A European perspective on the Canadian
guidelines for bipolar disorder
expert consensus have been developed to increase
awareness of the misdiagnosis of bipolar disorder
and the growing number of potential treatments,
mainly pharmacological, but also, more recently,
Network for Mood and Anxiety Disorders (11)
represents the most recent such document. It is a
comprehensive text of what we currently know and
how that may have an impact on clinical decision
making. Not only Canadian psychiatrists, but also
anybody involved in the care of bipolar patients
across the world, including patients themselves and
their relatives, will be happy to see such a balanced,
and evidence-based document come to press.
Methodology of the Canadian guideline
All guidelines have similar objectives, but they
often reach different conclusions. This will usually
be due to the methodology employed to appraise
the evidence. The approach used by the Canadian
group is well described. The process included
rating the strength of evidence, the inclusion of
issues not only of efficacy, but also tolerability,
clinical experience, sample case reports, and the
expertise of the professionals involved in this
project. The eclectic approach reflects the variety
of evidence that bears on clinical decision making.
It also includes sections on difficult issues such as
pregnancy, and the treatment of bipolar II sub-
types. The guideline is relatively specific and moves
to a finer grained level of recommendations than
some that have preceded it. This is simultaneously
an apparent strength and a potential weakness.
Clearly we would like to have a complete and
believable summary of preferred actions for all
clinical circumstances, even individual cases. Tra-
ditionally, experts are supposed to know what to
do. The weakness in any guideline is where to draw
the line between statements that are based on a
consensus derived from convincing evidence and
those that are really statements of opinion, how-
ever widely the opinion may be shared. To be more
concrete means usually to move away from the
most reliable evidence, because reliable evidence is
usually a statement of average effects in average
patient populations. To depend more on current
opinion carries the further risk of becoming
outdated before other similar documents, as more
evidence about the management of bipolar disor-
In a sense, there can be no objection to very
detailed appraisals, if the operational rules are
explicit. However, they also need to be valid. We
have a specific concern that the approach to
levels of evidence has encouraged an over-gener-
ous ranking of some treatment options. From
our point of view, level 2 is too inclusive. It gives
the same rank to a medicine with one positive
adequately powered placebo-controlled trial (12)
plus a positive randomized trial against an active
comparator, as to a medicine with a single
underpowered, ?equal? efficacy trial against any
Vieta E, Nolen WA, Grunze H, Licht RW, Goodwin G. A European
perspective on the Canadian guidelines for bipolar disorder.
Bipolar Disord 2005: 7 (Suppl. 3): 73–76. ª Blackwell Munksgaard, 2005
Eduard Vietaa, Willem A Nolenb,
Heinz Grunzec, Rasmus W Lichtd
and Guy Goodwine
aBipolar Disorders Program, Hospital Clı ´nic,
University of Barcelona, IDIBAPS, Barcelona,
Spain,bDepartment of Psychiatry, University of
Groningen Medical Centre, Groningen, The
Netherlands,cDepartment of Psychiatry, Ludwig-
Maximilians-University, Munich, Germany,dMood
Disorders Research Unit, Aarhus University
Psychiatric Hospital, Risskov, Denmark,eUniversity
Department, Warneford Hospital, Oxford, UK
Bipolar Disorders 2005: 7 (Suppl. 3): 73–76
Copyright ª Blackwell Munksgaard 2005
comparator. This approach elevates the import-
ance of some treatment choices that have not
addition, to rely on secondary outcomes from
some trials involving newer drugs, can bias the
appraisal. Examples of where we believe this
methodology has led to surprising conclusions
are the claimed efficacy of the combination of
lithium and divalproex in acute bipolar depres-
sion, while the only study assessing this combi-
nation in acute bipolar depression (13) was an
underpowered, non-placebo controlled trial. Yet,
this guideline accords to it the same level of
evidence – level 2 – as a well-powered, positive
placebo-controlled trial of quetiapine (14), or two
positive trials (one versus placebo, and the other
versus an active comparator) of an MAOI
(tranylcypromine) (15, 16). Other drugs, such as
according to the available evidence for acute
treatment of bipolar depression, although the
long-term lamotrigine data may justify its rank-
ing as first line. Other examples are the equival-
ent ranking for maintenance
olanzapine (with a number of well-designed
positive trials) (17) and divalproex or aripiprazole
(for which much less strong evidence is avail-
able), and the support for the efficacy of divalp-
maintenance therapy. This recommendation de-
rives from secondary analyses of the acute mania
studies. Such analysis is usually underpowered
and large and unexpected effects may represent
type I errors. These examples are just several that
relate to second-level recommendations. It may
be argued that second-level treatment is inher-
ently uncertain, that variable recommendations
are inevitable from guideline to guideline, but
that it may not matter much. Our concern is that
specific recommendations can assume a power
that can be subtly unrelated to the evidence, and
that the identification of uncertainty can be more
helpful than an unwarranted preference for one
treatment over another.
inclinical trials. In
A European perspective on the major clinical
The appraisal of scientific evidence should be
reliable and not have political, religious, ethnic or
geographical boundaries. We concede, however,
that Europe is a slightly more conservative clinical
environment than the USA and Canada and is
slower to introduce changes in accepted treatment
algorithms. This may be related to cultural issues
(18), such as greater attention to tradition, and
reimbursement policies. However, some recom-
mendations on the major treatment issues appear a
bit surprising from a European perspective, and
may be summarized as follows.
but is considered third-line therapy behind, for
example, oxcarbazepine. We acknowledge the
potential side effects of haloperidol, but efficacy is
usually primary in a dangerous state like severe
mania. The efficacy data for oxcarbazepine are very
limited. Haloperidol is efficacious and probably
faster acting than most alternatives, on the basis of
recent trials where it has been the active comparator
in placebo-controlled trials of risperidone, olanza-
pine, quetiapine, ziprasidone, and aripiprazole (19).
It surely remains a valuable option for severely ill
patients who may not respond or have not respon-
ded to lithium, divalproex, or atypical antipsychot-
ics. We are not particularly convinced by the view
that the potential for long-term continuation is
necessarily paramount in acute mania.
Another trans-Atlantic difference of interpretation
has to do with the use of antidepressants in bipolar
disorder. There is evidence that they are efficacious
in acute bipolar depression (20), usually in combi-
nation with lithium, valproate, or olanzapine. The
trials are disappointingly few but they cannot be
ignored on the grounds that all antidepressants
cause switching and mood instability. The tricyclics
do increase switch rates and rapid cycling (21).
However, SSRIs do not appear to be so likely to do
so in controlled trials and may even protect against
depressive relapse in a proportion of patients (22).
There is an urgent need for trials assessing the
long-term efficacy and safety of antidepressants in
bipolar depression (23). Nevertheless, the Cana-
dian guideline looks quite sensitive and balanced,
in comparison with, for example the APA position,
which we believe moves beyond the evidence (1).
As for maintenance treatment, lithium has a long
tradition in Europe. We fully agree with lithium
being ranked as level 1 evidence, not only because
of the classic (and in some respects methodologi-
cally limited) placebo-controlled trials carried out
in the early 1970s, but also because of more recent
placebo and/or active control long-term studies
(24–26). It is, however, a bit surprising that
Vieta et al.
divalproex is ranked first-line too, despite the
absence of good positive long-term trials and the
lack of evidence for antisuicidal effects (27). In
addition, clear recommendations of optimal serum
levels for these two drugs in maintenance treatment
might have been useful.
In these indications, the guideline tries to provide
useful insights despite the poor available evidence.
We miss the emphasis on the high risk of post-
partum mania in patients who discontinue medi-
cation during pregnancy (28). The latest data
indicating a lesser absolute risk of teratogenicity
for lithium than previously believed (and the
higher risks of divalproex) (29, 30), are not
emphasized enough from our perspective. In
regard to children, there is growing concern about
the very high comorbidity rates of bipolar disorder
and descriptions of comorbidity with attention
deficit hyperactivity disorder. It is a consensus
among European psychiatrists that there may be a
problem, looking to the other side of the Atlantic.
This issue should have been more extensively
addressed in the guideline. Moreover, children
and adolescents seem to be regarded as a homo-
geneous group – the terms are used almost
interchangeably in the text. While adult termin-
ology may be appropriate post-pubertally, there is
much less agreement that it is for children. The
extrapolation of rules for both diagnosis and
treatment from adults to pre-pubertal children
appears frankly hazardous to many European
Tolerability issues are well described in the appro-
priate section. Perhaps the study that is mentioned
to illustrate weight gain is not the best example: it
shows very low rates because weight gain was
accounted for only after randomization. Most
weight gain would have occurred during the open
The Canadian guideline for the management of
patients with bipolar disorder represents a fine
effort to supply a useful, evidence-based, and
clinician-friendly tool for clinical practice in and
beyond the borders of Canada. The authors have
improved on many of the downsides of other
similar available documents (32). Nevertheless, we
do not entirely accept the approach to gradation of
evidence and, hence, we doubt the universal
appropriateness of all the advice it offers. At the
end of the day, clinical decisions are made on the
basis of a culturally influenced balance of evidence
for efficacy, safety and tolerability, clinical experi-
ence, and reimbursement policies that go clearly
beyond what a document such as this can provide.
We envisage a lot of work for the authors if they
aim to update their guideline periodically, because
their level of specificity is quite high, and therefore,
subject to change. However, we certainly welcome
it as an excellent contribution to improving prac-
tice in Europe.
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Eduard Vieta, MD, PhD
University of Barcelona
Villarroel 170 ⁄Rossello 140
08036 Barcelona, Spain
Fax: +34 93227 5477
Vieta et al.