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. 
 

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. 
 

History 
Lithium carbonate is, by far, the most common treatment option for bipolar disorders (Suppes, Rush, Kraemer, & Webb, 1998).  Following the discovery of lithium’s 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 1950’s because of it’s 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). 

Efficacy 
     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 lithium’s maintenance effect.  Bowden’s 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 lithium’s 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 
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 patient’s 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 1998 ). 
 
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 (SSRI’s) function on neurotransmitters (Hokin).  The primary difference between lithium and SSRI’s appears to be that SSRI’s 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 extremes (Hokin).   
 

History 
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 1950’s 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). 

Efficacy 
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 lithium’s 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 & Zarate). 

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). 
 
Side Effects 
     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. 
 

History 
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 1970’s 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).  

Efficacy 
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 clearly evident. 

Side Effects 
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 & Ghaeni). 

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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