Alternatives to lithium and divalproex in the maintenance treatment of bipolar disorder

Objectives: The role of lithium carbonate in the maintenance treatment of bipolar disorder is well established. Unfortunately, many patients fail to respond adequately to this agent or are unable to tolerate its adverse effects. Divalproex has become a commonly used alternative to lithium, but it also is ineffective or poorly tolerated in many patients. This article attempts to review the available data on maintenance therapy in bipolar disorder with a variety of anticonvulsants and antipsychotics (both conventional and novel), with reference to relevant studies in acute mania and bipolar depression as well.
Methods: Evidence on maintenance therapy and relevant acute-phase data were collected using MEDLINE database searches.
Results: Data on maintenance therapy with agents other than lithium and divalproex are sparse, and often derived from open, uncontrolled studies. Implications and flaws of available data are discussed.
Conclusions: Other than lithium, there are few robust double-blind data to support the use of a variety of agents in the maintenance phase. However, uncontrolled data suggest that a number of agents merit further study.     

Prophylactic treatment of bipolar disorder in pregnancy and breastfeeding: focus on emerging mood stabilizers

OBJECTIVES: Bipolar disorders are reported to have a high incidence during childbearing years and the need may arise to start or continue a pharmacological treatment during pregnancy and the postpartum period. In the last few years several investigations have evaluated the efficacy of emerging mood-stabilizing agents in the treatment of bipolar disorders, such as lamotrigine, olanzapine, risperidone, quetiapine, aripiprazole and ziprasidone. A number of studies, which examined the use of oxcarbazepine, point to its potential usefulness in prophylactic treatment. The aim of this review is to compare information from the literature on the safety of lamotrigine, oxcarbazepine, risperidone, olanzapine, and quetiapine to the safety data on classic mood stabilizers during pregnancy and the postpartum period. METHODS: A computerized search carried out from 1980 to April 5, 2006 led to the summarization of the results. (References were updated after acceptance and prior to publication.) RESULTS: Emerging mood stabilizers show uncertain safety parameters in pregnancy and lactation. Limited information on lamotrigine and oxcarbazepine does not suggest a clear increase in teratogenicity, while olanzapine appears to be associated with a higher risk of metabolic complications in pregnant women. Data about risperidone and quetiapine are still inconclusive. Finally, the literature on the safety of these compounds in breastfeeding is anecdotal. CONCLUSIONS: Untreated pregnant bipolar women are at an increased risk of poor obstetrical outcomes and relapse of affective symptoms. On the other hand, classic antiepileptic drugs are well-known human teratogens, whereas data on lithium are partially ambiguous. The safety of emerging mood stabilizers in pregnancy and breastfeeding has not been examined extensively. Therefore, when approaching bipolar disorder, if possible, each episode must be considered separately.     

Atypical antipsychotics as "mood stabilizers": a retrospective chart review

BACKGROUND: Introduction and common usage of atypical antipsychotics in maintenance therapy for bipolar disorders is an innovative perspective. The aim of the present study was to compare the efficacy of atypical antipsychotics (AA) used either as monotherapy or in combination with a mood stabilizer (MS) in the maintenance treatment. METHOD: 55 patients treated with AA either alone or in combination with a MS for bipolar I disorder which were followed up for 6 months were retrospectively evaluated. Clinical status was evaluated with Bech Rafaelsen Mania Rating Scale (BRMRS), 24-item Hamilton Depression Scale (HAMD) and Clinical Global Impressions Scale (CGI). RESULTS: Having similar demographic and clinical backgrounds, patients on with both treatment groups had significant clinical improvement. During the maintenance phase, numbers of total attacks were not significantly different between the two treatment groups. CONCLUSION: Our naturalistic, controlled retrospective observations suggest the potential use of atypical antipsychotics in the long-term management of bipolar I disorder. Larger and prospective studies are needed to determine the role of atypical antipsychotics more clearly in the maintenance treatment of bipolar disorder. To the best of our knowledge this is the first study comparing MS+AA with only AA treatment regimen.     

Pharmacological interventions for acute bipolar mania: a systematic review of randomized placebo-controlled trials

OBJECTIVES: We conducted a systematic review and meta-analysis of randomized, placebo-controlled trials in acute bipolar mania to summarize available data on drug treatment of mania. METHODS: We included trials of medications licensed in the USA or UK for the treatment of any phase of bipolar disorder. Outcomes investigated were changes in mania scores, attrition, extrapyramidal effects and weight change. Data were combined through meta-analyses. RESULTS: We included 13 studies (involving 3,089 subjects) and identified 2 studies for each of the following medications: carbamazepine, haloperidol, lithium, olanzapine, quetiapine, risperidone, valproate semisodium and aripiprazole. All drugs showed significant benefit compared with placebo for reduction in mania scores. Compared with placebo, for all antipsychotics pooled, response to treatment (> or =50% reduction in Young Mania Rating Scale scores) was increased more than 1.7 times [relative risk (RR) = 1.74, 95% confidence interval (CI) = 1.54, 1.96]; for all mood stabilizers pooled, response to treatment was doubled (RR 2.01, 95% CI = 1.66, 2.43). Overall withdrawals were 34% fewer (24-43%) with antipsychotics, and 26% fewer (10-39%) with mood stabilizers. However, for carbamazepine, aripiprazole and lithium an increase in risk of withdrawal could not be excluded. Small but significant increases in extrapyramidal side effects occurred with risperidone and aripiprazole. CONCLUSIONS: Antipsychotics and mood stabilizers are significantly more effective than placebo for the treatment of acute mania. Their effect sizes are similar. Small differences between effect sizes may be due to differences in the patients included in the studies or to chance. Carbamazepine and lithium may be more poorly tolerated, and antipsychotics cause more extrapyramidal side effects.     

The management of bipolar disorder in primary care: a review of existing and emerging therapies

Recent evidence suggests that the prevalence of bipolar disorder is as much as fivefold higher than previously believed, and may amount to nearly 5% of the population, making it almost as common as unipolar major depression. It is, therefore, not unrealistic to assume that primary care or family physicians will frequently encounter bipolar patients in their practice. Such patients may present with a depressive episode, for a variety of medical reasons, for longer-term maintenance after stabilization, and even with an acute manic episode. Whatever the reason, a working knowledge of current trends in the acute and longer-term management of bipolar disorder would be helpful to the primary care physician. In addition, an understanding of important side-effects and drug interactions that occur with drugs used to treat bipolar disorder, which may be encountered in the medical setting, are paramount. This paper will attempt to review existing and emerging therapies in bipolar disorder, as well as their common drug interactions and side-effects.     

Equally increased risk for metabolic syndrome in patients with bipolar disorder and schizophrenia treated with second-generation antipsychotics

Objective: Although second-generation antipsychotics (SGAs) are widely used in treating schizophrenia and bipolar disorder, their effects on dyslipidemia, glucose intolerance, metabolic syndrome (MetS), and coronary heart disease (CHD) risk are less well documented for bipolar disorder. We compared bipolar disorder and schizophrenia patients receiving SGAs to determine whether MetS prevalence is influenced by the primary psychiatric diagnosis or concomitant mood stabilizer treatment. Methods: Admission assessment of MetS criteria (abdominal obesity, fasting hypertriglyceridemia, low high-density lipoprotein cholesterol, hyperglycemia, arterial hypertension) and the calculated 10-year CHD risk in bipolar disorder and schizophrenia patients treated with SGAs and closely matched for age, sex, and race. Results: Compared to schizophrenia patients (n = 111), those with bipolar disorder (n = 74) had lower body mass index (27.1 ± 5.3 versus 29.9 ± 8.1, p = 0.0053), were more likely treated with mood stabilizers (60.8 versus 36.0, p = 0.0009), and less likely treated with clozapine (1.3% versus 15.3%, p = 0.0017) or two antipsychotics (10.8% versus 34.2%, p = 0.0003). Despite these differences, bipolar disorder and schizophrenia patients had comparable rates of MetS (43.2% versus 45.9%, p = 0.71) and predicted CHD events (10-year risk >10%: 18.9% versus 23.4%, p = 0.47). Using ≥100 mg/dL as the adapted glucose criterion, MetS rates were 54.0% in both diagnostic groups (p = 1.0). Mood stabilizer co-treatment was not associated with MetS or its individual criteria. Conclusions: Patients with bipolar disorder and schizophrenia who are treated with SGAs have similarly high rates of MetS. These findings suggest a shared susceptibility to antipsychotic-related metabolic dysregulations that is not primarily related to psychiatric diagnosis or concomitant mood stabilizer treatment.     

Acute bipolar mania: a systematic review and meta-analysis of co-therapy vs. monotherapy

INTRODUCTION: The aim of this meta-analysis was to systematically review the effectiveness of co-therapy compared with monotherapy for people with bipolar mania. METHOD: MEDLINE, Embase, Psychinfo, The Cochrane Library and reference lists of retrieved studies were searched without language restrictions for randomized controlled trials evaluating co-therapy compared with monotherapy for acute bipolar mania. Each trial was assessed for susceptibility to bias. Data on mania outcomes, withdrawals, extrapyramidal symptoms and weight were extracted and pooled effect estimates summarized as relative risks (RR) or differences in mean values (MD) where appropriate. RESULTS: Eight eligible studies were included (1124 participants). Significant reductions in mania (Young Mania Rating Scale, YMRS) scores were shown for haloperidol, olanzapine, risperidone and quetiapine as co-therapy compared with monotherapy with a mood stabilizer. For atypical antipsychotics combined, the pooled difference in mean scores was 4.41 (95% CI: 2.74, 6.07). Significantly more participants on co-therapy met the response criterion (at least 50% reduction in YMRS score), RR 1.53 (1.31, 1.80). With some drugs, co-therapy decreased tolerability compared with monotherapy, and resulted in greater weight gain. There were insufficient data to compare one co-therapy regimen with another. CONCLUSION: The addition of antipsychotic treatment to established mood-stabilizer treatment is more effective than mood-stabilizer treatment alone.     

Excess incidence and risk factors for recurrent pneumonia in bipolar disorder

Aim

Patients with bipolar disorder (BD) tend to have poorer outcomes after pneumonia and could have a higher risk for recurrence of pneumonia. We aimed to investigate the incidence and risk factors of recurrent pneumonia in patients with BD.

Methods

In a nationwide cohort of BD patients (derived from the National Health Insurance Research Database in Taiwan) who were hospitalized for pneumonia between 1996 and 2012, we identified 188 patients who developed recurrent pneumonia after a baseline pneumonia episode. Applying risk‐set sampling at a 1:2 ratio, 353 matched controls were selected from the study cohort. We used multivariate conditional logistic regression analysis to explore the association between recurrent pneumonia and physical illness, concomitant medications, and psychotropic drugs.

Results

The findings showed that the incidence of recurrent pneumonia in BD was 6.60 cases per 100 person‐years, which was higher than that in the general population. About 10% (9.24%) of cases with recurrent pneumonia died within 30 days of hospitalization. Patients had increased risk of recurrent pneumonia if they had hypertension, diabetes mellitus, cancer, or asthma. Conversely, psychotropic drugs, both first‐ and second‐generation antipsychotics, which are known to increase susceptibility to baseline pneumonia, were not associated with risk of pneumonia recurrence.

Conclusion

We found an excess incidence of recurring pneumonia in patients with BD, and this risk was associated with pre‐existing medical conditions but not psychotropic agents. Physicians should carefully consider the comorbid medical conditions of patients with BD that could lead to recurrent pneumonia.     

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.     

Effectiveness of maintenance therapy of lithium vs other mood stabilizers in monotherapy and in combinations: a systematic review of evidence from observational studies

Objectives

For the first time to present a systematic review of observational studies on the efficiency of lithium monotherapy in comparison with other maintenance mood stabilizers in monotherapy and in combination.

Methods

As part of the International Society for Bipolar Disorders (ISBD) Task Force on Lithium Treatment, we undertook a systematic literature search of non‐randomized controlled observational studies on (i) lithium monotherapy vs treatment with another maintenance mood stabilizer in monotherapy and (ii) lithium in combination with other mood stabilizers vs monotherapy.

Results

In eight out of nine identified studies including a total of < 14 000 patients, maintenance lithium monotherapy was associated with improved outcome compared with another mood stabilizer in monotherapy, including valproate, lamotrigine, olanzapine, quetiapine, unspecified anticonvulsants, carbamazepine/lamotrigine, unspecified atypical antipsychotics and unspecified antipsychotics. Among the four identified studies including a total of > 4000 patients comparing maintenance combination therapy with maintenance monotherapy, a few combination therapies were found to be superior to monotherapy in some analyses, but many were not.

Conclusions

The results show the superiority in real life of lithium monotherapy compared with monotherapy with other maintenance mood stabilizers. The four largest register‐based studies largely addressed confounding, but, as ever, residual confounding cannot be excluded. Nevertheless, the observational findings substantially add to the findings from randomized controlled trials, whose designs often limit the validity of comparison between medicines.     

The effectiveness of mood stabilizers and antiepileptic medication for the management of behaviour problems in adults with intellectual disability: a systematic review

Background Psychotropic medications are used to manage behaviour problems in adults with intellectual disability (ID). One group of psychotropic medication are mood stabilizers such as lithium and some antiepileptic drugs. Method A comprehensive systematic review was performed to determine the evidence base for the effectiveness of mood stabilizers in the management of behaviour problems among adults with ID. Electronic searches of PsycInfo, Medline, Embase and Cinahl databases were conducted, as well as a thorough hand search for relevant literature. We reviewed primary trials relating to adults only that satisfied strict inclusion criteria. Results One randomized controlled trial (RCT) relating to lithium use and two non‐RCTs, one on lithium and the other on carbamazepine, were revealed. In addition, one prospective non‐controlled trial on sodium valproate and three retrospective case series studies were discovered, of which one considered the efficacy of lithium, one valproate and one topiramate. Conclusions The current evidence lends some support for the use of lithium and some antiepileptic mood stabilizer medication for the management of behaviour problems in adults with ID. However, because most studies reviewed here are riddled with obvious methodological constrains, the findings have to be interpreted with caution.     

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.     

Serotonin in mania and in the mechanism of action of mood stabilizers: a review of clinical studies

Objectives: Serotonin (5-hydroxytryptamine, 5-HT) was implicated in the pathophysiology of manic-depressive illness as early as 1958. Although extensive evidence has accumulated since then to support 5-HT's role in depression, relatively fewer studies examined its role in mania. The purpose of this paper was to review and summarize the current state of knowledge on the role of 5-HT in mania and its treatment.

Methods: We systemically reviewed clinical studies of 1) 5-HT function in mania and 2) 5-HT in the mechanism of action of mood stabilizers, including lithium and anticonvulsants.

Results: Review showed that cerebrospinal fluid, postmortem, platelet, neuroendocrine challenge, and tryptophan depletion studies provided some evidence to support the hypothesis that a 5-HT deficit is involved in mania and that enhancement of 5-HT neurotransmission exerts a mood-stabilizing effect.

Conclusions: There is some evidence from clinical studies for the contribution of 5-HT in mania and in the mechanism of action of mood stabilizers. However, it is very likely that other neurotransmitters also play important roles. Future directions for research include 1) in vivo study of 5-HT receptor subtypes using positron emission tomography, 2) investigation of the interaction between 5-HT and other neurotransmitter systems, and 3) determination of the relationships between diagnostic subtypes of mania and 5-HT function and other neurotransmitter systems.     

Antidepressants in bipolar disorder: the case for caution

The 2002 American Psychiatric Association (APA) guidelines for the treatment of bipolar disorder recommended more conservative use of antidepressants. This change in comparison with previous APA guidelines has been criticized, especially from some groups in Europe. The Munich group in particular has published a critique of assumptions underlying the conservative recommendations of the recent APA treatment guidelines. In this paper, we re-examine the argument put forward by the Munich group, and we demonstrate that indeed, conceptually and empirically, there is a strong rationale for a cautious approach to antidepressant use in bipolar disorder, consistent with, and perhaps even more strongly than, the APA guidelines. This rationale is based on support for the following four propositions: (i) The risk of antidepressant induced mood-cycling is high, (ii) Antidepressants have not been shown to definitively prevent completed suicides and reduce mortality, whereas lithium has, (iii) Antidepressants have not been shown to be more effective than mood stabilizers in acute bipolar depression and have been shown to be less effective than mood stabilizers in preventing depressive relapse in bipolar disorder and (iv) Mood stabilizers, especially lithium and lamotrigine, have been shown to be effective in acute and prophylactic treatment of bipolar depressive episodes. We therefore draw three conclusions from this interpretation of the evidence: (i) There are significant risks of mania and long-term worsening of bipolar illness with antidepressants, (ii) Antidepressants should generally be reserved for severe cases of acute bipolar depression and not routinely used in mild to moderate cases and (iii) Antidepressants should be discontinued after recovery from the depressive episode, and maintained only in those who repeatedly relapse after antidepressant discontinuation (a minority we judge to represent only about 15–20% of bipolar depressed patients).     

拉莫三嗪治疗双相心境障碍对照研究

目的：探讨拉莫三嗪治疗双相情感障碍的疗效与安全性。方法：双相心境障碍患者135例,其中双相抑郁78例,躁狂57例。将患者随机分为3组,每组抑郁相26例,躁狂相19例。疗程32周。前8周为急性期治疗阶段,对照组抑郁相只服选择性5-羟色胺回收抑制剂（SSRI）类抗抑郁剂,躁狂相只服利培酮;拉莫三嗪组在对照组用药的基础上加服拉莫三嗪;碳酸锂组在对照组用药的基础上加服碳酸锂。后24周为巩固治疗阶段,所有患者随机分为两组,只服拉莫三嗪或碳酸锂。采用汉密尔顿抑郁量表（HAMD）、Young躁狂评定量表（YMRS）、治疗中出现的症状量表（TESS）评定疗效及安全性。结果：急性期治疗结束后,无论躁狂相还是抑郁相,拉莫三嗪组和碳酸锂组的临床疗效显著高于对照组（P〈0．01或〈0．05）。巩固治疗阶段两组相比,拉莫三嗪的抗抑郁作用较好,碳酸锂的抗躁狂作用较强。不良反应发生率,碳酸锂组40％,拉莫三嗪组22％。巩固治疗阶段病情复发率,拉莫三嗪组8％,碳酸锂组11％,两组差异无显著性（P〉0．05）。结论：拉莫三嗪作为心境稳定剂治疗双相情感障碍疗效可靠,不良反应小,与碳酸锂相比,抗抑郁作用更强。