SEMINAR

Seminar

Bipolar disorder

Bruno Müller-Oerlinghausen, Anne Berghöfer, Michael Bauer

Bipolar, or manic-depressive, disorder is a frequent, severe, mostly recurrent mood disorder associated with great
morbidity. The lifetime prevalence of bipolar disorder is 1·3 to 1·6%. The mortality rate of the disease is two to three times
higher than that of the general population. About 10–20% of individuals with bipolar disorder take their own life, and
nearly one third of patients admit to at least one suicide attempt. The clinical manifestations of the disease are
exceptionally diverse. They range from mild hypomania or mild depression to severe forms of mania or depression
accompanied by profound psychosis. Bipolar disorder is equally prevalent across sexes, with the exception of rapid
cycling, a severe and difficult to treat variant of the disorder, which arises mostly in women. Because of the high risk of
recurrence and suicide, long-term prophylactic pharmacological treatment is indicated. Lithium salts are the first choice
long-term preventive treatment for bipolar disorder. They also possess well documented antisuicidal effects. Second
choice prophylactic treatments are carbamazepine and valproate, although evidence of their effectiveness is weaker.

The prevention of future episodes (recurrences) and the
acute management of depressive and manic episodes are
the major goals in the treatment of bipolar disorders.1,2
However, the results of a growing number of longitudinal
outcome studies show that the effects of even aggressive
drug treatment are often much less favourable than
previously thought. Full recovery between episodes is not
achieved in all patients and, as a consequence, bipolar
disorder is one of the leading causes of disability.3 The high
rate of disability and the loss of life through suicide
contribute to the economic burden of bipolar illness to
society. A cost-of-illness study for bipolar disorder reported
total costs to society in the USA in 1991 of US$45 billion,
which is about 70% of that for schizophrenia.4
The difficulty of investigating this disease lies in the fact
that views on diagnosis and treatment of bipolar disorder
have changed over time, and, in modern psychiatry,
controversies and unresolved differences exist about many
issues related to the identification, clinical presentation,
course, and management of the disorder. In particular,
there are differences between the European and the North-
American approach. This seminar has attempted to choose
those positions that seem particularly useful for clinical
practice.
Diagnostic features
There are two main types of mood disorder, each with
different sex and genetic characteristics: major depressive
(unipolar) and manic-depressive (bipolar). Bipolar disorder
can be further subdivided into bipolar I disorder, a
recurrent mood disorder, featuring either one or more
manic or mixed episodes, or both manic and mixed
Lancet 2002; 359: 241–47
episodes and at least one major depressive episode, or
bipolar II disorder, characterised by one or more episodes
of major depression and at least one hypomanic episode
(panel 1). According to the criteria of the American
Psychiatric Association,1 a manic episode is defined as a
distinct period during which patients experience
abnormally and persistently raised, expansive, or irritable
mood. Although manic episodes and hypomanic episodes
have many similar symptoms, the mood disturbance in
hypomanic episodes is not sufficiently severe to cause
pronounced impairment in social or occupational
functioning. A mixed episode is characterised by a period of
at least 1 week in which the criteria are met for both manic
and major depressive episodes. The characteristic feature of
a major depressive episode is a period of at least 2 weeks
with either depressed mood or with a loss of interest or
pleasure in almost all activities.1 Manic episodes occur
much less frequently than episodes of depression. Bipolar
disorder occurs nearly equally in women and men, and
displays strong familial patterns of inheritability.2 The
disorder is more frequent in creative people, such as artists,
and their relatives, than in normal controls.5 The disorder is
often associated with substance abuse, particularly in the
USA. This finding should be accounted for in assessment
of study results.
Diagnostic criteria and definitions for bipolar disorder
have changed over the years. Most recently, bipolar
disorder has been defined as a continuum of phenotypes,
ranging from a pattern of mild depression and brief
hypomania to one of severe rapid cycling or predominantly
mania with psychotic features. The heterogeneity of bipolar
disorder is reflected in the large variation of related
pathophysiological, genetic, and other biological and
clinical findings. A primary research issue involves the

Department of Psychiatry, Research Group of Clinical Search strategy

Psychopharmacology, Freie Universität Berlin, Berlin, Germany
A computer-aided search of MEDLINE database for 1966 to
(Prof B Müller-Oerlinghausen MD); Institute of Social Medicine,
November, 2000, was done with the subject headings “bipolar
Epidemiology, and Health Economics, Charité Hospital, Humboldt
disorder” and various subjects pertinent for this review.
University, Berlin (A Berghöfer MD); and Neuropsychiatric Institute
and Hospital, Department of Psychiatry and Biobehavioral A review of identified report bibliographies and an intensive
Sciences, University of California Los Angeles (UCLA), search by hand with standard textbooks on bipolar disorder
Los Angeles, CA, USA (M Bauer MD) was also done. Because of the large number of articles
identified and the limitations for quoting references in this
Correspondence to: Prof Bruno Müller-Oerlinghausen, Jebensstr 3,
article, authors made selections according to the valid criteria
10623 Berlin, Germany
of what is judged evidence-based-medicine.
(e-mail: bmoe@zedat.fu-berlin.de)

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 SEMINAR
Panel 1: DSM-IV classification of bipolar disorders
DSM-IV category Criteria
Bipolar I disorder One or more manic or mixed episodes,
usually accompanied by one or more major
depressive episodes
Bipolar II disorder Recurrent major depressive episodes with To describe current (or most recent) episode:
one or more hypomanic (milder than manic) Hypomanic
episodes
Cyclothymic disorder Chronic (>2 years), fluctuating mood
disturbance, involving numerous periods
of mild hypomanic and depressive
symptoms that do not meet criteria
for a major depressive episode
Bipolar disorder Disorders with bipolar features that do not Examples:
not otherwise meet criteria for any specific bipolar
specified disorder
DSM-IV=Diagnostic and Statistical Manual of Mental Disorders, 4th edn.
development of valid diagnostic subclassifications, which
will help to integrate the many diverse and apparently
contradictory findings, and to assist with the development
of differential, cause-specific selection of treatment options.
According to a national survey in the USA,6 half of patients
have to wait at least 5 years for a correct diagnosis of bipolar
disorder, which is only made after they have visited, on
average, four doctors.
Course of illness
The peak age of onset falls between age 15 and 24 years,
although there is often a 5–10-year interval before
treatment is obtained.1 If the onset of symptoms occurs
after age 60 years, the condition is probably secondary
to other medical causes—eg, neurological (trauma,
neoplasm, multiple sclerosis, epilepsy), endocrine
(hyperthyroidism, Cushing’s disease), infectious (AIDS),
inflammatory (systemic lupus erythematosus) disorders.
Bipolar disorder has a high rate of recurrence; more than
90% of individuals who have a single manic episode will
have future episodes.3 And the natural course of the illness
is highly variable. Ten to 15% of patients will have more
than ten episodes during their lifetime.1,2
The clinical subtypes could have distinct biological
underpinnings and might, therefore, respond differently to
treatment and run a different course (panel 1). In
10–15% of individuals, a variant of bipolar disorder with a
rapid cycling pattern is seen, in which four or
more episodes occur during 12 months that meet the
242
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Course specifiers and examples
To describe current (or most recent) episode:
Mild, moderate, severe without psychotic features
Severe with psychotic features
In partial or full remission
With catatonic features
With postpartum onset
To describe current (or most recent) major depressive episode:
Chronic
With melancholic features
With atypical features
To describe pattern of episodes:
With or without full interepisode recovery
With seasonal pattern
With rapid cycling (⭓4 episodes in previous 12 months)
Depressed
To describe current (or most recent) major depressive episode
and pattern of epsiodes:
See bipolar I disorder
Over 2 years any symptom-free intervals last no
longer than 2 months
Very rapid cycling (over days)
Recurrent hypomanias without depressive symptoms
Indeterminate whether primary or secondary (due to a general
medical condition or substance abuse)
criteria for a major depressive, manic, mixed, or hypomanic
episode. In these patients, episodes are demarcated either
by partial or full remission for at least 2 months or by a
switch to an episode of opposite polarity—eg, major
depressive episode to manic episode.1 In addition to being a
woman, other factors associated with rapid cycling include
the use of tricyclic antidepressants and the presence of overt
or subclinical hypothyroidism.
Pathophysiology
In-vivo biochemical studies, neuropathological studies, and
studies with new neuroimaging techniques are
being done to try to understand the cause of bipolar
disease.7–9
One traditional line of research focuses on potential
changes to the function of neurotransmitters such as
norepinephrine, dopamine, and serotonin. In the 1970s,
many thought that bipolar disorder was caused by an
imbalance between cholinergic and catecholaminergic
neuronal activity, since centrally active cholinergic agonists
had antimanic properties.10 Lower than normal
concentrations of choline—a direct precursor of acetyl-
choline—have been reported in red blood cells of patients
with bipolar disease and a history of predominantly manic
episodes. Furthermore, concentrations of the dopamine
metabolite homovanillic acid are usually decreased in the
cerebrospinal fluid of depressed patients,11 whereas
concentrations of serotonin and ␥-aminobutyric acid might
be reduced. At necropsy, concentrations of the serotonin
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metabolite, 5-hydroxyindol acetic acid, and 5-hydroxy-
tryptamine are reduced in individuals who had bipolar
disease.9 Results of a study with photo emission tomography
showed greatly reduced 5-hydroxytryptamine-1A receptor
binding in the midbrain raphe and mesotemporal cortex
(amygdala, hippocampus) of unmedicated patients with
bipolar depression compared with controls.12 These results
are in line with basic and clinical research, which indicates
that the serotonergic system is involved in the pathogenesis
of affective illness.
Another hypothesis that dates back to the 1970s suggests
that the change of electrolyte fluxes in individuals with
bipolar disorder is caused by a deficit of the membrane
sodium potassium-ATPase. In fact, concentrations of
erythrocyte ATPase are lower in patients with bipolar
disorder than in healthy controls.13
The most consistent findings in structural imaging
studies are periventricular magnetic resonance tomography
T2-signal white-matter hyperintensities, and an
enlargement of the lateral and third ventricle.14,15 These
structural abnormalities are of uncertain origin and are
unspecific. However, the periventricular hyperintensities
are more common in bipolar disorder than in
schizophrenia.15 Abnormalities in cortical and subcortical
structures, in particular the amygdala and basal ganglia,
have been described in several structural and functional
imaging studies. Similar to investigations in major
depressive disorder, results of most studies with positron
emission tomography in patients with bipolar depression
show decreased metabolism in the prefrontal cortex.8
Drevets and colleagues16 reported a specific metabolic
decrease in the subgenual prefrontal cortex in patients with
bipolar depression compared with healthy controls. This
decrease in blood flow and glucose metabolism did not alter
with remission of the depression, indicating that an
anatomical abnormality might, at least in part, account for
the metabolic change.16 Findings of two studies17,18 with
magnetic resonance imaging indicate a bilateral amygdala
enlargement but no enlargement of the hippocampus. A
dysfunction of the amygdala has also been reported in an
affect-recognition paradigm using functional magnetic
resonance imaging technology.19 In summary, there is some
indication for a dysfunction in prefrontal-limbic-subcortical
circuitary underlying bipolar disorder. However, the
specificity of these findings, and their relevance to the
pathophysiology of the disorder, remains unknown.8,15
Cell counts done at necropsy suggest a decrease in glial
number and density in the prefrontal cortex of patients.
This finding might bear some relation to another area of
neuropathological research in bipolar disorder—changes of
post-receptor signalling.20 Since findings suggest that the
action of lithium occurs downstream of the synaptic site,
much research has been directed to the function of second
messenger systems. Various findings, such as increased
signalling via increased coupling of adenylcyclase to
G-proteins, suggest abnormal patterns of activity in the
interconnected prefrontal-subcortical and limbic circuits.
However, whether or not these abnormalities are a cause or
an effect of chronic illness remains unknown.8
Of all the endocrine systems thought to be linked to the
pathophysiology of bipolar disorder, the hypothalamic-
pituitary-thyroid axis is the prime candidate. Disturbances
of affect and mood, such as major depression and bipolar
disorder, are associated with disturbances of peripheral
thyroid hormone metabolism. Abnormalities in thyroid
function are of particular importance in the clinical course
of patients with the rapid cycling variant of bipolar disorder.
They have a much higher frequency (about 25%) of grade
II hypothyroidism (defined as increased concentration of
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SEMINAR
serum basal thyroid-stimulating hormone with a normal
serum thyroxine value) than depressed patients in general
(2–5%). Thyroid hormones have profound effects on mood
and behaviour, and seem to be able to modulate the
phenotypic expression of major affective illness.21
Genetic factors
Results of family-studies and twin-studies suggest a genetic
basis for bipolar disorder.22 The lifetime risk of bipolar
disorder in first-degree relatives of a bipolar patient is
40–70% for a monozygotic twin and 5–10% for all other
first-degree relatives. However, the mode of inheritance
seems complex, indicating a non-Mendelian inheritance
and a contribution by several genes. Genomic imprinting
and mitochondrial inheritance are also thought to
contribute to the inheritance pattern. Because of the large
variation of phenotypes seen in patients with bipolar
disorder, genetic factors probably only have a small effect,
and environmental and developmental factors are also
important in the development of the disorder.23
In fact, molecular genetic studies, although hinting at
potentially relevant gene loci (18p11, 18q22, 4p16, 21q21,
Xq26), have not yet consistently identified specific genes
related to bipolar disorder. This difficulty in identifying
specific genes might be partly due to an insufficient
demarcation of bipolar disorders from disorders of the
bipolar spectrum, leading to heterogeneous patient
samples. One group of researchers overcame this difficulty
by recruiting only those patients with excellent lithium
responsiveness.24
Based on pathophysiological findings, candidate genes
are mainly selected in accordance with their importance for
neurotransmission. Variants of the serotonin transporter
gene might be relevant to the probability of developing
bipolar illness, whereas variants of the catechol-O-
methyltransferase gene might modify the course of illness.
Among many negative or non-replicated controversial
results, two positive findings have emerged: the positive
association between bipolar disorder and the phospholipase
C-␥1 isozyme; and the genes for corticotropin-releasing
hormone and proenkephalin.25,26
Management
In view of the devastating course of bipolar disorder,
prevention strategies that are effective, evidence-based, and
safe need to be developed. In the meantime, the choice of
treatments for bipolar disorder is constantly being revised,
as new drugs become available and anticonvulsants take on
an increasingly important role. New treatment regimens to
counteract resistance to primary treatment or prophylaxis
have also been developed. Here, we review and comment
on evidence available for treatment options for the long-
term and acute management of bipolar disorder.
Long-term treatment (panel 2)
The main aim in the treatment of bipolar disorder is to
prevent recurrences and suicidal acts. A patient who has
had at least two episodes in 5 years (either manic or
depressive) should start prophylactic treatment.1 Lithium
salts are the most effective long-term preventive treatment
for bipolar disorder, irrespective of manic or depressive
recurrences, as shown in a multitude of controlled studies27
and several meta-analyses.28 Response rates in early
controlled studies in the 1960s and 1970s ranged from 70%
to 80%. During the next few decades, however, these
response rates could not always be replicated in clinical
practice, and doctors began to wonder whether lithium was
the best treatment option. Some researchers also claimed a
secondary loss of efficacy in initially lithium-responsive
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patients.29 However, such claims were mainly case reports
and have remained controversial, since they are not
supported by studies in larger, well documented patient
groups.30 Furthermore, the observed drop in response rates
were probably a result of the wide-spread use of lithium in
less-controlled settings and of the introduction of modern
diagnostic systems that broadened the criteria of bipolar
disorder in the 1990s.28,31 As well as the need to distinguish
between the efficacy and the effectiveness of a specified
pharmacological treatment,31 it is necessary to distinguish
subtypes of bipolar illness to achieve maximum response in
long-term treatment. A substantial number of patients with
bipolar disease show psychiatric comorbidity, substance
abuse, psychotic features, and medication-induced rapid
cycling, and therefore deviate considerably from the
original picture of manic-depressive illness. To date,
lithium remains the first choice for maintenance treatment
of patients with bipolar disorder who have a classical course
of illness without mood-incongruent psychotic features and
without psychiatric comorbidity.32
The treatment options for bipolar disorder have
broadened since the emergence of anticonvulsants.
Carbamazepine, for example, compared with lithium and
placebo, is effective in the long-term treatment of bipolar
disorder, although it is not approved for this indication
worldwide. Carbamazepine is more effective than lithium in
the long-term treatment of patients with bipolar spectrum
disorder, but less effective in the treatment of classical
bipolar disorder.33,34
Although valproic acid and its congeners have been used
to treat affective disorders since the 1960s only some open
studies suggest prophylactic efficacy in bipolar disorder.35,36
Patients with rapid cycling or mixed states might benefit
particularly from treatment with such drugs,37,38 but
evidence from long-term studies to support a notion of
specific target groups for valproic acid is lacking. Because
evidence for an episode-preventive effect from controlled
studies is absent, valproic acid has received approval in the
USA only for use in acute mania, and should be used for
maintenance therapy only when lithium or carbamazepine
are not tolerated or are ineffective. In this context, it should
be noted that there is no generally accepted definition of
“mood stabiliser”, a term introduced only recently and
possibly promoted for commercial reasons. A compound
having shown to be effective in acute mania should not be
labelled a “mood stabiliser” until its efficacy in prevention
of the recurrence of manic and depressive episodes has
been proven.
Promising results on the efficacy of the newer
anticonvulsants, lamotrigine, gabapentin, and topiramate,
are emerging from open studies. Until evidence from
controlled studies is available, these drugs should be
reserved for refractory cases.
The mode of action of mood stabilisers cannot be fully
explained, since our understanding of the pathophysiology
of bipolar disorder is still fragmentary. However, evidence
indicates that at least some of the mood stabilising agents
share one or more common mechanisms. How does a
simple ion such as lithium exert such complex effects on
multiple biological systems and affect both manic and
depressive symptoms? Results of preclinical and clinical
studies suggest that lithium might effect postsynaptic signal
transduction through the inhibition of the synthesis,
release, and function of second messengers. Lithium
dampens the overactive phosphatidylinositol pathway.
Furthermore, various lithium effects on calcium signalling,
as well as antikindling effects, have been seen.20,39 The
antimanic and antiaggressive properties of lithium are
possibly related to its serotonin-agonistic action. Reports of
244
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Panel 2: Long-term treatment of bipolar disorders
Established options, evidence Lithium salts
from various controlled studies Carbamazepine
Possibly efficacious, wide- Valproic acid
spread in clinical practice,
limited evidence
Weak evidence Calcium antagonists
Experimental as monotherapy, Anticonvulsants:
limited evidence as adjunct lamotrigine, gabapentine,
treatment topiramate
Thyroid hormones:
levothyroxine
Atypical neuroleptics:
clozapine, olanzapine
neuroprotective and neurotrophic effects of lithium have
raised considerable interest,40 since a large reduction of
brain-cell volume is seen in bipolar disorder. Atypical
neuroleptics, such as clozapine, might also have mood-
stabilising and potentially antisuicidal effects in bipolar
disorder.41
Adjunctive supraphysiological doses of levothyroxine are
an effective treatment option for refractory bipolar
disorder.42,43 A latent hypofunction of the thyroid axis in
rapid-cycling bipolar disorder might explain why high doses
of levothyroxine, when added to treatment with lithium and
other psychotropic drugs, can reverse the refractory
pattern.44 Panel 2 shows other agents suitable for
prophylactic use.
The use of long-term medication should be based on
solid evidence. However, drugs are often approved before
such evidence is available. Additionally, off-label use of
valproic acid and atypical antipsychotics for long-term
treatment of bipolar disorder, which is not based on
sufficient scientific evidence, has increased in several
countries.
Discontinuation of long-term treatment in patients with
bipolar disorder commonly occurs in clinical practice.
There is substantial evidence that in a large proportion of
patients an abrupt discontinuation of lithium treatment
leads to a sudden increase of affective morbidity, a rebound
effect.45 If lithium is gradually discontinued, the risk of early
recurrences, particularly of mania, are reduced.46 There is
limited evidence that a rebound might not arise in patients
with a classical course of bipolar disorder who experience
full remission between episodes and show only mood
congruent symptoms during acute episodes.47 A
discontinuation of other mood-stabilising drugs might
cause similar reactions; however, comparable studies are
still lacking. The risk of suicide also increases after
interruption of long-term treatment.48 Patients have to be
informed about the risks and implications of stopping their
long-term treatment.
Prevention of suicide
The reduction of suicidal acts should be an essential
measure in the assessment of efficacy and effectiveness of
every treatment. Such data do not exist for any of the
accepted pharmacological and psychological treatment
strategies in mood disorders. However, during the past
decade, evidence from retrospective and prospective studies
has suggested that long-term lithium prophylaxis can
reduce the risk of suicide, and even normalise the excess
mortality rate, which is also a result of increased
cardiovascular risk.48,49 In a large, prospective, 2·5-year,
randomised trial of 234 patients with bipolar or
schizoaffective disorder, there were no suicidal acts in the
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lithium group, whereas there were six suicides and some
suicide attempts in the carbamazepine group (p<0·01).50–52
This antisuicidal effect of lithium might be related to its
well-known antiaggressive effect and its predominantly
presynaptic serotonin-agonistic action. Furthermore, some
clinical findings suggest that the antisuicidal property of
lithium acts independently of its episode-preventive effect.
Treatment of acute mania (panel 3)
Since its introduction in 1949, lithium has remained the
drug of choice in acute manic states.53 Lithium
monotherapy is generally effective in mania of mild or
moderate severity, and is most effective in euphoric mania.
During the acute manic phase, lithium should be initiated
at higher doses than in prophylactic treatment, to achieve
serum concentrations of 1·0–1·2 mmol/L
(vs 0·6–0·8 mmol/L in long-term treatment). Since the
therapeutic effect is delayed by at least 1 week,
benzodiazepines should be given concomitantly during the
first 7 days. In instances of severe mania or psychotic
symptoms, additional antipsychotic or anticonvulsant
medications are usually required.
Carbamazepine, which also has a delayed onset of action,
has been widely used in the treatment of acute mania. The
drug has an antimanic effect comparable to that of the
antipsychotics, but does not cause extrapyramidal side-
effects. Initial high-dose treatment is usually badly
tolerated, since the drug causes vertigo and ataxia.
However, the sedative effect might be of advantage.54
Valproic acid is also effective in the treatment of acute
mania.38 Unlike carbamazepine, this drug does not interact
with others, and is therefore especially suitable for
combined treatment regimens.55 Furthermore, loading
doses are well tolerated and exert a rapidly sedating effect.
The incidence of adverse events is low. With this regimen,
an early response after 1–4 days can be expected. Patients
with so-called mixed (concurrent depressive symptoms) or
dysphoric manic states seem to benefit from treatment with
valproic acid.
Antipsychotics exert a rapid and powerful effect in all
manic states,56 and are often used to control hyperactivity
and psychotic features in severe manic states. They are
widely used, not only in Europe, but also in the USA.57
However, the use of antipsychotics in patients with affective
disorders is associated with a high frequency of neurological
and mental side-effects, and they should, therefore, only be
given in combination with mood stabilising agents and only
Panel 3: Treatment of acute mania
Form of manic state Treatment options
Mild, moderate, and Lithium salts initially combined
euphoric with benzodiazepines
Carbamazepine initially
combined with benzodiazepines
Valproic acid
Olanzapine
Severe, incooperative, Lithium salts plus antipsychotics
psychotic, and euphoric Carbamazepine plus antipsychotics
Valproic acid plus antipsychotics
if necessary
Olanzapine plus one mood stabiliser
Mixed or dysphoric type Valproic acid
Additional somatic Electroconvulsive therapy
complications (cardiac
disease, pregnancy)
Refractory mania Electroconvulsive therapy
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SEMINAR
over a limited period, to avoid tardive dyskinesia. Results of
a large controlled trial58 show that the dose of haloperidol
needed to control acute manic symptoms can be reduced
by addition of valproic acid. Atypical antipsychotics such as
clozapine and olanzapine exhibit antimanic properties in
addition to their antipsychotic properties59 with a far lower
risk of extrapyramidal motor side-effects than typical
neuroleptics. Olanzapine is approved for this indication in
the USA.60 A few studies have also been done to assess the
efficacy of clozapine and risperidone.61
Adjunctive benzodiazepines are used to control
hyperactivity in acute mania, thus reducing the need for
antipsychotics. Clonazepam and lorazepam are especially
effective when given before the onset of antimanic activity
associated with lithium or carbamazepine. There is only
limited clinical evidence that calcium channel blockers such
as verapamil and nimodipine exert antimanic effects.
Electroconvulsive therapy has a more rapid onset than
any drug and is one of the best proven treatment options in
acute manic states.62 However, because of the stigma
attached to the treatment in different countries, electro-
convulsive therapy is reserved for special clinical
conditions—namely medical diseases that rule out
pharmacological treatments, including pregnancy and
manic states refractory to drug treatment.1
Treatment of bipolar depression (panel 4)
When a patient with bipolar disorder has a breakthrough
episode of depression, despite continuing mood
stabilisation treatment, physicians face a challenge. Bipolar
depression is frequently longlasting, severe, and disabling,
and is associated with a pronounced suicide risk. Overall,
treatment of bipolar depression has been understudied
compared with that of unipolar depression.63,64 Almost all
antidepressants effective in the treatment of unipolar major
depression are effective in treatment of bipolar depression.
However, response rates to antidepressant medications are
lower in patients with bipolar disorder than in those with
unipolar major depression.63,64 Furthermore, treatment of
bipolar disorder depression with antidepressants,
particularly tricyclics, is complicated by the risk of a rapid
switch to mania, or by the induction and acceleration of
rapid cycling.
If a patient who is not taking a mood stabiliser becomes
depressed, treatment with lithium should be initiated. If the
patient does not respond, or has severe depression, an
Panel 4: Treatment of bipolar depression
Depressive state Treatment options
In absence of prophylactic treatment
Mild and moderate Lithium
Interpersonal psychotherapy,
cognitive behavioural therapy
Severe Lithium plus antidepressant
Breakthrough depression under prophylactic treatment
Mild and moderate Optimisation of prophylactic treatment
with mood stabiliser
Severe Current mood stabiliser plus selective
serotonin reuptake inhibitors or second
mood stabiliser
Depression in rapid Strictly avoid antidepressants
cycling Current mood stabiliser plus second
mood stabiliser
Addition of levothyroxine
Refractory depression Electroconvulsive therapy
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antidepressant should be added.64 Patients who have a
breakthrough depression while taking a mood stabiliser
might benefit from treatment optimisation—eg, increase of
serum concentrations to the upper end of the therapeutic
value, or addition of thyroid hormone if thyroid function is
low, or both. However, in most instances, an antidepressant
or second mood stabiliser will need to be administered.
There is some evidence that the selective serotonin
reuptake inhibitors (SSRIs) are more tolerable and might
have a lower risk of inducing manic switches or rapid
cycling than tricyclics.63–65 In a 6-week double-blind study,66
the SSRI antidepressant paroxetine showed equal efficacy
to the tricyclic agent amitriptyline in patients with ongoing
lithium prophylaxis, although the time of onset of
improvement was more rapid in the paroxetine-lithium
group. Some doctors prefer to add a second mood
stabiliser, particularly in those with rapid cycling.67,68
Monotherapy with lamotrigine has the same low switching
rate as placebo, perhaps indicating a special application of
this drug in the management of bipolar depression.67 In
patients with rapid cycling, antidepressants should be
strictly avoided, optimising the current mood stabiliser or
adding a second mood stabiliser. In instances of severe and
refractory bipolar depressive episodes, electroconvulsive
therapy is recommended because of its proven strong anti-
depressant efficacy, especially in patients with delusions.1
Adjunctive levothyroxine in supraphysiological doses can
be used for treatment of patients with refractory bipolar
depression or refractory rapid cycling.43,44 In view of the
effects of lithium on the phosphatidylinositol cycle, inositol
has also been proposed as an add-on treatment in bipolar
depression.69
Non-pharmacological strategies
Psychotherapy used to be the only treatment available for
bipolar disorder, which was thought to be caused by
environmental and developmental factors. Since the
introduction of effective drugs, and the emergence of
pathophysiological and genetic findings, however,
psychotherapy has been temporarily pushed aside as a
treatment. Nevertheless, environmental stress can play a
(restricted) part in triggering manic or depressive
episodes.70 Furthermore, certain dysfunctional cognitions,
related to unipolar depression, are also seen in remitted
bipolar patients.71 During the past decade, specific
psychotherapy has been shown to be an effective addition
to drug treatment in some situations. Psychotherapy is, for
example, used to improve patient medication compliance
and acceptance of the illness, and to modify environmental
risk factors.72
There is a range of psychotherapeutic interventions
available for treatment of major depression. Psychodynamic
psychotherapy and psychoanalysis attempt to clarify
intrapsychic processes that lead to affective dysbalance.
Cognitive behaviour therapy focuses on irrational and
dysfunctional attitudes of the patient that trigger depressive
symptoms. Interpersonal therapy works on interpersonal
losses and role disputes. Both cognitive behaviour therapy
and interpersonal therapy are effective in the treatment of
acute, mild, and moderate depression. In severe depression,
however, psychotherapy can only be effective in addition to
drug treatment. Further optimisation of individualised
long-term treatment strategies might imply well-being
therapy73 and selected approaches from complementary
medicine.74
In long-term treatment of bipolar disorder careful
psychoeducation is an important component of any
treatment plan. The way that a patient functions between
episodes can be improved by working on problems
246
For personal use. Only reproduce with permission from The Lancet Publishing Group.
associated with stigmatisation by the illness, low self-esteem
after episodes, disturbed interpersonal relations, legal
conflicts caused by reckless or violent behaviour in mania,
and social and occupational disabilities. Maintainance of a
regular pattern of daily activities, as addressed by
interpersonal and social rhythm therapy, might help with
interepisodic stability.75
Conflict of interest statement
M Bauer received a grant from the Deutsche Forschungsgemeinschaft
(German Research Council; BA 1504/3-1) and honoraria from Eli Lilly
and Company for serving on a consultancy panel in 2000.
B Müller-Oerlinghausen received a quarterly honorarium between 1999
and spring 2001 from Eli Lilly and Company for acting as the national
principal investigator of a national multicentre study in psychiatry.
Acknowledgments
We thank Paul Grof for advice in preparation of the report.
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