Treatment Guidelines

18.1

18

Background

Treatment guidelines constitute one of the important developments in the field of

psychiatry, after the introduction of the operationalized diagnostic criteria in the
frame of modern classification systems and the advancing of evidence-based
medicine (EBM) also in psychiatry. They emerged as an important element in order
to summarize and clarify the research data and to the extent this is possible, to
standardize treatment on the basis of evidence. They also emerged as a response to
the need of many clinicians for algorithms, which would be able to carry research
findings to the everyday clinical practice by organizing information from diverse
sources into an easily accessible and reliable format.
To fulfil the above goals and satisfy these needs, in principle, the development of
algorithms obeys the rules of EBM and is based primarily on research data from
studies conducted in a rigorous way. However, these data cannot always support the
decision-making, and often in the real-world clinical practice, the recommendations
fail to satisfy the needs of the individual patient. Therefore, a supplementary method
is to utilize expert opinion or clinical consensus. In the last few years, the consumer
opinion as well as economic issues have an increasing strength and importance and
may play a significant role in the shaping of steps. The standard approach in the
development of algorithms as this has been shaped in the last 20 years is to utilize
EBM standards for the earlier steps; however, as algorithms move from earlier to
later steps, the evidence become more and more insufficient, and expert opinion or
clinical consensus gradually take over. Socioeconomic forces from patient
advocates, the industry and the economic interest of the government and insurance
companies exert pressure already since the beginning and the first step and up to the
end of the procedure.
Eventually, the use of algorithms and guidelines is supposed to bring benefits for
the patients in terms of a more favourable overall outcome as a combination of
better efficacy and safety/tolerability. It is also supposed to bring benefits for the
health system in general, since the use of algorithms and guidelines facilitates
Springer-Verlag Berlin Heidelberg 2015
K.N. Fountoulakis, Bipolar Disorder: An Evidence-Based Guide to Manic
Depression, DOI 10.1007/978-3-642-37216-2_18

643

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Treatment Guidelines

clinical decision-making, reduces clinically inappropriate or cost-inefficient clinical

practice decisions, provides similar treatment across different installations and
provides a metric to assess patient response and a framework to estimate the cost of
treatment (Fountoulakis et al. 2005).
However, on the other hand, there are several potential risks associated with the
use of algorithms and guidelines (Rush et al. 1999). The biggest problem is that
often the evidence might be insufficient to lead to the development of an algorithm
and the consensus panels whose decisions will cover the gap often express biased
opinions. The use of algorithms may increase the costs disproportionally in
comparison to benefits, and this poses important ethical dilemmas, especially when
efficacy collides with safety and cost. It is important to have in mind that rigid algorithms may be difficult to follow or to keep, especially when they demand much
time and sophisticated skills to gather the necessary clinical information. They may
thus lead to poorer standard of care because of fast and inappropriate application,
and what is of prime importance is that rigid algorithms might be subject to inappropriate use by the administration with important legal and ethical implications.
Deviation from algorithms may constitute an excuse for legal action by malpractice
lawyers.

18.2

List of Existing Guidelines

A list of guidelines has been created after systematic search of the literature
(Fountoulakis et al. 2005, 2012; Fountoulakis and Vieta 2008). So far, the search for
treatment guidelines for BD resulted in 52 papers concerning published structured
treatment algorithms proposed by official panels (Expert consensus guidelines are
released for the treatment of bipolar disorder. Consensus Development Conferences
1997; AACAP 1997; Allen et al. 2001; APA 1994, 1995, 2002; Barreira et al. 1999;
Dennehy 2000; Gilbert et al. 1998; Goldberg 2000; Goodwin et al. 1997; Goodwin
2003, 2009; Grunze et al. 2002, 2003, 2004, 2009, 2010, 2013; Jobson 1997;
Kusumakar et al. 1997; Licht et al. 2003; McClellan and Werry 1997; Montgomery
2001; Rush et al. 1999, 2003; Sachs et al. 2000; Suppes et al. 1995, 2001, 2002,
2003; ODowd 2006; Frances et al. 1996; Bauer et al. 1999; Yatham et al. 2005,
2006, 2009, 2013a, b; Ng et al. 2009; Hirschfeld 2005; International Consensus
Group on the evidence-based pharmacologic treatment of bipolar I and II depression 2008; International consensus group on depression prevention in bipolar disorder 2011; Australian and New Zealand clinical practice guidelines for the treatment
of bipolar disorder 2004; NCCfMH 2006; Jon et al. 2009; Nolen et al. 2008;
Beaulieu et al. 2012; Bond et al. 2012; McIntyre et al. 2012; Rosenbluth et al. 2012;
Schaffer et al. 2012). An additional source is the National Institute of Clinical
Excellence (NICE) whose guidelines concerning BD are available in draft format
and will be finalized by the end of 2014 (NICE 2014). A number of other national
and international guidelines and algorithms exist in the internet. The most important sources and bodies concerning the development of guidelines for the treatment
of BD are shown in Table 18.1. In the text that follows, only the most recent

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Critical Review of the Most Important Guidelines

645

Table 18.1 Major sources of guidelines (in alphabetical order)

Body
American Psychiatric Association (APA)
British Association for Psychopharmacology
Canadian Network for Mood and Anxiety group
(CANMAT)
Collegium International
NeuroPsychopharmacologicum (CINP)
European College of NeuroPsychopharmacology
(ECNP)
National Institute of Clinical Excellence (NICE)
Texas Medication Algorithm Project.
World Federation of Societies of Biological
Psychiatry (WFSBP)

Country
USA
UK
Canada

Comments
Stopped in 2008

International

To be published in 2015

Europe

Last in 2000

UK
USA
International

To be published in 2014
Stopped in 2002

guidelines will be analyzed in depth concerning their specific recommendations,

and this because the author wishes to avoid confusing the reader with obsolete
information.

18.3

Critical Review of the Most Important Guidelines

18.3.1 American Psychiatric Association Treatment

Guidelines for BD
Historically, the first detailed operational treatment guidelines concerning BD were
those of the American Psychiatric Association in 1994 (APA 1994, 1995). Their
development was under the auspices of the Steering Committee on Practice
Guidelines and was based on expert opinion and reviewers which evaluated all
available evidence. A second and last version was published in 2002 (APA 2002),
while a third version in 2010 never made it to publication because of unresolved
issues concerning conflict of interest.
A characteristic of the 1994 version was that it identified five types of medications: Mood stabilizers (lithium, valproate and carbamazepine), antimanic agents,
antidepressant agents, adjunctive medication and new or atypical medications. It
was also giving priority to lithium and considered it as first choice for all phases of
BD. Interestingly, lithium was considered to be superior to neuroleptics even during
the acute manic phase. Valproate and carbamazepine were considered to be a second choice of treatment, while benzodiazepines and neuroleptics were considered
effective in the rapid control of agitation during the acute mania phase, but lithium
was considered more effective specifically concerning the normalization of mood.
At that time, it is important to note that most data which were utilized concerned
chlorpromazine. Antidepressants were considered to be efficacious in the treatment
of bipolar depression but were also considered to worsen the overall course of

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BD. ECT was reserved as the last resort, and the possibility to induce mania was
stressed. Psychosocial interventions were recommended but without specific targets
for them.
These guidelines were revised in 2002 (APA 2002). This new version was much
advanced, and the work group classified the guidelines into three categories reflecting the support from clinical data: (I) recommended with substantial clinical confidence, (II) recommended with moderate clinical confidence, and (III) may be
recommended on the basis of individual circumstances.
Overall the APA 2002 guidelines coded the generally accepted treatment of BD
without any radical suggestions. They did not suggest any detailed algorithms but
rather they attempted to evaluate treatment options by reviewing the existing data.
The term mood stabilizer was omitted, because of the absence of a consensus
definition on what exactly this term should mean; however, in essence, those
agents previously considered as being stabilizers (e.g. lithium, valproex) were
treated by the guidelines as such. There was a clear suggestion that psychosocial
therapies should be used only in combination with pharmacotherapy. The work
group was reserved concerning the usefulness of atypical antipsychotics and considered them an adjunct treatment option. Olanzapine was clearly stated as a valid
alternative at dosages over 15 mg/day, but it was also stressed that except from the
acute manic phase, data were inconclusive, although olanzapine monotherapy or
in combination with fluoxetine might be effective in the treatment of bipolar
depression. The work group also clearly stated that higher doses of lithium so as
to keep serum levels at 0.81.0 meq/l may be more effective during the maintenance phase.
In 2008 the APA developed a draft of new guidelines after a thorough review of
the literature; however, eventually they were never published because of unresolved
issues pertaining to the conflict of interest. Since then, the development of guidelines by the APA has stopped.

18.3.2 The Canadian Network for Mood and Anxiety Treatments

and International Society on Bipolar Disorder Guidelines
(CANMAT/ISBD)
The Canadian Network for Mood and Anxiety Treatments (CANMAT) (Yatham
et al. 2013a) published guidelines for the first time in 1997 (Kusumakar et al. 1997)
and revised editions followed in 2005, 2007 and 2009 (Yatham et al. 2005, 2006,
2009). In 2013 the most recent version appeared as a collaboration of the CANMAT
with the International Society on Bipolar Disorders (ISBD) (Yatham et al. 2013b).
The CANMAT/ISBD guidelines were based on an extensive review of the literature and data from clinical trials. Also the support for use from the experience
coming from the clinical practice and the safety and tolerability of the intervention
were considered in formulating the clinical recommendations. Eventually every
intervention was categorized into a first, second, or third line, or as not
recommended.

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The CANMAT/ISBD guidelines concern a range of populations (e.g. children,

women and the elderly) and also provide specific recommendations on how to manage BD-II. They tried to incorporate an international perspective and to reflect international variations in practice. A number of additional guidelines were issued by
CANMAT to treat special cases of mood disorder patients with psychiatric and
somatic comorbidity (McIntyre et al. 2012; Rosenbluth et al. 2012; Beaulieu et al.
2012; Bond et al. 2012; Schaffer et al. 2012).
The most recent 2013 version of the CANMAT/ISBD guidelines (Yatham et al.
2013b) suggest that for the treatment of acute manic episodes, the first-line recommendation is monotherapy with lithium, divalproex, divalproex ER, olanzapine,
risperidone, quetiapine, quetiapine XR, aripiprazole, ziprasidone, asenapine or
paliperidone ER and adjunctive therapy with risperidone, quetiapine, olanzapine,
aripiprazole, asenapine on lithium or divalproex. The second line includes monotherapy with carbamazepine, carbamazepine ER, ECT or haloperidol and combination
therapy with lithium plus divalproex. The third line of treatment includes monotherapy
with chlorpromazine, clozapine, oxcarbazepine, tamoxifen or cariprazine and combination therapy with lithium or divalproex plus haloperidol, lithium plus carbamazepine or adjunctive tamoxifen. They do not recommend monotherapy with
gabapentin, topiramate, lamotrigine, verapamil, tiagabine and combination therapy
with risperidone or olanzapine plus carbamazepine.
For the treatment of acute BD-I depression as first-line option, they recommend
monotherapy with lithium, lamotrigine, quetiapine or quetiapine XR and combination therapy with lithium or divalproex or olanzapine plus an SSRI, lithium plus
divalproex and lithium or divalproex plus bupropion. The second line includes
monotherapy with divalproex or lurasidone and combination therapy with quetiapine plus an SSRI, adjunctive modafinil and lithium or divalproex plus lamotrigine
or lurasidone. The third line includes monotherapy with carbamazepine, olanzapine or ECT or combination therapy with lithium plus carbamazepine or pramipexole, lithium or divalproex plus venlafaxine, lithium plus MAOI, lithium or
divalproex or atypical antipsychotic plus a tricyclic antidepressant, lithium or divalproex or carbamazepine plus an SSRI plus lamotrigine and quetiapine plus
lamotrigine. They do not recommend monotherapy with gabapentin, aripiprazole
or ziprasidone and combination therapy with adjunctive ziprasidone or
levetiracetam.
For the maintenance treatment, the first-line recommendation includes monotherapy with lithium, lamotrigine, divalproex, olanzapine, quetiapine, risperidone
LAI and aripiprazole and adjunctive therapy with quetiapine, risperidone LAI,
aripiprazole or ziprasidone on lithium or divalproex. The second-line monotherapy
includes carbamazepine and paliperidone ER and combination therapy with lithium
plus divalproex or carbamazepine, lithium or divalproex plus olanzapine, risperidone or lamotrigine and olanzapine plus fluoxetine. The third-line monotherapy
includes asenapine, and the adjunctive therapy includes phenytoin, clozapine, ECT,
topiramate, omega-3-fatty acids, oxcarbazepine, gabapentin and asenapine. They do
not recommend monotherapy with gabapentin, topiramate or antidepressants and
adjunctive therapy with flupenthixol.

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Overall the CANMAT/ISBD guidelines reflect a clinically oriented mentality in

their development. They are close to the practice of the average clinician; they organize it and protect the clinician from known caveats. However, they are not always
in accord with the hard data available, especially concerning bipolar depression.

18.3.3 The Texas Medication Algorithm Project (TMAP)

for the Treatment of BD
These guidelines were started developing in 1995, and the first publication came in
1999 (Rush et al. 1999; Gilbert et al. 1998), and their most recent and last version
was published in 2002 (Suppes et al. 2002). There were efforts to empirically validate and assess the earlier versions of the algorithm (Suppes et al. 2003), and the
areas of outcome which were expected to improve were defined (better quality of
life, increased productive activity, less reliance on treatment system, fewer negative
social outcomes like arrest, prison time, etc., decreased cost) (Rush et al. 2003).
At that time, there was little evidence to support the development of algorithms
for BD-II and rapid cycling disorder, so the algorithm was focused only on BD-I
and the panel suggested the use of the guidelines in BD-II also.
The TMAP was revolutionary for a number of reasons. These guidelines were
developed by a panel of academic clinicians and researchers, practicing clinicians in
the TDMHMR system, administrators, advocates and consumers. It was the first to
involve as many stakeholders as possible in BD. Another breakthrough issue was
the core proposal that all bipolar patients should receive continuous treatment with
an antimanic agent and thus follow the algorithm concerning the treatment of mania/
hypomania with an intermittent use of the depression algorithm. This constituted a
shift in the way we understand and practice the treatment of BD, and it is the basis
of our current concept and practice. Finally it was the first algorithm to put an atypical antipsychotic (olanzapine) as first-choice treatment and equal to lithium and
divalproex. Two important recommendations were made concerning the maintenance phase. The first was that maintenance treatment is considered to be necessary
only for patients with two manic episodes or with one which was severe or for those
patients with a positive family history of affective disorder. For the rest of patients
(first manic episode without family history), it is recommended to gradually discontinue treatment usually after the completion of 6 months in full remission. In terms
of nomenclature, an important element was that they consider mania and antimanic
medication as the core of BD and its treatment, putting depression at a somewhat
lower level. Antidepressant medication was considered as an adjunctive therapy to
the antimanic. Lithium, anticonvulsants and atypical antipsychotics were grouped
under the label antimanic agents in the mania/hypomania algorithm. However, at
the stage 1 of the depression algorithm, their label changes to mood stabilizers
without any explanation for this change. In an earlier paper from this panel, the term
mood stabilizer includes lithium, carbamazepine and divalproex, but not atypical
antipsychotics (Suppes et al. 2001). However, the most recent paper put lithium and
divalproex at a similar position with atypical antipsychotics.

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Critical Review of the Most Important Guidelines

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The validation of the early versions of these guidelines was attempted by their
use in 69 acutely ill BD patients with satisfactory results (Suppes et al. 2001), but
further testing of the algorithms (but not of the final version) (Suppes et al. 2002)
was unimpressive (Suppes et al. 2003).
Overall the TMAP was a breakthrough effort and was the first to adopt a number
of innovations which today are considered the standard in our conceptualizing of
the treatment of BD. It was short-lived, however, and it stopped producing algorithms after 2002.

18.3.4 The World Federation of Societies of Biological Psychiatry

(WFSBP) Guidelines for the Biological Treatment of BD
This work group published guidelines for bipolar depression in 2002 (Grunze et al.
2002), mania in 2003 (Grunze et al. 2003) and maintenance treatment in 2004
(Grunze et al. 2004). A second wave of guidelines was published during 2009
2013 (Grunze et al. 2009, 2010, 2013).
The latest WFSBP guidelines utilized a modified version of the PORT method to
grade the data concerning efficacy and afterwards utilized a secondary classification
to include also safety and tolerability.
For the treatment of acute mania, as first-choice agents are ranked aripiprazole,
valproate, risperidone and ziprasidone. As second choice, olanzapine, quetiapine,
asenapine, carbamazepine, haloperidol and lithium were recommended. The third
choice includes chlorpromazine, paliperidone, phenytoin, pimozide and tamoxifen.
The fourth includes amisulpride, clonazepam, clozapine, levetiracetam, lorazepam,
nimodipine, oxcarbazepine, retigabine, zonisamide, zotepine and ECT. The fifth
and final choice includes verapamil.
With the utilization of this classification, the WFSBP suggests that concerning
the treatment of acute mania, the first step includes monotherapy with first-choice
agents. The second step would be the switching to another first-choice agent or
combine two first-choice agents. Similarly the third step includes combination of
two first-choice agents. The fourth and fifth steps include combinations of agents
essentially according to the judgement of the therapist.
For the treatment of acute bipolar depression, the WFSBP guidelines suggest
that first-choice agent is only quetiapine, while their next best option includes olanzapine, fluoxetine, lamotrigine, valproate, OFC, lithium plus lamotrigine, adjunctive modafinil, N-acetylcysteine on lithium or valproate and FEWP plus
carbamazepine. A variety of combinations are proposed as next steps.
For the treatment during the maintenance phase, the guidance is more complex,
and on the basis of the available data, the WFSBP guidelines suggest the use of
aripiprazole, lamotrigine, lithium, quetiapine, olanzapine and risperidone, but they
note that not all of them prevent both mania and depression. They also note the
problems because of the metabolic syndrome induced by some of these agents when
used for prolonged periods of time. They also suggest the avoiding of typical antipsychotics because of the risk to induce tardive dyskinesia.

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Overall the WFSBP guidelines are based on the existing research evidence and
try to avoid suggestions which are not evidence based, but at the same time, they try
to provide the clinician with solutions. They constitute a step forward towards the
evidence-based pharmacotherapy and evidence-based psychiatry.

18.3.5 British Association for Psychopharmacology (BAP)

The BAP issued guidelines for the treatment of BD for the first time in 2003
(Goodwin 2003) and revised them in 2009 (Goodwin 2009). Both versions were
based on a consensus panel after extensive review of the literature
The 2009 guidelines cover the assessment and treatment of BD in a global way
and strongly suggest a multidisciplinary approach in the frame of enhanced care.
For acute mania, they recommend antipsychotics or valproate for the more severe
cases and antipsychotics, lithium, valproate or carbamazepine for the milder ones.
In case of refractoriness, they recommend combination treatment or ECT.
For acute bipolar depression, they recommend ECT for the more severe cases
and quetiapine or lithium for the milder ones, plus an SSRI if needed.
It is interesting that for the maintenance phase, it is the first guidelines, the only
one so far, that suggest the choice of treatment on the basis of predominant polarity.
Thus, they recommend maintenance treatment with lithium, aripiprazole, quetiapine, valproate or olanzapine if the predominant polarity is manic and lamotrigine or
quetiapine if the predominant polarity is depressive.

18.3.6 The UK National Institute of Clinical Excellence (NICE)

Treatment Guidelines for BD
The NICE issued the first version of guidelines for the treatment of BD in 2006, and
the revised version is expected to be published officially in September 2014; however, a draft version was available online at the time of the writing of the current
chapter and it is discussed here (NICE 2014).
Concerning acute mania, the draft of the 2014 NICE guidelines recommends the
use of olanzapine, risperidone, quetiapine or haloperidol. If the patient does not
respond, it is recommended to change to another antipsychotic, and the choice
should be made also on the basis of previous response if it exists. If the patient is
already under treatment with lithium or valproate, then the recommendation is to
increase dosage to the highest permitted and reassessment should follow before the
changing of medication. If an antidepressant is in place, it should be discontinued.
The second step includes combination of lithium or valproate plus an antipsychotic,
and the third step demands hospitalization. The NICE warns against the use of gabapentin, lamotrigine and topiramate in acute mania.
Concerning acute bipolar depression, the NICE recommends olanzapine, OFC,
quetiapine, lamotrigine, lithium and valproate. If the patient is already under treatment with lithium or valproate, then the recommendation is to increase the dosage

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Critical View of Treatment Guidelines for BD

651

to the highest permitted, and reassessment should follow before the changing of
medication. The next step includes combination of lithium or valproate plus quetiapine or OFC. The third step includes lithium plus lamotrigine or olanzapine and
valproate plus lamotrigine. The NICE warns against the use of gabapentin and
topiramate.
During the maintenance phase, the NICE guidelines recommend as first-line
treatment the continuation of the treatment the patient received during the acute
phase and led to the resolution of the symptoms. Irrespective of polarity, the continuation of this treatment should be done for at least 36 months. In case the patient
does not wish to follow this, it is recommended to change treatment to lithium,
olanzapine, quetiapine, valproate or lithium plus valproate. Again the NICE warns
against the use of gabapentin and topiramate.

18.4

Critical View of Treatment Guidelines for BD

As discussed in previous chapters, BD has a complex clinical picture and an even

more complex treatment. Only recently hard data became available concerning the
efficacy and safety of various treatment options and many beliefs have been discredited. Still we know little concerning the treatment of many aspects of the disorder.
It is almost impossible for the research findings to make it to the everyday clinical practice rapidly and in a proper way by themselves. Clinicians do not have the
time to dig into primary research papers and might not have the background to read
them critically. Treatment guidelines serve the purpose of gathering and evaluating
the research data and synthesize them into a comprehensive and operational treatment algorithm. If this is not possible, because the data are often not sufficient, the
classification of treatment options according to efficacy and safety/tolerability is
also an important task for guidelines.
In the past, the difference in the treatment views between the academic authorities in Europe and the USA was prominent. The European view was in favour of the
use of antipsychotics and antidepressants, while the US approach was in favour of
mood stabilizers. This difference no longer exists at least concerning antipsychotics. However, the reality is that in spite of previous algorithms, the use of antipsychotics to treat acute mania was widespread both in Europe (Licht et al. 1994) and
in the USA (Chou et al. 1996) often as monotherapy. This practice was based on
evidence that antimanic properties of antipsychotics are different from their sedative ones and might relate to dopamine receptor blockade (Cookson 2001).
The various treatment guidelines generally seem to have a common starting
point, best described by the 1994 APA guidelines (APA 1994), which interestingly
seem to reflect the opinion of many clinicians still today. Some guidelines try to
keep up with the evidence; others rely more on expert opinion. The greatest problem
guidelines face is from the second-line recommendation and beyond. At this level,
after monotherapy with first-line agents fails, data are sparse. Guidelines insist in
suggesting monotherapy as the first option, although data suggest that such an
approach is effective in less than half of patients and is likely to leave residual

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symptoms. It is rather true that guidelines sacrifice much effectiveness in favour of

safety and fewer adverse effects. However, the reality is that suboptimally treated
BD is a potentially disabling and lethal disease.
The three most recent guidelines (NICE, CANMAT/ISBD and WFSBP) agree in
that first-choice treatment for acute mania should be olanzapine, quetiapine, risperidone, lithium and valproate. The guidelines of CANMAT/ISBD and of WFSBP
agree that the second-line treatment includes haloperidol and lithium plus valproate.
The combination of lithium or valproate plus an antipsychotic is proposed as
second-line treatment by NICE and WFSBP, while the CANMAT/ISBD consider it
as first-line option. There is no agreement concerning the third-line option. ECT is
considered as second line by the CANMAT/ISBD and as third-line option by the
WFSBP. It should be noted that the NICE excludes from recommendations aripiprazole and asenapine due to high cost without a corresponding higher efficacy. It
also excludes paliperidone because it considers it to be an active metabolite of risperidone which should not be considered separately. It did not consider cariprazine
because the pharmaceutical company which markets it refused to provide the NICE
with the data required, while ziprasidone is not marketed in the UK.
Concerning acute bipolar depression, these guidelines agree that the first-line
option is lamotrigine, lithium, quetiapine, olanzapine (the CANMAT/ISBD suggest
in combination with an SSRI) and valproate (again the CANMAT/ISBD suggest in
combination with an SSRI). The combination of olanzapine with fluoxetine (OFC)
is suggested by the NICE specifically, while the CANMAT/ISBD suggests the combination of olanzapine with any SSRI except paroxetine. According to the WFSBP,
the OFC is the second-line recommendation. The second- and third-line options
have little in common. The combination of lithium plus lamotrigine is the secondline option for WFSBP and CANMAT/ISBD and third line according to NICE. The
combination of venlafaxine plus lithium or valproate is the third-line option according to CANMAT/ISBD and second line according to WFSBP. The NICE guidelines
suggest the use of lithium and valproate monotherapy as first-line option and their
combination with another agent as second- and third-line option. They also do not
recommend gabapentin or topiramate at any phase of the disorder.
The CANMAT/ISBD guidelines suggest a greater variety of treatment options
and include ECT also as first- or second-line treatment depending on the severity of
the clinical picture and the clinical judgement of the therapist. The WFSBP guidelines are reserved towards the efficacy of lithium at least as monotherapy, and they
seem to be more open to novel suggestions (e.g. FEWP). Eventually they strongly
recommend quetiapine, the OFC, the combination of an antimanic agent plus an
SSRI, lamotrigine as monotherapy but also in combination with lithium and adjunctive treatment with modafinil.
For the maintenance phase, the three guidelines agree concerning the use of lithium, olanzapine and quetiapine as first-line treatment options in the maintenance
treatment for the prevention of any mood episode. Valproate is also recommended
as the first-line treatment option but second line according to the WFSBP due to
equivocal research data. Lamotrigine is recommended by the WFSBP and the
CANMAT/ISBD mainly for the prevention of depressive episodes, while the NICE

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Critical View of Treatment Guidelines for BD

653

prefers to recommend lithium but not lamotrigine. The CANMAT/ISBD guidelines

recommend the use of atypical antipsychotics as prophylactic therapy but only concerning the prevention of manic episodes, with the exception of quetiapine which is
recommended also for the prevention of depressive episodes. The WFSBP and the
CANMAT/ISBD agree almost perfectly concerning the third-line treatment options.
It is evident that there are many issues that need further study, data are rare and
insufficient and many questions remain unanswered. Overall it seems that disagreements are more than agreements even though all treatment guidelines claim to be
evidence based. Probably this is because of the different way to approach and
utilize the data. A point of relative consensus is that antidepressants do not have a
major role in the treatment of bipolar depression at least as monotherapy with the
exception of fluoxetine, especially in combination with olanzapine.
Furthermore, the NICE takes under serious consideration the financial cost, and
because of this, it significantly narrows its suggestions. The WFSBP takes special
consideration of adverse events, while the CANMAT/ISBD provide with a greater
variety of options while leaving the consideration of the adverse events to the
therapist.
There is a nonspecific consensus among guidelines that the second line of treatment should include various combinations of first-line agents although often this is
not supported by the data.
Guidelines also agree that there is lack of hard data concerning the treatment of
mixed episodes and rapid cycling. On the contrary, they agree that although there is
also a lack of hard data, hypomania should be treated the same way as mania. All
agents are somewhat considered to be more effective towards one pole of the illness
in comparison to the other. More specifically, lithium, valproate, carbamazepine
and antipsychotics are all more effective for the treatment and prevention of mania
and to a lesser degree for depression, while on the contrary, lamotrigine is more
effective for the treatment and prevention of depression and to a lesser degree for
mania.
It is important to note that in spite of the publication of various treatment guidelines, clinicians do not seem to widely adopt any of them. Their impact on clinical
practice is quite limited even in the USA. After the publication of the first APA 1994
guidelines, only about 16 % of manic patients without psychotic features, 38 % with
mania with psychotic features, 31 % of bipolar depressed with psychotic features
and 17 % of bipolar depressed without psychotic features were reported to be treated
according to treatment guidelines (Lim et al. 2001).
Several studies registered the prescribing patterns in Europe and the USA and
their results are most interesting. They reported at the dawn of the twenty-first century, up to 23 % of diagnosed bipolar patients did not receive any medication at all,
half were under antidepressants, half under a mood stabilizer (lithium or anticonvulsant) and one-third was receiving antipsychotics. According to the same authors,
only 20 % of patients were on monotherapy, and half of them were receiving at least
three agents, while 18 % did not receive any mood stabilizer (lithium or anticonvulsant) at all. Discontinuation rates for lithium were between 50 and 60 % (Levine
et al. 2000; Frangou et al. 2002).

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The pressure to develop guidelines for the treatment of severe and disabling
mental disorders becomes stronger and stronger because of the need to provide
better treatment in combination with a lower cost. However, sufficient empirical
data are not always sufficient and the evaluation of guidelines in the real-world
environment does not always support their use, as many times they lead to an
increased cost without an impressive improvement in the treatment outcome. To
complicate things more, the installations where the algorithms were tested are not
representative of the average treatment setting.
It is almost certain that the generalization of the use of evidence-based guidelines
for the treatment of bipolar disorders will improve treatment outcome and at the
same time lower the cost of bipolar illness even though they may increase the shortterm cost for medication and rehabilitation programs. But the least these algorithms
may achieve is to ensure a minimum quality of treatment and care and the minimum
necessary discipline from the side of the therapist.
However, the psychiatric community should guard the right of the therapist to
make independent decisions concerning treatment, on the basis of the individual
patient and available scientific data; that means algorithms cannot replace education
and training and may not be considered a golden standard of treatment the deviation from which should be justified. Such an extreme situation may lead to unnecessary legal complications.
On the technical field, there are several issues that need to be clarified. These
include the term mood stabilizer, the usefulness of newer antipsychotics, the treatment of the acute phase of bipolar depression, the true value of combination therapy,
whether antimanic properties of medication are distinct from sedation effects, the
treatment of mixed features and rapid cycling, the role of psychosocial interventions
and the assessment and treatment of the neurocognitive deficit, the functional
impairment and disability which often burden the patients and their families during
symptom-free intervals.

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