atypical antipsychotic with the largest body of evi-
dence in mania, although data is emerging on other atypical antipsychotics in-
cluding risperidone and ziprasidone. Data regarding the atypical agents in other
phases of the illness are awaited. The options available for this difficult to treat
condition is increasing with the new range of agents.
Bipolar disorder is a severe and recurrent disor-
der, with a lifetime prevalence estimated at 1.6 to
.8%. The illness is associated with significant
proic acid (valproate) and carbamazapine, and
even these do not have the full range of clinical
effects necessary in bipolar disorder.
1
morbidity and mortality, and has pervasive effects
in most spheres of life.[ There are a limited num-
ber of standard treatments, including lithium, val-
Of additional concern is that current studies of
outcomes in this illness are far from optimal. Tohen
et al.[2] followed 75 patients postmania over a 4-
1]

1
408
Berk et al.
year period who were receiving standard treatment.
Only 28% were in remission, 72% had at least 1
episode of mania or depression, and there was a 4%
mortality rate in the study. Keck et al.[ studied the
course of 134 patients for a year on standard treat-
ment. Syndromal recovery occurred in 48% of the
sample and full syndrome resolution only in 26%.
Of substantial concern is that functional recovery
was present in a mere 24% of these patients.
Suicide rates in patients with bipolar disorder
are estimated at 10 to 19%, with a greater risk in
males, and in the mixed, psychotic and depressive
phases of the disorder. There is clearly an urgent
need for additional therapeutic options.
This review summarises data on the newer and
emerging therapeutic options for patients with bi-
polar disorder, which include anticonvulsants,
atypical antipyschotics, omega-3 fatty acids, and
electroconvulsive therapy (ECT) and transcranial
magnetic stimulation. A literature search was con-
ducted on Medline which was augmented by man-
ual searches of key words.
nificantly more patients on lamotrigine with bipo-
lar II disorder were still in the study than those on
placebo. 41% of lamotrigine patients versus 26%
of placebo patients (p = 0.03) were stable without
relapse for 6 months of monotherapy. Frye et al.[
reported that in a group of patients with predomi-
nantly rapid cycling, lamotrigine was superior to
3]
12]
[13]
both placebo and gabapentin. Walden et al.
found an equivalent outcome in patients with rapid
cycling in a small (n = 14) study comparing lithium
and lamotrigine.
Nonblind studies have suggested that lamotrig-
[14,15]
ine may have an antidepressant effect.
In a
double-blind study of 437 patients with unipolar
depression, both lamotrigine 200 mg/day and desi-
pramine 200 mg/day were differentiated from pla-
cebo on the Clinical Global Impression Scales (CGI)
of Severity of Illness (CGI-S) and of Improvement
(
CGI-I) but not on the 17-item Hamilton Rating
[16]
Scale for Depression (HAM-D) at week 8. In a
double-blind, placebo-controlled study of 195 pa-
tients with bipolar depression, lamotrigine at doses
of 50 and 200 mg/day showed significant efficacy on
the Montgomery Åsberg Rating Scale (MADRS).
However, the HAM-D scale, which was chosen as
the primary outcome measure, did not differentiate
between the groups.[
1
. Anticonvulsants
1
.1 Lamotrigine
17]
Lamotrigine is perhaps the best studied novel
anticonvulsant in bipolar disorder. It has a diverse
range of mechanisms of action, including inhibi-
tion of voltage-dependant sodium channels, inhibi-
tion of excitatory amino acids such as glutamate
and aspartate, and calcium antagonism. It may also
block serotonin 5-HT3 receptors and act to poten-
Case reports suggesting the use of lamotrigine in
refractory mania are available.[ A small (n = 30)
randomised, controlled trial comparing lamotrig-
ine and lithium in acute hospitalised patients with
18]
mania found equivalent efficacy between the 2
treatments.[
19,20]
Because of the need for slow dose
tiate dopaminergic transmission.[
4,5]
escalation, lamotrigine is not a practical option for
the treatment of mania. Nevertheless, efficacy in
the manic phase is of theoretical importance in es-
tablishing efficacy in multiple phases of the illness
in order to fulfil various definitions of a mood sta-
biliser.
A chart review study of lamotrigine in patients
with treatment-resistant bipolar disorder suggested
effectiveness.[6] Lamotrogine was also effective in
a nonblind 48-week study of 75 patients with treat-
[
7]
ment-resistant bipolar disorder. In addition, non-
blind data has suggested a role for lamotrigine in
Lamotrigine has been investigated in related
conditions, including schizoaffective disorder,
where case reports of efficacy are published,[ as
well as borderline personality disorder, which is
argued by the authors to have some relation to bi-
rapid cycling bipolar disorder.[
8-10]
However, in a
21]
placebo-controlled study in patients with rapid cy-
cling no significant treatment difference was found
where time to intervention was the primary out-
come measure.[ Nevertheless, in this study, sig-
11]
[22]
polar disorder.
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Drugs 2001; 61 (10)

Emerging Treatment Options in Bipolar Disorders
1409
This increasing body of clinical data suggests
that lamotrigine has substantial potential in the
therapy of bipolar disorder. The results of longer
term maintenance trials are awaited, and will more
clearly define the role of this agent.
Psychiatric Rating Scale, MADRS, CGI and
Global Assessment.
Given the absence of a consistent positive body
of data to date, further data from controlled clinical
trials are necessary to define the potential clinical
role of topiramate in bipolar disorder.
1
.2 Topiramate
1
.3 Gabapentin
Gabapentin has also attracted attention as a po-
tential therapeutic agent in bipolar disorder. Its pri-
mary mechanism of action is to increase brain
GABA levels in a dose-dependant manner. Impor-
tantly, it lacks any propensity to dependence and
tolerance, unlike the benzodiazepines. Its attrac-
tiveness is increased by the most benign adverse
event profile of the newer anticonvulsants.
Topiramate is an anticonvulsant that augments
γ-aminobutyric (GABA)ergic neurotransmission
as well as having glutamate antagonist properties.
The drug has been a focus of clinical interest in
bipolar disorder, not least because it is associated
with weight loss.[
23]
However, of concern is a re-
ported rate of emergence of depression of around
5% in epilepsy trials, and depression is listed as
1
A number of encouraging nonblind studies with
gabapentin have been reported, in indications such
an adverse event in the US package insert in 8% of
patients at a dosage of 220 to 400 mg/day and 13.4%
[
24]
as treatment refractory disorder, mania depression,
of patients receiving 600 to 1000 mg/day.
In
mixed states and rapid cycling.[
32-40]
However, a
addition, there are case reports of the emergence of
psychotic symptoms in patients with epilepsy
placebo-controlled trial of adjunctive therapy with
gabapentin 900 to 3600 mg/day in patients with
bipolar I disorder who were in either a manic, hy-
pomanic or mixed state has been reported by Pande
et al.[ In this study, the response to placebo (n =
treated with topiramate.[
25]
There are a number of case reports[26] and non-
blind studies suggesting topiramate may be effec-
41]
tive in bipolar disorder. Marcotte[
27]
retrospec-
5
9) was significantly greater than that to gaba-
tively reported a benefit in 62% of 58 outpatients.
McElroy et al.[28] in a nonblind study of 54 patients
suggested efficacy, particularly in patients with
rapid cycling and mania. A nonblind on-off study
pentin (n = 58) on the YMRS, and no differences
between the groups emerged on the HAM-D or any
other secondary outcome measures. Similarly, in a
double-blind crossover study by Frye and col-
leagues in patients with refractory mood disor-
ders,[ the CGI response rates were 52% for
lamotrigine, 26% for gabapentin and 23% for pla-
cebo. However, no controlled data on gabapentin
in maintenance or the depressive phase of the dis-
order are available. The negative trial results to
date do not support a clear role for gabapentin in
bipolar disorder.
of 10 patients with mania suggested the drug was
effective.[
29]
In a randomised, single-blind com-
12]
parison of topiramate and sustained release bu-
propion (amfebutamone) added to a mood stabi-
liser in patients with bipolar depression, the 2
drugs were of comparable efficacy.[30]
However, the only available controlled data on
topiramate in mania are negative and as yet unpub-
lished.[ This was a recently completed, industry-
sponsored, multicentre, double-blind, placebo-
controlled study of the safety and efficacy of
topiramate in the treatment of acute manic or
mixed episodes. The primary outcome measure
was improvement in patients with bipolar I disor-
der on the Young Mania Rating Scale (YMRS).
Secondary outcome measures included the Brief
31]
However, there appears to be accumulating ev-
idence of the efficacy of gabapentin in anxiety dis-
orders.[
42]
1
.4 Others
A double-blind, placebo-controlled trial sug-
gesting efficacy of phenytoin in combination with
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Drugs 2001; 61 (10)

1
410
Berk et al.
haloperidol in mania has been reported. The authors
suggest that efficacy of phenytoin maybe related to
inhibition of voltage-gated sodium channels.[
There are a number of novel anticonvulsants that
are likely to be targets for future investigation. The
tween olanzapine and placebo were demonstrated
in week 3 in one trial and week 1 in the other. In these
2 studies response rates were 48.6 and 64.8% for
olanzapine versus 24.2 and 42.9% for placebo, re-
spectively. Drop-out rates due to ‘lack of efficacy’
were 28.6% in the olanzapine group and 47.8% in
the placebo group (p = 0.02).
43]
first case reports of utility of tiagabine have ap-
peared in the literature.[
44,45]
However, a nonblind
case series of 8 patients with mania showed no ef-
Both trials had a short wash-out period (1 to 4
days). The effect of abrupt medication discontinu-
ation in bipolar illness is documented and this phe-
nomenon could have had a greater effect on the
placebo groups than on the active treatment arm of
[
46]
ficacy and significant adverse events.
Cases of
aggravation of mania[ and utility with zonisam-
47]
[
48]
ide in mania in a nonblind case series have been
reported. Other novel anticonvulsants such as
remacemide may be future targets of investigation.
It may be prudent to note that the mechanism
whereby certain anticonvulsants have efficacy in
bipolar disorder is poorly understood. In addition,
it is unlikely that the mechanisms underpinning ef-
ficacy in seizures will overlap with those responsi-
ble for efficacy in mood disorders. Anticonvulsants
differ substantially in their mechanisms of action,
and it would be most unlikely if efficacy in any of
the phases of bipolar disorder would turn out to be
a class effect of anticonvulsants.
[53]
the study.
There was no significant difference in the treat-
ment of psychotic versus nonpsychotic patients
with mania with either olanzapine or placebo in the
first study. It has been previously documented that
patients with psychotic mania will respond simi-
larly to patients with non-psychotic mania if
[
54]
treated with mood stabilisers. The results in the
second study[ showed a high placebo response
of 43% and an olanzapine response of 65% on the
YMRS.
52]
Olanzapine did not induce depressive symp-
toms in either study. Only in the second study did
olanzapine show a statistically significant im-
provement in depressive symptoms as measured on
the 21-item HAM-D scale (p = 0.05). Olanzapine
displayed few extrapyramidal adverse effects with
results not significantly different to placebo despite
the high doses used. This finding is significant
given the sensitivity of bipolar patients to the de-
2
. Atypical Antipsychotics
There have recently been developments in the
use of the new atypical antipsychotic drugs for the
treatment of bipolar disorder. These new agents
will be individually discussed here and the data
supporting their use in dipolar disorder reviewed.
The situation is changing so rapidly that even re-
cent reviews of the newer agents have already be-
come dated.[
49,50]
[55]
velopment of these symptoms.
A further comparative study with olanzapine in
mania has also been published. Berk et al. com-
2
.1 Olanzapine
[56]
pared olanzapine with lithium in a small trial of 4
weeks’ duration and found no statistically signifi-
cant difference in efficacy between the 2 agents. To
date, no controlled data exist for the use of olanzap-
ine in bipolar depression or maintenance. Roth-
schild et al.[ showed some bipolar patients who
were psychotically depressed did respond to
olanzapine. Mania induction by olanzapine seems
to be very rare but has been documented in isolated
cases.[
Olanzapine has recently been approved by the
US Food and Drug Administration (FDA) for use
in acute mania. Two double-blind, placebo-con-
[
51,52]
trolled trials have appeared in the literature.
These 2 studies involved patients in the manic,
rapid cycling and mixed phases of the illness either
with or without psychotic features. According to
these 2 studies, efficacy superior to placebo was
demonstrated by olanzapine for the treatment of
mania. Statistically significant differences be-
57]
58-61]
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Drugs 2001; 61 (10)

Emerging Treatment Options in Bipolar Disorders
1411
Further study is clearly needed to elucidate the
precise role of olanzapine in the treatment of this
complex disorder, particularly in the maintenance
and depressive phases of the disorder.
ported with ziprasidone (n = 131) versus placebo
(n = 64) at all time-points after baseline.
3. Novel Therapeutic Options
2
.2 Risperidone
3.1 Omega-3 Fatty Acids
Very little controlled data exist for the use of
risperidone in bipolar disorder. The first double-
blind controlled trial (Segal et al.[62]) compared
risperidone 6mg daily to lithium and haloperidol
in mania. No significant differences between the 3
groups were noted except for the induction of ex-
trapyramidal adverse effects in which risperidone
and haloperidol were not statistically significantly
different. This suggests that the dose of risperidone
may need to be lower in bipolar mood disorder.
Sachs[ compared add-on risperidone 1 to 6
mg/day, haloperidol 2 to 12 mg/day or placebo in
Inhibition of neuronal signal transduction sys-
tems is a common mechanism amongst mood sta-
bilisers. Omega-3 fatty acids dampen phosphatidyl
inositol and arachidonic acid mediated signal
transduction. In addition, there is now evidence of
impaired phospholipid metabolism and impaired
fatty acid-related signal transduction processes in
both depression and bipolar disorder.[
77]
In a small (n = 30) 4-month, double-blind, pla-
cebo-controlled trial comparing omega-3 fatty
acids with olive oil, in addition to treatment as
usual, there was a significantly longer period of
remission in the omega-3 group.[ These data,
while preliminary, offer a promising new avenue
of investigation in this disorder.
63]
78]
1
58 patients who were receiving either lithium or
valproic acid for the management of acute mania.
Risperidone was superior to placebo as measured
by the YMRS and CGI at end-point (3 weeks) com-
[
64]
3.2 Electroconvulsive Therapy and
Transcranial Magnetic Stimulation
pared with placebo. Tohen et al. and Ghaemi et
[
65]
al. added risperidone to other mood-stabilising
agents and found it to be effective. Ghaemi and
ECT has a long history of utility in bipolar dis-
order.[ In addition to unequivocal efficacy in the
depressive phase of the disorder, there is extensive
evidence of antimanic efficacy.[ Furthermore,
there is some evidence of the efficacy of mainte-
[
66]
Sachs
looked at the 6-month follow-up of
79]
risperidone (mean dose 2.75 mg/day) addition to
other medications patients with bipolar disorder.
They found no mania induction in this nonblind
study and 50% of these patients showed improve-
80]
nance ECT (M-ECT), given monthly, in treatment-
ment. However, there are cases of induction of ma-
refractory patients with bipolar disorder.[
81,82]
Be-
nia with risperidone.[
67-71]
Clearly much further
cause of logistical constraints and ongoing public
concerns regarding ECT, it is an option that re-
mains low in most treatment algorithms.
study with this agent is needed.
2
.3 Quetiapine and Ziprasidone
Transcranial magnetic stimulation (TMS) is a
promising research tool with potential therapeutic
uses in mood disorders. Early researchers reported
transient mood effects on patients receiving this
form of treatment for neurological disorders and
suggested further investigations. Controlled trials
of TMS in major depression suggest that it may be
a promising avenue for future investigation in bi-
polar disorder.[
To date no controlled studies have been publish-
ed on the use of quetiapine in bipolar illness. A
number of nonblind studies have been publish-
ed.[
72-75]
In these reports quetiapine seems to have
been effective and well tolerated at doses ranging
from 40.4 to 425 mg/day. Data from controlled tri-
als are needed.
83,84]
A 3-week, double-blind, placebo-controlled
trial of ziprasidone in mania has been published.[
Significant differences in the MRS score were re-
76]
In a 14-day, double-blind trial of 16 patients
with mania, a significant improvement in patients
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Adis International Limited. All rights reserved.
Drugs 2001; 61 (10)

1
412
Berk et al.
6
. Sporn J, Sachs G. The anticonvulsant lamotrigine in treatment-
receiving right prefrontal TMS was seen. This may
imply laterality opposite to its effect in depres-
sion.[ Although much remains to be elucidated
regarding the mechanism, technique and efficacy
of TMS, it appears to be a potentially fruitful can-
didate for further research.
resistant manic-depressive illness. J Clin Psychopharmacol
1
997; 17: 185-9
85]
7. Calabrese JR, Bowden CL, McElroy SL, et al. Spectrum of
activity of lamotrigine in treatment-refractory bipolar disor-
der. Am J Psychiatry 1999; 156: 1019-23
8. Fatemi SH, Rapport DJ, Calabrese JR, et al. Lamotrigine in
rapid-cycling bipolar disorder. J Clin Psychiatry 1997; 58:
5
22-7
9
. Bowden CL, Calabrese JR, McElroy SL, et al. The efficacy of
lamotrigine in rapid cycling and non-rapid cycling patients
with bipolar disorder. Biol Psychiatry 1999; 45: 953-8
3
.3 Others
1
0. Hamer RM, Simpson PM. The efficacy of lamotrigine in rapid
cycling and non-rapid cycling patients with bipolar disorder
Vagus nerve stimulation has shown some prom-
ise in depression, including resistant bipolar de-
pression, and maybe another possibility for future
research.[ Tamoxifen, a protein kinase C inhibi-
tor, was studied in a single-blind case series of 7
patients. The mean decrease in Y-MRS scores was
[
letter]. Biol Psychiatry 1999; 46: 1711-2
1
1. Calabrese JR, Suppes T, Bowden CL, et al. A double-blind,
placebo-controlled, prophylaxis study of lamotrigine in rapid-
cycling bipolar disorder. Lamictal 614 Study Group. J Clin
Psychiatry 2000; 61: 841-50
86]
1
1
1
2. Frye MA, Ketter TA, Kimbrell TA, et al. Aplacebo-controlled
study of lamotrigine and gabapentin monotherapy in refrac-
tory mood disorders. J Clin Psychopharmacol 2000; 20 :
1
0.29, and 5 of the 7 patients exhibited a >50%
6
07-14
decrement in scores. Further controlled data is an-
3. Walden J, Schaerer L, Schloesser S, et al. An open longitudinal
study of patients with bipolar rapid cycling treated with lith-
ium or lamotrigine for mood stablization. Bipolar Disord
ticipated.[
87]
2
000 Dec; 2 (4): 336-9
4. Fornaro P, Cultera S, Lunardi G, et al. Clinical effects and
plasma levels of lamotrigine in depressed outpatients. Prelim-
inary results from an open trial. Biol Psychiatry 1997; 42
Suppl. 1: 41S
4
. Conclusion
A range of new therapeutic options is under in-
vestigation for the treatment of bipolar disorder.
Most of these are agents adopted from the arma-
mentarium of other disorders. A poor under-
standing of the basic pathophysiology of bipolar
disorder hampers the search for therapeutic op-
tions. Nevertheless, there is a growing number of
candidate options. While some of these may not
survive the rigours of adequate double-blind, con-
trolled studies, the list of options for this difficult-
to-treat condition is certain to grow.
15. Kusumakar V, Yatham LN. An open study of lamotrigine in
refractory bipolar depression. Psychiatry Res 1997; 72: 145-8
1
6. Londborg P, Cutler N, Cunningham L, et al. Lamotrigine in the
treatment of unipolar depression. Presented at the American
Psychiatric Association Annual Meeting 1999 May; New Or-
leans (LA)
7. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind
placebo-controlled study of lamotrigine monotherapy in out-
patients with bipolar I depression. Lamictal 602 Study Group.
J Clin Psychiatry 1999; 60: 79-88
1
18. Koek RJ, Yerevanian BI. Is lamotrigine effective for treatment-
refractory mania? [letter]. Pharmacopsychiatry 1998; 31: 35
1
9. Ichim L, Berk M, Brook S. Lamotrigine compared with lithium
in mania: a double-blind randomized controlled trial. Ann
Clin Psychiatry 2000; 12: 5-10
2
0. Berk M. Lamotrigine and the treatment of mania in bipolar
disorder. Eur Neuropsychopharmacol 1999; 9 Suppl. 4:
S119-23
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Correspondence and offprints:Dr Michael Berk, Department
of Psychiatry, University of Melbourne, Swanston Centre,
P.O. Box 281, Geelong, Victoria, 3220, Australia.
E-mail: mikebe@barwonhealth.org.au
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Adis International Limited. All rights reserved.
Drugs 2001; 61 (10)