Pharmacological Treatments of
Bipolar Disorder and
Subtypes: A Review
by David E. Cox
The present paper reviews some of the most
common pharmacological treatments of bipolar disorder to determine their
efficacy, their mechanisms of action, and their potential side effects.
Lithium carbonate appears to be the most efficient and commonly prescribed
medication as well as the one demonstrating the greatest maintenance effect
and flexibility among the treatments covered in this review. Novel antipsychotic
drugs appear to have the highest degree of efficacy and potential among
all of the treatments reviewed other than lithium. However, due to
the potentially serious side effects that can cause some patients extreme
discomfort and can be life threatening, the common occurance of noncompliance
can lead to reduced efficacy. The inconsistencies in the literature appears
to indicate that while the anticonvulsant class of drugs may be extremely
effective for some patients diagnosed with bipolar disorder, there are
at least an equal number of individuals that do not respond to these drugs.
Although further research is required, treatment algorithms have been shown
to demonstrate effective therapeutic qualities. Further research is needed
in the areas of atypical antipsychotic drugs and other medications that
are still in the early stages of research.
Common Pharmacological Treatments
Bipolar Disorder: A Review
Diagnostic criteria for bipolar disorder
include one or more incidents of manic behavior characterized by disruption
of sleep patterns, rapid or pressurized speech, increased distractibility,
and a marked increase in goal-oriented activities (Diagnostic and Statistical
Manual of Mental Disorders, 4th ed. American Psychiatric Association,
1994). These manic episodes are accompanied by one or more major
depressive episodes that include symptoms such as reduced pleasure or interest
in most activities, unintended weight loss, disruption of appetite, loss
of energy and agitation or retardation of psychomotor activities (DSM
IV, 1994). Two major subtypes of bipolar disorder are defined in
the DSM IV; bipolar I subtype indicates a higher incidence of manic
manifestations and bipolar II is defined as a higher occurrence of depressive
episodes (Walsh, 1998). In addition to the two major subtypes, numerous
variations of bipolar I subtype have been discovered as well as axis II
characterlogical manifestations such as cyclothymia (Manning, Connor, &
Sahai, 1998). Bipolar disorder is frequently misdiagnosed, as a recent
study has found; up to 40% of individuals currently diagnosed with bipolar
disorder had been diagnosed with unipolar depression or another disorder
prior to their current diagnosis and frequently not diagnosed at all (Goodwin
& Ghaeni, 1998). Despite the apparent cases that are not accurately
accounted for, bipolar disorder still maintains a lifetime prevalence somewhere
between 1% and 2% with a modal expression of 1.6% (Goodwin & Ghaeni).
Genetic factors have also been shown to play a major role in the development
of bipolar disorder; in fact this disorder has a higher degree of genetic
determinant than any other disorder with some estimates indicating as high
as 85% (K. J. Tarnowski, personal communication, 1998).
A major concern associated with bipolar
disorder is the high suicide rate among the population diagnosed with this
disorder. Bipolar disorder has been shown to have the highest suicide
rate among all disorders (Tondo, Baldessarini, Hennen, & Floris, 1998).
The suicide rate for this population has been estimated to be between 15%
and 50%, depending on the study (K.J. Tarnowski, personal communication,
1998). As such a large variation would indicate, the exact suicide
rate is extremely difficult to verify categorically. However, some
studies have shown that suicidal behaviors are greatly increased within
experimental lithium groups when compared to the placebo control groups
(Dunner, 1998). Due to this high mortality rate, in addition to the
strong evidence of genetic penetrance and lifetime prevalence of bipolar
disorder, the need for safe and effective treatment options is clear.
The purpose of the current review will
be to examine the data available regarding some of the most common pharmacological
treatment options available including lithium treatments, antipsychotic
agents, treatment algorithms, and anticonvulsant medications. Particular
attention will be given to the side effects and efficacy of these treatments.
This study will attempt to determine the state of current research regarding
these treatments and suggest directions for future research.
Lithium carbonate is, by far, the most
common treatment option for bipolar disorders (Suppes,
Rush, Kraemer, & Webb, 1998). Following the discovery of lithiumís
ability to stabilize the mood in agitated persons by an Australian scientist
in 1949 lithium carbonate was used as a treatment for manic behavior in
Europe for years prior to its acceptance in the United States (Walsh, 1998).
The primary reasons that the United States was so far behind Europe in
this regard was due to the fact that lithium carbonate had been banned
in the United States during the 1950ís because of itís toxicity when used
as a salt substitute. Additionally, American psychologists diagnosed
manic behavior very infrequently, often opting for a diagnosis of schizophrenia
(Dunner, 1998). Despite this slow start in the United States, lithium carbonate,
alone or in conjunction with other pharmacological or therapeutic treatments,
currently accounts for approximately 85% of initial treatment options,
according to Olfson, Marcuss, Pincus, and Zito (1998).
As a plentiful,
naturally occurring element, lithium provides a high quality, efficient
treatment option with the added feature of a maintenance effect for a relatively
marginal cost (Walsh, 1998). Although other options exist that can
be successfully applied to the treatment of bipolar disorders, it is the
added feature of the maintenance effect of lithium that accounts for its
popularity as a treatment option (Dunner, 1998). Studies by Baastrup
and Schou (1967), as cited in Dunner, indicated that lithium decreased
incidents of bipolar episodes within a population diagnosed with heterogeneous
forms of bipolar disorder. The Baastrup and Schou study showed a
66% rate of prevention of bipolar behavioral occurrences within the experimental
lithium condition versus a 29% decrease in such behaviors among the control
placebo group (Dunner). More recent studies such as Bowden (1998)
have confirmed the efficacy of lithiumís maintenance effect. Bowdenís
study found that bipolar episodes were decreased in 80% of the lithium
experimental condition compared to 40% in the placebo control condition.
It has been indicated that the maintenance effect of lithium has been shown
to be most efficient when used in conjunction with one or more additional
pharmacological (Suppes et al., 1998) or therapeutic treatments (Salomon,
1998). While studies such as those by Baastrup and Schou and Bowden
clearly demonstrated the efficacy of the maintenance effect of lithium
therapy in controlling both manic and depressive episodes, it is important
to note that lithium has only been shown to reduce the intensity and frequency
of these behaviors and there is no indication that it completely eliminates
such behaviors (Dunner, 1998).
In addition to the primary control effect
and the maintenance effect, lithium has also been shown to reduce suicidal
behaviors among the diagnosed population (Tondo, et al., 1998). The
study by Tondo et al. suggested that the suicidal behavioral control effect
of lithium can be quite pronounced as is evidenced by their finding that
suicidal rates within individuals who were abruptly removed from lithium
therapy was more than double that of their counterparts who were slowly
taken off of the lithium. Recent studies seem to support this aspect
of lithiumís performance but have shown a much higher reduction in suicidal
behaviors when the lithium treatment is augmented by the prescription of
antidepressant medication (Bowden, 1998; Tondo et al.). It is important
for the clinician to keep in mind that antidepressants should be avoided
when treating an individual diagnosed with bipolar I disorder, as there
is an increased risk of an antidepressant induced manic episode (Boerlin,
Gitlin, Zoellner, & Hammen, 1998). In addition to the additive
effect of antidepressants in individuals diagnosed with bipolar disorder
subtype II, use of therapeutic options also increase the control of suicidal
behaviors (Salomon, 1998).
Side-effects associated with lithium treatment,
although pervasive due to the fact that lithium is distributed throughout
the body (Bowden, 1998), are usually minor and of limited duration. These
effects can include gastrointestinal distress, increased thirst, minor
hair loss, water retention, outbreaks of acne, increase in weight, minor
hand or arm tremors, and increased frequency of urination (Walsh, 1998).
More serious side effects of lithium are generally caused by the build-up
of lithium to toxic levels in the bloodstream (Walsh). Due to the
marginal difference between the minimum level required for therapeutic
effect and the maximum amount required for toxicity, constant monitoring
is required to ensure that a balance is maintained (K. J. Tarnowski, personal
communication, 1998). Lithium therapy has been shown to be effective
at approximately 1 milligram and reaches toxic levels at 2 milligrams,
allowing for a very small margin of difference (Bowden, 1998). At
the toxic level, serious physical consequences can result in the damage
of the circulatory, neurological and/or the gastrointestinal systems to
varying degrees (Walsh, 1998). The risk for negative physical consequences
has been shown to be greater among the elderly, young children and pregnant
women (Dunner, 1998). To properly monitor the level of lithium in
a patientís blood, studies suggest measures
should be taken every two to four months during the first year of treatment
and approximately every six months for subsequent years (Walsh,1998; Bowden
Mechanism of Action
There have been numerous theories that
have attempted to discover how lithium is able to effectively maintain
both manic and depressive manifestations of bipolar disorders (Dunner,
1998). However, the exact mechanism of action was not discovered
until earlier this year. Researchers from the University of Wisconsin,
Madison, indicated that lithium acts upon the stimulatory neurotransmitter
of glutamate, providing a bi-directional force that ultimately results
in a relative stasis in mood (Hokin, 1998 as cited in the University of
Wisconsin News). This mode of operation is not all that different
from the manner in which Selective Serotonergic Reuptake Inhibitors (SSRIís)
function on neurotransmitters (Hokin). The primary difference between
lithium and SSRIís appears to be that SSRIís seem to only inhibit reuptake
of the neurotransmitter during the depressive stage to ensure ample serotonin
is available. In addition to inhibiting reuptake during depressive cycles
it is believed that during the manic phase, when levels of glutamate are
extremely high, lithium aids in increasing the reuptake process, thus doing
double duty on the same neurotransmitter (Hokin). The exact mechanism
responsible for this effect appears to be a reuptake element that accounts
for the level of glutamate and subsequently adjusts to control for both
Before lithium therapy came into prevalence,
antipsychotic agents were the preferred treatment
option for bipolar disorder (Tohen & Zarate, 1998). Agents such
as the neuroleptic drug chlorpromazine were first introduced in the 1950ís
to reduce mortality due to exhaustion and dehydration among patients during
periods of increased agitation (Tohen & Zarate). Currently, neuroleptics
are most frequently used for the treatment of schizophrenia and schizotypal
disorders, although they can also be used to treat patients who are not
responsive to lithium treatment or experience the extreme side effects
of lithium (Manning, Connor, & Sahai, 1998). Primarily, neuroleptics
are used in the treatment of acute manic episodes; their effectiveness
as a long-term treatment of bipolar disorder is negligible. Among
the antipsychotic agents, neuroleptics are the most commonly used agents
for treatment of bipolar disorders and within this class, chlorpromazine
is the most frequently used although studies indicate that thioxthixene
and haloperidol are equally effective in the treatment of acute manic episodes
(Tohen & Zarate). Recently, researchers have shown great interest
in the effects of atypical or novel antipsychotics such as clozapine, risperidone,
olanzypine and sentindole on bipolar disorder symptoms (Tohen & Zarate).
The neuroleptic class of medications were
originally believed to be more successful in curbing episodes of acute
mania; however a recent meta-analysis of the most comprehensive studies
in this area seems to indicate that lithium has the advantage over neuroleptics
for this application (Tohen & Zarate, 1998). Recent trends seem
to indicate an increase in the prescribing of neuroleptics in conjunction
with lithium therapy as a treatment option for individuals diagnosed with
bipolar disorder (Bowden, 1998). Despite lithiumís overall advantage,
neuroleptics are frequently the preferred method of first treatment of
acute mania due to their quicker activation and superior control of psychomotor
skills (Tohen & Zarate). There is a lack of conclusive data concerning
the maintenance effect of neuroleptics despite their frequent use in long-term
treatment of bipolar disorder. This apparent paradox could be due
to the fact that neuroleptics are merely used in conjunction with lithium
therapy, with their primary role being the control of acute mania until
lithium has the opportunity to become effective. Although initial
studies indicate this conjunctive treatment option is moderately effective
and devoid of the presumed toxicity, there seems to be a greater probability
for depressive episodes among the individuals utilizing this option (Tohen
Atypical or novel antipsychotic agents
such as risperidone, clozapine, olanzipine and sentindole have been investigated
as a possible treatment option with varying degrees of success. Studies
on risperidone have shown that it may provide some degree of prevention
of manic and depressive episodes but overall, the findings are inconclusive,
lacking a comparative analysis with lithium or the other neuroleptics.
More thorough investigations have been conducted on clozapine and tend
to indicate that it is more effective both as a monotherapy and as an additive
treatment with lithium therapy. Clozapine is similar to the other
neuroleptics in that it appears to be more efficient in the treatment of
individuals during manic episodes than those in depressive states (Walsh,
1998). The other novel antipsychotic agents, olnzapine and setindole,
are just beginning to be investigated and although initial trials appear
to be promising, much more research is needed before any conclusions can
be proposed (Tohen & Zarate).
The side effects
associated with neuroleptic drugs, some of which can be life-threatening,
create a high degree of discomfort for the patient, which consequently
leads to high incidents of noncompliance (Tohen & Zarate, 1998).
These side effects are limited to parkinsonism, dystonia, akathisia, neuroleptic
malignant syndrome and tardive dyskinisia with varied symptoms ranging
from apathy and difficulty expressing emotions to reduced motivation and
impaired psychomotor skills (Perkins & Lieberman, 1998). While
these symptoms and side effects may be tolerable among the schizophrenic
population that comprises the primary recipient group of the neuroleptics,
(Perkins & Lieberman), the side effects are found to be intolerable
for many individuals diagnosed with bipolar disorder (Tohen & Zarate,
1998). The more benign and tolerable side effects of the neuroleptics
include increased salivation, loss of equilibrium, unintended weight gain,
fever and increased heart rate (Nordstrom, Farde, Nyberg & Karlsson,
1995). Certain studies have indicated that individuals diagnosed
with bipolar disorder have an increased probability of experiencing both
the major and minor side effects associated with the neuroleptic class
of medication when compared to those taking them for treatment of schizophrenia
or schizoaffective disorders, in particular, the probability of experiencing
these side effects were shown to be extremely high when clozapine was used
in conjunction with lithium therapy (Tohen & Zarate).
Mechanism of Action
Although the exact mechanism of action
of the neuroleptics appears to be unknown, Perkins and Lieberman (1998)
suggested that neuroleptics operate on particular neuroreceptors within
the central nervous system, applying a different mode of attack than the
other medications reviewed. Clozapine and the other atypical antipsychotic
agents have been proposed to operate on numerous receptor sites, thus providing
a more broadly based method of attack seemingly accounting for their increased
efficacy when used in treating the symptoms of bipolar disorder (Nordstrom
et al., 1998). Walsh (1998) postulated that the action of neuroleptics
on dopamine and serotonin may be responsible for the fast-acting properties
associated with them. Although this review does not encompass a great
amount of information on the mechanism of action for neuroleptics, current
research particularly in the area of the atypical antipsychotics should
yield a greater understanding of these drugs in the near future.
The anticonvulsant class of medication
was initially used in seizure control applications; during these applications
it was found that these drugs, particularly carbamazipine, divalproex and
valproate, were found to significantly improve the mood of some of the
individuals using them for seizure control (Walsh, 1998). By the late 1970ís
carbamazipine and valproate were accepted as substitutes for lithium for
individuals diagnosed with bipolar disorders that did not respond to lithium
treatment or experienced extreme side effects (Walsh). Although findings
are inconsistent regarding the efficacy of anticonvulsant medications in
the treatment of bipolar disorder, many current studies indicate that this
class of drugs is becoming a more and more desirable alternative to lithium
for many individuals (Walsh).
There appears to be a great deal of inconsistency
in the literature regarding the efficacy of the anticonvulsant class of
drugs. A study by Calabrese and Delucci (1990) produced results that
indicated anticonvulsant medications (carbamazapine) had superior results
in the controlling of bipolar (rapid cycling subtype) symptoms than lithium
(Walsh, 1998). Other studies have indicated that although this superiority
could be shown in bipolar I disorder, particularly during onset or early
stages, the results have not been consistently replicated (Walsh).
These studies indicate that divalproex and valproate appear to be particularly
effective as an additive to lithium therapy whereas carbamazapine is incompatible
with lithium therapy (Walsh). However promising the results from
these studies appear to be there are an equal number of studies that refute
the effectiveness of anticonvulsant medications. Certain studies
have indicated that the anticonvulsant medication, divalproex, failed to
show an improved effect of bipolar symptoms over the placebo control groups
(Goodwin & Ghaeni, 1998). Another study that compared carbamazapine
with lithium therapy found the suicide rate to be much higher among the
carbamazapine group with a ratio of 9:0 (Goodwin & Ghaeni). Goodwin
and Ghaeni acknowledged that their studies have turned up inconsistencies,
particularly regarding the study involving divalproex, that seem to indicate
that the different responses may be attributed to subtle differences in
the course of the individual disorder, making the need for further research
Among the carbamazapine drugs, side effects
are extremely mild and short term including
loss of appetite, gastrointestinal distress, loss of equilibrium, loss
of psychomotor skills, confusion, double vision (Walsh, 1998). A more serious
side effect resulting in the reduction of white blood cell counts can occur
but it is extremely rare (Walsh). With the valproate side effects are limited
and fairly mild; they may include headaches, nausea, reduced psychomotor
skills, hair loss and weight gain (Goodwin & Ghaeni, 1998). Although
extremely rare, liver damage can be a serious side effect of valproate
(Goodwin & Ghaeni). Because the side effects are both limited
and mild and toxicity is not a concern, the anticonvulsant medications
have a higher rate of compliance than lithium or antipsychotic agents (Goodwin
Mechanism of Action
Like the antipsychotic agents, the exact
mechanism of action for this class of drugs is not exactly known.
Goodwin and Ghaeni (1998) propose that carbamazapine functions by blocking
the reuptake of norepinepherine which prevents the sodium channel impulses
from repeatedly firing and inhibit the enzymes that break down gama aminobutyric
acid (GABA) thus making more of the neurotransmitters available during
the manic and depressive episodes. It has been theorized that GABA
has an anti-manic mechanism that limits manic episodes by blocking the
reuptake of GABA; it is by this same method that carbamazapine makes more
norepinepherine available to reduce depressive episodes (Walsh, 1998).
Goodwin and Ghaeni found that individuals diagnosed with bipolar disorders
and prescribed carbamazapine in conjunction with lithium therapy were six
times less likely to engage in suicidal behaviors when compared with individuals
involved in other treatment options.
It has been suggested that valproate is
a much more recent addition to the pharmacological treatment options available
to those diagnosed with bipolar disorders, having only been approved for
this purpose in 1995 (Walsh, 1998). Valproate functions very similar
to carbamazapine by increasing available GABA through the destruction of
GABA antagonists (Walsh).
As has been suggested throughout the descriptions
of various treatments, most of them have the greatest efficacy when treated
in conjunction with another pharmacological treatment option. Recent
studies indicate that a highly regimented treatment option that combines
patient and symptom specific treatments provides the optimal therapeutic
effect (Suppes et al., 1998). While obvious limitations prevent the
treatment algorithms from being thoroughly investigated, the ability to
implement a plan that is not limited to a single
cause and effect relationship and can be modified to fit various diagnostic
criteria make a highly viable treatment option (Suppes et al). In
the first empirical investigation of treatment algorithms, Suppes et al.
examined a four-tiered treatment algorithm of medications utilizing mood
stabilizers, antidepressants, anticonvulsant and antipsychotic agents.
Results indicate that after four months of the treatment algorithm, 50%
of their subjects (n=14) demonstrated a 30% improvement in their condition
as measured by the Brief Psychiatric Rating Scale, (Suppes et al.).
Furthermore, their results indicate that 36% of their subjects (n=10) reached
a plateau of stability in mood; 46% (n=13) remained in a state of mood
instability; and 18% (n=5) were lost due to attrition.
While this study provides some degree
of support for the efficacy of treatment algorithms, the most important
data may be found in examining the most efficient algorithms. While
patients ended the study, on average, taking more medication than at the
beginning of the study, the improvement over baseline BPRS scores seems
to indicate an improvement of overall patient condition (Suppes et al.).
Algorithm configurations indicate a shift in medications being utilized
by patients within the study. The greatest shift came via individuals
who stopped using the lithium treatment option (25%) and individuals who
began taking the anticonvulsant medications (51%) (Suppes et al.).
In addition, while the use of mood stabilizers and anticonvulsants comprised
the bulk of the algorithm conversions, use of antidepressants and antipsychotic
agents were extremely limited (Suppes, et al.).
The evidence presented in this review seems
to indicate that treatment options utilizing antipsychotic agents have
the lowest efficacy in the treatment of bipolar disorder of all the options
reviewed. Despite its efficacy in treating acute mania and as an
additive treatment with lithium therapy seem to indicate that antipsychotic
agents seem to be better suited for the treatment of schizophrenia than
it is for treatment of bipolar disorder. Further research is needed
before definite conclusions can be made regarding the atypical or novel
antipsychotic agents, but initial studies indicate that these agents, particularly
clozapine, hold great promise in the treatment of bipolar disorders.
Lithium carbonate remains the most highly effective and widely prescribed
treatment option for bipolar disorders. The maintenance effect provides
the stability patients need to efficiently work through the symptoms and
cycles of this disorder. The flexibility of lithium for additive treatment
options makes it a particularly valuable and versatile medication.
The inconsistency in the literature makes the efficacy of the anticonvulsant
medications dubious at best. These inconsistent findings are confounded
in regard to all of the primary areas of concern that were outlined in
the beginning of this review, including the ability of the drug to provide
a maintenance effect, the ability to deal with acute manic episodes and
the control of suicidal behaviors. Treatment algorithms seem to provide
a very efficient method of treatment. The Suppes et al. study provides
a solid body of research to build on. Most of the pharmacological treatments
that have been discussed in this review have been shown to be more efficient
when combined with other treatment options. The treatment algorithm
allows more of a tailoring of treatments to match the symptoms of the individual
patient. Certainly, great care must be taken when combining treatment
options and more research is needed in this area to provide sufficient
data regarding the safety and efficacy of combinations of treatments in
such an algorithm. A great deal of
future research is needed in order to ascertain the best possible treatment
or combinations of treatments for this disorder. Particular attention
should be given to the relatively new but promising atypical or novel antipsychotic
medications as well as the medications still in early stages of investigations.
Clearly, the recent discovery of the mechanism of action for lithium can
provide a great deal of research possibilities aimed at determining how
this knowledge can assist in gaining the maximum benefits of lithium while
limiting the risks of toxicity.
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