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 Copyright ª Blackwell Munksgaard 2006
Bipolar Disorders 2006: 8: 721–739 BIPOLAR DISORDERS

Guidelines Update

Canadian Network for Mood and Anxiety

Treatments (CANMAT) guidelines for the
management of patients with bipolar disorder:
update 2007
Yatham LN, Kennedy SH, O’Donovan C, Parikh SV, MacQueen G,
McIntyre RS, Sharma V, Beaulieu S for CANMAT guidelines group.
Canadian Network for Mood and Anxiety Treatments (CANMAT)
guidelines for the management of patients with bipolar disorder: update
2007.
Bipolar Disord 2006: 8: 721–739. ªBlackwell Munksgaard, 2006
In 2005, the Canadian Network for Mood and Anxiety Treat-
ments (CANMAT) published guidelines for the management of
bipolar disorder. This update reviews new evidence since the
previous publication and incorporates recommendations based on
the most current evidence for treatment of various phases of
bipolar disorder. It is designed to be used in conjunction with the
2005 CANMAT Guidelines. The recommendations for the
management of acute mania remain mostly unchanged. Lithium,
valproate and several atypical antipsychotics continue to be
recommended as first-line treatments for acute mania. For the
management of bipolar depression, new data support quetiapine
monotherapy as a first-line option. Lithium and lamotrigine
monotherapy, olanzapine plus selective serotonin reuptake
inhibitors (SSRI), and lithium or divalproex plus SSRI/bupropion
continue to remain the other first-line options. First-line options
in the maintenance treatment of bipolar disorder continue to be
lithium, lamotrigine, valproate and olanzapine. There is recent
evidence to support the combination of olanzapine and fluoxetine
as a second-line maintenance therapy for bipolar depression. New
data also support quetiapine monotherapy as a second-line option
for the management of acute bipolar II depression. The impor-
tance of comorbid psychiatric and medical conditions cannot be
understated, and this update provides an expanded look at the
prevalence, impact and management of comorbid conditions in
patients with bipolar disorder.
Lakshmi N Yathama, Sidney H
Kennedyb, Claire O’Donovanc,
Sagar V Parikhb, Glenda
MacQueend, Roger S McIntyreb,
Verinder Sharmae and Serge
Beaulieuf for CANMAT guidelines
group*
a
Department of Psychiatry, University of British
Columbia, Vancouver, BC, bDepartment of
Psychiatry, University of Toronto, Toronto, ON,
c
Department of Psychiatry, Dalhousie University,
Halifax, NS, dMcMaster University, Hamilton, ON,
e
Department of Psychiatry, University of Western
Ontario, London, ON, fDepartment of Psychiatry,
McGill University, Montreal, QC, Canada, *See
Appendix for members of the CANMAT guidelines
group
Key words: bipolar disorder – CANMAT –
depression – guidelines – maintenance – mania –
treatment
Received 16 June 2006, revised and accepted for
publication 25 August 2006
Corresponding author: Lakshmi N Yatham, MBBS,
FRCPC, MRCPsych (UK), University of British
Columbia, 2255 Wesbrook Mall, Vancouver, BC
V6T 2A1, Canada. Fax: + 1 604 822 7922;
e-mail: yatham@interchange.ubc.ca

hope to provide annual updates, starting with this

Section 1. Introduction
In 2005, the Canadian Network for Mood and
Anxiety Treatments (CANMAT) published guide-
lines for the management of bipolar disorder (BD)
(1). The previous Canadian guidelines for BD were
published in 1997. To maintain currency, it is our
set.
Search strategies, and assessment of evidence
were undertaken as described in the original article.
The purpose of this update is to add previously
unpublished material to the guidelines; to expand
the discussion of differential diagnosis and man-
721
Yatham et al.

agement of bipolar patients who have comorbid
psychiatric or medical conditions, and to extend
the issue of safety and monitoring, particularly
with regard to metabolic dysregulation associated
with BD and its treatment. This update is designed
to be used in conjunction with the 2005 CANMAT
Guidelines (1).
We anticipate that this initiative will ensure that
the CANMAT guidelines for treatment of BD
remain current and useful for the practicing
clinician.
Section 2. Foundations of management
Two new studies confirm the benefit of chronic
disease management programs for BD (2, 3). A
randomized controlled trial (RCT) in 441 subjects,
assessed a 2-year systematic intervention program
that included a structured group psychoeducation-
al program, monthly telephone monitoring of
mood symptoms and medication adherence, feed-
back to treating mental health providers, facilita-
tion of appropriate follow-up care, and as-needed
outreach and crisis intervention (2). The interven-
tion significantly reduced manic symptoms, with a
non-significant trend toward improvement in
depressive symptoms, at a modest financial cost.
Similarly, an RCT with 306 military veterans
with BD assessed an intervention consisting of:
(i) patient self-management skill augmentation
through psychoeducation; (ii) provider decision
support through simplified practice guidelines; and
(iii) augmented access/continuity and information
flow through use of a nurse care coordinator (3).
The intervention successfully reduced the burden
of manic symptoms over a 3-year period, with a
non-significant trend towards improvement in
depressive symptoms, and further demonstrated
an improvement in overall function and quality of
life. Both studies used the same manual to provide
psychoeducation (Bauer M, McBride L. Structured
Group Psychotherapy for Bipolar Disorder, 2nd
edn. New York: Springer, 2003). These studies
provide level 1 support for chronic disease man-
agement strategies for BD, and provide evidence of
the efficacy of psychoeducation from this manual.
Symptom characterization in BD may need to be
revised in view of recent reports of mixed symp-
tomatology (4, 5). A recent study systematically
recorded both mania and depression rating scales
for every clinic visit in a sample of 908 patients
followed over 7 years, from the USA and Europe
(4). This study suggested a new clinical state of
Ômixed hypomaniaÕ, where subjects have significant
depressive symptoms while meeting criteria for a
hypomanic episode. In addition, Ôdepressed mixed
statesÕ were common in a group of 254 ostensibly
unipolar depression patients, who experienced
substantial hypomanic symptoms while depressed
(5). Therefore, it appears that episode definition in
BD may need substantial clarification. In practice
this may mean that symptoms of both mania and
depression should be carefully delineated, even
when an episode appears to be ÔobviousÕ.

CANMAT has received unrestricted educational grant support from Janssen-Ortho, Eli Lilly & Co., and AstraZeneca. LNY
has received grant funding from Servier, AstraZeneca, Janssen, Eli Lilly & Co., GlaxoSmithKline, Novartis and Pfizer; has
served as a speaker and a consultant/member of advisory boards for AstraZeneca, Novartis, Janssen, Eli Lilly & Co.,
GlaxoSmithKline, Bristol-Myers Squibb, Oryx and Pfizer; and does not hold any stocks or have any other conflicts with
industry. SHK has received grant funding from AstraZeneca, Eli Lilly & Co., GlaxoSmithKline, Janssen-Ortho, Lundbeck and
Merck Frosst; has received consultation fees from Advanced Neuromodulation Systems, Inc., Biovail, Boehringer Ingelheim,
Eli Lilly & Co., GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Pfizer, Servier and Wyeth Laboratories; and has served
on the speakers bureaus for Biovail, Eli Lilly & Co., GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Servier and Wyeth
Laboratories. COD has been a consultant to and served on the speakers bureaus and advisory boards for AstraZeneca, Wyeth
Laboratories and Biovail. SVP has received unrestricted educational grants from Wyeth Laboratories, Janssen-Ortho, Eli Lilly
& Co., AstraZeneca, GlaxoSmithKline, Novartis and Biovail; and speaker’s honoraria from AstraZeneca, Eli Lilly & Co.,
Biovail and Wyeth Laboratories. GMacQ has received grant funding from Lundbeck, AstraZeneca, Eli Lilly & Co., Sanofi-
Aventis, Biovail and Janssen; has acted as a consultant to or served on the advisory boards for Eli Lilly & Co., Janssen, Wyeth
Laboratories, GlaxoSmithKline and Organon; and has served on the speakers bureaus for Eli Lilly & Co., Janssen,
AstraZeneca, Novartis, Lundbeck, Wyeth Laboratories, Organon, Merck, GlaxoSmithKline and Biovail. RSMcI reports
commercial associations with AstraZeneca, Eli Lilly & Co., Janssen-Ortho, Organon, Wyeth, Lundbeck, GlaxoSmithKline,
Oryx, Biovail, Pfizer and Prestwick. VS reports commercial associations with Eli Lilly & Co., Janssen Pharmaceutica Products,
Novartis Pharmaceuticals Corporation, AstraZeneca Pharmaceuticals LP and Servier. SB has received grant funding from
CIHR, FRSQ, NARSAD, RSMQ and the Stanley Foundation; research support from AstraZeneca, Biovail and Eli Lilly &
Co., Janssen-Ortho, Lundbeck, Merck-Frosst, Novartis, Pfizer and Servier; acted as a consultant to and served on the advisory
boards for AstraZeneca, Eli Lilly & Co., GlaxoSmithKline, Janssen-Ortho and Oryx; and served on the speakers bureaus for
AstraZeneca, Biovail, Eli Lilly & Co., GlaxoSmithKline, Janssen-Ortho, Lundbeck, Organon, Oryx and Wyeth-Ayerst.

722
 CANMAT guidelines for bipolar disorder

Suicide risk Divalproex. The efficacy of divalproex for the

Additional data support the benefits of lithium in
reducing suicidal behavior. A systematic review of
RCTs found the risk of suicide was reduced by
almost 75% in patients receiving lithium compared
to placebo or other treatments (6). Clinical trials
tend to be biased toward more severely ill patients;
however, a database review of all patients pre-
scribed lithium in Denmark found that the rate of
suicide decreased with increasing number of lith-
ium prescriptions (7).
Section 3. Acute management of bipolar mania
Pharmacological treatment of manic episodes
Pharmacological management of acute manic epi-
sodes should follow the process outlined in Fig. 3.1
(1). There are few new data, and those available do
not impact the overall treatment recommendations
(Table 3.3).
Step 1. Review general principles and assess
medication status.
No changes from 2005 guidelines.
Step 2. First-line therapies.
management of acute mania is well established
(Level 1) (1). New data also support the efficacy of
an extended-release formulation of divalproex
(Level 2) (8).
Atypical antipsychotics. Substantial RCT data sup-
port the efficacy of atypical antipsychotic mono-
therapy with olanzapine, risperidone, quetiapine,
ziprasidone, and aripiprazole for the first-line
treatment of acute mania (Level 1) (1). A 3-week
RCT, completed in India, further supports the
effect of risperidone for the treatment of acute
mania (Level 1) (9), with remission rates of 42%
compared to 13% with placebo (10).
A 3-week RCT reporting the efficacy of ziprasi-
done that was previously cited in abstract form (11)
has now been published (12). Extension data from
this and another 3-week trial (13) demonstrated
that the majority of responders (92.5%) at 3 weeks
continued to respond after 12 weeks (14). Simi-
larly, abstracts of RCTs supporting the efficacy of
aripiprazole as superior to placebo (15) or haloper-
idol (16) in the treatment of acute mania have
now been published (17, 18). Aripiprazole and
ziprasidone continue to be unavailable in Canada,

Assess safety/functioning
Establish treatment setting
Step 1 D/C antidepressants
Review general Rule out medical causes
principles D/C caffeine, alcohol and illicit substances
and Behavioral strategies/rhythms, psychoeducation
assess medication
status Not on medication On first-line agent
or first-line agent
+

Step 2
Initiate Li, DVP,
Initiate/optimize, Lithium or Atypical 2 drug combination
AAP, or 2 drug
check compliance DVP antipsychotic (Li or DVP + AAP)
combination
No response
Step 3 Add or Add or switch to Replace 1 or both
Add-on or switch to AAP Li or DVP agents with other
switch therapy first-line agents
No response

Step 4 Replace 1 or both Consider CBZ (OXC)

Add-on or agents with other or CAP or clozapine
switch therapy first-line agents or ECT
No response

Step 5 Consider adding levetiracetam,

Add-on novel or phenytoin, tamoxifen, mexilitine,
experimental agents omega-3-fatty acids, calcitonin

Fig. 3.1. Treatment algorithm for acute mania. AAP ¼ atypical antipsychotic; CAP ¼ conventional antipsychotic; CBZ ¼ carba-
mazepine; D/C ¼ discontinue; DVP ¼ divalproex; Li ¼ lithium; OXC ¼ oxcarbazepine; ECT ¼ electroconvulsive therapy.

723
Yatham et al.

Table 3.3. Recommendations for pharmacological treatment of acute bipolar mania

Options Treatments

First-line Lithium, divalproex, olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, lithium or

divalproex + risperidone, lithium or divalproex + quetiapine, lithium or divalproex + olanzapine
Second-line Carbamazepine, oxcarbazepine, ECT, lithium + divalproex
Third-line Haloperidol, chlorpromazine, lithium or divalproex + haloperidol, lithium + carbamazepine, clozapine
Not recommended Monotherapy with gabapentin, topiramate, lamotrigine, verapamil, tiagabine, risperidone + carbamazepine

ECT ¼ electroconvulsive therapy.

so recommendations are based largely on reported
efficacy data and adverse event profiles of these
agents.
Step 3. Add-on or switch therapy (alternate first-
line therapies).
No changes from 2005 guidelines.
Step 4. Second- and third-line therapies.
Second-line options. New data confirm the efficacy
of the extended release formulation of carbamaze-
pine for the treatment of acute mania (19). There
is currently no evidence that tolerability is
improved by the extended release formulation,
and carbamazepine remains a second-line choice.
Additional open-label and chart review data add to
the support for efficacy of adjunctive oxcarbaze-
pine (20, 21).
Step 5. Add-on novel or experimental agents.
No changes from 2005 guidelines.
Section 4. Acute management of bipolar depression
Pharmacological treatment of depressive episodes
Pharmacological management of acute depressive
episodes should follow the process outlined in
Fig. 4.1 (1). There have been a number of new
clinical trials in bipolar depression that have
changed the treatment recommendations for bipo-

Step 1 Assess safety/functioning

Review general Behavioural strategies/rhythms
principals Psychoeducation
& On DVP On OLZ, RIS, On first-line Not on
assess medication ARI or ZIP agent medication
status

Add SSRI/BUP Add SSRI, Li

Step 2 or add/switch to or LAM LAM Li QUE OLZ Li or DVP Li+DVP
Initiate/optimize, Li , LAM or or switch to Li,
check compliance +SSRI +SSRI/ BUP
QUE LAM or QUE

No
response

Step 3 Add/switch Add Add SSRI, Li Switch to QUE, Switch Li or Add

Add-on or to Li SSRI/BUP or or LAM or QUE+SSRI, Li, DVP to QUE SSRI/BUP
switch therapy or QUE add/switch to switch to Li, Li+SSRI/BUP or OLZ or switch
LAM or QUE LAM or or LAMa or switch Li or DVP to
No OLZ+SSRI SSRI/BUP to LAM or QUE
response LAMb

Step 4
Add-on or
switch therapy Replace one or both agents with
alternate first- or second-line agents
No
response
Step 5
Consider ECT or other third-line option
Add-on or switch therapy

Fig. 4.1. Treatment algorithm for the management of bipolar I depression. ARI ¼ aripiprazole; BUP ¼ bupropion; DVP ¼ dival-
proex; ECT ¼ electroconvulsive therapy; LAM ¼ lamotrigine; Li ¼ lithium; OLZ ¼ olanzapine; QUE ¼ quetiapine; RIS ¼ ris-
peridone; SSRI ¼ selective serotonin reuptake inhibitor; ZIP ¼ ziprasidone.
a
Or switch the SSRI to another SSRI.
b
Or switch the SSRI or BUP to another SSRI or BUP.

724
 CANMAT guidelines for bipolar disorder

Table 4.3. Recommendations for pharmacological treatment of acute bipolar I depressiona

Options Treatments

First-line Lithium, lamotrigine, lithium or divalproex + SSRI, olanzapine + SSRI, lithium + divalproex, lithium or
divalproex + bupropion, quetiapine monotherapyb
Second-line Quetiapine + SSRI, lithium or divalproex + lamotrigineb
Third-line Carbamazepine, olanzapine, divalproex, lithium + carbamazepine, lithium + pramipexole, lithium or
divalproex + venlafaxine, lithium + MAOI, ECT, lithium or divalproex or AAP + TCA, lithium or divalproex
or carbamazepine + SSRI + lamotrigineb, adjunctive EPAb, adjunctive riluzoleb, adjunctive topiramateb
Not recommended Monotherapy with gabapentin

a
The management of a bipolar depressive episode with antidepressants remains complex. The clinician must balance the desired effect
of remission with the undesired effect of switching and inducing rapid cycling.
b
New. AAP ¼ atypical antipsychotic; EPA ¼ eicosapentaenoic acid; ECT ¼ electroconvulsive therapy; MAOI ¼ monoamine oxidase
inhibitor; SSRI ¼ selective serotonin reuptake inhibitor; TCA ¼ tricyclic antidepressant.

lar depression (Table 4.3). In the 2005 guidelines
the only first-line options for monotherapy for
bipolar depression were lithium and lamotrigine.
There is now sufficient evidence to recommend
quetiapine monotherapy as a first-line option as
well. New data confirm the efficacy of the combi-
nation of olanzapine plus fluoxetine as a first-line
choice, and demonstrate that it is at least as
effective as lamotrigine, if not more so. Finally,
there is new evidence to support the use of
divalproex monotherapy and adjunctive lamotri-
gine as second-line options.
Step 1. Review general principles and assess
medication status.
No changes from 2005 guidelines.
Step 2. Initiate or optimize therapy and check
adherence (first-line therapies).
Lamotrigine. Lamotrigine continues to be recom-
mended as a first-line choice for bipolar depres-
sion, based on two RCTs that showed that about
40–50% of patients responded, which was twice
that seen in the placebo group (Level 1) (22, 23).
Futher, a recent RCT in patients who had
breakthrough bipolar depression while on lithium
showed that lamotrigine add-on was significantly
superior to placebo add-on in treating depressive
symptoms as indicated by significantly greater
improvements in MADRS scores (Van der Loos
M and Nolen W: Lamotrigine as add-on to
lithium in bipolar depression. Presented at the
Fifth European Stanley Conference on Bipolar
Disorder, Barcelona, October 5–7, 2006).
Recently, a large RCT showed that the combina-
tion of olanzapine plus fluoxetine was slightly, but
statistically significantly, better than lamotrigine
monotherapy, but lamotrigine was better tolerated
(24). Olanzapine plus fluoxetine was associated
with statistically significantly greater improvement
in depressive and manic symptoms compared to
lamotrigine; however, effect sizes were small
(0.24–0.26) and there were no differences in
response rates.
Quetiapine monotherapy. At the time of publi-
cation of the 2005 bipolar guidelines, only one
RCT had demonstrated the antidepressant efficacy
of quetiapine monotherapy for the treatment
of bipolar depression (which has since been
published) (25). Remission rates were 52.9% in
the groups taking 600 mg/day and 300 mg/day of
quetiapine compared to 28.4% for placebo. Since
this was the first study to demonstrate the efficacy
of an atypical antipsychotic as monotherapy for
bipolar depression, it was felt premature to recom-
mend monotherapy as a first-line option until the
findings had been replicated. A second, large,
8-week RCT has now confirmed the antidepressant
efficacy of quetiapine monotherapy (26), and it can
now be recommended as a first-line option for
bipolar depression (Level 1). Further analysis of
the original study (25) demonstrated a significant
improvement in health-related quality of life (27).
Olanzapine + fluoxetine. While there was sufficient
evidence to recommend the combination of olanza-
pine plus fluoxetine as a first-line choice for bipolar
depression, only 1 trial was available (28). A second,
large RCT has now assessed this combination (Level
2) (24). In a 7-week RCT, the combination of
olanzapine and fluoxetine was as or more effective
than lamotrigine, but lamotrigine was better toler-
ated. Olanzapine plus fluoxetine was associated with
statistically significantly greater improvement in
depressive and manic symptoms compared to
lamotrigine. However, effect sizes were small
(0.24–0.26) and there were no differences in response
rates. In addition, the combination was associated
with more treatment-emergent adverse events,
greater weight gain, and elevated lipids and HbA1c.
One of the criticisms of the original study was
that it did not include a fluoxetine alone treatment
725
Yatham et al.
regimen, which raised the possibility that the
olanzapine plus fluoxetine combination may be no
more effective than fluoxetine alone. This new trial
also does not address this issue. A small, recent
RCT did include both monotherapy groups, as well
as the combination, but failure to detect differences
in improvements in depressive symptoms between
groups, including the placebo group, were attrib-
uted to inadequate sample size (29).
Step 3. Add-on or switch therapy (alternate first- or
second-line therapies).
Adjunctive antidepressants. A Step 3 strategy for a
patient, with an inadequate response to a combi-
nation of lithium or divalproex plus an SSRI or
bupropion, or olanzapine plus an SSRI, would be
to switch the antidepressant. For example, switch
to an alternate SSRI.
Adjunctive lamotrigine. Although there was no
previous controlled trial evidence for lamotrigine
as an add-on to lithium or divalproex, the addition
of lamotrigine was recommended in Step 2 or Step
3 based on the fact that lamotrigine monotherapy
was effective. This strategy is now supported by a
small RCT reporting that the addition of lamo-
trigine was as effective as adding an SSRI to
lithium or divalproex for patients with bipolar
depression (Level 2) (30). A more recent larger RCT
also now supports this strategy (Van der Loss M
and Nolen W: Lamotrigine as add-on to lithium in
bipolar depression. Presented at the Fifth European
Stanley Conference on Bipolar Disorder, Barcelona,
October 5–7, 2006). In the STEP-BD study,
lamotrigine was numerically more effective than
inositol or risperidone for patients with treatment-
resistant bipolar depression already receiving
combination therapy with lithium, divalproex or
carbamazepine plus an antidepressant (Level 3) (31).
Step 4. Add-on or switch therapy (alternate first- or
second-line therapies.
No changes from 2005 guidelines.
Step 5. Add-on or switch therapy (third-line
therapies).
Divalproex monotherapy. Previously, support for
divalproex monotherapy for bipolar depression
was available only from uncontrolled trials (32,
33). This strategy has now shown efficacy in a small
placebo-controlled RCT (Level 2) (34).
Adjunctive eicosapentaenoic acid (EPA). In a
12-week RCT in 85 patients with bipolar depres-
sion, adjunctive eicosapentaenoic acid (EPA) was
726
more effective than placebo in improving depres-
sive symptoms (Level 2) (35).
Adjunctive riluzole. Preliminary, open-label data
suggest that adjunctive riluzole may improve
bipolar depression when added to lithium therapy
(Level 3) (36).
Adjunctive topiramate. A single-blind trial suggest-
ed that adjunctive topiramate was as effective as
adjunctive bupropion when added to ongoing
therapy with divalproex, lithium or atypical anti-
psychotics (Level 3) (37).
Clinical questions and controversies
• Are there differences in manic switch rates
between newer antidepressants?
An analysis of data from 228 acute (10-week)
RCTs of bupropion, sertraline, or venlafaxine as
adjuncts to a mood stabilizer further supported the
possibility of a higher risk of manic switch among
patients treated with venlafaxine and lower risk
with bupropion and sertraline (38).
Section 5. Maintenance therapy for bipolar disorder
Psychosocial interventions for maintenance therapy
Psychoeducation. An RCT reporting on 5-year
follow-up results found that a 21-week group
psychoeducation program as adjunct to standard
pharmacological management significantly re-
duced the rate of relapse of both hypo/manic and
depressive episodes (39).
Cognitive-behavior therapy (CBT). In an RCT
examining the role of adjunctive CBT for relapse
prevention over 30 months, patients in the CBT
group had significantly fewer days in bipolar
episodes; however, CBT had no significant effect
on relapse reduction after the first year (40).
Similarly, in an RCT of CBT in 253 patients,
more than half the patients had a recurrence by
18 months, with no significant differences be-
tween groups (41). Patients were offered 22
sessions of CBT, but 40% did not receive
significant portions of the CBT. Post hoc anal-
yses showed that a small group of patients with
fewer than 12 lifetime episodes did experience a
benefit from the intervention. Together, these two
trials suggest that the long-term effectiveness of
CBT may be limited but the role of booster
sessions in maintenance of efficacy needs further
exploration.
 CANMAT guidelines for bipolar disorder

Table 5.5. Recommendations for maintenance pharmacotherapy of bipolar disorder

Options Treatments

First-line Lithium, lamotrigine monotherapy (lamotrigine mainly for those with mild manias), divalproex, olanzapine
Second-line Carbamazepine, lithium + divalproex, lithium + carbamazepine, lithium or divalproex + olanzapine,
aripiprazole, risperidone, quetiapine, ziprasidone, lithium + risperidone or quetiapine, lithium +
lamotrigine or SSRI or bupropion, olanzapine + fluoxetinea
Third-line Adjunctive phenytoin, clozapine, ECT, topiramate, omega-3-fatty acids, oxcarbazepine, or gabapentina
Not recommended Adjunctive flupenthixol, monotherapy with gabapentin, topiramate or antidepressants

ECT ¼ electroconvulsive therapy; SSRI ¼ selective serotonin reuptake inhibitor.

a
New.

response to an other therapy, the addition of

Interpersonal and social rhythm therapy (IPS-
quetiapine resulted in improvements in depressive
RT). In a comparison of IPSRT to intensive
(48, 49) and manic symptoms (49, 50) and a
clinical management, there was no difference in
reduced probability of manic/mixed and depressive
the time to stabilization of acutely ill patients with
relapses (49, 51) over 24–78 weeks.
BD (42). However, over the 2-year follow-up,
patients treated with IPSRT acutely had a signif-
Combination therapy. There is little evidence to
icantly lower rate of recurrence whether they
support combination therapies for the long-term
continued IPSRT or were switched to intensive
maintenance treatment of patients with BD (1).
clinical management.
While the combination of lithium plus carbamaze-
pine was recommended (Level 2), additional sup-
Pharmacological treatments for maintenance therapy port for this therapy comes from a post hoc
analysis of 46 patients showing a significant
First-line options
reduction of 56% in hospitalized days per year
Olanzapine. Olanzapine has been shown to be an
during combination therapy compared to previous
effective first-line option in the prevention of both
monotherapy with either agent alone; however,
manic and depressive episodes (1). A 48-week RCT
there were more adverse effects (52).
reporting the efficacy of olanzapine maintenance
In a 6-month RCT in patients with BD depres-
therapy compared to placebo that was cited in
sion, there were significantly greater improvements
abstract form (43) has now been published (44).
in depressive and manic symptoms with the com-
Time to symptomatic relapse into any mood
bination of olanzapine and fluoxetine compared
episode (median 174 versus 22 days) and relapse
with lamotrigine, and there was no significant
rate (46.7% versus 80.1%) was significantly supe-
difference in the rate of depressive or manic
rior with olanzapine compared to placebo.
relapses (Level 2) (53). These data support the
Post hoc analysis of a study comparing olanza-
use of olanzapine plus fluoxetine combination for
pine and lithium for relapse prevention (45) dem-
maintenance therapy for patients with bipolar I
onstrated that olanzapine and lithium were equally
depression.
effective overall, but olanzapine was more effective
in preventing manic/mixed relapse/recurrence in
Third-line options
patients in early-stage illness (46).
Other agents. Additional data support the use of
adjunctive gabapentin as a third-line option for the
Second-line options
long-term treatment of BD in some patients. In a
Carbamazepine. While data suggested that carba-
small RCT in euthymic patients, the addition of
mazepine was as effective as lithium for mainte-
gabapentin to lithium, divalproex or carbamaze-
nance treatment, no placebo-controlled trials were
pine for relapse prevention significantly improved
available (1). In a recent RCT, carbamazepine was
overall clinical global impression (CGI) compared
found to be as effective as lithium and more
to placebo, but no recurrent episodes were reported
effective than placebo for maintenance treatment
in either group (Level 2) (54).
over 12 months in patients with stable bipolar I
disorder (Level 2) (47).
Bipolar disorder with rapid cycling
Other atypical antipsychotics. Several recent open-
First-line options
label and cohort studies further support the use of
Lithium and divalproex are recommended first-line
adjunctive quetiapine for maintenance treatment.
therapies for the long-term management of
In patients who had generally had an inadequate
727
Yatham et al.
Table 5.6. Pharmacological maintenance treatment of bipolar disorder with rapid cycling
Options Treatments
First-line Lithium, divalproex
Second-line Lithium + divalproex, lithium + carbamazepine, lithium or divalproex + lamotriginea,b, olanzapinea
Third-line Lithium or divalproex + topiramate, quetiapine, risperidone, clozapine, oxcarbazepine, levothyroxine
Not recommended Antidepressants
a
New.
b
The recommendation for lamotrigine has been downgraded to second-line, adjunctive therapy in the light of 2 negative placebo-
controlled trials (55–57).
patients with BD and rapid cycling (Table 5.6) (1).
Lamotrigine was previously recommended as a
first-line option for some patients. However,
because of additional negative data, it has now
been downgraded to a second-line, adjunctive
therapy (see below).
Second-line options
Lamotrigine. In the 2005 Guidelines (1), lamotri-
gine was recommended as a first-line option based
on evidence of lower recurrence rates compared to
placebo in a 6-month RCT (55). However, the
primary outcome of time to intervention for mood
symptoms was not significant, and sub-analysis
revealed that the recurrence rates were not signif-
icantly lower for patients with BD I, but only for
patients with BD II. It was concluded that lamo-
trigine may be useful as monotherapy for patients
with BD II and rapid cycling, but combination
with lithium or divalproex may be required in
patients with BD I. A second unpublished trial also
reported no significant difference between lamo-
trigine and placebo in a similar primary endpoint of
time to intervention in patients with rapid cycling
(56, 57). However, lamotrigine was significantly
more effective in time to intervention for a depres-
sive episode compared to placebo. Analysis accord-
ing to BD I or II diagnosis is not available.
Further analysis has suggested that lamotrigine
has the potential to complement lithium and
divalproex through its greater efficacy for depres-
sive symptoms (58). Based on these data, the
recommendation for lamotrigine for rapid cycling
BD I was downgraded to a second-line, adjunctive
treatment option.
Olanzapine. In the 2005 Guidelines, atypical anti-
psychotics were recommended as third-line options
for the maintenance treatment of patients with
rapid cycling, because long-term data were not
available (1). Post hoc analysis of a 47-week trial
comparing divalproex and olanzapine (59) found
that, as with other treatments, patients with rapid
cycling did less well over the long-term than those
without rapid cycling (60). Olanzapine was as
728
effective as divalproex against manic symptoms in
patients with rapid cycling, but was superior in
patients without rapid cycling (Level 3) (60); this
suggests that olanzapine is a useful second-line
option for maintenance therapy for patients with
rapid cycling BD.
Section 6. Special populations
Issues in the management of bipolar disorder in women
Divalproex and polycystic ovary syndrome. The
findings of studies that examined the association
between divalproex use and polycystic ovary syn-
drome (PCOS) have been contradictory (61–64).
However, a more recent study suggests that PCOS
features such as new-onset oligoamenorrhea with
hyperandrogenism were more common in women
on divalproex (10.5%) compared to those on other
anticonvulsants or lithium (1.4%) (65).
Management of acute episodes during preg-
nancy. Minor anomalies have been reported, but
no increased risk of major malformations has been
observed with most antidepressants during preg-
nancy or lactation (66, 67). The exception is
paroxetine, which has been associated with a
twofold risk in major congenital malformations,
particularly cardiac septal defects, compared to
other antidepressants (68). Use of paroxetine
during pregnancy has also been associated with a
risk of tremors in the newborn, due to drug
discontinuation though parturition (68). Therefore,
paroxetine is not recommended for use during
pregnancy.
Maintenance therapy during pregnancy. Data sug-
gest that among women administered lithium
throughout delivery, higher lithium concentration
at delivery was associated with lower Apgar scores,
longer hospital stays, and higher rates of central
nervous system and neuromuscular complications
in infants (69). Lithium concentrations can be
reduced by brief suspension of therapy 24–48 h
before delivery.

Management of bipolar disorder during the postpar-
tum period. An analysis of 129 women found that
primiparity and delivery complications were inde-
pendently associated with an episode of postpar-
tum psychosis (70).
A prospective cohort study found that olanza-
pine, alone or in combination with an antidepres-
sant or mood stabilizer, was associated with a
lower risk of postpartum mood episodes (18%
versus 57%) than treatment with antidepressants,
mood stabilizers, or no medication for a minimum
of 4 weeks after delivery (71). An open-label trial
found that divalproex was not significantly more
effective than monitoring without pharmacothera-
py for the prevention of postpartum episodes of
BD (72).
Issues in the management of bipolar disorder in children
and adolescents
Acute and maintenance treatment of pediatric bipo-
lar disorder
Lithium. In an RCT, pediatric patients with BD
who were in remission with the combination of
lithium and divalproex were randomized to dis-
continue 1 agent (73). There was no significant
difference in relapse or discontinuation rates be-
tween lithium or divalproex maintenance therapy
over 76 weeks (Level 2) (73).
Divalproex. As mentioned above, divalproex was
as effective as lithium for maintenance treatment in
pediatric patients (Level 2) (73). Open-label data
also suggested the efficacy of divalproex in pediat-
ric patients with mixed mania over a 6-month
period (74).
Atypical antipsychotics. A large RCT in adoles-
cents demonstrated that olanzapine was signifi-
cantly more effective than placebo (Level 2) (75). In
addition, olanzapine was found to be as effective as
risperidone in an open trial in preschool-age
children (aged 4–6 years) (76).
Previous data showed that the combination of
quetiapine plus divalproex was more effective than
divalproex alone in mania (77). More recently, an
RCT in adolescents showed that response rates for
manic symptoms were higher with quetiapine
monotherapy compared to divalproex monothera-
py, and onset of symptom improvement occurred
more rapidly (Level 2) (78).
Additional open trials support the efficacy of
risperidone in acute and 6- to 10-month mainte-
nance treatment for children and adolescent patients
(Level 3) (79, 80), including preschool-age children
(4–6 years) (76).
CANMAT guidelines for bipolar disorder
Retrospective chart review data suggest the
efficacy of aripiprazole in children and adolescents
(Level 4) (81, 82). However, adverse events may
limit its use in younger children (81). Aripiprazole
continues to be unavailable in Canada, so recom-
mendations are based on the reported efficacy data
and adverse event profile of these agents.
Lamotrigine. In an open trial, lamotrigine as
monotherapy or as an add-on to current medica-
tions was found to be effective in adolescents with
BD depression, with no significant adverse events
(Level 3) (83).
Other therapies. An RCT suggested the therapeu-
tic benefit of topiramate monotherapy in children
and adolescents with mania (84). However, the
trial was discontinued prematurely when studies of
topiramate in adults failed to show efficacy, and
was inadequately powered to yield conclusive
results (84). A case series suggested there may
be some benefit with adjunctive topiramate in
hospitalized pediatric patients (85). In a small
case series of pediatric patients with BD and
attention-deficit hyperactivity disorder (ADHD),
a common comorbidity, the addition of ato-
moxetine to mood stabilizers was an effective
therapy for ADHD without inducing hypo/manic
episodes (86).
Issues in the management of bipolar disorder in older
patients
Comorbidity. A recent survey confirmed that there
is a high prevalence of alcohol use disorders (38%)
in older patients with BD, but that this is lower
than in younger patients (87). Dysthymia (7%),
generalized anxiety disorder (9.5%) and panic
disorder (12%) were also common 12-month
comorbidities, but again, the rates of dysthymia
and panic disorder were lower than those seen in
younger patients.
Treatment of bipolar disorder in older adults. In a
pilot study of elderly patients with BD, treatment
based on the Systematic Treatment Enhancement
Program for Bipolar Disorder (STEP-BD) stand-
ardized protocols resulted in symptom reduction;
however, most older patients did not experience a
sustained remission (88).
Issues in the management of bipolar disorder in patients
with comorbid psychiatric conditions
Substance abuse disorders. Divalproex was previ-
ously demonstrated to have efficacy in patients
729
Yatham et al.
with substance abuse disorders without BD. In an
RCT in acutely ill patients with both BD and
substance abuse disorder, specifically alcoholism,
divalproex significantly decreased heavy drinking
compared to placebo (89).
Issues in the management of bipolar disorder in patients
with comorbid medical conditions
Prevalence and impact. The burden of medical
comorbidity in patients with BD is significant. In 1
survey, 44% of patients had at least 1 comorbid
medical condition (90). As expected the prevalence
of comorbid medical conditions increases with age,
from 30% among those in their 20s, to 50% in
those in their 50s, and 67% in those in their 70s
(90). Comorbid medical conditions complicate the
diagnosis and management of the illness, have a
negative impact on patient outcomes, overall
general health, and quality of life, and may
contribute to higher mortality rates (90–95). A
population-based study found that the most fre-
quent cause of excess deaths among patients with
BD was comorbid medical illness, with a twofold
increase in mortality from natural causes compared
to the general population (93). Common comorbid
general medical conditions include: overweight/
obesity, type 2 diabetes, cardiovascular disease,
obesity, migraine, hepatitis C, HIV, dementia,
lower back pain, chronic obstructive pulmonary
disease (COPD), asthma, and allergies (Table 6.7)
(91, 96–103).
Compared to the general population, patients
with BD are up to twice as likely to die of
cardiovascular disease (93, 94, 104, 105). This may
be related to the increased risk of obesity, diabetes
and metabolic syndrome. A high risk of developing
type 2 diabetes is well documented in patients with
BD, with reported rates of 9.9–26% (91, 106, 107)
compared to 2.8–3.4% in the general population
(106, 108). The risk of metabolic syndrome is also
elevated to 30–56% (109, 110) among patients with
BD, compared to about 24% (111) in the general
population (USA data). Metabolic syndrome is a
constellation of abnormalities including abdominal
obesity, hypertension, dyslipidemia, insulin resist-
Table 6.7. Medical conditions occurring more frequently in patients with
bipolar disorder compared to the general population
• Type 2 diabetes • Hepatitis C
• Metabolic syndrome • HIV
• Cardiovascular disease • Lower back pain
• Obesity • Asthma
• Chronic obstructive pulmonary disease • Allergies
• Migraine • Dementia
730
ance, and dysglycemia (see Section 8) (112, 113).
Patients with the metabolic syndrome are at
significant risk of developing diabetes, coronary
heart disease, and stroke. While the risk of diabetes
and metabolic syndrome is elevated in patents with
BD in general, there is additional risk for patients
taking antipsychotic medications.
In the Canadian Community Health Survey
(CCHS), individuals with a lifetime history of a
mood disorder were more likely to be obese (body
mass index, BMI > 30) than were individuals
without a mood disorder (19% and 15%, respec-
tively; p < 0.001) (114). The higher risk of
obesity associated with a mood disorder was
significant in women but not in men. Other
surveys have reported that 58–68% of patients
with BD were either overweight or obese
(BMI ‡ 25) (115, 116).
Being overweight or obese is among the most
common factors influencing the development of
high blood pressure and diabetes (117). In addi-
tion, obesity and overweight have a significant
negative impact on the course of bipolar illness and
health-related quality of life (115, 116, 118).
Obesity is associated with more manic episodes,
arthritis, diabetes, suicide, and cancer, and limited
occupational functioning, while both overweight
status and obesity were associated with more
hypertension compared to normal weight status
(115).
Migraine is another common comorbidity in
patients with BD, with a prevalence of 24–44%
(100, 119–122) compared to about 10% in the
general population (121). The rate of migraine
was even higher in patients with BD II, at 65–
77% (120, 122). The prevalence of comorbid
migraine in BD was higher in women (34.7%)
than in men (14.9%) (121). Bipolar patients with
migraine had a greater number of anxiety disor-
ders (121, 123), higher use of health care
resources, and greater dysfunction compared to
those without (121).
Patients with BD are at increased risk of
developing dementia, and the risk increases with
increasing number of episodes (102, 103). Hepatitis
C (5.9% versus 1.1%) (91) and HIV (0.8% versus
0.5%) are more common in patients with BD,
which may be the result of the high prevalence of
substance use disorders, including intravenous
street drug use (124). Other conditions that are
more common among patients with BD than in
the general population include lower back pain
(15.4% versus 10.6%) (91), COPD (10.6% versus
9.4%) (91), asthma (17% versus 10%) (100),
and allergies (42% versus 29%) (100). Not
surprisingly, BD patients have health care costs

that are more than double those of general medical
outpatients (125).
Clearly it is imperative that patients with BD are
assessed for possible comorbid conditions (see
Section 8), especially those that occur frequently
in this patient group, as the presence of another
illness can affect pharmacotherapeutic choice.
Treatment of bipolar disorder in patients with medical
comorbidities
Few studies have been conducted on the manage-
ment of comorbid medical conditions in patients
with BD. However, choice of therapy in such
patients should consider any evidence of benefit
or harm on both the BD and the comorbid
condition.
Increased cardiovascular risk in patients with
BD should be an important consideration. Many
atypical antipsychotics have the potential to
increase cardiovascular risk by causing weight
gain, dyslipidemia, metabolic syndrome, and dia-
betes (see Section 8). Analysis of 2 RCTs showed
that lithium was also associated with weight gain,
while lamotrigine was weight-neutral (126).
Adjunctive topiramate may be beneficial in con-
trolling lithium, divalproex or olanzapine-associ-
ated weight gain in patients with BD (127–129).
However, metformin was not effective in the
prevention of olanzapine-associated weight gain
in patients with schizophrenia (130).
Long-term lithium treatment appears to have a
positive effect, if only indirectly, on reducing
the incidence of cardiovascular disease among
patients with BD (131). In addition, long-term
treatment with lithium, antipsychotics or tricyclic
antidepressants was associated with reduced
overall mortality compared to not taking these
medications for more than 6 months (132). Com-
binations of these medications were associated
with greater reductions in mortality compared to
monotherapy.
While divalproex (133), topiramate (133) and
gabapentin (133) have shown utility in treating
migraine, no studies of these drugs have yet been
Table 7.2. Recommendations for pharmacological treatment of acute bipolar II depression
Options Treatments
First-line Insufficient evidence
Second-line Lithium, lamotrigine, lithium or divalproex + antidepressants, lithium + divalproex, atypical
antipsychotics + antidepressants, quetiapinea
Third-line Switch to alternate antidepressant
Not recommended See text on antidepressants for recommendations regarding antidepressant monotherapy
a
New.
CANMAT guidelines for bipolar disorder
reported in patients with BD. Similarly, some
treatments used for BD have been studied in
patients with dementia (134, 135). A retrospective
analysis found that divalproex had a beneficial
effect on behavioral, mood and cognitive measures
in elderly nursing home residents with dementia
(134). However, an RCT in patients with psychotic
symptoms associated with dementia failed to show
any superior benefit of olanzapine or risperidone
over placebo in improving neuropsychiatric func-
tioning (135).
Topiramate has been associated in case reports
with various medical conditions, including meta-
bolic acidosis (136–139), nephrolithiasis (140–142),
and glaucoma (143–145), while oxcarbazepine has
been linked to the induction of the syndrome of
inappropriate antidiuretic hormone secretion (SI-
ADH) (146).
Section 7. Bipolar II disorder: acute and maintenance
management
Acute management of bipolar II depression
Atypical antipsychotics. The first ÔBOLDERÕ study
assessing quetiapine in bipolar depression has
now been published (25). In this report, the effect
size on Montgomery Asberg Depression Rating
Scale (MADRS) in the bipolar I sample was very
large (1.09 and 0.91 on 600 and 300 mg, respec-
tively), with a smaller effect size in the bipolar II
sample (0.39 and 0.28, respectively) (Level 2,
negative) (25). Further analysis of the bipolar II
subgroup found that quetiapine was significantly
more effective than placebo in patients with BD II
and rapid cycling but not in those without rapid
cycling (147). The second BOLDER study,
recently presented in abstract form, showed
significant benefit in the patients with bipolar II
depression (Level 2) (26). A post hoc analysis,
pooling the patients with bipolar II depression
from both BOLDER trials, demonstrated benefits
in both rapid and non-rapid cycling depression,
with a moderate effect size on MADRS of 0.54 in
those on 600 mg and 0.45 in those on 300 mg
731
Yatham et al.

Table 7.4. Recommendations for maintenance treatment of bipolar II disorder

Options Treatments

First-line Lithium, lamotrigine

Second-line Divalproex, lithium or divalproex or atypical antipsychotic + antidepressant,
combination of 2 of: lithium, lamotrigine, divalproex, or atypical antipsychotic
Third-line Carbamazepine, atypical antipsychotic, ECT
Not recommended Gabapentin

ECT ¼ electroconvulsive therapy.

(148). Thus quetiapine monotherapy can be gain and obesity are shown in Table 8.2. Strategies
recommended as a second-line choice. Further for preventing and managing weight gain in
recommendation will await publication of these patients with BD should include diagnostic assess-
studies. ment of the risk factors for weight gain, regular
assessment of weight, BMI, and waist circumfer-
ence, as well as risk factors for cardiovascular
Maintenance therapy for bipolar II disorder
disease (Table 8.3). A survey showed that patients
Third-line options with BD had higher levels of total calorie and
Antidepressants. In a 6-month RCT in patients carbohydrate intake, and lower levels of physical
with BD II and bipolar not otherwise specified activity compared to age- and sex-matched con-
who had responded to fluoxetine, relapse rates trols (151). This emphasizes the importance of
were 43% with continued fluoxetine and 100% recommending a healthy diet and exercise regimen.
with placebo, but the sample size was too small to Practitioners choosing therapies for the manage-
show statistical significance. Although no hypo-
manic switch was observed, there was a signifi-
cantly greater mean increase in manic symptom Table 8.2. Risk factors for weight gain and obesity
scores with fluoxetine (149).
• Increased age • Coffee consumption
• Male gender • Comorbid binge-eating disorder
Section 8. Safety and monitoring • Income level • Number of previous
depressive episodes
The 2005 CANMAT guidelines for the manage- • Excessive carbohydrate • Treatment with medications
ment of bipolar disorder provided general recom- consumption associated with weight gain
alone or in combination
mendations for initial and follow-up laboratory • Low rates of exercise
investigations and monitoring for patients with BD
(1). A recent study suggested that there is a linear From (96, 115).
relationship between serum valproate levels and
therapeutic efficacy (150). However, there have also
been concerns that maintenance therapy with
Table 8.3. Strategies for preventing and treating obesity in patients with
valproate is associated with increased incidence of bipolar disorder
polycystic ovary syndrome and an erosion of bone
density (65). • Diagnostic assessment
It is becoming increasingly recognized that • Psychiatric comorbidity: binge-eating disorder, substance
use disorders
patients with BD are at increased risk of comorbid • Medical comorbidity: baseline body mass index, blood
medical conditions, which may be further increased pressure, fasting glucose, triglycerides, lipids
by some of the treatments for BD (see Section 6). • Family history: obesity, type 2 diabetes mellitus,
Several risk factors for cardiovascular disease are hypertension, cardiovascular disease
elevated in patients with BD, particularly with • Prevention
• Healthy diet
atypical antipsychotic treatment; these include • Minimum weekly exercise regimen
overweight/obesity, diabetes, metabolic syndrome, • Treatment
and dyslipidemia. • Consider choice of pharmacotherapy for bipolar disorder
based on evidence of efficacy from randomized,
controlled trials and side effects
Overweight and obesity • Pharmacotherapy: orlistat, sibutramine, topiramate,
metformin
Patients with BD have a greater risk of being
overweight and obesity. Risk factors for weight Reprinted with permission from (96).

732
 CANMAT guidelines for bipolar disorder

ment of BD should consider those that have a Table 8.6. National Cholesterol Education Program Adult Treatment Panel
lower risk of weight gain. Weight gain has been III (NCEP ATP III) criteria for metabolic syndrome (‡ 3 of the following)
associated with lithium, divalproex and, to varying Risk factor Defining level
degrees, with the atypical antipsychotics (1).
Abdominal obesity Waist circumference
Men > 102 cm
Metabolic syndrome and type 2 diabetes Women > 88 cm
Fasting plasma glucose ‡ 6.1 mmol/L
Patients with BD appear to be at higher risk of Blood pressure ‡ 130/85 mmHg
developing hyperglycemia, metabolic syndrome, Triglyceride ‡ 1.7 mmol/L
and type 2 diabetes compared to the general HDL-C
Men < 1.0 mmol/L
population (see Section 6). This puts bipolar Women < 1.3 mmol/L
patients with diabetes at even higher risk of
cardiovascular events. Several studies report an HDL-C ¼ high-density lipoprotein cholesterol.
elevated risk of diabetes and hyperglycemia in Adapted from (112).
patients treated with atypical antipsychotics. The
risk appears to be higher with clozapine and be assessed for a diagnosis of diabetes (Table 8.5)
olanzapine and lower with risperidone, quetiapine, or metabolic syndrome (Table 8.6). The Canadian
ziprasidone and conventional antipsychotics (152– Diabetes Association recommends screening for
154). diabetes using fasting plasma glucose (FPG) be
Patients with BD, particularly those on atypical performed every 3 years in individuals ‡ 40 years
antipsychotics or those with additional risk factors of age, with more frequent or earlier testing
for the development of diabetes (Table 8.4), should with either an FPG or 2hPG in a 75-g oral
glucose tolerance test (OGTT) being considered
in people with additional risk factors for diabetes
Table 8.4. Risk factors for type 2 diabetes and metabolic syndrome (Table 8.4). The American Diabetes Association
recommended a schedule of follow-up monitoring
• Age ‡ 40 years • Vascular disease for patients on atypical antipsychotics (Table 8.7)
• First-degree relative with diabetes • Hypertension
• Member of high-risk population • Dyslipidemia
(155).
(e.g., Aboriginal, Hispanic, • Overweight
South Asian, Asian, African) • Abdominal obesity
• Presence of complications • Schizophrenia
Dyslipidemia
associated with diabetes • Polycystic ovary Dyslipidemia is also an important cardiovascular
• History of impaired fasting glucose, syndrome
or impaired glucose tolerance • Acanthosis nigricans
risk factor, with data suggesting that 48–71% of
• History of gestational diabetes patients with BD have dyslipidemia (109, 110).
• History of delivery of a macrosomic Patients treated with atypical antipsychotics will
infant generally experience some degree of elevation of
low density lipoprotein (LDL) cholesterol and
Adapted from (156).
triglyceride levels and a decrease in high-density
lipoprotein (HDL) cholesterol levels (1, 157, 158).
Table 8.5. Canadian Diabetes Association criteria for diagnosis of diabetes
Mood stabilizers may also cause dyslipidemia
(157). A meta-analysis examining the effects of
FPG ‡ 7.0 mmol/L atypical antipsychotics on lipid levels in patients
Fasting ¼ no caloric intake for at least 8 h with schizophrenia included 5 studies and more
or
Casual PG ‡ 11.1 mmol/L + symptoms of diabetes than 50,000 patients (158). The risks [odds ratio
Casual ¼ any time of the day, without regard to the interval since (OR)] of dyslipidemia with the different agents
the last meal were: clozapine, 1.47 (1.12–1.93), olanzapine, 1.41
Classic symptoms of diabetes ¼ polyuria, polydipsia, and (1.14–1.74), quetiapine 1.19 (1.11–1.28), risperi-
unexplained weight loss done 1.12 (1.00–1.26), ziprasidone 1.1 (0.94–1.29),
or
2hPG in a 75-g OGTT ‡ 11.1 mmol/L
and aripiprazole 0.82 (0.67–1.00). An RCT with 6–
12-month follow-up found striking differences in
A confirmatory laboratory glucose test (an FPG, casual PG, or a the effects of olanzapine and risperidone on lipid
2hPG in a 75-g OGTT) must be done in all cases on another day levels (159). Mean triglyceride levels and triglycer-
in the absence of unequivocal hyperglycemia accompanied by ide/HDL-C ratios decreased with risperidone, but
acute metabolic decompensation.
FPG ¼ fasting plasma glucose; OGTT ¼ oral glucose tolerance
significantly increased with olanzapine. The increas-
test. es in lipids in the olanzapine group were not
Reprinted with permission from (156). associated with BMI or change in BMI.
733
Yatham et al.

Table 8.7. Monitoring protocol for patients on second-generation antipsychoticsa

Baseline 4 weeks 8 weeks 12 weeks Quarterly Annually Every 5 years

Personal/family history X X
Weight (body mass index) X X X X X
Waist circumference X X
Blood pressure X X X
Fasting plasma glucose X X X
Fasting lipid profile X X X

a
More frequent assessments may be warranted based on clinical status.
Reprinted with permission from (155).

Table 8.8. Canadian recommendations for the management of dyslipidemia

Target level

LDL-C level Total cholesterol

Risk category (10-year risk of coronary artery disease) (mmol/L) HDL-C ratio

High (‡ 20%, or history of diabetes mellitusa or any < 2.5 and < 4.0
atherosclerotic disease)
Moderate (11–19%) < 3.5 and < 5.0
Low (£ 10%) < 4.5 and < 6.0

LDL-C ¼ low-density lipoprotein cholesterol; HDL-C ¼ high-density lipoprotein cholesterol.

a
Includes patients with chronic kidney disease and those on long-term dialysis.
Reprinted with permission from (160).

Canadian recommendations for the management Department of Psychiatry, University of Montreal,

of dyslipidemia emphasize treating to lipid targets
based on cardiovascular risk factors (including
gender, age, systolic blood pressure, smoking sta-
tus, total cholesterol and HDL-C) (160) (Table 8.8).
The CANMAT group recommends a collabo-
rative care model that not only includes a multidis-
ciplinary psychiatry team, but also a family
physician, an endocrinologist and a dietician, for
the management of patients with BD and cardio-
vascular risk factors or metabolic abnormalities.
Although the evidence base remains limited, there
are a growing number of self-help, Internet-based,
education and exercise programs available for
patients with BD.
Appendix
CANMAT Guidelines Group
Co-chairs. Lakshmi N Yatham, Sidney H Kennedy
Section leaders. Claire O’Donovan, Sagar Parikh,
Glenda MacQueen, Roger S McIntyre, Verinder
Sharma, Serge Beaulieu
Committee members. Martin Alda, Department of
Psychiatry, Dalhousie University, Halifax, NS;
Philippe Baruch, Department of Psychiatry, Laval
University, Quebec City, QC; Andree Daigneault,
734
QC; Roumen Milev, Department of Psychiatry,
Queen’s University, Kingston, ON; L Trevor
Young, Department of Psychiatry, University of
Toronto, Toronto, ON; Arun Ravindran, Depart-
ment of Psychiatry, University of Toronto,
Toronto, ON; Ayal Schaffer, Department of
Psychiatry, University of Toronto, Toronto, ON;
Mary Connolly, Mood Disorders Service, Victoria,
BC; Chris P Gorman, University of Calgary,
Calgary, AB, Canada.
References
1. Yatham LN, Kennedy SH, O’Donovan C et al. Canadian
Network for Mood and Anxiety Treatments (CANMAT)
guidelines for the management of patients with bipolar
disorder: consensus and controversies. Bipolar Disord
2005; 7 (Suppl. 3): 5–69.
2. Simon GE, Ludman EJ, Bauer MS, Unutzer J, Operskal-
ski B. Long-term effectiveness and cost of a systematic
care program for bipolar disorder. Arch Gen Psychiatry
2006; 63: 500–508.
3. Bauer M, McBride L, Williford W et al. Collaborative
care for bipolar disorder, Part II: impact clinical
outcome, function, and costs. Psychiatr Serv 2006; 59:
937–945.
4. Suppes T, Mintz J, McElroy SL et al. Mixed hypomania
in 908 patients with bipolar disorder evaluated prospec-
tively in the Stanley Foundation Bipolar Treatment
Network: a sex-specific phenomenon. Arch Gen Psychi-
atry 2005; 62: 1089–1096.

5. Akiskal HS, Benazzi F, Perugi G, Rihmer Z. Agitated
ÔunipolarÕ depression re-conceptualized as a depressive
mixed state: implications for the antidepressant-suicide
controversy. J Affect Disord 2005; 85: 245–258.
6. Cipriani A, Pretty H, Hawton K, Geddes J. Lithium in the
prevention of suicidal behavior and all-cause mortality in
patients with mood disorders: a systematic review of
randomized trials. Am J Psychiatry 2005; 162: 1805–1819.
7. Kessing L, Sondergard L, Kvist K, Andersen P. Suicide
risk in patients treated with lithium. Arch Gen Psychiatry
2005; 62: 860–866.
8. Bowden C, Calabrese J, Swann A et al. Divalproex
Sodium, Extended-Release Versus Placebo in the Treat-
ment of Acute Mania. New Research Abstracts, Annual
Meeting of the American Psychiatric Association,
Toronto, May 20–25, 2006 [Abstract NR186].
9. Khanna S, Vieta E, Lyons B et al. Risperidone in the
treatment of acute mania: double-blind, placebo-con-
trolled study. Br J Psychiatry 2005; 187: 229–234.
10. Gopal S, Steffens D, Kramer M, Olsen M. Symptomatic
remission in patients with bipolar mania: results from a
double-blind, placebo-controlled trial of risperidone
monotherapy. J Clin Psychiatry 2005; 66: 1016–1020.
11. Segal S, Riesenberg R, Ice K, English P. Ziprasidone in
mania: a 21-day randomized, double-blind, placebo-con-
trolled trial. J Eur Coll Neuropsychopharmacol 2003; 13
(Suppl. 4): 345 [Abstract P.2.152].
12. Potkin S, Keck P, Segal S, Ice K, English P. Ziprasidone
in acute bipolar mania: a 21-day randomized, double-
blind, placebo-controlled replication trial. J Clin Psycho-
pharmacol 2005; 25: 301–310.
13. Keck P, Versiani M, Potkin S et al. Ziprasidone in the
treatment of acute bipolar mania: a 3-week, placebo-
controlled, double-blind, randomized trial. Am J Psychi-
atry 2003; 160: 741–748.
14. Ramey T, Murray S, Giller E et al. Ziprasidone efficacy
and safety in acute bipolar mania: 12-week study. Eur
Neuropsychopharmacol 2005; 15: 440 [Abstract].
15. Hadjakis W, Marcus R, Abou-Gharbia N et al. Aripip-
razole in acute mania: results from a second placebo-
controlled study. Bipolar Disord 2004; 6 (Suppl.): 39–40
[Abstract 351].
16. Bourin M, Auby P, Marcus R et al. Aripiprazole Versus
Haloperidol for Maintained Treatment Effect in Acute
Mania. Presented at the 156th American Psychiatric
Association Annual Meeting, San Francisco, CA, May
17–22, 2003 [Abstract NR467].
17. Sachs G, Sanchez R, Marcus R et al. Aripiprazole in the
treatment of acute manic or mixed episodes in patients
with bipolar I disorder: a 3-week placebo-controlled
study. J Psychopharmacol 2006; 20: 536–546.
18. Vieta E, Bourin M, Sanchez R et al. Effectiveness of
aripiprazole versus haloperidol in acute bipolar mania:
double-blind, randomized, comparative 12-week trial. Br
J Psychiatry 2005; 187: 235–242.
19. Weisler R, Keck P, Swann A et al. Extended-release
carbamazepine capsules as monotherapy for acute mania
in bipolar disorder: a multicenter, randomized, double-
blind, placebo-controlled trial. J Clin Psychiatry 2005; 66:
323–330.
20. Conway C, Chibnall J, Nelson L et al. An open-label trial
of adjunctive oxcarbazepine for bipolar disorder. J Clin
Psychopharmacol 2006; 26: 95–97.
21. Pratoomsri W, Yatham L, Sohn C, Solomons K, Lam R.
Oxcarbazepine add-on in the treatment of refractory
bipolar disorder. Bipolar Disord 2005; 7 (Suppl. 5): 37–
42.
CANMAT guidelines for bipolar disorder
22. Calabrese J, Bowden C, Sachs G et al. A double-blind
placebo-controlled study of lamotrigine monotherapy in
outpatients with bipolar I depression. Lamictal 602 Study
Group. J Clin Psychiatry 1999; 60: 79–88.
23. Frye M, Ketter T, Kimbrell T et al. A placebo-controlled
study of lamotrigine and gabapentin monotherapy in
refractory mood disorders. J Clin Psychopharmacol 2000;
20: 607–614.
24. Brown E, McElroy S, Keck P et al. A 7-week comparison
of olanzapine/fluoxetine combination versus lamotrigine
in the treatment of bipolar I depression. J Clin Psychiatry
2006; 67: 1025–1033.
25. Calabrese JR, Keck PE Jr, Macfadden W et al. A
randomized, double-blind, placebo-controlled trial of
quetiapine in the treatment of bipolar I or II depression.
Am J Psychiatry 2005; 162: 1351–1360.
26. Thase M, McCoy R, Chang W, Macfadden W. Efficacy of
Quetiapine Monotherapy in Bipolar Depression: A Con-
firmatory Double-blind, Placebo-controlled Study (The
BOLDER II Study). New Research Abstracts, Annual
Meeting of the American Psychiatric Association,
Toronto, May 20–25, 2006 [Abstract NR600].
27. Macfadden W, Endicott J, Rajagopalan K, Minkwitz M,
Gaddy J. Efficacy of quetiapine in improving quality of
life in patients with bipolar depression. Eur Neuropsy-
chopharmacol 2005; 15: 410 [Abstract P.2.044].
28. Tohen M, Vieta E, Calabrese J et al. Efficacy of olanza-
pine and olanzapine-fluoxetine combination in the treat-
ment of bipolar I depression. Arch Gen Psychiatry 2003;
60: 1079–1088.
29. Amsterdam J, Shults J. Comparison of fluoxetine, olanza-
pine, and combined fluoxetine plus olanzapine initial
therapy of bipolar type I and type II major depression –
lack of manic induction. J Affect Disord 2005; 87: 121–130.
30. Schaffer A, Zuker P, Levitt A. Randomized, Double-
blind, Pilot Trial Comparing Lamotrigine Versus Citalo-
pram for the Treatment of Bipolar Depression. New
Research Abstracts, Annual Meeting of the American
Psychiatric Association, Toronto, May 20–25, 2006
[Abstract NR283].
31. Nierenberg A, Ostacher M, Calabrese J et al. Treatment-
resistant bipolar depression: a STEP-BD equipoise rand-
omized effectiveness trial of antidepressant augmentation
with lamotrigine, inositol, or risperidone. Am J Psychiatry
2006; 163: 210–216.
32. Calabrese J, Markovitz P, Kimmel S, Wagner S. Spectrum
of efficacy of valproate in 78 rapid-cycling bipolar
patients. J Clin Psychopharmacol 1992; 12: 53–56.
33. Winsberg M, De Golia S, Strong C, Ketter T. Divalproex
therapy in medication-naive and mood stabilizer-naive
bipolar II depression. J Affect Disord 2001; 67: 207–212.
34. Davis L, Bartolucci A, Petty F. Divalproex in the
treatment of bipolar depression: a placebo-controlled
study. J Affect Disord 2005; 85: 259–266.
35. Frangou S, Lewis M, McCrone P. Efficacy of ethyl-
eicosapentaenoic acid in bipolar depression: randomized
double-blind placebo-controlled study. Br J Psychiatry
2006; 188: 46–50.
36. Zarate C, Quiroz J, Singh J et al. An open-label trial of
the glutamate-modulating agent riluzole in combination
with lithium for the treatment of bipolar depression. Biol
Psychiatry 2005; 57: 430–432.
37. McIntyre R, Mancini D, McCann S et al. Topiramate
versus bupropion SR when added to mood stabilizer
therapy for the depressive phase of bipolar disorder: a
preliminary single-blind study. Bipolar Disord 2002; 4:
207–213.
735
Yatham et al.
38. Leverich GS, Altshuler LL, Frye MA et al. Risk of
switch in mood polarity to hypomania or mania in
patients with bipolar depression during acute and
continuation trials of venlafaxine, sertraline, and
bupropion as adjuncts to mood stabilizers. Am J
Psychiatry 2006; 163: 232–239.
39. Colom F, Vieta E. Efficacy of Group Psychoeducation
in Bipolar Disorders: 5-Year Outcome. New Research
Abstracts, Annual Meeting of the American Psychiatric
Association, Toronto, May 20–25, 2006 [Abstract
NR27].
40. Lam DH, Hayward P, Watkins ER, Wright K, Sham P.
Relapse prevention in patients with bipolar disorder:
cognitive therapy outcome after 2 years. Am J Psychiatry
2005; 162: 324–329.
41. Scott J, Paykel E, Morriss R et al. Cognitive-behavioral
therapy for severe and recurrent bipolar disorders:
randomized controlled trial. Br J Psychiatry 2006; 188:
313–320.
42. Frank E, Kupfer DJ, Thase ME et al. Two-year outcomes
for interpersonal and social rhythm therapy in individuals
with bipolar I disorder. Arch Gen Psychiatry 2005; 62:
996–1004.
43. Tohen M, Bowden C, Calabrese J et al. Olanzapine
Versus Placebo for Relapse Prevention in Bipolar Disor-
der. Presented at 156th American Psychiatric Association
Annual Meeting, San Francisco, CA, May 17–22, 2003
[Abstract NR197].
44. Tohen M, Calabrese J, Sachs G et al. Randomized,
placebo-controlled trial of olanzapine as maintenance
therapy in patients with bipolar I disorder responding to
acute treatment with olanzapine. Am J Psychiatry 2006;
163: 247–256.
45. Tohen M, Greil W, Calabrese JR et al. Olanzapine versus
lithium in the maintenance treatment of bipolar disorder:
a 12-month, randomized, double-blind, controlled clinical
trial. Am J Psychiatry 2005; 162: 1281–1290.
46. Ketter T, Houston J, Adams D et al. Differential efficacy
of olanzapine and lithium in preventing manic or mixed
recurrence in patients with bipolar I disorder based on
number of previous manic or mixed episodes. J Clin
Psychiatry 2006; 67: 95–101.
47. Filovska V, Jackovcevska M, Krsteska R. Lithium and
carbamazepin in long-term treatment of bipolar disorder.
Eur Neuropsychopharmacol 2005; 15: 634 [Abstract
P.8.064].
48. Milev R, Abraham G, Zaheer J. Add-on quetiapine for
bipolar depression: a 12-month open-label trial. Can
J Psychiatry 2006; S1: 523–530.
49. Hardoy M, Garofalo A, Carpiniello B, Calabrese J, Carta
M. Combination quetiapine therapy in the long-term
treatment of patients with bipolar I disorder. Clin Pract
Epidemol Ment Health 2005; 1: 7.
50. Pae C, Kim T, Kim J et al. Long-term treatment of
adjunctive quetiapine for bipolar mania. Prog Neuropsy-
chopharmacol Biol Psychiatry 2005; 29: 763–766.
51. Hardoy M, Carta M, Garofalo A, Calabrese J. Quetiapine
in long-term add-on therapy of patients with bipolar I
disorder inadequately responsive to treatment. Eur Neu-
ropsychopharmacol 2005; 15: 465 [Abstract P.3.025].
52. Baethge C, Baldessarini R, Mathiske-Schmidt K et al.
Long-term combination therapy versus monotherapy with
lithium and carbamazepine in 46 bipolar I patients. J Clin
Psychiatry 2005; 66: 174–182.
53. Brown E, Dunner D, Adams D et al. Olanzapine/
Fluoxetine Combination Versus Lamotrigine in the
Long-term Treatment of Bipolar I Depression. New
736
Research Abstracts, Annual Meeting of the American
Psychiatric Association, Toronto, May 20–25, 2006
[Abstract NR189].
54. Vieta E, Goikolea J, Martı́nez-Arán A et al. Double-
blind, randomized, placebo-controlled, prophylaxis study
of adjunctive gabapentin for bipolar disorder. J Clin
Psychiatry 2006; 67: 473–477.
55. Calabrese J, Suppes T, Bowden C 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: 841–850.
56. A multicenter, double-blind, placebo-controlled, flexible-
dose evaluation of the safety and efficacy of lamotrigine in
the long term treatment of subjects who have bipolar
disorder with rapid cycling. GlaxoSmithKline Clinical
Trial Register. Aug 18, 2005. http://ctr.gsk.co.uk/Sum-
mary/lamotrigine/II_SCAB2005.pdf [accessed on 24 Aug
2006].
57. Goldsmith DR, Wagstaff AJ, Ibbotson T, Perry CM.
Lamotrigine: a review of its use in bipolar disorder. Drugs
2003; 63: 2029–2050.
58. Calabrese J, Rapport D, Youngstrom E et al. New data
on the use of lithium, divalproate, and lamotrigine in
rapid cycling bipolar disorder. Eur Psychiatry 2005; 20:
92–95.
59. Tohen M, Ketter T, Zarate C et al. Olanzapine versus
divalproex sodium for the treatment of acute mania and
maintenance of remission: a 47-week study. Am J Psychi-
atry 2003; 160: 1263–1271.
60. Suppes T, Brown E, Schuh L, Baker R, Tohen M. Rapid
versus non-rapid cycling as a predictor of response to
olanzapine and divalproex sodium for bipolar mania and
maintenance of remission: post hoc analyses of 47-week
data. J Affect Disord 2005; 89: 69–77.
61. Rasgon NL, Altshuler LL, Gudeman D et al. Medication
status and polycystic ovary syndrome in women with
bipolar disorder: a preliminary report. J Clin Psychiatry
2000; 61: 173–178.
62. O’Donovan C, Kusumakar V, Graves GR, Bird DC.
Menstrual abnormalities and polycystic ovary syndrome
in women taking valproate for bipolar mood disorder.
J Clin Psychiatry 2002; 63: 322–330.
63. McIntyre R, Mancini D, McCann S, Srinivasan J,
Kennedy S. Valproate, bipolar disorder and polycystic
ovarian syndrome. Bipolar Disord 2003; 5: 28–35.
64. Rasgon NL, Altshuler LL, Fairbanks L et al. Reproduc-
tive function and risk for PCOS in women treated for
bipolar disorder. Bipolar Disord 2005; 7: 246–259.
65. Joffe H, Cohen LS, Suppes T et al. Valproate is associated
with new-onset oligoamenorrhea with hyperandrogenism
in women with bipolar disorder. Biol Psychiatry 2006; 59:
1078–1086.
66. Misri S, Kostaras D, Kostaras X. The use of selective
serotonin reuptake inhibitors during pregnancy and lac-
tation: current knowledge. Can J Psychiatry 2000; 45:
285–287.
67. Gentile S. The safety of newer antidepressants in preg-
nancy and breastfeeding. Drug Saf 2005; 28: 137–152.
68. The Health Products and Food Branch. Important safety
information on Paxil (paroxetine) and possible increased
risk of birth defects. Health, Canada. http://www.
hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/pax-
il_3_hpc-cps_e.html [accessed on 12 Oct 2005].
69. Newport DJ, Viguera AC, Beach AJ et al. Lithium
placental passage and obstetrical outcome: implications
for clinical management during late pregnancy. Am
J Psychiatry 2005; 162: 2162–2170.

70. Blackmore E, Jones I, Doshi M et al. Obstetric variables
associated with bipolar affective puerperal psychosis. Br
J Psychiatry 2006; 188: 32–36.
71. Sharma V, Smith A, Mazmanian D. Olanzapine in the
prevention of postpartum psychosis and mood epi-
sodes in bipolar disorder. Bipolar Disord 2006; 8: 400–
404.
72. Wisner KL, Hanusa BH, Peindl KS, Perel JM. Prevention
of postpartum episodes in women with bipolar disorder.
Biol Psychiatry 2004; 56: 592–596.
73. Findling R, McNamara N, Youngstrom E et al.
Double-blind 18-month trial of lithium versus divalp-
roex maintenance treatment in pediatric bipolar disor-
der. J Am Acad Child Adolesc Psychiatry 2005; 44:
409–417.
74. Pavuluri M, Henry D, Carbray J, Naylor M, Janicak P.
Divalproex sodium for pediatric mixed mania: a 6-month
prospective trial. Bipolar Disord 2005; 7: 266–273.
75. Tohen M, Kryzhanovskaya L, Carlson G et al. Olanza-
pine in the Treatment of Acute Mania in Adolescents with
Bipolar I Disorder: A 3-week, Randomized, Double-blind
Placebo-controlled Study. New Research Abstracts,
Annual Meeting of the American Psychiatric Association,
Toronto, May 20–25, 2006 [Abstract NR291].
76. Biederman J, Mick E, Hammerness P et al. Open-label,
8-week trial of olanzapine and risperidone for the treat-
ment of bipolar disorder in preschool-age children. Biol
Psychiatry 2005; 58: 589–594.
77. Delbello M, Schwiers M, Rosenberg H, Strakowski S. A
double-blind, randomized, placebo-controlled study of
quetiapine as adjunctive treatment for adolescent mania.
J Am Acad Child Adolesc Psychiatry 2002; 41: 1216–1223.
78. DelBello MP, Kowatch RA, Adler CM et al. A double-
blind randomized pilot study comparing quetiapine and
divalproex for adolescent mania. J Am Acad Child
Adolesc Psychiatry 2006; 45: 305–313.
79. Biederman J, Mick E, Wozniak J et al. An open-label trial
of risperidone in children and adolescents with bipolar
disorder. J Child Adolesc Psychopharmacol 2005; 15:
311–317.
80. Biederman J, Mick E, Wozniak J et al. A prospective
open-label long-term treatment trial of risperidone
monotherapy in children and adolescents with bipolar
disorder. Eur Neuropsychopharmacol 2005; 15: 602
[Abstract P.7.024].
81. Rugino TA, Janvier YM. Aripiprazole in children and
adolescents: clinical experience. J Child Neurol 2005; 20:
603–610.
82. Biederman J, McDonnell MA, Wozniak J et al. Aripip-
razole in the treatment of pediatric bipolar disorder: a
systematic chart review. CNS Spectr 2005; 10: 141–148.
83. Chang K, Saxena K, Howe M. An open-label study of
lamotrigine adjunct or monotherapy for the treatment of
adolescents with bipolar depression. J Am Acad Child
Adolesc Psychiatry 2006; 45: 298–304.
84. Delbello MP, Findling RL, Kushner S et al. A pilot
controlled trial of topiramate for mania in children and
adolescents with bipolar disorder. J Am Acad Child
Adolesc Psychiatry 2005; 44: 539–547.
85. Barzman DH, DelBello MP, Kowatch RA et al. Adjunc-
tive topiramate in hospitalized children and adolescents
with bipolar disorders. J Child Adolesc Psychopharmacol
2005; 15: 931–937.
86. Hah M, Chang K. Atomoxetine for the treatment of
attention-deficit hyperactivity disorder in children and
adolescents with bipolar disorders. J Child Adolesc
Psychopharmacol 2005; 15: 996–1004.
CANMAT guidelines for bipolar disorder
87. Goldstein BI, Herrmann N, Shulman KI. Comorbidity in
bipolar disorder among the elderly: results from an
epidemiological community sample. Am J Psychiatry
2006; 163: 319–321.
88. Gildengers AG, Mulsant BH, Begley AE et al. A pilot
study of standardized treatment in geriatric bipolar
disorder. Am J Geriatr Psychiatry 2005; 13: 319–323.
89. Salloum I, Cornelius J, Daley D et al. Efficacy of
valproate maintenance in patients with bipolar disorder
and alcoholism: a double-blind placebo-controlled study.
Arch Gen Psychiatry 2005; 62: 37–45.
90. Beyer J, Kuchibhatla M, Gersing K, Krishnan KR.
Medical comorbidity in a bipolar outpatient clinical
population. Neuropsychopharmacology 2005; 30: 401–
404.
91. Kilbourne A, Cornelius J, Han X et al. Burden of general
medical conditions among individuals with bipolar disor-
der. Bipolar Disord 2004; 6: 368–373.
92. McIntyre RS, Konarski JZ, Misener VL, Kennedy SH.
Bipolar disorder and diabetes mellitus: epidemiology,
etiology, and treatment implications. Ann Clin Psychiatry
2005; 17: 83–93.
93. Osby U, Brandt L, Correia N, Ekbom A, Sparen P. Excess
mortality in bipolar and unipolar disorder in Sweden.
Arch Gen Psychiatry 2001; 58: 844–850.
94. Weeke A, Juel K, Vaeth M. Cardiovascular death and
manic-depressive psychosis. J Affect Disord 1987; 13:
287–292.
95. Fenn HH, Bauer MS, Altshuler L et al. Medical comor-
bidity and health-related quality of life in bipolar disorder
across the adult age span. J Affect Disord 2005; 86: 47–60.
96. Keck PE, McElroy SL. Bipolar disorder, obesity, and
pharmacotherapy-associated weight gain. J Clin Psychi-
atry 2003; 64: 1426–1435.
97. McIntyre R, Konarski J, Yatham L. Comorbidity in
bipolar disorder: a framework for rational treatment
selection. Hum Psychopharmacol 2004; 19: 369–386.
98. McElroy SL. Diagnosing and treating comorbid (compli-
cated) bipolar disorder. J Clin Psychiatry 2004; 65 (Suppl.
15): 35–44.
99. Sajatovic M. Bipolar disorder: disease burden. Am
J Manag Care 2005; 11: 80–84.
100. Calabrese J, Hirschfeld R, Reed M et al. Impact of
bipolar disorder on a US community sample. J Clin
Psychiatry 2003; 64: 425–432.
101. Matthews A, Hauser P. Hepatitis C Testing, Infection,
and Treatment Rates among Patients with Bipolar
Disorder and Substance Use Disorders. New Research
Abstracts, Annual Meeting of the American Psychiatric
Association, Toronto, May 20–25, 2006 [Abstract
NR249].
102. Kessing LV, Nilsson FM. Increased risk of developing
dementia in patients with major affective disorders com-
pared to patients with other medical illnesses. J Affect
Disord 2003; 73: 261–269.
103. Kessing LV, Andersen PK. Does the risk of developing
dementia increase with the number of episodes in patients
with depressive disorder and in patients with bipolar
disorder? J Neurol Neurosurg Psychiatry 2004; 75: 1662–
1666.
104. Sharma R, Markar HR. Mortality in affective disorder.
J Affect Disord 1994; 31: 91–96.
105. Harris E, Barraclough B. Excess mortality of mental
disorder. Br J Psychiatry 1998; 173: 11–53.
106. Cassidy F, Ahearn E, Carroll B. Elevated frequency of
diabetes mellitus in hospitalized manic-depressive
patients. Am J Psychiatry 1999; 156: 1417–1420.
737
Yatham et al.
107. Regenold WT, Thapar RK, Marano C, Gavirneni S,
Kondapavuluru PV. Increased prevalence of type 2
diabetes mellitus among psychiatric inpatients with bipo-
lar I affective and schizoaffective disorders independent of
psychotropic drug use. J Affect Disord 2002; 70: 19–26.
108. Wild S, Roglic G, Green A, Sicree R, King H. Global
prevalence of diabetes: estimates for the year 2000 and
projections for 2030. Diabetes Care 2004; 27: 1047–1053.
109. Fagiolini A, Frank E, Scott JA, Turkin S, Kupfer DJ.
Metabolic syndrome in bipolar disorder: findings from the
Bipolar Disorder Center for Pennsylvanians. Bipolar
Disord 2005; 7: 424–430.
110. D’Mello D, Narang S, Agredano G. The Prevalence and
Clinical Consequences of the Metabolic Syndrome in
Patients with Bipolar Disorder. New Research Abstracts,
Annual Meeting of the American Psychiatric Association,
Toronto, May 20–25, 2006 [Abstract NR201].
111. Ford ES, Giles WH, Dietz WH. Prevalence of the
metabolic syndrome among US adults: findings from the
third National Health and Nutrition Examination Survey.
JAMA 2002; 287: 356–359.
112. NCEP. Executive Summary of the Third Report of the
National Cholesterol Education Program (NCEP) Expert
Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III).
JAMA 2001; 285: 2486–2497.
113. Alberti KG, Zimmet PZ. Definition, diagnosis and clas-
sification of diabetes mellitus and its complications. Part
1: diagnosis and classification of diabetes mellitus provi-
sional report of a WHO consultation. Diabet Med 1998;
15: 539–553.
114. McIntyre R, Konarski J, Wilkins K, Soczynska J,
Kennedy S. Obesity in bipolar disorder and major
depressive disorder: results from a national community
health survey on mental health and well-being. Can
J Psychiatry 2006; 51: 274–280.
115. McElroy SL, Frye MA, Suppes T et al. Correlates of
overweight and obesity in 644 patients with bipolar
disorder. J Clin Psychiatry 2002; 63: 207–213.
116. Fagiolini A, Frank E, Houck P et al. Prevalence of obesity
and weight change during treatment in patients with
bipolar I disorder. J Clin Psychiatry 2002; 63: 528–533.
117. Heart and Stroke Foundation of Canada. The growing
burden of heart disease and stroke in Canada. 2003
www.cvdinfobase.ca\cvdbook [accessed on 20 June 2003].
118. Fagiolini A, Kupfer D, Houck P, Novick D, Frank E.
Obesity as a correlate of outcome in patients with bipolar
I disorder. Am J Psychiatry 2003; 160: 112–117.
119. Mahmood T, Romans S, Silverstone T. Prevalence of
migraine in bipolar disorder. J Affect Disord 1999; 52:
239–241.
120. Fasmer O. The prevalence of migraine in patients with
bipolar and unipolar affective disorders. Cephalalgia
2001; 21: 894–899.
121. McIntyre R, Konarski J, Wilkins K et al. The prevalence
and impact of migraine headache in bipolar disorder:
results from the Canadian community health survey.
Headache 2006; 26: 1–10.
122. Low NC, Du Fort GG, Cervantes P. Prevalence, clinical
correlates, and treatment of migraine in bipolar disorder.
Headache 2003; 43: 940–949.
123. Fasmer OB, Oedegaard KJ. Clinical characteristics of
patients with major affective disorders and comorbid
migraine. World J Biol Psychiatry 2001; 2: 149–155.
124. Morriss R, Mohammed FA. Metabolism, lifestyle and
bipolar affective disorder. J Psychopharmacol 2005; 19:
94–101.
738
125. Simon GE, Unutzer J. Health care utilization and costs
among patients treated for bipolar disorder in an insured
population. Psychiatr Serv 1999; 50: 1303–1308.
126. Sachs G, Bowden C, Calabrese JR et al. Effects of
lamotrigine and lithium on body weight during mainten-
ance treatment of bipolar I disorder. Bipolar Disord 2006;
8: 175–181.
127. Yoon B, Bae A, Sea Y, Kim J, Kim M. Combination of
topiramate in acute mania. Eur Neuropsychopharmacol
2005; 15: 440 [Abstract P.2.212].
128. McIntyre R, Riccardelli R, Binder C, Kusumakar V. Open-
label adjunctive topiramate in the treatment of unstable
bipolar disorder. Can J Psychiatry 2005; 50: 415–422.
129. Vieta E, Sanchez-Moreno J, Goikolea J et al. Effects on
weight and outcome of long-term olanzapine-topiramate
combination treatment in bipolar disorder. J Clin Psy-
chopharmacol 2004; 24: 374–378.
130. Baptista T, Martinez J, Lacruz A et al. Metformin for
prevention of weight gain and insulin resistance with
olanzapine: a double-blind placebo-controlled trial. Can
J Psychiatry 2006; 51: 192–196.
131. Ahrens B, Grof P, Moller HJ, Muller-Oerlinghausen B,
Wolf T. Extended survival of patients on long-term
lithium treatment. Can J Psychiatry 1995; 40: 241–246.
132. Angst J, Angst F, Gerber-Werder R, Gamma A. Suicide
in 406 mood-disorder patients with and without long-term
medication: a 40–44-year follow-up. Arch Suicide Res
2005; 9: 279–300.
133. Mathew N. Antiepileptic drugs in migraine prevention.
Headache 2001; 41 (Suppl. 1): 18–24.
134. Meinhold JM, Blake LM, Mini LJ et al. Effect of
divalproex sodium on behavioral and cognitive problems
in elderly dementia. Drugs Aging 2005; 22: 615–626.
135. Deberdt WG, Dysken MW, Rappaport SA et al. Com-
parison of olanzapine and risperidone in the treatment of
psychosis and associated behavioral disturbances in
patients with dementia. Am J Geriatr Psychiatry 2005;
13: 722–730.
136. Burmeister JE, Pereira RR, Hartke EM, Kreuz M.
Topiramate and severe metabolic acidosis: case report.
Arq Neuropsiquiatr 2005; 63: 532–534.
137. Groeper K, McCann ME. Topiramate and metabolic
acidosis: a case series and review of the literature. Paediatr
Anaesth 2005; 15: 167–170.
138. Ozer Y, Altunkaya H. Topiramate induced metabolic
acidosis. Anaesthesia 2004; 59: 830.
139. Ko CH, Kong CK. Topiramate-induced metabolic acid-
osis: report of two cases. Dev Med Child Neurol 2001; 43:
701–704.
140. Lamb EJ, Stevens PE, Nashef L. Topiramate increases
biochemical risk of nephrolithiasis. Ann Clin Biochem
2004; 41: 166–169.
141. Takhar J, Manchanda R. Nephrolithiasis on topiramate
therapy. Can J Psychiatry 2000; 45: 491–493.
142. Kuo RL, Moran ME, Kim DH et al. Topiramate-induced
nephrolithiasis. J Endourol 2002; 16: 229–231.
143. Alore PL, Jay WM, Macken MP. Topiramate, pseudo-
tumor cerebri, weight-loss and glaucoma: an ophthalmo-
logic perspective. Semin Ophthalmol 2006; 21: 15–17.
144. Mansoor Q, Jain S. Bilateral angle-closure glaucoma
following oral topiramate therapy. Acta Ophthalmol
Scand 2005; 83: 627–628.
145. Hilton EJ, Hosking SL, Betts T. The effect of antiepileptic
drugs on visual performance. Seizure 2004; 13: 113–128.
146. Cilli AS, Algun E. Oxcarbazepine-induced syndrome of
inappropriate secretion of antidiuretic hormone. J Clin
Psychiatry 2002; 63: 742.

147. Vieta E, Suppes T, Raines S, Macfadden W. Quetiapine
for the treatment of bipolar II depression. Eur Neuropsy-
chopharmacol 2005; 15: 421 [Abstract P.2.069].
148. Hirschfeld R, Suppes T, Vieta E et al. Quetiapine Mono-
therapy for Bipolar II Depression: Pooled Results from
two Placebo-controlled Studies. New Research Abstracts,
Annual Meeting of the American Psychiatric Association,
Toronto, May 20–25, 2006 [Abstract NR227].
149. Amsterdam J, Shults J. Fluoxetine monotherapy of
bipolar type II and bipolar NOS major depression: a
double-blind, placebo-substitution, continuation study.
Int Clin Psychopharmacol 2005; 20: 257–264.
150. Allen MH, Hirschfeld RM, Wozniak PJ, Baker JD,
Bowden CL. Linear relationship of valproate serum
concentration to response and optimal serum levels for
acute mania. Am J Psychiatry 2006; 163: 272–275.
151. Elmslie JL, Mann JI, Silverstone JT, Williams SM,
Romans SE. Determinants of overweight and obesity in
patients with bipolar disorder. J Clin Psychiatry 2001; 62:
486–491; quiz 92–93.
152. Gianfrancesco F, Pesa J, Wang RH, Nasrallah H. Assess-
ment of antipsychotic-related risk of diabetes mellitus in a
Medicaid psychosis population: sensitivity to study design.
Am J Health Syst Pharm 2006; 63: 431–441.
153. Emsley R, Turner HJ, Schronen J et al. Effects of
quetiapine and haloperidol on body mass index and
glycemic control: a long-term, randomized, controlled
trial. Int J Neuropsychopharmacol 2005; 8: 175–182.
154. Sumiyoshi T, Roy A, Anil AE et al. A comparison of
incidence of diabetes mellitus between atypical antipsy-
View publication stats
CANMAT guidelines for bipolar disorder
chotic drugs: a survey for clozapine, risperidone, olanza-
pine, and quetiapine. J Clin Psychopharmacol 2004; 24:
345–348.
155. American Diabetes Association. Consensus development
conference on antipsychotic drugs and obesity and diabe-
tes. Diabetes Care 2004; 27: 596–601.
156. Canadian Diabetes Association. Canadian Diabetes
Association, 2003 Clinical Practice Guideline for the
Prevention and Management of Diabetes in Canada.
Can J Diabetes 2003; http://www.diabetes.ca/cpg2003/
default.aspx [accessed on 23 October 2006].
157. Gergerlioglu HS, Savas HA, Celik A et al. Atypical
antipsychotic usage-related higher serum leptin levels and
disabled lipid profiles in euthymic bipolar patients. Neu-
ropsychobiology 2006; 53: 108–112.
158. L’Italien G, Newcomer J, Tuomari V et al. Dyslipidemia
Risk Differs According to Atypical Antipsychotic Use: A
Review and Meta-analysis. New Research Abstracts,
Annual Meeting of the American Psychiatric Association,
Toronto, May 20–25, 2006 [Abstract NR392].
159. Meltzer H. The metabolic consequences of long-term
treatment with olanzapine, quetiapine and risperidone: are
there differences? Int J Neuropsychopharmacol 2005; 8:
153–156.
160. Genest J, Frohlich J, Fodor G, McPherson R. Recom-
mendations for the management of dyslipidemia and the
prevention of cardiovascular disease: summary of the 2003
update. CMAJ 2003; 169: 921–924.
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