Alternatives to lithium in the treatment of bipolar disorder.

Bipolar disorder is a serious mental illness affecting a large number of Americans. While lithium, the treatment of choice for this disorder, is usually effective, a substantial number of individuals with bipolar disorder are not helped by lithium or are intolerant to its side effects. Consequently, investigators are searching for alternative drugs in order to treat lithium-resistant patients. Although a number of alternative drug treatments have been discussed in the literature, only the anticonvulsants carbamazepine and valproate appear to warrant serious consideration at this time. Future research will further define their roles as antimanic agents.     

Placebo effect in randomized, controlled studies of acute bipolar mania and depression.

Randomized, double-blind, placebo-controlled, parallel group clinical trials have been the standard methodology for establishing the efficacy of new treatments for patients with bipolar disorder in manic, mixed, or depressive episodes. We examine the placebo response rate in acute treatment trials of acute mania (and mixed states) and bipolar depression. Also addressed are potential variables associated with placebo response, strategies to minimize placebo response, the optimum duration of placebo-controlled acute treatment trials, possible alternatives to the use of placebo, and the ramifications of these issues with regard to the design of studies in children, adolescents, and older adults with bipolar disorder.     

Observational study designs for bipolar disorder — What can they tell us about treatment in acute mania?

Randomised controlled trials may have generalisability limitations when applied to the complex treatment of patients with bipolar disorder. Observational study designs can inform us about the diversity of bipolar disorder treatment in naturalistic settings. The aim of this paper was to describe the treatments prescribed for acute mania in a large prospective observational study of bipolar disorder. Patients with a manic/mixed episode were enrolled in EMBLEM (European Mania in Bipolar Longitudinal Evaluation of Medication) if they initiated or changed oral medication with antipsychotics, lithium and/or anticonvulsants. The use of monotherapy or combination therapy for treatment of acute mania, concomitant medications and rate of treatment switching during the 12-week acute treatment phase were assessed. Of the 3459 patients, 36% were treated with one drug and 64% with combination therapy. 55% of patients initiating combination therapy started on an atypical antipsychotic plus lithium or an anticonvulsant. Patients prescribed combination therapy at baseline were more clinically severe, were more often treated as inpatients and had more manic episodes in the previous year compared with the monotherapy group. Treatment switching occurred in 54.4% of patients over the 12-week acute phase. Many patients were taking at least one concomitant medication at baseline (69.4%) and week 12 (50.5%). The results of this observational study show that treatment for mania is complex with multiple combinations of treatment and frequent switching during an acute episode.     

Somatic treatment of bipolar disorder in children and adolescents.

The currently available data from randomized, controlled trials and a considerable amount of open clinical data suggest that adolescent-onset bipolar disorder probably responds to the same agents as adult-onset bipolar disorder. Research examining psychopharmacologic treatment approaches in the early-onset bipolar disorder is limited, however. Methodologic problems include small sample sizes, lack of comparison groups, retrospective designs,and lack of standardized measures. In addition, sometimes no clear differentiation is made between mania and bipolar disorder, the latter term being used broadly in the literature. Often the studies show that symptoms improve because of treatment, but the functioning of the patients does not improve significantly. More research is clearly needed in all aspects of this disorder but especially in examining the efficacy of various types of treatment, its longitudinal course, and diagnostic issues. The indications for, and the overall duration of, long-term maintenance therapy need further study.Many adolescents and children with bipolar disorder do not respond to any of the first-line pharmacologic treatments; therefore, studies with novel agents should be extended to patients in this age range. Furthermore, physicians will probably continue to use combination therapies when confronted by either lack of efficacy or delayed onset of efficacy with a single agent. Thus, such resultant drug-drug interactions also should also be systematically studied [97].     

What is a "mood stabilizer"? An evidence-based response

OBJECTIVE: The term "mood stabilizer" is widely used in the context of treating bipolar disorder, but the U.S. Food and Drug Administration (FDA) does not officially recognize the term, and no consensus definition is accepted among investigators. The authors propose a "two-by-two" definition by which an agent is considered a mood stabilizer if it has efficacy in treating acute manic and depressive symptoms and in prophylaxis of manic and depressive symptoms in bipolar disorder. They review the literature on the efficacy of agents in any of these four roles to determine which if any agents meet this definition of mood stabilizer. METHOD: The authors conducted a comprehensive review of English-language literature describing peer-reviewed, U.S. Agency for Healthcare Research and Quality class A controlled trials in order to identify agents with efficacy in any of the four roles included in their definition of a mood stabilizer. The trials were classified as positive or negative on the basis of primary outcome variables. An "FDA-like" criterion of at least two positive placebo-controlled trials was required to consider an agent efficacious. The authors also conducted a sensitivity analysis by raising and relaxing the criteria for including trials in the review. RESULTS: The authors identified 551 candidate articles, yielding 111 class A trials, including 81 monotherapy trials with 95 independent analyses published through June 2002. Lithium, valproate, and olanzapine had unequivocal evidence for efficacy in acute manic episodes, lithium in acute depressive episodes and in prophylaxis of mania and depression, and lamotrigine in prophylaxis (relapse polarity unspecified). Thus, only lithium fulfilled the a priori definition of a mood stabilizer. Relaxing the quality criterion did not change this finding, while raising the threshold resulted in no agents fulfilling the definition. CONCLUSIONS: When all four treatment roles are considered, the evidence supported a role for lithium as first-line agent for treatment of bipolar disorder. The analysis also highlights unmet needs and promising agents and provides a yardstick for evaluating new treatment strategies.     

Somatic treatment of bipolar disorder in children and adolescents

The currently available data from randomized, controlled trials and a considerable amount of open clinical data suggest that adolescent-onset bipolar disorder probably responds to the same agents as adult-onset bipolar disorder. Research examining psychopharmacologic treatment approaches in the early-onset bipolar disorder is limited, however. Methodologic problems include small sample sizes, lack of comparison groups, retrospective designs, and lack of standardized measures. In addition, sometimes no clear differentiation is made between mania and bipolar disorder, the latter term being used broadly in the literature. Often the studies show that symptoms improve because of treatment, but the functioning of the patients does not improve significantly. More research is clearly needed in all aspects of this disorder but especially in examining the efficacy of various types of treatment, its longitudinal course, and diagnostic issues. The indications for, and the overall duration of, long-term maintenance therapy need further study. Many adolescents and children with bipolar disorder do not respond to any of the first-line pharmacologic treatments; therefore, studies with novel agents should be extended to patients in this age range. Furthermore, physicians will probably continue to use combination therapies when confronted by either lack of efficacy or delayed onset of efficacy with a single agent. Thus, such resultant drug-drug interactions also should also be systematically studied [97].     

Lithium: still a major option in the management of bipolar disorder

Still after more than 50 years, lithium is a major treatment of bipolar disorder, even though it has not been promoted by the pharmaceutical industry over the last decades. In recent years the evidence base on lithium for bipolar disorder has substantially increased due to results from a number of trials. Therefore, a review of this evidence is timely. The efficacy of lithium as an acute treatment and as a maintenance treatment of bipolar disorder was evaluated through a review of the evidence, focusing on modern, randomized, parallel-group designed trials. Additionally, the evidence was sought translated into the proper use of lithium in clinical practice. Lithium's antimanic efficacy has been convincingly demonstrated. However, as blood monitoring due to the risk of toxicity is required and due to an insufficient response in highly agitated patients, lithium monotherapy has a limited place in the acute treatment of severe manic states. For acute bipolar depression, results are conflicting. Recent maintenance trials have added substantially to the documentation of lithium's long-term stabilizing properties in bipolar disorder, and these properties have been demonstrated independently of any acute response to lithium. Finally, it is now beyond doubt that not only does lithium prevent mania, but also depression in bipolar disorder. Lithium is still to be considered a major if not the most important mood- stabilizer, at least for maintaining long-term stability in patients with bipolar disorder. The potential risks of lithium should be weighed up against its benefits and the fact that serious adverse effects are usually avoidable.     

Third generation anticonvulsants in bipolar disorder: a review of efficacy and summary of clinical recommendations

BACKGROUND: To review the literature on efficacy of third generation anticonvulsants for treatment of bipolar disorder and provide clinical recommendations. METHOD: Open and controlled studies, case reports, and case series on the efficacy of lamotrigine, gabapentin, topiramate, tiagabine, and zonisamide were located through electronic searches of several databases, by manual search of proceedings of international meetings, and through contacting authors of recent reports. RESULTS: Lamotrigine is the best studied anticonvulsant and has efficacy in acute bipolar depression and in longer term treatment of bipolar depression as well as rapid-cycling bipolar II disorder but not in acute mania. Open reports suggest usefulness of gabapentin as an adjunct in bipolar disorder, but double-blind trials failed to confirm efficacy in acute mania and treatment-resistant rapid-cycling bipolar disorder. Topiramate is reported to be effective in acute mania and rapid-cycling bipolar disorder in several open studies, but methodological problems in a double-blind study led to a failed study in acute mania. However, topiramate may lead to weight loss in some patients. Zonisamide deserves further investigation, but tiagabine does not appear to be useful in acute mania. CONCLUSION: Lamotrigine clearly fills an unmet need in treating bipolar depression and rapid-cycling bipolar disorder. Other third generation anticonvulsants with the exception of tiagabine offer promise but require confirmation of their efficacy from double-blind studies.     

Lithium - a continuing story in the treatment of bipolar disorder

OBJECTIVE: To review the literature on the use of lithium in the treatment of bipolar disorder and highlight the evidence base supporting its efficacy and safety. METHOD: A selective literature review. RESULTS: Lithium is widely believed to be effective against acute mania, acute bipolar depression and in relapse prevention to either mania or depression. In fact, the data supporting efficacy in acute treatment are less impressive than is often claimed, whereas for relapse prevention and suicide prevention no other agent has comparable depth of support. Lithium is best described as the bench mark treatment for bipolar disorder, rather than the gold standard, because only a minority of patients show major clinical benefit. There is a developing need for further trials against new alternatives and in combination studies. CONCLUSION: Lithium has a continuing important role in the clinical management of bipolar disorder. Its under-utilization in North America reflects opinion rather than evidence and the demonstrated anti-suicide effects should help to reignite interest in its use.     

Lamotrigine and antiepileptic drugs as mood stabilizers in bipolar disorder

OBJECTIVE: To review the clinical trials literature on the use of antiepileptic drugs (AED) as mood stabilizers and to suggest an evidence-based approach when utilizing these agents in bipolar disorder. METHOD: The literature is reviewed and subdivided into the following sections: carbamazepine and oxcarbazepine, valproate, lamotrigine, gabapentin and other AED, and discussion. RESULTS: Data exist to support the use of carbamazepine and valproate - and to a lesser extent, oxcarbazepine - in the management of acute manic episodes associated with bipolar I disorder. Lamotrigine, gabapentin, and other AED have not demonstrated consistent anti-manic effects. Clinical trials data favor lamotrigine over all other AED in the treatment of acute bipolar I depression and in rapid cycling bipolar disorder (particularly type II), although the absence of an active comparator in these lamotrigine trials must be noted. Lamotrigine, carbamazepine, and valproate all have evidence supporting their roles as potential long-term mood stabilizers to prevent bipolar relapse, with lamotrigine having a stronger effect in the prevention of depression. CONCLUSION: The AED are a heterogeneous group of medications with differential spectrum of efficacy in the treatment of bipolar disorder.     

Aims and results of the NIMH systematic treatment enhancement program for bipolar disorder (STEP-BD)

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.     

Clinical experience with anticonvulsant medication in pediatric epilepsy and comorbid bipolar spectrum disorder

Anticonvulsant drugs are first-line treatments for both bipolar mood disorder and epilepsy; however, few studies have explored treatment options when these disorders co-occur. The aim of this study was to identify bipolar disorder symptoms common in pediatric epilepsy and to determine whether anticonvulsant monotherapy might be a practical treatment consideration. A retrospective chart review identified 38 children with bipolar spectrum disorder and epilepsy comorbidity. Two mental health clinicians independently assessed psychiatric diagnoses, symptoms, and assigned retrospective CGI-I ratings for psychiatric symptoms. Common bipolar symptoms included impulsivity, psychomotor agitation, and explosive rage. Forty-two medication trials with 11 different anticonvulsants were identified. Of the 30 instances in which anticonvulsant monotherapy was attempted, carbamazepine, divalproex sodium, lamotrigine, and oxcarbazepine were associated with better psychiatric CGI-I ratings than other monotherapies (P<0.01). Results suggest that in many cases, selected anticonvulsants appeared to simultaneously treat both epilepsy and mood disorder. Controlled trials are necessary to further ascertain optimal anticonvulsant usage.     

Atypical antipsychotics for bipolar disorder.

Atypical antipsychotic agents have been widely investigated for their efficacy in acute mania. The data to date suggest that olanzapine,risperidone, quetiapine, aripiprazole, and ziprasidone are effective, with no significant differences in antimanic efficacy among these agents. These agents are effective as an alternative to lithium or divalproex as monotherapy or in combination with these mood stabilizers. The data concerning their utility in acute bipolar depression and maintenance treatment of bipolar disorder are limited. The studies to date suggest that olanzapine has modest acute antidepressant properties but probably has efficacy comparable to lithium and divalproex in preventing manic and depressive episodes. Quetiapine seems to have robust antidepressant properties, but these data need to be replicated in further trials before quetiapine can be recommended as a first-line agent for acute bipolar depression. Aripiprazole has shown promise in preventing manic episodes in one 6-month study, but further studies with at least 1-year duration and larger sample sizes are needed before this agent can be recommended as a monotherapy for prophylaxis of bipolar disorder. It is currently unknown if risperidone, aripiprazole, and ziprasidone have any efficacy in treating acute bipolar depression. Similarly, long-term studies are needed to ascertain the role of risperidone, quetiapine, and ziprasidone in the maintenance treatment of bipolar disorder. Overall, the atypical antipsychotic agents as a group represent an effective and relatively safe addition to the armamentarium for the treatment of bipolar disorder.     

The role of lamotrigine in the management of bipolar disorder

Lamotrigine has emerged with a distinct place in the pharmacological treatment of bipolar disorder, with the potential to treat and prevent bipolar depression, which is the dominant and arguably most disabling and under-treated phase of the illness. This review examines the published clinical trials of lamotrigine in bipolar treatment. While the data supports its tolerability and safety, the strongest evidence for its efficacy lies in the prevention of bipolar depression, with weaker evidence for the treatment of acute bipolar depression, refractory unipolar and bipolar depression, and rapid cycling bipolar disorder. The total number of published well designed trials is small, even the maintenance evidence is derived from two studies. However, this relative inadequacy compares favorably with the alternative treatment options for bipolar depression, which are marked by poor efficacy or risk of polarity switch. The designation of lamotrigine as first-line treatment for bipolar depression prophylaxis should be done in cognizance of this context, and it would seem prudent to await greater evidence of efficacy before designating lamotrigine as first-line treatment for other bipolar indications. Further randomized controlled trials are required to consolidate the available findings and to explore the boundaries of lamotrigine’s efficacy, which may encompass the soft spectral disorders.     

Antiepileptic Drugs in Mood-Disordered Patients

Summary:  Bipolar disorder is a common, recurrent, often severe mental disorder that, without adequate treatment, is associated with high rates of morbidity and mortality. We review the evidence on the efficacy of a spectrum of antiepileptic drugs (AED) in bipolar disorder. Most studies have been carried out with carbamazepine (CBZ), valproate (VPA), and lamotrigine (LTG). All three of these AEDs have been shown to be of value in the management of patients with bipolar illnesses. VPA and CBZ seem to exert stronger antimanic effects and, to a lesser degree, acute antidepressant efficacy. LTG seems to be effective against depression and mania, with a more robust activity against depression. No firm evidence supports a role for vigabatrin, tiagabine, topiramate, or levetiracetam in these disorders.     

An evidence-based medicine strategy for achieving remission in bipolar disorder

Controlled trials have demonstrated the efficacy of several classes of drugs for achieving acute response in bipolar mania and depression. For many years, clinical response has been the primary outcome in the majority of short-term efficacy studies. However, there is a growing consensus that the optimal goal in the long-term management of bipolar disorder is remission. The purpose of this article is to briefly summarize the clinical importance of remission in bipolar disorder and to review data on the effectiveness of available treatments for achieving and sustaining remission.     

Risperidone for bipolar disorders

Atypical antipsychotic medications are a relatively new, increasingly prominent component of the treatment armamentarium for bipolar disorder -- a development that provides more options for potentially improved outcomes for patients and families affected by bipolar disorder. The US Food and Drug Administration-approved bipolar indications for risperidone include monotherapy for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. Risperidone is also approved in over 30 countries worldwide for bipolar mania either as monotherapy, adjunct therapy, or both monotherapy and adjunct therapy. A number of controlled and open-label treatment trials have shown risperidone's efficacy and tolerability in the manic phase of bipolar disorder. Risperidone has also been reported to be useful in the longer-term treatment of bipolar disorder. This drug profile of risperidone for bipolar disorder will address the chemistry, pharmacodynamics, pharmacokinetics and metabolism of risperidone, clinical trials in bipolar disorder, postmarketing surveillance, safety, tolerability and regulatory issues. Finally, a discussion of potential future directions, a summary of key issues and information resources are provided.     

A review of bipolar disorder among adults

OBJECTIVE: This paper reviews the epidemiology, etiology, assessment, and management of bipolar disorder. Special attention is paid to factors that complicate treatment, including noncompliance, comorbid disorders, mixed mania, and rapid cycling. Advances in biopsychosocial treatments are briefly reviewed, including new health service models for providing care. METHODS: A MEDLINE search was done for the period from January 1988 through October 1997 using the key terms of bipolar disorder, diagnosis, and treatment. Papers selected for further review included those published in English in peer-reviewed journals. Preference was given to articles reporting randomized, controlled trials. RESULTS: Bipolar disorder is a major public health problem. The etiology of the disorder appears multifactorial. Diagnosis often occurs years after onset of the disorder. Comorbid conditions are common. Management includes a lifetime course of medication and attention to psychosocial issues for patients and their families. Standardized treatment guidelines for the management of acute mania have been developed. New potential treatments are being investigated. CONCLUSIONS: Assessment of bipolar disorder must include careful attention to comorbid disorders and predictors of compliance. Randomized trials are needed to further evaluate the efficacy of medication, psychosocial interventions, and other health service interventions, particularly as they relate to the management of acute bipolar depression, bipolar disorder co-occurring with other disorders, and maintenance prophylactic treatment.