1
Florida Heart CPR*
Bipolar Disorder Medications
2 hours
Learning Objectives
Upon completion of this course, participants will be able to:
1. Identify the important diagnostic elements of bipolar disorder.
2. Assess the current clinical interventions and treatments, both
pharmacologic and behavioral.
3. Review pharmacologic interventions in bipolar depression and rapid
cycling bipolar disorder.
Introduction
Bipolar affective disorder, when narrowly defined, has a lifetime incidence of 0.31.5/100.[1] Overall, patients with severe affective disorders have a risk of completed
suicide of 6% to 15%.[2,3] Traditionally, bipolar disorder and its predecessor, manicdepressive psychosis, have been considered as intermittent disorders with good
interepisode recovery.[4] However, recently it has been shown that patients may have
social, marital, occupational, and cognitive dysfunction even when supposedly
recovered.[5] A number of factors are of importance in the management of bipolar
disorder, including the subtype of episode (manic, depressed, or mixed); the nature of
recovery; the cycling frequency and precipitant, if any, for recurrence; and the onset and
evolution of the underlying illness. On average, 4 episodes occur every 10 years;
however, up to a quarter of patients develop rapid cycling disorder, which is defined as
4 or more episodes occurring within a year.[6] Patients with bipolar disorder often have
comorbid anxiety and substance abuse. Such comorbidity is associated with an earlier
age at onset and worsening course of bipolar illness. Established addictive problems
should be independently assessed and treated.[7] Personality problems are also
common. Kay and colleagues,[8] after excluding patients with a history of alcohol use
disorder, demonstrated axis II comorbidity in almost a quarter of euthymic bipolar
patients. As with all psychiatric disorders, treatment strategies in bipolar disorder must
be based on an overall management plan that incorporates both pharmacologic and
psychological approaches.
Diagnosis
Bipolar disorder is often undiagnosed or misdiagnosed as another psychiatric disorder,
most commonly unipolar disorder. As mentioned above, it is also frequently comorbid
with both Axis I and Axis II disorders. Mania is fundamental to the diagnosis of bipolar 1
disorder. Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)
criteria for mania are as follows[6]:
Florida Heart CPR*
Bipolar Disorder
2
1. A distinct period of abnormally and persistent elevated, expansive, or irritable
mood, lasting at least 1 week (or any duration if hospitalization is necessary).
2. During the period of mood disturbance, 3 (or more) of the following symptoms
have persisted (4 if the mood is only irritable) and have been present to a
significant degree:
a.
b.
c.
d.
e.
Inflated self-esteem or grandiosity
Decreased need for sleep (eg, feels rested after only 3 hours of sleep)
More talkative than usual or pressure to keep talking
Flight of ideas or subjective experience that thoughts are racing
Distractibility (ie, attention too easily drawn to unimportant or irrelevant
external stimuli)
f. Increase in goal-directed activity (either socially, at work, at school, or
sexually) or psychomotor agitation
g. Excessive involvement in pleasurable activities that have a high potential
for painful consequences (eg, engaging in unrestrained buying sprees,
sexual indiscretions, or foolish business investments).
3. The symptoms do not meet criteria for a mixed episode.
4. The mood disturbance is sufficiently severe to cause marked impairment in
occupational functioning or in usual social activities or relationships with others,
or to necessitate hospitalization to prevent harm to self or others, or there are
psychotic features.
5. The symptoms are not due to the direct physiologic effects of a substance (eg, a
drug of abuse, a medication, or other treatment) or a general medical condition
(eg, hyperthyroidism).
Hypomania is not associated with significant functional impairment and, with major
depression, defines bipolar 2 disorder. The DSM-IV definition is:
1. A distinct period of at least 4 days of elevated, expansive, or irritable mood;
2. The presence of 3 or more of 7 diagnostic symptoms (4 symptoms if the mood is
only irritable);
3. An unequivocal change in functioning;
4. This change and disturbance is observable by others;
5. The episode does not meet criteria for mania; and
6. The symptoms are not due to the effects of a substance or a general medical
condition.
For bipolar depression, individuals must fulfil DSM-IV criteria for a major depressive
episode within the context of a bipolar disorder.
1. The criteria are met both for a manic episode and for a major depressive episode
(except for duration) nearly every day during at least a 1-week period;
Florida Heart CPR*
Bipolar Disorder
3
2. The mood disturbance is sufficiently severe to cause marked impairment in
occupational functioning or in usual social activities or relationships with others,
or to necessitate hospitalization to prevent harm to self or others, or there are
psychotic features; and
3. The symptoms are not due to the direct physiologic effects of a substance (eg, a
drug of abuse, a medication, or other treatment) or a general medical condition
(eg, hyperthyroidism).
Delay in diagnosis occurs because the illness may start nonspecifically and the
diagnosis of mood elevation is missed or symptoms are attributed to circumstances of
personality disturbance.
Many authors now believe that full mania (induced by antidepressants or stimulants)
should be regarded as bipolar disorder, although DSM-IV does not allow this. Alcohol
abuse is the most common clinical comorbidity.
Goal of Therapy
Ideally, successful treatment should treat both mania and depression, prevent
recurrence, and improve quality of life between episodes.
Psychological Treatments
Enhancement of patient care may be facilitated by psychological interventions based on
behavioral and cognitive psychology. In line with current practice in other areas of
psychiatry, these psychological treatments should complement and inform treatment
with medications rather than replace it. The components of psychological treatment
include psychoeducation aimed at improving evaluation of the personal risk posed by
the illness; self monitoring; self regulation, including action plans and modification of
behaviour; and increased adherence to medicines. There is some evidence to suggest
that use of these strategies may improve the outcome at least with respect to relapse of
mania.[9]
Pharmacologic Treatments: Available Compounds
Lithium
Lithium has been used in bipolar affective disorder for 50 years[10] and is one of the
most extensively studied drugs in bipolar disorder. Lithium has proven efficacy in
treating mania with a response rate of 60% to 80% in classic euphoric mania. The use
of lithium in maintenance treatment of bipolar affective disorder is supported by
randomized controlled trials (RCTs), naturalistic studies,[11,12] and a Cochrane review.[13]
Lithium has established efficacy in the treatment of bipolar depression. [14,15] Its use may
be associated with reduced healthcare costs and mortality, including suicide.[16,17]
However, a substantial number of patients do not respond adequately to lithium, with
relatively poor outcomes in mixed states and rapid cycling[18-20] and in young males,
Florida Heart CPR*
Bipolar Disorder
4
those who are poorly compliant, those who have a history of head injury, those with
severe mania, and those with comorbidity.[21] Lithium has a significant side effect burden
and a narrow therapeutic index. Abrupt withdrawal is associated with a high rate of
relapse -- a phenomenon that may limit lithium's clinical usefulness.[20]
Despite lithium's proven value as a treatment, there is a need for new treatments with
increased efficacy, especially in refractory mania, mixed states, bipolar depression, and
rapid cycling. Recent research has focused on drugs that may either be used as
alternatives to or additional therapy with lithium.
Antipsychotics
Neuroleptics have been used as antimanics since the 1950s. Typical antipsychotics are
effective antimanics, and this effect does not appear to be linked to sedation per se. A
wide range of manic symptoms respond, including core symptoms such as elation.
Controlled trials have compared the efficacy of lithium with antipsychotics (both typical
and atypical) in acute mania, and these have yielded consistent results. Lithium exerts
comparable but slower therapeutic effects but may be superior for affective symptoms
than typical antipsychotics. Lithium does exert an effect against psychotic symptoms.
The antipsychotics are superior to lithium for the treatment of patients with marked
psychomotor agitation.[22] In a trial comparing treatment of patients with mania and
mixed states with 6 mg of risperidone, 10 mg of haloperidol, or 800-1200 mg of lithium,
there were comparable improvements in all 3 groups.[23] Antipsychotics are useful in
combination with mood stabilizers and 2 small trials suggest an additive effect with
lithium in schizoaffective or psychotic mania.[24,25] Surveys of clinical practice indicate
that antipsychotics are also used in the long-term treatment of bipolar disorder, despite
a lack of evidence supporting this strategy.[26,27] This is particularly important when one
considers the possibility of inducing extrapyramidal side effects, neuroleptic malignant
syndrome, and tardive dyskinesia. Additionally, long-term use of these drugs may
reduce the risk of manic episodes at the cost of increasing the rate of depressive
episodes.[28]
Atypical Antipsychotics
Mania
The efficacy in mania of the atypical antipsychotics has been demonstrated in
randomized placebo-controlled trials.[29-31] The most robust data are for olanzapine, with
2 placebo-controlled trials involving a total of 254 patients. In the later olanzapine trial, a
higher starting dose of 15 mg was used, and this was associated with a faster response.
A significant improvement in Young-Mania Rating Score (Y-MRS) was reported after 1
week. When comparing the atypicals with mood stabilizers, no difference in efficacy
between lithium and either olanzapine or risperidone monotherapy was noted in 2 small
trials.[23,32] The results of the acute phase of a trial by Tohen and colleagues [33]
comparing olanzapine with valproate in mania have been recently reported. After 3
weeks, the olanzapine-treated group had a greater remission and response rates and a
Florida Heart CPR*
Bipolar Disorder
5
greater mean fall in Y-MRS than the divalproex group. There are also open trials and
case reports that support the use of olanzapine in mixed states.[34,35]
The successful use of clozapine in treatment-refractory acute bipolar mania has been
reported in some studies.[36-38] There are case reports of patients with treatmentresistant manic symptoms responding to quetiapine,[39,40] and there is an RCT of
ziprasidone demonstrating efficacy in mania.[41]
Bipolar Depression
Observational studies suggest some antidepressant potential for clozapine, risperidone,
and olanzapine.[28] In an RCT of 30 bipolar depressed patients, sulpiride was shown to
be as effective as amitriptyline as augmentation to lithium.[42]
Maintenance
Open trials suggest that clozapine monotherapy may provide effective mood
stabilization in patients refractory to standard treatments. Maintenance data with most
other atypicals is sparse, but open-label extensions of antimanic trials are promising,
with effects possibly not confined to psychotic symptoms. There is little evidence
suggestive of induction of depression, and there appears to be a low side effect
profile.[30]
Relapse Prevention
A recent Cochrane review has confirmed that lithium has efficacy in the prevention of
relapse in bipolar disorder. However, the preventive action of lithium is greater for
relapse into mania than depression.[13] The efficacy of anticonvulsants (particularly
preparations of sodium valproate) for relapse prevention in bipolar disorder has not
been demonstrated.[43] There has been a preliminary report of a randomized doubleblind trial of olanzapine vs lithium in the prevention of relapse of bipolar disorder. [44] In
this large double-blind trial, patients were randomized from a combination of olanzapine
and lithium to monotherapy with either drug for at least 1 year. Of note, the effects of
lithium withdrawal were totally mitigated by monotherapy with olanzapine, suggesting
that this should be a preferred treatment for patients who wish to be withdrawn from
lithium. In terms of overall relapse, there was a highly significant improvement in terms
of relapse into mania for the olanzapine group greater than the lithium group (28%
manic relapse for lithium, 14% for olanzapine). There were no differences between
these groups with respect to relapse into depression. This is a very important study that
suggests that olanzapine has a role in the prevention of relapse and mania and
potentially works just as well as lithium for the relapse of bipolar depression.
Mood Stabilizers
Antipsychotics and Mood Stabilizers
Florida Heart CPR*
Bipolar Disorder
6
A number of studies have suggested that add-on of atypical antipsychotics to mood
stabilizers may improve outcomes in bipolar disorder.[45] A recent study has evaluated
the efficacy of olanzapine in combination with valproate or lithium for the treatment of
mania in patients partially nonresponsive to valproate or lithium monotherapy. [46] This
was a 6-week, double-blind, randomized, placebo-controlled trial that aimed to
determine the efficacy of combined therapy of olanzapine with either valproate or lithium
compared with monotherapy with either valproate or lithium alone in treating acute
manic or mixed bipolar episodes. Patients with bipolar disorder (n = 344 manic or
mixed) who had an inadequate response to more than 2 weeks of either lithium or
valproate therapy were randomized to receive cotherapy (ie, olanzapine plus mood
stabilizer or monotherapy, or placebo plus mood stabilizer). Olanzapine cotherapy
improved patients' Y-MRS total scores significantly more than monotherapy, and the
clinical response rates were significantly higher with cotherapy. Olanzapine cotherapy
improved the 21-item Hamilton Depression (HAM-D) rating scores significantly more
than monotherapy. In patients with mixed episodes with moderate to severe depressive
symptoms, olanzapine cotherapy improved HAM-D 21 scores by 10.31 points compared
with 1.57 for monotherapy. Extrapyramidal symptoms were not significantly changed
from baseline in either treatment group. The authors concluded that compared with the
use of valproate or lithium alone, the addition of olanzapine provides superior efficacy in
the treatment of manic or mixed bipolar episodes.
Anticonvulsants
The use of anticonvulsants in bipolar disorder has led to the observation that processes,
which appear to be similar to kindling phenomena, occur in the natural history of bipolar
and unipolar affective disorders.[47] Most anticonvulsant drugs with mood-stabilizing
properties also inhibit the electrically induced kindling of seizure activity in animals.
However, the mood stabilizing properties of anticonvulsants may not be mediated by the
same mechanisms that mediate seizure control in epilepsy.
Sodium Valproate
Sodium valproate is the most frequently prescribed mood stabilizer in the United States
and is increasingly used in Europe. It is no longer restricted to patients who have failed
to respond to or are intolerant of lithium, but is increasingly being used as first-line
monotherapy.
Trial evidence. The evidence mostly supports the role of sodium valproate in the
treatment of acute mania, particularly with dysphoric or mixed presentations. [48,49]
Several controlled studies suggest that it has a more rapid onset than lithium and may
be the better tolerated of the two.[48] One small study comparing valproate with an
antipsychotic showed similar efficacy in the reduction of affective or psychotic
symptoms in the acute treatment of mania.[50] The antimanic efficacy of valproate does
not appear to be compromised by the presence of depressive features in patients with
mixed states. Moreover, valproate may be effective in treating the depressive symptoms
concurrently.[49,51]
Florida Heart CPR*
Bipolar Disorder
7
Sodium valproate's long-term efficacy in bipolar maintenance is supported by open
studies.[18] However, in a recent parallel group randomized controlled 12-month followup trial with placebo and lithium, no significant differences in efficacy were seen
between any of the groups on the primary outcome measure of time to relapse to
mania. An advantage of valproate was seen on some of the secondary measures, such
as time in the study or the occurrence of depression.[52] There are many open studies
showing good response in rapid cycling disorder.[53]
Clinical use. Valproate semi-sodium (in the United States, divalproex sodium) has
been launched for the acute treatment of manic episodes associated with bipolar
disorder. It is marketed as Depakote in the United Kingdom. It is a compound of sodium
valproate and valproic acid in a ratio of 1 to 1. There is a widespread tendency to
confuse these licensed compounds with preparations of sodium valproate used in
epilepsy.
For valproate semi-sodium, a dose of 1000-3000 mg is usually associated with the best
response. There is no clear relationship between plasma level and response,[54]
although therapeutic efficacy at plasma levels of less than 45 mg/L is doubtful. The
optimum blood level appears to be 60-90 mg/L, with 100-120 mg/L in special
circumstances. There is a greater side effect burden in doses above 125 mg/L.[55] Side
effects are gastrointestinal disturbance including nausea, weight gain, hepatic
dysfunction, neurological problems including tremor and sedation, and hair loss.
Accelerated oral loading at a dose of 30 mg/kg for the first 2 days followed by 20 mg/kg
for the next 7 results in serum valproate levels attaining therapeutic levels more rapidly
and as safely as standard dosage regimes.[56]
Carbamazepine
The efficacy of carbamazepine in treating mania and bipolar depression and in
prophylaxis has been shown in some studies, but evidence for its acute efficacy in
bipolar depression and overall prophylactic efficacy is not strong.[57] A 2-year
randomized double-blind trial by Moleman and colleagues[58] examined the efficacy in
maintenance treatment and demonstrated a 40% risk of relapse per year, the overall
relapse rate being nonsignificantly greater than that seen with lithium. Griel and
colleagues[59] also compared the relative efficacy of carbamazepine and lithium in
maintenance of bipolar disorder. When using broad outcome criteria, they noted an
overall superior efficacy of lithium. Open trials suggest a role for carbamazepine in rapid
cycling and mixed states.[60] There have been suggestions that it loses efficacy over
time.[61] It is, however, effective in the acute-phase treatment of mania, as shown by a
placebo-controlled cross-over study.[62] As noted above, comparator trials with lithium
have revealed disparate results.[22] Several small double-blind placebo-controlled
studies suggest modest but statistically significant symptom reduction in bipolar
depression.[63] Additive effects have been reported with lithium.[63-68] Side effects are
common and include sedation, tremor, diplopia, weight gain, and rash. It induces liver
enzymes and so enhances metabolism of other drugs, including the oral contraceptive
pill and atypical antipsychotics.[69]
Florida Heart CPR*
Bipolar Disorder
8
Lamotrigine
Controlled trials have suggested some efficacy for lamotrigine in mania, [70] some
patients with rapid cycling disorder,[71,72] and bipolar depression.[73,74] In bipolar
depression, Calabrese and colleagues[73] demonstrated a dose-dependant significant
improvement in response rate (50% improvement in HAM-D at week 7) compared with
placebo in outpatients with bipolar depression treated with 50 or 200 mg per day of
lamotrigine. Frye and colleagues[74] compared lamotrigine monotherapy with gabapentin
monotherapy and placebo in 31 patients with refractory unipolar or bipolar depression.
They demonstrated significantly greater efficacy (50% improvement in Clinical Global
Impression Scale) in the group receiving lamotrigine compared with both the placeboand gabapentin-treated patients. Doses were titrated to a maximum of 500 mg of
lamotrigine (mean dose, 274 mg) or 4800 mg of gabapentin (mean dose, 3987 mg). To
examine the efficacy of lamotrigine in rapid cycling disorder, Calabrese and
colleagues[72] added lamotrigine to patients' existing medication and titrated to clinical
effect. A total of 182 stabilized patients were tapered off other psychotropics and
randomly assigned to lamotrigine or placebo monotherapy. Significantly more
lamotrigine patients were stable without relapse after 6 months of monotherapy.
Lamotrigine is metabolized in the liver, and the most common adverse effects are
headache, nausea, diplopia, dizziness, and ataxia. A skin rash occurs in 4% to 5% of
patients early in treatment. Rashes are more common in the elderly; those on
polypharmacy, particularly valproate, which inhibits the metabolism of lamotrigine; and
where there has been a rapid escalation of dose. In most cases, the rash is mild and
may subside spontaneously with or without drug withdrawal; but in some patients, there
is an associated generalized illness with a few developing erythema multiforme,
Stevens Johnson syndrome, or angioedema. Lamotrigine can be cautiously
reintroduced safely in patients who have had a mild rash associated with its first
introduction.[75] However, there have been cases of fatality reported. It is therefore
advisable to titrate the drug slowly and withdraw at the first signs of a rash. Lamotrigine
does not induce p450 enzymes and has no significant pharmacokinetic effects on
concentrations of commonly used psychotropic medication. However, carbamazepine
reduces and valproate increases lamotrigine levels. Carbamazepine may also have a
pharmacodynamic but not a pharmacokinetic interaction with lamotrigine, leading to
neurotoxicity.[76]
Gabapentin
Gabapentin has a high therapeutic index and a relatively benign side-effect profile. Side
effects reported with gabapentin are transient and minor, the most common being
somnolence, dizziness, ataxia, and fatigue.[77] It is not associated with hepatic or
haematologic problems. It has a wide dose range of 900-3000 mg/day. Gabapentin's
use in rapid cycling bipolar disorder, mania, and bipolar depression was supported by
open trials.[78-80] However, disappointingly, these findings have not been replicated in
RCTs, 2 of which have been negative.[76,81]
Florida Heart CPR*
Bipolar Disorder
9
Topiramate
Topiramate is a new antiepileptic drug that is used as adjunctive therapy for partial
onset seizures. It enhances GABA activity and blocks glutamate at non N-methyl Daspartate (NMDA) receptors. Preliminary open observations of adjunctive topiramate
treatment suggest that it may have antimanic or anticycling effects in some patients with
bipolar disorder, including those who are treatment resistant, and may be associated
with appetite suppression and weight loss.[82-87] There is one case report of topiramate
monotherapy in maintenance treatment of bipolar disorder.[88]
Tiagabine
Elevated brain levels of GABA have been reported in patients with euthymic bipolar
disorder using nuclear magnetic spectroscopy compared with healthy controls. [89] In
theory, this may be reversed by the novel anticonvulsant tiagabine, which reduces the
reuptake of GABA into neuronal and glial cells. Preliminary case reports have yielded
conflicting results. The most promising report uses doses much lower than those typical
for the treatment of seizures.[90-92]
Other Interventions
Electroconvulsive Therapy (ECT)
ECT is an effective treatment of bipolar disorder.[93] A 50-year review suggests that 66%
of manic patients respond to ECT[94]; furthermore, there is a good response to ECT in
manic patients who have failed to respond to an antipsychotic or lithium.[95] Analysis of
sequential therapeutic trials conducted over a 16-year period suggest that ECT followed
by lithium maintenance is superior in efficacy to treatment with lithium or antipsychotics
in hospitalized manic patients.[96] Maintenance or continuation ECT has been shown to
reduce the incidence of relapse in patients with previously refractory depressive
episodes.[97]
Transcranial Magnetic Stimulation (TMS)
There is preliminary evidence of therapeutic efficacy of TMS in bipolar disorder.[98,99]
However, there are also reports of hypomania induced by TMS. [100,101]
Thyroid Hormones
The role of thyroid hormones in bipolar disorder continues to be of interest. Low levels
of thyroxin (T4) have been associated with more affective episodes during maintenance
treatment with lithium.[102] Whether this mood instability is causally related to low free T 4
levels and whether it can be attenuated with thyroxin replacement remains to be studied
Florida Heart CPR*
Bipolar Disorder
10
in a controlled setting. Open trials suggest efficacy for thyroxin as an augmenting agent
in resistant bipolar depression and rapid cycling disorder.[103-105]
Fatty Acids
A 4-month, double-blind, randomized, placebo-controlled trial of bipolar patients in
remission has shown that augmentation with 9.6 g/day of omega 3 fatty acids prolongs
the period of remission. The underlying mechanism may be the inhibition of signal
transduction in neuronal membranes.[106] This study has limitations of design, but
nonetheless may represent a landmark in drug development.[107]
Treatment Approaches
Bipolar disorder is almost always recurrent.[108] Thus, there is a need for prophylaxis,
particularly in patients with recurrent episodes, severe illness, or where there is a strong
family history.[109] This need must be considered alongside the evidence of increased
relapse and suicide rate after discontinuation of lithium.[110,111] Lithium is the most
frequently used initial mood stabilizer in Europe. In North America, it is now sodium
valproate. Randomized, controlled trials to date have lacked sufficient power to
demonstrate a difference in efficacy between these drugs. In selecting an initial mood
stabilizer, the wealth of clinical experience with lithium and its possible antisuicide effect
should not be overlooked. Sodium valproate should be considered, particularly for
patients with poor prognostic factors for lithium such as those with mixed states or rapid
cycling disorder. Recent evidence suggests olanzapine may have a role in
maintenance.[44] A combination of 2 or more mood stabilizers may be synergistic in
cases of treatment resistance.[64]
Rapid Cycling
Rapid cycling bipolar disorder is defined as at least 4 affective episodes a year and is
observed in 13% to 20% of the bipolar population. It can occur sporadically at any point
in the course of the illness. It is probably associated with a reduced response rate to
lithium. Rapid cycling is more common in women and in those with bipolar II disorder. It
may be precipitated and exacerbated by antidepressant use or minor dysfunction of the
thyroid axis.[112] The ideal long-term treatment is monotherapy with a mood stabilizer.
However, because there is a high rate of lithium nonresponse,[113] valproate is the initial
mood stabilizer of choice. If monotherapy is inadequate and a rapid cycling patient
develops mania, treatment options are to add a second mood stabilizer, preferably
lithium or carbamazepine or an atypical antipsychotic, before combining 2 mood
stabilizers with an atypical.
Bipolar Depression
The depressive phase of bipolar disorder can be very disabling. This phase is
associated with the highest comorbidity, suicide risk, impairment of functioning, and
reduction in quality of life.[114,115] Active treatment is therefore appropriate. Some
Florida Heart CPR*
Bipolar Disorder
11
treatments may precipitate mania and increase cycle frequency.[116] To facilitate
appropriate treatment selection, it is very important to differentiate bipolar from unipolar
depression. This is often a difficult task, and bipolar disorder may be unrecognized for
many years.[117] A family history of bipolar disorder, especially in younger patients, is an
important distinguishing characteristic. The course of illness, especially early onset, and
more frequent episodes also helps.[97]
There are few data available on the treatment of bipolar depression. Young and
colleagues[118] examined combining mood stabilizers or adding an antidepressant to a
mood stabilizer in a study of 27 patients and found no difference in efficacy between
adding a mood stabilizer or an antidepressant. However, these authors found fewer
drop outs in the antidepressant group. A recent study showed that the risk of an
antidepressant precipitating mania is reduced by coadministration with a mood
stabilizer.[119] In cases of psychotic bipolar depression, a sensible initial strategy is to
combine a mood stabilizer, an atypical antipsychotic, and an antidepressant.
Antidepressant use without a mood stabilizer should not be undertaken lightly in bipolar
disorder. Treatment strategy is influenced by factors such as patients' previous
response to treatment, drug interactions, safety and tolerability profile, and lethality in
overdose. Bupropion and paroxetine are recommended because of a possibly reduced
risk of inducing hypomania, mania, and rapid cycling vs the tricyclics.[120-123] Additionally,
there is a role for venlafaxine for severe melancholic bipolar depression. [109,124]
Mania and Hypomania
In treating mania, it is vital to make a clear assessment and diagnosis. Treatment
setting is of great importance, with a clear need to assure safety and reduce
overstimulation. The primary aim of treatment is to resolve symptoms as quickly and
safely as possible. Antipsychotics are frequently used in acute and continuation
treatment of (hypo)mania worldwide. The atypical antipsychotics are generally preferred
over the typicals.[109] Patients with pure uncomplicated mania respond well to all
available agents. Specific poor response indicators for lithium include severe, psychotic
mania with mixed or depressive features and a history of rapid cycling, numerous
previous episodes, or a course in which mania follows depression.[48,125] Treatment
response should be reviewed after 3 days of valproate loading, 7-10 days of lithium, and
14 days of carbamazepine. There is little empirical evidence to support different
treatment strategies for nonresponse in mania. The options include switching or
combining mood stabilizers and antipsychotic drugs. If the patient is tolerating the initial
drug, it would seem prudent to add rather than substitute new medication. Combinations
may be synergistic and optimize results without pushing a single agent to toxic levels.
Before combining medication, it is important to consider if the initial agent has been
given at an adequate dose and for an adequate length of time and to consider potential
pharmacokinetic interactions.[65] There is evidence in treatment resistance to support
the use of clozapine and ECT.
Mixed States
Florida Heart CPR*
Bipolar Disorder
12
The overall incidence of mixed states in patients with bipolar disorder may be around
30% to 40%.[126] Compared with pure states, patients in mixed states typically have
higher levels of anxiety and arousal, an increased rate of psychosis and suicide, [115] and
a poorer outcome.[127,128] It is important, though at times difficult, to distinguish mixed
mania from agitated depression. Both states present with psychomotor signs of inner
tension, but agitated depression does not have the goal-directed hyperactivity that is
present in both pure and mixed mania.[129] Mixed states are associated with a significant
risk of substance abuse and suicide.[130] Antidepressant therapy may worsen the
inherent mood instability and, indeed, antidepressants can precipitate mixed states.
Treatment should be aimed at reducing the severe increased arousal and the
underlying affective dysregulation. Sodium valproate may be used; however, many
clinicians prefer to use an atypical antipsychotic in order to gain rapid symptom relief.
Conclusion
Treatment strategies in bipolar disorder must involve consideration of the overall illness,
not just the current episode. Psychological interventions should help the patient to learn
about destabilizing factors and prodromes of relapse and to accept the nature of the
illness. The aim of management should be recovery and responsible participation of the
sufferer in treatment, not simply limited improvement and compliance. All the wellestablished drugs appear to be more effective in treating and preventing mania than
depression. Lithium is reported to have specific antisuicidal effects, but few data are
available on the antisuicidal effects of carbamazepine and valproate. Lithium has the
drawback of high rates of relapse when it is stopped. The relative effects upon stoppage
of other agents are unknown. Although valproate and carbamazepine may be more
effective than lithium for mixed states and rapid cycling disorder, much treatment
resistance remains. New medications for bipolar depression, mixed states, and rapid
cycling disorder are urgently needed: new anticonvulsants and atypical antipsychotics
are potential candidates that are currently being investigated. Of the atypical
antipsychotics, a large number of clinical trials have been published on olanzapine.
These have established olanzapine's antimanic effects and the benefits of addition of
olanzapine to placebo, and recent reports suggest a preventive effect particularly for
relapse into mania. For other atypicals, fewer data are available.
References
1. Weissman MM, Bland RC, Canino GJ, et al. Cross-national epidemiology of
major depression and bipolar disorder. JAMA. 1996;276:293-299.
2. Inskip H, Harris E, Barraclough B. Lifetime risk of suicide for affective disorder,
alcoholism and schizophrenia. Br J Psychiatry. 1998;172:35-37.
3. Jamison K. Suicide and bipolar disorder. J Clin Psychiatry. 2000;9:47-51.
4. Kraepelin E. Psychiatrie ein lehrbuch fur studierende und arzte. Leipzig,
Germany, Barth, 1899.
Florida Heart CPR*
Bipolar Disorder
13
5. Ferrier IN, Stanton BR, Kelly TP, Scott J. Neuropsychological function in
euthymic patients with bipolar disorder. Br J Psychiatry. 1999;175:246-251.
6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric
Press; 2000.
7. McElroy S, Altshuler L, Suppes T, et al. Axis I psychiatric co-morbidity and its
relationship to historical illness variables in 288 patients with bipolar disorder. Am
J Psychiatry. 2001;158:420-426.
8. Kay JH, Altshuler LL, Ventura J, Mintz J. Prevalence of axis II comorbidity in
bipolar patients with and without alcohol use disorders. Ann Clin Psychiatry.
1999;11:187-195.
9. Perry A, Tarrier N, Morriss R, McCarthy E, Limb K. Randomised controlled trial of
efficacy of teaching patients with bipolar disorder to identify early symptoms of
relapse and obtain treatment. BMJ. 1999;318:149-153.
10. Cade J. Lithium salts in the treatment of psychotic excitement. Med J Aust.
1949;14:349-352.
Florida Heart CPR*
Bipolar Disorder
14
Florida Heart CPR*
Bipolar Disorder Assessment
1. Patients with bipolar disorder often have comorbid anxiety and _______.
a. Eating disorders
b. Overweight
c. Substance abuse
d. None of the above
2. Ideally, successful treatment should:
a. Treat both mania and depression
b. Prevent recurrence
c. Improve quality of life between episodes
d. All of the above
3. Bipolar disorder is almost always _______.
a. Determined by genetics
b. Acute
c. Recurrent
d. Determined by the environment
4. Rapid cycling bipolar disorder is defined as at least ____ affective episodes a
year.
a. 2
b. 4
c. 6
d. 8
5. This phase is associated with the highest comorbidity, suicide risk, impairment of
functioning, and reduction in quality of life.
a. Depressive
b. Manic
c. Positive
d. Hypomanic
6. Compared with pure states, patients in mixed states typically have:
a. higher levels of anxiety and arousal,
b. an increased rate of psychosis and suicide
c. poorer outcomes
d. all of the above
7. A combination of 2 or more mood stabilizers may be ______ in cases of
treatment resistance.
a. Synergistic
b. Detrimental
Florida Heart CPR*
Bipolar Disorder
15
c. Too costly
d. None of the above
8. This drug is the most frequently prescribed mood stabilizer in the United States
and is increasingly used in Europe. It is increasingly being used as first-line
monotherapy.
a. Carbamazepine
b. Lamotrigine
c. Gabapentin
d. Sodium Valproate
9. This has been found to be an effective treatment of bipolar disorder.
Maintenance or continuation of this treatment has been shown to reduce the
incidence of relapse in patients with previously refractory depressive episodes.
a. Fatty acids
b. ECT
c. Thyroid hormones
d. Tiagabine
10. While sodium valproate is most commonly used in North America, the most
common form of this drug used in Europe is lithium. These are both:
a. Antidepressants
b. Stimulants
c. Mood stabilizers
d. Analgesics
Florida Heart CPR*
Bipolar Disorder