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Journal of Affective Disorders 86 (2005) 1 – 10
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Special review article
Treatment guidelines for bipolar disorder: A critical review
K.N. Fountoulakisa,T, E. Vietab, J. Sanchez-Morenob, S.G. Kaprinisa,
J.M. Goikoleab, G.S. Kaprinisa
a
3rd Department of Psychiatry, Aristotle University of Thessaloniki, Greece
Clinical Institute of Psychiatry and Psychology, Bipolar Disorders Program, Hospital Clinic, University of Barcelona, Spain
b
Received 9 September 2004; accepted 6 January 2005
Abstract
Introduction: The development of treatment guidelines emerged as an important element so as to standardize treatment and to
provide clinicians with algorithms, which would be able to carry research findings to the everyday clinical practice.
Material and method: The MEDLINE was searched with the combination of each one of the key words dmaniaT, dmanicT,
dbipolarT, dmanic-depressionT, dmanic-depressiveT with dtreatment guidelinesT.
Results: The search was updated until March 1st, 2004 and returned 224 articles. Twenty-seven papers concerning the
publication of treatment algorithms were traced.
Discussion: Despite supposedly being evidence-based, guidelines for the treatment of bipolar disorder vary significantly across
committees or working groups. Overall, however, at the first stage of the mania/hypomania algorithm, monotherapy with
lithium, divalproex sodium or olanzapine is generally recommended. At latter stages combination therapy is strongly
recommended. It is clearly stated that in bipolar depression antidepressants should be used only in combination with antimanic
agents in order to avoid switching of phases. During the maintenance phase all patients should receive antimanic agents, while
some may need the addition of antidepressants. The most recent guidelines emphasize the use of atypical antipsychotics for
mania and lamotrigine for depression. The main problem with guidelines is that they are rapidly outdated and that the evidence
base relies mainly on registration monotherapy trials that hardly reflect treatment in routine clinical conditions.
Conclusion: Treatment guidelines may be useful to avoid non-evidence-based treatment decisions, but they are quickly out-ofdate and may not fully apply to the clinical setting. The more recent guidelines point the value of atypical antipsychotics,
lithium, and valproate in the treatment of mania; the role of lithium, lamotrigine, and olanzapine as options for maintenance
therapy; and the scarcity of options for the treatment of bipolar depression. Psychoeducation is also supported by most
guidelines as an adjunctive treatment.
D 2005 Elsevier B.V. All rights reserved.
Keywords: Anticonvulsants; Antidepressants; Antipsychotics; Bipolar disorder; Evidence-based guidelines; Lithium; Mania; Mood stabilizers;
Treatment
T Corresponding author. Tel.: +30 2310 435702.
E-mail address: [email protected] (K.N. Fountoulakis).
0165-0327/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jad.2005.01.004
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K.N. Fountoulakis et al. / Journal of Affective Disorders 86 (2005) 1–10
Contents
1. Introduction . . . . .
2. Material and method
3. Results. . . . . . . .
4. Discussion . . . . . .
References . . . . . . . .
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1. Introduction
The development of treatment guidelines emerged
as an important element so as to standardize treatment
and to provide clinicians with algorithms, which
would be able to carry research findings to the
everyday clinical practice, by organizing information
from diverse sources into an easily accessible format.
The aim of the current study is to review contemporary available treatment guidelines for bipolar
disorder. Although several issues are relevant (adolescence, old age, pregnancy, comorbid conditions) this
article focuses on the treatment guidelines concerning
otherwise physically healthy and physiologically stable
adults suffering from bipolar disorders.
2. Material and method
The MEDLINE was searched with the combination
of each one of the key words dmaniaT, dmanicT,
dbipolarT, dmanic-depressionT, dmanic-depressiveT with
dtreatment guidelinesT and dtreatment algorithmsT. The
search returned 224 articles. The search was updated
until March 1st, 2004. Finally the review process based
on the titles and abstracts selected 84 of them for further
study. Among them there were 23 papers concerning
structured treatment algorithms proposed by official
panels (1997; AACAP, 1997; Allen et al., 2001;
American Psychiatric Association, 1994, 1995, 2002;
Barreira et al., 1999; Bauer et al., 1999; Frances et al.,
1996; Gilbert et al., 1998; Goodwin, 2003; Grunze et
al., 2002; Grunze et al., 2003; 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). Another three papers on
treatment guidelines (Goodwin et al., 1997; Jobson,
1997; Kusumakar et al., 1997) were traced by scanning
the references list of review papers (Dennehy, 2000;
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Goldberg, 2000). One last paper published in July 2004
(Grunze et al., 2004) was brought by one of the authors
(E.V.) who participated in that paper’s task force, thus
raising the total number of guidelines reviewed here to
27. The guidelines are presented and discussed in the
results section according to the chronological order the
specific organization or panel started its effort to
develop algorithms. The most important sources of
guidelines are shown in Table 1.
3. Results
American Psychiatric Association treatment guidelines: The first detailed operational treatment guidelines concerning bipolar disorder published, were
those of the American Psychiatric Association (American Psychiatric Association, 1994, 1995, 2002).
Their development was based on expert opinion and
reviewers which evaluated all available evidence. The
first version was published in 1994. In that version,
five types of medication were identified: Mood
Table 1
Major sources of guidelines development (in alphabetical order)
1.
2.
3.
4.
American Psychiatric Association (APA)
British Association for Psychopharmacology
Canadian Network for Mood and Anxiety group
Danish Psychiatric Association and the Child and Adolescent
Psychiatric Association in Denmark
5. Department of Veterans Affairs
6. ECNP Consensus Meeting March 2000 Nice
7. Expert Consensus Guideline Series
8. Expert Consensus Guideline Series: Medication Treatment of
Bipolar Disorder 2000
9. Texas Medication Algorithm Project
10. The Expert Consensus Guidelines for treating depression in
bipolar disorder
11. The Expert Consensus Panel for Bipolar Disorder
12. World Federation of Societies of Biological Psychiatry
(WFSBP)
K.N. Fountoulakis et al. / Journal of Affective Disorders 86 (2005) 1–10
stabilizers (lithium, valproate, and carbamazepine),
antimanic agents, antidepressant agents, adjunctive
medication, and new or atypical medications. Lithium
was considered the first choice in all phases of bipolar
illness and superior to neuroleptics during the acute
manic phase. Valproate and carbamazipe were considered as a second choice of treatment, and rather less
effective than lithium. Benzodiazepines and neuroleptics were considered effective in the rapid control
of agitation during the acute mania phase, but lithium
was considered more effective concerning the normalization of mood. Antidepressants although effective in
the treatment of bipolar depression are considered to
worsen the overall course of bipolar disorder. ECT is
reserved as the last resort, and the possibility to induce
mania is stressed.
These guidelines were revised in 2002. 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.
Mania/hypomania: The guidelines recommend the
use of lithium plus an antipsychotic or valproate plus
an antipsychotic as the first line of treatment (I). It is
suggested that for less severely ill patients monotherapy with lithium, valproate, or an antipsychotic
such as olanzapine may be sufficient (I). For mixed
episodes, valproate may be recommended over
lithium (II). Also atypical antipsychotics are preferred
over typical ones (I), and most of the evidence support
the use of olanzapine or risperidone (II). The second
line of medication treatment includes the combination
of two first line medications (I), adding carbamazepine or oxcarbazepined (II) or adding an antipsychotic
(I). ECT should also be considered (I). When
psychotic features are present, the use of an antipsychotic is necessary (II). Bipolar depression: The
first line medication treatment is either lithium (I) or
lamotrigine (II). It is important that antidepressant
monotherapy is not recommended (I). Alternatively,
simultaneous treatment with lithium and an antidepressant (III) or ECT (I) may be used. The second line
of treatment concerns optimizing the dose (II), adding
lamotrigine (I), bupropion (II), paroxetine (II), or
other newer antidepressants or venlafaxine or a
Monoaminoxidase inhibitor (MAOI) (II). ECT should
3
also be considered (I). When psychotic features are
present, the use of an antipsychotic is necessary (I).
Rapid cycling: Identify and treat medical conditions,
drug or alcohol abuse (I), or various medication that
may contribute to cycling (II). Use lithium or
valproate and maybe lamotrigine (I). Combinations
of medications are often necessary (II). Maintenance
phase: Use lithium (I) and valproate (I) with possible
alternatives being lamotrigine, carbamazepine or
oxcarbazepine (II). Generally the agent that was
successfully used for the treatment of the acute phase
should be kept also during the maintenance phase (I).
ECT maintenance sessions should also be considered
(II). Antipsychotics should be discontinued unless
they are required for control of persistent psychotic
symptoms (I). Non-pharmacological treatments:
Interpersonal and cognitive-behavioral psychotherapy
as well as psychodynamic psychotherapy may be used
in addition to pharmacotherapy (II), although empirical studies are inconclusive. During the maintenance
phase, it is suggested that patients are likely to benefit
from the application of a concomitant psychosocial
intervention (II). Psychoeducational approaches may
be more useful. Comments: These guidelines largely
code generally accepted treatment without any radical
suggestions. There is a clear suggestion that psychosocial therapies should be used only in combination
with pharmacotherapy. Atypical antipsychotics are
considered an adjunct treatment option. The work
group also clearly states that higher doses of lithium
so as to keep serum levels at 0.8–1.0 meq/l may be
more effective during the maintenance phase.
The international psychopharmacology algorithm project for Bipolar Disorder (Suppes et al.,
1995) was based largely on expert consensus. Lithium
is considered to be the drug of choice for a first,
second or third episode of mania. If there has been
poor response or intolerance to lithium, or in cases of
rapid cycling or mixed mania which respond poorly to
lithium, the work group suggested first the use of
valproate (as more supported by data) and afterwards
carbamazepine. The addition of neuroleptics and/or
benzodiazepines may be warranted. Before determining that response is inadequate the work group
specifies a trial of at least two to three weeks, with
lithium serum levels at least 0.8 meq/l or levels of
carbamazepine or valproate corresponding to their
established levels for the treatment of epilepsy. ECT is
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K.N. Fountoulakis et al. / Journal of Affective Disorders 86 (2005) 1–10
suggested for refractory patients. The work group did
not reach a consensus concerning the treatment of
bipolar depression.
The 1st International Psychopharmacology
Algorithm meeting produced therapeutic algorithms
generally similar to the APA guidelines (Goodwin et
al., 1997; Jobson, 1997).
American Academy of Child and Adolescence
Psychiatry: Practice parameters for the assessment
and treatment of children and adolescents with
bipolar disorder (1997; McClellan and Werry, 1997):
These guidelines concern the treatment of children
and adolescents and thus are outside the focus of the
current review.
The Canadian Network for Mood and Anxiety
Treatments (CANMAT) (Kusumakar et al., 1997).
Mania/hypomania/mixed: The first choice of treatment for classic mania is lithium or divalproex. For
more severe cases ECT is recommended. For psychotic or agitated patients it is recommended to use an
antipsychotic or a benzodiazepine. Refractory patients
should be treated with combinations of mood stabilizers. For mixed episodes divalproex or carbamazepine is recommended as the first choice. Bipolar
depression: Treatment with a mood stabilizer; ECT is
recommended for suicidal or patients with psychotic
features. For refractory patients combinations of mood
stabilizers with antidepressants are recommended
along with ECT. Maintenance treatment: Treatment
with mood stabilizer at optimal levels, with simultaneous discontinuation of all other agents once the
patient is asymptomatic. Maintain treatment for 6–12
months after a single episode. For recurrent patients or
for patients with family history maintenance treatment
should be kept for life long. Non-pharmacological
treatments: Cognitive-behavioural and interpersonal
psychotherapy as adjunctive therapy in bipolar
depression. Comments: These guidelines are generally
in accord with the 1994 APA guidelines.
The Expert Consensus Guidelines for treating
depression in bipolar disorder (1997; Frances et al.,
1996, 1998). Mania: For patients with classic,
euphoric mania, lithium and valproate are recommended. Valproate is recommended as the treatment of
choice for mixed episodes, dysphoric mania, and
mania in rapid cycling patients. Carbamazepine is
considered a first line alternative for mixed episodes
and for rapid cycling while lithium is also a first line
alternative for mixed episodes. Adjunctive antipsychotics and/or benzodiazepines may be necessary,
particularly if the patient has psychotic symptoms,
agitation, or insomnia. The second line of treatment
includes combinations of first line medications, ECT
and atypical antipsychotics. Bipolar depression: The
first line treatment for severe non-psychotic bipolar
depression is the combination of a mood stabilizer
plus an antidepressant. For milder episodes monotherapy with a mood stabilizer may be sufficient. For
psychotic cases the first choice is ECT or the
combination of an antidepressant, a mood stabilizer
and an antipsychotic. SSRIs and buproprion are
considered the antidepressants of choice and should
be tapered faster than in unipolar depression. For
refractory patients, add lithium or an anticonvulsant
and use augmentation strategies or ECT. Continuation
(2–6 months): Optimize the dose of the mood
stabilizer. Other medications (antidepressants, antipsychotics, benzodiazepine) should be gradually
tapered. Maintenance phase: Long-term or lifetime
prophylaxis with a mood stabilizer is recommended.
Non-pharmacological treatments: The authors also
provide a detailed guide for psychotherapeutic and
rehabilitation programs. Comments: These guidelines
are in accord with the 1994 APA guidelines.
The clinical practice guidelines for bipolar
disorder from the Department of Veterans Affairs
(Bauer et al., 1999). Mania/hypomania/mixed: The
first choice is a mood stabilizer (lithium, valproate,
carbamazepine and ECT). Valproate may be less
effective than lithium in acute mania but more
effective in mixed episodes. The patient should be
maintained for 3 weeks on a therapeutic serum level
(0.5–1.5 mmol/l for lithium, 45–125 Ag/ml for
valproate, 4–15 Ag/ml for carbamazepine). ECT is
the choice for refractory patients. Bipolar depression:
Lithium is the first choice. The second step is to
optimize the dosage and to add a second mood
stabilizer to lithium and wait for another 6 weeks.
ECT is another option, and the authors indirectly
suggest that it should be considered before antidepressant medication. Antidepressants of all classes are
considered a second line of choice. If the patient
responds to antidepressant treatment, the agent should
be tapered and discontinued within 6–12 weeks,
although a subgroup of patients may require antidepressant treatment over extended periods of time.
K.N. Fountoulakis et al. / Journal of Affective Disorders 86 (2005) 1–10
For refractory patients the authors recommend augmentation strategies, combinations of antidepressants,
ECT and alternative therapies like sleep deprivation or
light therapy. Rapid cycling: Identify and treat
conditions that may induce rapid cycling. Lithium is
the first choice and other mood stabilizers are the
second choice. Combination of mood stabilizers is the
next step. Psychotic features: If psychotic features are
present, a high or medium potency conventional or an
atypical antipsychotic should be added, and should be
discontinued 2–6 months after the resolution of
psychotic symptoms. Comments: In essence, these
guidelines are similar to the early (1994) APA
guidelines.
The Texas Medication Algorithm Project
(TMAP) for the treatment of bipolar disorder (Gilbert
et al., 1998; Rush et al., 1999, 2003; Suppes et al.,
2001, 2002, 2003). These guidelines were started
developing in 1995, the first publication came in
1999 and their most recent version in 2002. Mania/
hypomania: First stage: monotherapy with lithium,
divalproex or olanzapine. Divalproex is recommended
for any presentation of mania/hypomania, lithium is
not recommended for dysphoric mania. In case of
partial response, add a second agent rather than
replacing the existing one. Second stage: combination
therapy (choose among lithium, divalproex, oxcarbazepine, olanzapine, and risperidone). Third stage: try a
different combination. Fourth stage: use directly an
atypical antipsychotic in combination with lithium
divalproex or oxcarbazepine. For patients with psychotic features it is recommended to proceed directly to
this stage after stage 1. Fifth stage: proceed to triple
therapy with the combination of lithium, an anticonvulsant (divalproex or oxcarbazepine) and an atypical
antipsychotic (olanzapine, risperidone, quetiapine, or
ziprasidone). Sixth stage: ECT or clozapine. Seventh
stage: double antipsychotic therapy (conventional
neuroleptics included), topiramate, lamotrigine, or
other agents in various combinations according to the
clinician’s opinion. Bipolar depression: First stage:
optimization of mood stabilizing medication as
described in the mania/hypomania algorithm. If the
patient suffers also from major depression that warrants
treatment, the clinician should proceed to stage 2, and
add an SSRI (fluoxetine, paroxetine, sertraline fluvoxamine, and citalopram), buproprion extended release,
or lamotrigine to existing medications. Third stage: add
5
lithium, another antidepressant (venlafaxine or nefazodone) or a second one from stage 2 agents. At stage 4,
use a combination of antidepressants from different
classes, and choose from SSRIs, buproprion SR,
lamotrigine, venlafaxine, and nefazodone. At the 5th
stage, the clinician is prompted to change antidepressant medication to a monoaminoxidase inhibitor
(MAOI) or to add an atypical antipsychotic. At the
6th stage, use ECT and dexploratoryT treatments
(inositol, stimulants, dopamine agonists, hormones,
conventional antipsychotics, tricyclic antidepressants—TCAs, omega-3 fatty acids, and acupuncture).
Continuation phase: The treatment should be continued for at least 3 months at the dose effective during the
acute phase. Maintenance phase: All patients should
receive antimanic agents, while some will need the
addition of antidepressants, at the lowest possible dose.
Patients with 2 manic episodes or 1 which was severe or
those with a positive family history of affective
disorder will need a lifetime treatment. For the rest of
patients gradually discontinue treatment 6 months in
full remission. Comments: This group considers mania
and antimanic medication as the core of bipolar
disorder and its treatment, putting depression at a
somewhat lower level, which is against empirical data.
In addition, several therapies like ECT or TCAs, with
proven efficacy are included only at the later stages,
because of potential adverse effects or consumers’
opinion, however, this strategy puts them at the same
level with therapies without any scientific support, like
acupuncture. Finally the testing of the algorithms (but
not of the final version (Suppes et al., 2002)) did not
produce impressive results (Suppes et al., 2003).
The Expert Consensus Guideline Series Medication Treatment of Bipolar Disorder (Sachs et al.,
2000): Mania: 1st step: For euphoric mania or
hypomania the first choice is lithium or divalproex,
while divalproex is preferred for dysphoric or mixed
mania and if psychotic features are present. For the
latter case, the addition of antipsychotics (olanzapine
and risperidone) is recommended. Conventional antipsychotics are considered only when psychotic
features are present. 2nd step: switching in case of
lack of response or add another mood stabilizer (of
those recommended in the 1st step) in case of partial
response after 2–3 weeks. 3rd step: addition of
carbamazepine or clozapine or ECT. 4th step: use
various agents as topiramate, nimodipine, omega-3-
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K.N. Fountoulakis et al. / Journal of Affective Disorders 86 (2005) 1–10
fatty acids, tiagabine, etc. Bipolar depression: 1st
step: For milder episodes start with a mood stabilizer
(Lithium or Valproex) alone. In severer ones add an
antidepressant (SSRI or SNRI) and if psychotic
features are present add an antipsychotic (Olanzapine
or risperidone). ECT may be a first line option. The
use of antidepressants and antipsychotics should last
from 1.5 to 5–6 months. 2nd step: use combinations
of one or more mood stabilizers, antidepressants, and
antipsychotics and switching to different agents. ECT
and clozapine are valid alternatives. Other approaches
include light therapy, augmentation strategies, stimulants, omega-3-fatty acids, sleep deprivation etc.
Rapid cycling: Monotherapy with divalproex, lithium,
carbamazepine, or lamotrigine; combinations and
atypical antipsychotics for refractory patients. Avoid
antidepressants or use non-SSRIs. Maintenance treatment: The treatment proved effective during the acute
phase is recommended, with the exception of those
patients suffering mainly from depressive episodes
and treated with divalproex monotherapy. For those
patient combination therapy with lithium plus divalproex is recommended. Antipsychotics should be
discontinued, but for some patients in need for
continuous antipsychotic medication, the therapist
may choose between olanzapine, risperidone, and,
alternatively, quetiapine. In case of a breakthrough
manic episode, increase the dose of the stabilizer
already applied, add a second one, then add adjunctive
therapy and a third mood stabilizer. If there is a
depressive breakthrough episode, again optimize the
dosage of medication already applied, add a second
mood stabilizer (divalproex or lithium) or lamotrigine
or an antidepressant. Comments: This algorithm is too
much detailed (covers 30 pages) and structured step
by step; it reflects an overanalysis of expert opinion
but it does not seem to rely heavily either on hard data
or clinical experience.
The ECNP Consensus Meeting Guidelines for
Investigating Efficacy in Bipolar Disorder 2000
(Montgomery, 2001). This work group did not
directly provide any detailed treatment guidelines.
The general outline of the treatment plan suggested by
this work group is largely in accord with the APA
1994 guidelines.
The World Federation of Societies of Biological
Psychiatry Guidelines for the Biological Treatment
of Bipolar disorders. 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).
Mania: First line: for acute euphoric mania lithium,
valproate, olanzapine, risperidone, and carbamazepine; for mixed states of dysphoric mania valproate,
olanzapine, risperidone, and carbamazepine, but not
lithium. Typical antipsychotics should be avoided, but
they are the first line of choice for severe episodes of
mania and psychotic mania. In hypomanic episodes,
use low doses of lithium or valproate or the short-term
use of valproate or an atypical antipsychotic. Second
line: use of combinations of lithium and/or and
anticonvulsant plus an atypical antipsychotic or
ECT. Bipolar depression: First line: use lithium, or a
combination of antidepressants and mood stabilizers.
Second line: use various combinations of first line
agents, augmentation strategies and ECT. Maintenance phase: After a depressive episode, use a
combination of antidepressants (SSRIs) and mood
stabilizers (lithium, lamotrigine, valproate, or carbamazepine). After a manic episode, use lithium, an
anticonvulsant or an antipsychotic. In case first line
treatment fails, then the therapist should use combinations of first choice agents. Comments: These
guidelines seem to be the most balanced to date.
They are more advanced in comparison to the 1994
APA-like guidelines but at the same time they avoid
going too far in recommending novel strategies. They
favor the use of atypical antipsychotics and antidepressants, however with appropriate caution.
The Expert Consensus Guideline Series Treatment of Behavioral Emergencies (Allen et al.,
2001). Their first line for acute mania is the oral or
parenteral administration of the combination of a high
potency conventional antipsychotic or an atypical
antipsychotic (olanzapine or risperidone) plus a
benzodiazepine. Antipsychotic or benzodiazepine
monotherapy may be an alternative.
Guidelines from the Danish Psychiatric Association and the Child and Adolescent Psychiatric
Association in Denmark (Licht et al., 2003). Mania/
mixed: If the patient is not on prophylactic treatment
and for severely agitated patients, use an antipsychotic as a temporary supplement to treatment with
lithium or an antiepileptic drug. Treatment with
lithium or an antiepileptic may be sufficient even
in cases of psychotic mania. For mixed mania,
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K.N. Fountoulakis et al. / Journal of Affective Disorders 86 (2005) 1–10
Table 2
Guidelines for the treatment of acute mania
American Psychiatric
Association, 1994
American Psychiatric
Association, 2002
Texas Medication
Algorithm
Project 2002
British Association of
Pharmacology 2003
World Federation of
Societies of Biological
Psychiatry 2003
1st choice
Li
Li, Vp, Olz
Vp, Cbz
APs only for the
rapid control
of agitation
Severe: APs, Vp
Mild–Mod: Li, Cbz
(Li or Vp)+AP
Clozapine
ECT
Li, Vp, Olz, Ris, Cbz
2nd step
Severe: Li or Vp+AP
Mild–Mod: Li, Vp, Olz
Various combinations
of two 1st choice agents
ECT
valproate or olanzapine is recommended. If the
patient was already on prophylactic treatment, then
the prophylactic agent already applied should be
raised, and the addition of an atypical antipsychotic
or of a second prophylactic agent should be
considered. Antidepressant drugs should be discontinued. Refractory patients should be treated with
ECT. Bipolar depression: If the patient does not
receive any prophylaxis and an depressive episode
emerges, lithium or lamotrigine monotherapy is
recommended for milder cases. If an antidepressant
is used, concomitant therapy with a prophylactic
agent should accompany the use of the antidepressant. In case the patient is already on lithium
prophylaxis, the first step should be to optimize
lithium dosage and then to add lamotrigine or an
antidepressant (SSRI). If the patient already receives
prophylactic treatment other than lithium, then
lithium, lamotrigine, or an antidepressant should be
added. In case of the presence of psychotic features,
an antipsychotic (preferably an atypical) should be
initiated. After the resolution of symptoms, antidepressants should be discontinued earlier than recom-
Various
combinations
of two 1st
choice agents
Combinations of
MS+aAPs
ECT
mended for unipolar depression. ECT should be
considered for refractory cases. Long-term treatment:
Prophylactic drug treatment if at least 2 episodes
occur within a period of 5 years although some
patients may need prophylaxis after only one
episode, judging on its severity. Duration of prophylaxis may range from 5 to 10 years. Lithium should
be the first choice. Comments: The Danish guidelines are restricted to fundamental issues; they were
developed with the Expert Opinion way.
British Association for Psychopharmacology:
Evidence-based guidelines for treating bipolar
disorder (Goodwin, 2003). Mania/mixed: For severe
manic or mixed episodes use antipsychotics or
valproate; for less severe episodes lithium or carbamazepine. The next step includes combination treatment (lithium or valproate plus an antipsychotic).
Also consider clozapine and ECT. Antipsychotics and
especially atypical ones should be used to treat
psychotic features. Bipolar depression: Combination
with an antidepressant (SSRIs) and an anti-manic
agent (lithium, valproate, or an antipsychotic). Antidepressant monotherapy is not recommended. For less
Table 3
Guidelines for the treatment of acute bipolar depression
American Psychiatric
Association, 1994
American Psychiatric
Association, 2002
Texas Medication
Algorithm Project 2002
British Association
of Pharmacology 2003
World Federation of
Societies of Biological
Psychiatry 2003
1st choice
Li
Li or La or Li+AD
ECT
Li, Vp, Olz monotherapy
or (Li, Vp, Olz)+(SSRI or La)
2nd step
Vp, Cbz
ECT
AD are considered
to worsen the
long-term course
of the illness
Combination of
1st choice agents
ECT
Various combinations
of two or more 1st
choice agents
ECT
Severe: SSRIs+AM
(Li, Vp, AP)
Milder: La, Li, Vp
TCAs
Augmentation
strategies
ECT
AD+MS
SSRIs +
(Li, La, Vp, Cbz)
Combination of 1st
choice agents
Augmentation
strategies
ECT
8
K.N. Fountoulakis et al. / Journal of Affective Disorders 86 (2005) 1–10
severe episodes, monotherapy with lithium, lamotrigine, or valproate. For refractory patients use TCAs,
augmentation strategies, and ECT. Antidepressants
should be tapered shortly after the resolution of
symptoms, after as little as 12 weeks. Long-term
treatment: Lithium is the first choice. The second line
consists of valproate, olanzapine, carbamazepine, and
maybe oxcarbazepine and lamotrigine. Refractory
patients may be treated with combinations of medications, clozapine or maintenance ECT.
4. Discussion
Bipolar illness has a complex clinical picture and
an even more complex treatment. There are more than
one traditional clinical approach to treatment with a
traditional difference between academic authorities in
Europe (in favor of the use of antipsychotics and
antidepressants) and the US (in favor of so-called
mood stabilizers).
The various treatment guidelines generally seem to
have a common starting point, best described by the
1994 APA guidelines (American Psychiatric Association, 1994). But by passing the years and after
revisions, today many guidelines deviate from this
starting point. The guidelines that seem to deviate
more than the others are the most recent Texas
algorithms (Suppes et al., 2002; Tables 2–4). The
most balanced seem to be those of the WFSBP
Table 5
Key agreements between the various guidelines and major questions
that remain unanswered
Key agreements between work groups:
Irrespective of phase: use antimanic agents/mood stabilizers
In depression: Never use antidepressant monotherapy, always add
an antimanic agent/mood stabilizer
There is lack of hard data concerning the treatment
of bipolar depression
There is lack of hard data concerning the treatment
of mixed episodes and rapid cycling
Hypomania should be treated the same way as mania
Li, Vp, Cbz, APs are all more effective for the treatment and
prevention of mania and to a lesser degree for depression
On the contrary La is more effective for the treatment and
prevention of depression and to a lesser degree for mania
Key questions:
Are there any true dmood stabilizersT or just dantimanic agentsT?
How should you best treat bipolar depression?
What is the role of antidepressants?
Do all ADs put the patient at risk to switch to mania
or rapid cycling?
Do antipsychotics work during the maintenance phase?
How should you best treat mixed states, hypomania,
and rapid cycling?
What is the true value of combinations of medications?
Should we use combinations earlier in treatment?
(Grunze et al., 2002, 2003) which allow the use of
multiple approaches with caution. The trend seems to
be the gradual acceptance of the use of atypical
antipsychotics as monotherapy and of antidepressants
Table 4
Guidelines for maintenance treatment
1st choice
2nd step
American Psychiatric
Association, 1994
American Psychiatric
Association, 2002
Texas Medication
Algorithm
Project 2002
British Association of
Pharmacology 2003
World Federation of
Societies of Biological
Psychiatry 2003
Continue the treatment
proved efficient during
the acute phase
Li or Vp possibly
Cbz, La, Ocbz
Continue the treatment
Li
After depression: AD+MS
ECT
Combination of 1st
choice agents
ECT
Combination of 1st
choice agents
AP should be
discontinued
AM (Li, Vp, Olz)
monotherapy or +AD
(intermittent use)
proved efficient during
the acute phase
Various combinations
of two or more
1st choice agents
Predominantly mania:
AM (Li, Vp, AP)
Predominantly
depression:
(AD or La)+AM
Clozapine
Combinations
ECT
SSRIs+(Li, La, Vp, Cbz)
After mania:
Li, MS, AP
Combination of 1st
choice agents
K.N. Fountoulakis et al. / Journal of Affective Disorders 86 (2005) 1–10
for a limited period in combination with antimanic
agents.
There are several key points of agreement between
algorithms, but there are also several points of
disagreement. Moreover, there are many issues that
need further study, data are rare and insufficient and
many questions remain unanswered (Table 5).
Since the publication of the most recent guidelines
in 2003, several new developments emerged. Practically all atypical antipsychotics have proven to be
efficacious in the treatment of acute mania (Vieta,
2003), olanzapine proved to be effective in the
prevention of relapse after a manic episode (Tohen
et al., in press) and, in combination with fluoxetine, in
the treatment of bipolar depression (Tohen et al.,
2003), quetiapine was better than placebo in bipolar
depression as well (Calabrese et al., in press), and
lamotrigine effectively prevented relapse in two longterm, controlled trials (Bowden et al., 2003; Calabrese
et al., 2004). Psychoeducation, cognitive-behavioral
therapy, and family intervention have been added
successfully to treatment as usual to improve the
outcome of the disease. Future guidelines should add
these new data to provide meaningful and updated
insight to the clinician. Many questions still remain
unanswered, however, the main reason being that the
evidence base for guidelines is still basically that
which emerges from registration placebo-controlled
trials, which enroll selected populations and tend to
address monotherapy as opposed to combinations
(Vieta and Carne, in press). Large, observational
studies are also needed, and their results should be
considered in future developments of current treatment guidelines.
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