Pediatric bipolar disorder: emerging diagnostic and treatment approaches

Children and adolescents who have bipolar disorder often are encountered in clinical settings and frequently require treatment with mood stabilizers and atypical antipsychotics. New screening and diagnostic tools are available to aid in the diagnosis of bipolar disorder in children and adolescents. Additional data supporting the use of mood stabilizers and atypical antipsychotics in this population also are emerging. Combinations of existing psychotropics remain the most effective treatment of pediatric bipolar disorder at this point. This article reviews the phenomenology and clinical characteristics of pediatric bipolar disorder and current approaches to pharmacotherapy. It is becoming apparent that bipolar disorder is often a chronic disorder in children and adolescents, much like diabetes, and is best managed with a combination of medications and psychosocial therapy.     

Acute and maintenance treatment of bipolar mania: the role of atypical antipsychotics

Abstract:  Bipolar disorder is a complex condition including depression, mania, and in many cases associated with comorbid anxiety symptoms and substance abuse. Mood stabilizers including lithium and divalproex have been considered standard therapy for the treatment of patients with bipolar disorder, but remission rates remain inadequate. Conventional antipsychotics have demonstrated efficacy for acute mania, but they appear to have little role in the maintenance treatment of bipolar disorder. Despite substantial evidence of efficacy and recent guideline recommendations, atypical antipsychotics remain underused for the treatment of bipolar disorder. Data from double-blind, controlled trials are available for a number of clinically meaningful efficacy measures, including improvement in manic symptoms, onset of action, response rates, remission rates, improvement in comorbid depressive symptoms, and induction/worsening of mania or depression. Atypical antipsychotics are effective both as alternatives to lithium or divalproex as monotherapy, or in combination with these mood stabilizers, in the acute and likely the maintenance treatment of mania. The atypical antipsychotics represent an effective and relatively safe addition to our armamentarium for the treatment of bipolar disorder.     

Treatment of bipolar mania with risperidone

In patients with bipolar disorder antipsychotics are frequently used for the treatment of acute manic episodes, either in monotherapy, in addition to a mood stabilizer or in patients refractory to lithium or other mood stabilizers. However, a number of studies demonstrated that the use of conventional neuroleptics is restricted -- particularly for long-term treatment and relapse prevention in bipolar disorder -- due to their side effect profile and their potential to induce or worsen depressive symptoms. In contrast, atypical antipsychotics have a better tolerability profile and fewer extrapyramidal side effects. A number of clinical studies showed that the atypical antipsychotic risperidone was effective and well tolerated in the treatment of bipolar mania. This was reported both for the treatment of acute episodes and for the maintenance therapy. Recent data suggest that risperidone can be used effectively either in addition to or even instead of a mood stabilizer. This review summarizes the available literature on risperidone in the treatment of bipolar disorders.     

Atypical antipsychotics in the treatment of bipolar affective disorders

Antipsychotics are commonly used in the treatment of bipolar affective disorder. The use of conventional antipsychotic agents, though effective as antimanic agents, is associated with a number of limitations such as their acute side effect profile and their unsufficient mood stabilizing activity. In addition, exposure to conventional neuroleptics poses a risk for the development of tardive dyskinesia, especially in mood disorder patients. Growing evidence suggests that the novel, so-called atypical neuroleptics may offer a number of advantages in the treatment of bipolar disorder, including their thymoleptic activity and minimal risk for acute and long-term extraypyramidal symptoms. Clinical experience with clozapine and olanzapine as mood stabilizers suggests greater antimanic than antidepressant properties, while risperidone may have greater antidepressant properties with some liability for triggering or exacerbating mania. The mood stabilizing properties of further atypical drugs are currently under investigation. This review focuses on the use of atypical antipsychotics in the treatment of bipolar disorder. We also present an overview concerning potential pharmakokinetic interactions based on the cytochrome P450 enzyme system when antipsychotics are combined with other mood stabilizing compounds. In conclusion, atypical antipsychotics should come to play an increasingly important role in the acute and long-term management of bipolar disorder, but there is a clear need for further controlled trials in this indication.     

Atypical antipsychotics: newer options for mania and maintenance therapy

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of bipolar disorder. In the past few years several atypical agents have received regulatory approval for use in bipolar mania. Through a review of randomized controlled trials for five commonly used atypical drugs, olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole, this article evaluates their efficacy in the acute and maintenance phases of bipolar disorder. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored.
Atypical antipsychotics appear to have broadly similar efficacy against manic symptoms of bipolar disorder, but there are important differences in their tolerability profiles, which are likely to be of particular relevance during long-term treatment. A brief assessment of tolerability issues surrounding the use of atypical agents in bipolar disorder and other aspects of treatment that have impact on the clinical effectiveness of the therapy are considered.     

Comparative efficacy of typical and atypical antipsychotics as add-on therapy to mood stabilizers in the treatment of acute mania.

BACKGROUND: Typical antipsychotics are commonly used in combination with mood stabilizers for acute mania. Although typical antipsychotics are effective, they have undesirable side effects such as induction of depressive symptoms and tardive dyskinesia. Atypical antipsychotics have more favorable side effect profiles, and recent evidence shows their efficacy in treating mania. Apart from a previous small study that compared risperidone with typical neuroleptics as add-on therapy to mood stabilizers, no studies to date have directly compared atypical antipsychotics with typical antipsychotics as add-on therapy to mood stabilizers in a clinically relevant, naturalistic setting. METHOD: This study is a chart review of all patients with DSM-IV-defined bipolar disorder, current episode mania (N = 204), admitted to the University of British Columbia Hospital during a 30-month period. Patients were separated into 3 groups according to the medications used: (1) mood stabilizer and typical antipsychotic, (2) mood stabilizer and atypical antipsychotic, and (3) combination: mood stabilizer plus a typical antipsychotic, then switched to mood stabilizer plus risperidone or olanzapine within I week. The atypical group was further subdivided into risperidone and olanzapine subgroups. Outcome was measured using Clinical Global Impressions-Severity of Illness (CGI-S) and -Improvement (CGI-I) ratings generated by review of clinical information in the chart. RESULTS: Patients treated with typical antipsychotics were more severely ill at admission and at discharge than those treated with atypical antipsychotics. Patients in the atypical (p < .005) and combination (p < .05) groups showed significantly greater clinical improvement at discharge than patients treated with typical antipsychotics. This difference was also significant in the subset of patients with psychotic features (p < .03). Risperidone and olanzapine were associated with fewer extrapyramidal side effects than were typical antipsychotics (risperidone vs. typical antipsychotics, chi2 = 8.72, p < .01; olanzapine vs. typical antipsychotics, chi2 = 16.9, p < .001). CONCLUSION: Due to their superior effectiveness and side effect profile when compared with typical antipsychotics. atypical antipsychotics are an excellent choice as add-on therapy to mood stabilizers for the treatment of patients with mania.     

Adjunctive olanzapine treatment in bipolar adolescents responding insufficiently to mood stabilizers

This report was aimed to evaluate the efficacy of olanzapine treatment as an adjunct therapy to mood stabilizers in the treatment of four adolescents responding insufficiently to mood stabilizers. All patients were diagnosed with bipolar I disorder according to DSM IV criteria. YMRS (Young mania rating scale) and CGI (Clinical global impression, improvement and therapeutic effectiveness scales) were used to evaluate overall response of the episode to the drugs. All patients with no adequate response to mood stabilizers did respond to adjunctive olanzapine treatment (10-30 mg/per day). It has been suggested that antipsychotics may be useful as an adjunct to mood stabilisers in bipolar disorder. However, further research is warranted regarding the use of atypical antipsychotics in children and adolescents.     

Clinical research on antipsychotics in bipolar disorder

Antipsychotics are commonly used in bipolar disorder, both for acute mania and in maintenance treatment. The authors review available clinical research concerning the use of both conventional and atypical antipsychotics in bipolar disorder and present recommendations for a number of key clinical situations based on this review. They also consider a number of important related questions, including whether there is evidence for an increased risk of tardive dyskinesia (TD) in patients with bipolar disorder, the potential role for antipsychotics in the treatment of bipolar depression, the role of antipsychotics in maintenance treatment of bipolar disorder, the potential for antipsychotics to induce depression in bipolar illness, and whether antipsychotics can be considered mood stabilizers with a place as monotherapy for bipolar mania. They conclude that standard treatment for acute mania should begin with a mood stabilizer, with benzodiazepines used as an adjunct for mild agitation or insomnia and antipsychotics used as an adjunct for highly agitated, psychotic, or severely manic patients. They also conclude that atypical antipsychotics are preferable to conventional antispychotics because of their more favorable side effect profile and reduced risk of tardive dyskinesia. They review the evidence for using atypical antipsychotics as first-line monotherapy for mania and conclude that more evidence concerning the risk of TD and their efficacy as maintenance treatment in bipolar disorder is needed before a conclusion can be made. Should the eventual risk of TD associated with atypical antipsychotics be found to be minimal and their efficacy in maintenance treatment found to be high, they could eventually be considered first line monotherapy for bipolar disorder. They conclude that treatment with an antipsychotic during bipolar depression should be limited to those patients who have psychosis and that atypical antipsychotics are preferred over conventional antipsychotics in this situation, not only because of their reduced risk of side effects but also because theoretically they may have antidepressant efficacy due to their effects on the serotonin system. The clinical research findings summarized in the article are, for the most part, supported by a recently published guideline based on a consensus of clinical experts.     

Influence of medication choice and comorbid diabetes: the cost of bipolar disorder in a privately insured US population

Background Bipolar disorder is the most expensive mental disorder for US employer health plans. No published studies have examined the impact of comorbid diabetes on the cost of treating bipolar disorder. The objectives of this work were to determine the direct costs incurred by patients with bipolar disorder in a US managed care plan, and to examine the influence (1) of drug therapy regimen on bipolar-related costs, and (2) of diabetes on bipolar-related and all-cause costs. Methods A retrospective analysis of claims in a US private insurance database from January 1, 1999 through December 31, 2002 was performed. The database included at least 4.7 million enrollees each year. Diagnosis codes were used to identify patients with bipolar disorder; patients with diabetes were identified using diagnosis codes and medication use. Results From 1999–2002, treated bipolar disorder was identified in 262 (33.9) [mean (standard deviation)] cases per 100,000 enrollees. Among patients with bipolar disorder in this cohort, between 6.3 and 7.4% were treated for diabetes each year. Among patients with newly treated bipolar disorder, 61.8% received initial therapy with only mood stabilizers, 24.3% received only atypical antipsychotics, and 13.9% received both. Mean all-cause cost for patients with bipolar disorder was US$2,690 in the 6 months before the first bipolar-related claim, and US$6,826 in the following year. Of the latter cost, bipolar-related cost was US$1,272. Patients with comorbid diabetes had much higher all-cause cost (US$11,317) than those without diabetes in the year following the first bipolar-related claim, but only slightly higher bipolar-related cost (US$1,349). Among newly treated bipolar disorder patients, all-cause and bipolar-related cost in the year after diagnosis was lowest in patients receiving only mood stabilizers. Ordinary least squares regression analysis found that treatment with mood stabilizers only was associated with 41% lower bipolar-related cost than treatment with atypical antipsychotics only (P < .001). Significant individual associations were also found between bipolar-related cost and bipolar disorder I diagnosis, severe bipolar disorder and comorbid personality disorders (P < .001 for each) but not comorbid diabetes (P = .27). Conclusions These results suggest that patients with bipolar disorder who receive only mood stabilizer therapy incur lower bipolar-related and all-cause cost than those receiving only atypical antipsychotics. In contrast to that for all-cause cost, comorbid diabetes had little impact on direct costs related to treating bipolar disorder itself.     

Defining the bipolar spectrum and treating bipolar II disorder

The treatment of bipolar II disorder may be complicated by the lack of a universal definition of the bipolar spectrum and by the limited number of studies focusing on bipolar II disorder pharmacotherapy. The appropriate first-line treatment for bipolar II disorder is still being studied, but according to the limited research, antidepressants, mood stabilizers, anticonvulsants, and atypical antipsychotics have been safe and effective in the acute and maintenance treatment of bipolar II depression and/or hypomania or mania. A consensus should be reached on the definition of the bipolar spectrum, and further research is needed to determine the best first-line treatment for bipolar II disorder.     

A typical mood stabilizers: a "typical role for atypical antipsychotics

OBJECTIVE: To assess the potential role of atypical antipsychotics as mood stabilizers.METHOD: A MedLine, PsychLIT, PubMed, and EMBASE literature search of papers published up to December 2004 was conducted using the names of atypical antipsychotics and a number of key terms relevant to bipolar disorder. Additional articles were retrieved by scrutinizing the bibliographies of review papers and literature known to the authors. Data pertinent to the objective was reviewed according to the various phases of bipolar disorder.RESULTS: The data is most substantive for the use of atypical antipsychotics in mania, to the extent that an argument for a class effect of significant efficacy can be made. This does not extend to bipolar depression, however, good data is now emerging for some agents and will need to be considered for each individual agent as it accumulates. As regards mixed states and rapid cycling the evidence is thus far sparse and too few maintenance studies have been conducted to make any firm assertions. However, with respect to long-term therapy the atypical antipsychotics do have clinically significant side-effects of which clinicians need to be aware.CONCLUSION: Based on the evidence thus far it is perhaps premature to describe the atypical antipsychotics as mood stabilizers. Individual agents may eventually be able to claim this label, however, much further research is needed especially with respect to maintenance and relapse prevention.     

Maintenance therapies in bipolar disorder: focus on randomized controlled trials

OBJECTIVE: Lithium remains the cornerstone of maintenance therapy for bipolar disorder despite growing use of other agents, including divalproex, lamotrigine, carbamazepine and the atypical antipsychotics. Lithium has the largest body of data to support its continued use as a prophylactic agent; however, most of this data comes from early studies that did not use contemporary analytic methods. Alternatives to lithium are needed because of the relatively high rate of non-response to lithium monotherapy and the drug's frequent side-effects. This article reviews available data with an emphasis on double-blind, placebo-controlled studies that examine the efficacy of lithium and other putative mood stabilizers: carbamazepine, divalproex, lamotrigine and olanzapine. METHOD: The authors reviewed key literature using Medline searches using key words: bipolar disorder, controlled trials, mood stabilizer, lithium, lomotrigine, divalproex, olanzapine, carbamazepine. RESULTS: Lithium remains the gold standard for overall preventative efficacy in bipolar disorder, especially to decrease manic or hypomanic relapse. Of the mood stabilizers that have marked prophylactic antimanic properties, lithium appears to possess the greatest antidepressant effect. Divalproex may also prevent recurrent bipolar mood episodes but the relative lack of controlled maintenance studies makes this less certain. There now exists an extensive and well-designed research database supporting the use of lamotrigine in the acute and prophylactic management of bipolar I disorder. Lamotrigine offers a spectrum of clinical effectiveness that complements lithium, in that it appears to stabilize mood 'from below baseline' by preventing episodes of depression and has been shown to be effective in rapid-cycling bipolar II disorder. Carbamazepine may be a useful alternative to lithium, divalproex and lamotrigine, particularly for patients with a history of mood-incongruent delusions and other comorbidities, but controlled data is more equivocal and it may lose some of its prophylactic effect over time. Emerging data continue to support the growing use of atypical antipsychotics, particularly olanzapine. CONCLUSIONS: Any monotherapy for use as a maintenance therapy of bipolar disorder appears to be inadequate for long-term use in the management of the majority of patients with bipolar disorder. Combination therapy has become the standard of care in the treatment of bipolar disorder and particularly in patients with treatment-refractory variants such as those with rapid-cycling. The emerging consensus is that patients on monotherapy, if followed for sufficiently long periods, will eventually require concomitant treatment to maintain a full remission. There exists a need for controlled trials that use random assignment to parallel arms including combination therapy followed by data analyses that include both relapse rate and survival techniques.     

Bipolar disorder maintenance treatment: monitoring effectiveness and safety

Bipolar disorder is a chronic illness that requires long-term treatment, the goal of which is to shorten or prevent mood episodes without increasing cycle frequency, thereby increasing the length of well periods. Treatment guidelines recommend mood stabilizers as first-line medications, and several atypical antipsychotics are also approved as monotherapy or as adjuncts to mood stabilizers for maintenance treatment. Combination therapy with 2 mood stabilizers or with a mood stabilizer and an antipsychotic may be necessary to achieve or maintain remission of the patient's symptoms. When treating patients with mood stabilizers and atypical antipsychotics during the maintenance phase, physicians should systematically monitor for adverse effects, particularly weight gain, and tolerability issues, and address those issues in a timely manner in order to enhance treatment adherence and improve patient outcomes.     

Role of aripiprazole in treating mood disorders

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of mood disorders. In the past few years, several atypical agents have received regulatory approval for use in mania. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers, such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Aripiprazole is a recently released antipsychotic medication that differs from other atypical antipsychotic agents by its mode of action as a dopamine D2 partial agonist. It is administered orally and has a long half-life. Randomized studies have demonstrated the efficacy of aripiprazole compared with placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, treatment of acute mania, and prevention of manic relapse in patients who responded to the drug during a manic episode. Further studies are ongoing in bipolar and unipolar depression. Aripiprazole is generally well tolerated compared with other antipsychotic medications, although commonly reported side effects include extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information regarding the comparative safety, efficacy and tolerability of aripiprazole in the treatment of affective disorders.     

Treatment-resistant bipolar disorder

Despite the remarkable increase in medications validated as effective in bipolar disorder, treatment is still plagued by inadequate response in acute manic or depressive episodes or in long-term preventive maintenance treatment. Established first-line treatments include lithium, valproate and second-generation antipsychotics (SGAs) in acute mania, and lithium and valproate as maintenance treatments. Recently validated treatments include extended release carbamazapine for acute mania and lamotrigine, olanzapine and aripiprazole as maintenance treatments. For treatment-resistant mania and as maintenance treatments, a number of newer anticonvulsants, and one older one, phenytoin, have shown some promise as effective. However, not all anticonvulsants are effective and each agent needs to be evaluated individually. Combining multiple agents is the most commonly used clinical strategy for treatment resistant bipolar patients despite a relative lack of data supporting its use, except for acute mania (for which lithium or valproate plus an SGA is optimal treatment). Other approaches that may be effective for treatment-resistant patients include high-dose thyroid augmentation, clozapine, calcium channel blockers and electroconvulsive therapy (ECT). Adjunctive psychotherapies show convincing efficacy using a variety of different techniques, most of which include substantial attention to education and enhancing coping strategies. Only recently, bipolar depression has become a topic of serious inquiry with the dominant controversy focusing on the place of antidepressants in the treatment of bipolar depression. Other than mood stabilizers alone or the combination of mood stabilizers and antidepressants, most of the approaches for treatment-resistant bipolar depression are relatively similar to those used in unipolar depression, with the possible exception of a more prominent place for SGAs, prescribed either alone or in combination with antidepressants. Future work in the area needs to explore the treatments commonly used by clinicians with inadequate research support, such as combination therapy and the use of antidepressants as both acute and adjunctive maintenance treatments for bipolar disorder.     

Pharmacotherapy of bipolar depression: An update

Bipolar affective disorder is a virulent illness with high rates of recurrence, disability, social impairment, and suicide. Although the manic or hypomanic episodes define the disorder, the depressions are more numerous and less responsive to treatment. As the initial depressive episodes are commonly misdiagnosed, initiation of therapy with mood stabilizers is often delayed, increasing the likelihood of treatment-emergent affective switches on antidepressant monotherapy. The empirical basis for selecting treatments for people with bipolar depression is weak, and only the combination of olanzapine and fluoxetine has received US Food and Drug Administration (FDA) approval. Conventional mood stabilizers are preferred for first-line therapies, although atypical antipsychotics are increasingly used, and FDA approval of quetiapine is pending. Antidepressants—particularly selective serotonin reuptake inhibitors and bupropion— are indicated when mood stabilizers are ineffective and for “breakthrough“ depressions.     

双相障碍不同首选用药间处方方式、不良反应、经济负担、依从性比较

目的比较首选心境稳定剂和首选抗精神病药治疗的双相障碍患者处方方式、不良反应、经济负担及药物治疗依从性等。方法对河北省11个地市39家精神卫生机构中接受心境稳定剂或抗精神病药治疗的240例双相障碍患者,采用自制调查问卷、临床总体印象病情严重程度量表(clinical global impressions scale-severity of illness,CGI-SI)、不良反应量表(treatment emergent symptom scale,TESS)、药物依从性评定量表(medication adherence rating scale,MARS)进行社会人口学、疾病临床特征、处方方式(联合用药情况)、精神类药物花费、不良反应及治疗依从性等方面的调查。结果首选抗精神病药治疗者(抗精神病药组)152例(63.3%),首选心境稳定剂治疗者(心境稳定剂组)88例(36.7%)。抗精神病药组与心境稳定剂组相比,住院患者构成比(90.1%vs.76.1%)、伴有精神病性症状患者构成比(27.0%vs.11.4%)、不良反应发生率(46.1%vs.31.8%)、精神类药物日花费(中位数12.00元vs.8.37元)和总花费(中位数344.61元vs.144.64元)均较高(P0.05)。但两组间药物处方方式、不良反应严重程度、MARS总分无统计学差异(P0.05)。结论河北省双相障碍患者以首选抗精神病药治疗为主,但首选抗精神病药并未减少之后的联合用药,且不良反应发生率及药物经济负担均明显高于首选心境稳定剂治疗者,所以心境稳定剂仍应作为双相障碍主要首选用药。     

Management of the depressive component of bipolar disorder

Acute bipolar depression (ABD) and breakthrough depression occurring during maintenance therapy of bipolar disorder are associated with significant morbidity and an increased risk of suicide. Lithium is an effective mood stabilizer for ABD, but its onset of antidepressant action is slow and additional antidepressant therapy is often prescribed. The extent to which other mood stabilizers (e.g., carbamazepine and valproate) have antidepressant activity is unclear. Preliminary initial research suggests three potential advantages that selective serotonin reuptake inhibitors have over tricyclic antidepressant for ABD: possibly greater efficacy, fewer adverse effects, and a lower frequency of antidepressant-induced mania. Bupropion may also have significant advantages. However, further research is needed to confirm these findings. Monoamine oxidase inhibitors are the antidepressant of choice for atypical bipolar depression. Electroconvulsive therapy (ECT) has the highest response rate of all treatments for ABD. Further research is needed to explore combination treatments with mood stabilizers and antidepressants for the effective treatment of ABD. Depression and Anxiety 4:190–198, 1996/1997. © 1997 Wiley-Liss, Inc.     

Pharmacotherapy of children and adolescents with bipolar disorder.

The identification and treatment of children and adolescents with a bipolar disorder is often challenging and difficult. Many of the psychotropic agents used to treat adults with bipolar disorder may also be-used to treat children and adolescents with these disorders. Further controlled trials using combination pharmacotherapy in children and adolescents with bipolar disorders are needed to advance the field of pediatric bipolarity and provide optimal care for these patients. There are multiple ongoing trials of mood stabilizers and atypical antipsychotics that will provide important controlled data that are currently lacking in the field.     

Treatment-resistant bipolar disorder

Over the last few years, the number of potential pharmacotherapies for bipolar disorder has greatly expanded. Yet the database for virtually all these newer treatments consists of case reports and case series. Among these newer treatments, recently released anticonvulsants are most promising. Lamotrigine has already shown efficacy for treating bipolar depression, while gabapentin's efficacy has yet to be documented in a controlled study. Alone among its medication class, topiramate, another anticonvulsant, is associated with weight loss. Novel antipsychotics are effective in treating acute mania. With the exception of clozapine, their efficacy as true mood stabilizers is still unknown. Utilizing combinations of mood stabilizers is common and appropriate but demands knowledge of potential pharmacokinetic interactions. Other approaches for treatment resistant bipolar disorder include high-dose thyroid hormones, calcium channel blockers, electroconvulsive therapy, and omega-3 fatty acids. Finally, the efficacy of adjunctive psychosocial strategies is a topic of active investigation.