Lamotrigine in the treatment of bipolar disorder

Lamotrigine is a novel anticonvulsant agent that has recently been introduced as a long-term treatment in bipolar disorder. Its role in the treatment of epilepsy is based on its actions to decrease ion channel conductance and antagonise glutamatergic function. Therefore, it has a mode of action unlike other agents used on a long-term basis in mood disorders. The evidence for efficacy is stronger for the prevention of depressive, rather than manic, episodes. The pivotal trials are in bipolar I disorder, but there is interest in its actions in patients with bipolar II and spectrum conditions. Its efficacy in other psychiatric conditions remains to be properly established. It is well tolerated and, with careful prescribing, the incidence of rash occurs no more than with placebo; however this is still a concern. Although usually well tolerated, headache, insomnia and drowsiness are probably the most common side effects.     

Anticonvulsants in the treatment of mood disorders: assessing current and future roles

Anticonvulsants are frequently used in the treatment of affective illnesses, especially for patients refractory to or intolerant of other treatments. The differential therapeutic roles of anticonvulsants, however, remain largely undetermined. The author reviews the available efficacy data for carbamazepine, oxcarbazepine, valproate, lamotrigine, gabapentin and topiramate. Valproate is efficacious in the monotherapy of acute manic presentations but confirmatory evidence of the efficacy of valproate in long-term maintenance has been elusive. Valproate and possibly carbamazepine, may provide a therapeutic advantage over lithium in non-classic bipolar conditions such as mixed mood states and rapid cycling conditions. Lamotrigine is unique among the anticonvulsants in its monotherapy efficacy for bipolar I depression. Emerging data also suggest a role for lamotrigine in the adjunctive treatment of depressive mixed states and rapid cycling conditions in the absence of prominent manic symptoms. Controlled trials have found gabapentin ineffective for acute mania and refractory bipolar conditions. The role of gabapentin in the treatment of other aspects of affective illness remains uncertain. Definitive statements regarding the differential psychotropic use of topiramate and oxcarbazepine are not possible, though active investigation is underway to better characterise the utility of topiramate. The author suggests that current diagnostic models utilised in controlled trials may limit identification of differential therapeutic benefits. Caution is advised in generalising from the ability or inability of an agent to demonstrate antimanic activity. Future studies of newer anticonvulsants should include dimensional perspectives and soft bipolar presentations, as the greatest contribution of the newer anticonvulsants may be in treatment of mood conditions other than acute mania.     

Oxcarbazepine in bipolar disorder: a critical review of the literature

Oxcarbazepine (OXC) is a keto-congener of carbamazepine, which has fewer side effects and drug interactions. However, the efficacy of OXC in treating bipolar disorder is not as well established as that of carbamazepine. This article is a systematic literature review of all studies regarding OXC and bipolar disorders, with particular attention to papers published in the last 6 years. Using the terms ‘oxcarbazepine and bipolar disorder’, ‘oxcarbazepine and mania’ or ‘oxcarbazepine and bipolar depression’, a computer-aided search of MEDLINE for the years 2000 – 2006 has been conducted. Since its introduction as an antiepileptic drug in early 2000, clinical research regarding the potential role of OXC in the treatment of bipolar disorder remains limited. There is a lack of double-blind, placebo-controlled studies. Studies recently published have small samples of patients, with insufficient follow-up periods and other methodological weaknesses. The efficacy of OXC in bipolar disorder has not been widely studied. Some authors recommend using OXC as monotherapy or as add-on therapy in refractory mania, although results are not conclusive. It is unknown whether OXC has efficacy in the maintenance treatment of bipolar disorder. OXC can be particularly useful as an add-on treatment in bipolar disorder patients for whom previous treatments have failed, or in patients who have difficulty tolerating adequate dosages of standard approved treatments.     

丙戊酸盐治疗双相情感障碍的研究进展

作为心境稳定剂,丙戊酸盐治疗各型双相情感障碍均有一定的疗效。近年来对各型双相情感障碍患者进行的临床研究证实：丙戊酸盐能改善躁狂症状;联合镇静药物治疗可有效改善抑郁症状;联合抗抑郁药物预防抑郁发作的疗效优于锂盐。丙戊酸盐与其他心境稳定剂联合治疗快速循环型双相情感障碍患者时可能更有益,也更适用于非快速循环型双相情感障碍患者的长程治疗。     

Aripiprazole for the treatment of bipolar disorder: a review of current evidence

Introduction: Several medications are available for the treatment of different phases of bipolar disorder, yet many of the drugs that are currently approved carry a substantial burden of side effects or do not lead all treated patients to remission.

Areas covered: This paper comprises a review and commentary regarding the use of oral and intramuscular aripiprazole in the acute and maintenance phases of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration of aripiprazole with other medications are provided. This paper presents practical strategies to translate the data from clinical research into clinical practice.

Expert opinion: Aripiprazole has proven to be an effective medication for the acute treatment of manic and mixed episodes, as well as for the prophylactic–maintenance phase of bipolar disorder in patients recovering from a manic/mixed episode. Choosing the appropriate dosing and tapering strategy, addressing the side effects, controlling withdrawal symptoms from previous medications and using adjunctive medications when necessary are key to successful treatment with aripiprazole.     

心境稳定剂在精神疾病治疗中的应用

目前临床上常用的心境稳定剂包括锂盐、抗惊厥药物和非典型抗精神病药物。此外,现还新上市了一些具有潜在心境稳定作用的药物或辅助用药。本文概要介绍主要心境稳定剂及其在精神疾病治疗中的应用。     

Special issues in the treatment of paediatric bipolar disorder

Paediatric bipolar disorder (PBD) is an increasingly diagnosed disorder affecting an estimated 1% of children and adolescents. Pharmacological treatment studies in PBD have lagged far behind those in adults. Children are currently treated with pharmacological agents, most of which have proven efficacy in adults. However, PBD is distinct from adult forms of bipolar disorder (BD) and may present unique treatment challenges. PBD often presents with rapid cycling and mixed manic states and a high co-morbidity with behavioural and attention disorders. Early onset depression may also be an early sign of PBD. Due to developmental considerations, the diagnosis of BD may be difficult to make in children without semi-structured interviews. This report discusses the special issues that should be considered when treating PBD and reviews the current literature regarding pharmacotherapy of this population. Mood stabilisers have been studied mostly in an open, uncontrolled fashion but there is growing evidence that lithium, divalproex and carbamazepine are effective in treating PBD. More recent treatment options include atypical antipsychotics and newer anticonvulsants. Other novel agents are currently being investigated in adult BD and may prove applicable to the paediatric form. Finally, based on the available data, a treatment algorithm for PBD is proposed.     

Combination of aripiprazole with mood stabilizers for the treatment of bipolar disorder: from acute mania to long-term maintenance

Introduction: Bipolar disorder is characterized by a complex set of symptoms, including recurrent manic, depressive or mixed episodes. Acute and long-term treatment of patients with bipolar disorder is mandatory to prevent symptom relapse and episode recurrences. Outcomes with monotherapy are often unsatisfactory in clinical practice, hence combinations of mood stabilizers and antipsychotics are widely utilized in patients showing no or partial response to, as well as intolerance to, monotherapies. This may offer a therapeutic advantage, however, the possibility of an increased incidence of side effects should be considered.

Areas covered: This paper reviews the current treatment guidelines for the treatment of bipolar disorder and examines the rationale behind the use of aripiprazole in combination with mood stabilizers for acute and long-term treatment of bipolar disorder.

Expert opinion: The combination of aripiprazole and mood stabilizers seems to offer an effective and relatively well-tolerated option for the treatment of acute mania and for the maintenance treatment of patients with bipolar I disorder. The combination presents a lower risk of metabolic side effects compared with other combination therapies, but increases the risk of extrapyramidal side effects with long-term treatment. The aripiprazole–valproate combination seems to be particularly promising in the treatment of patients with comorbidities such as anxiety and drug abuse, obsessive-compulsive disorder and bipolar disorder, as well as in mixed depressive disorder. Controlled trials are necessary in order to confirm these observations and to provide a useful insight for improving the use of drug combinations in bipolar patients.     

The combination of olanzapine and fluoxetine in mood disorders

Depression can occur either with or without alternation with periods of mania. Depression that alternates with mania (bipolar depression) is a particularly difficult problem in clinical practice. The evidence base of the treatment for this condition is not strong and the choices at best are limited. Furthermore, although there are a number of effective antidepressants for the non-cycling variety (‘unipolar’ major depression), > 50% of patients experience incomplete response to any given drug. Given the proportion of the population involved, these represent fairly sizeable markets. Studies over the last several years indicate that the combination of the novel antipsychotic olanzapine and the serotonin-selective re-uptake inhibitor (SSRI), fluoxetine, may be effective for both conditions. One trial in 28 patients showed that this combination was an effective treatment, compared to the individual components with unipolar depressed patients who had not responded to two antidepressants of different chemical classes. Two subsequent large-scale attempts at replication have resulted in failed trials. Patients randomly assigned to antidepressant monotherapies showed a good response, indicating that the populations being studied were not actually treatment-resistant; therefore, more research is needed. Alternatively, a recent study showed that monotherapy with olanzapine produced a greater effect than placebo in bipolar depression and the combination of olanzapine and fluoxetine yielded an even more robust response. However, important questions remain, e.g., the issue of comparative effectiveness, that is to say, whether the same result could occur with combinations of other novel antipsychotics and SSRIs. In addition, there remain significant concerns regarding the safety and tolerability of olanzapine in these populations. Essential questions about the potential for substantial weight gain, Type II diabetes and for the development of tardive dyskinesia (a syndrome of permanent, disfiguring abnormal involuntary movements) remain. These problems will have to be vigorously addressed in order to achieve a substantial market penetration for these conditions.     

Pharmacotherapy of mood disorders and psychosis in pre- and post-natal women

Introduction: Untreated mood and psychotic disorders can have substantial adverse impacts on the patient, the fetus and the family, while treatment can ameliorate such problems. To address concerns by clinicians about the risks of psychotropic medications, this review addresses the risk/benefit analysis of somatic therapies for psychiatric disorders during pregnancy and lactation.

Areas covered: All available research was reviewed on the impact on pregnancy and breastfeeding of mood and psychotic disorders, and of antidepressants, mood stabilizers, antipsychotic drugs, and electroconvulsive therapy. References cited in other reviews, case series, formal studies, pharmacologic discussions, and theoretical pieces were added. Available case control and other studies were critically reviewed and diverse explanations for their findings were considered.

Expert opinion: The potential benefits of treatment of mood and psychotic disorders often outweigh the risks after alternative therapies have been considered. Some medications, particularly paroxetine and valproate, pose greater risks during pregnancy, while the teratogenic risks of lithium have probably been overstated. There is more experience with first than with second generation antipsychotic drugs during pregnancy and lactation. Nursing an infant is possible while taking a number of antidepressants, mood stabilizers or antipsychotic drugs.     

Recent developments in the treatment of bipolar disorders

Recently, many new therapeutic options have become available for the treatment of bipolar disorder. Most of these options are agents originally developed to treat other conditions, such as anticonvulsants and antipsychotics. Some older agents have also been rediscovered or reformulated. New drug combinations and treatment strategies have enabled a more comprehensive treatment of the spectrum of bipolar symptoms, as well as bipolar disorder complicated by a range of comorbidities, to be targeted. A growing range of novel therapeutic options for the treatment of bipolar disorder is under investigation. This paper summarises some of the data regarding these potential therapeutic options.     

Lurasidone: efficacy and safety in the treatment of psychotic and mood disorders

Introduction: Lurasidone ([3aR,4S,7R,7aS]-2-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1yl-methyl] cyclohexylmethyl]-hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride; Latuda®) is a novel benzisothiazole, second-generation antipsychotic drug developed by Dainippon Sumitomo Pharma Corporation in Japan. Similar to other atypical antipsychotics it has a distinctive pharmacodynamic profile,

Areas covered: This review updates reported research findings on the efficacy, safety and tolerability of LRSD for treatment of psychotic and major affective disorders, with meta-analyses. Short-term efficacy of LRSD in schizophrenia is supported by several randomized, controlled trials with daily doses of 40–160 mg, yielding relatively modest symptomatic improvements. Lurasidone has regulatory approval for treatment of undefined duration in schizophrenia. Long-term benefits and effects in schizophrenia, and both short- and long-term use for other psychotic disorders and mania have not been tested. LRSD shows unusual efficacy in acute bipolar depression even without psychotic features. However, trials of adding LRSD to lithium or valproate for bipolar disorder have yielded inconsistent findings.

Expert opinion: Available research findings indicate that LRSD is effective and well-tolerated for short-term treatment of schizophrenia, and for acute bipolar depression. It has low risk of inducing weight-gain, metabolic, or cardiac abnormalities, but its risk of akathisia may exceed that of other modern antipsychotics. Needed is adequate long-term testing in schizophrenia and bipolar disorder and testing for other indications, including against alternative treatments.     

卡马西平单用及其与逍遥散合用治疗双相情感障碍随机双盲安慰剂对照临床研究

目的 评估卡马西平单用及其与逍遥散合用治疗双相情感障碍的疗效和安全性。方法 用随机双盲安慰剂对照方法，双相躁狂82例，双相抑郁76例，各随机分为3组。双相躁狂疗程8周，双相抑郁疗程12周。用Young与Bech—Rafaelsen躁狂量表、Hamilton与Montgomery—Asberg抑郁量表和临床总体印象量表评定疗效，用副反应量表观察药物不良反应。结果 双相躁狂患者3组药物临床有效率分别为：逍遥散合用卡马西平为79％，卡马西平单用为64％，安慰剂为45％，3组比较有显著性差异（P〈0．05）。双相抑郁患者3组药物临床有效率分别为：逍遥散合用卡马西平为75％，卡马西平单用为59％，安慰剂为33％，3组比较有显著性差异（P〈0．05）。逍遥散合用卡马西平较卡马西平单用，在头昏、视力模糊、皮疹、恶心发生率增加。结论 逍遥散作为辅助药物治疗双相障碍有效，但能增加卡马西平药物不良反应发生率。     

Comparison of the Internal State Scale to Clinician-Administered Assessments in Patients with Bipolar Disorder and Alcohol Abuse or Dependence

Abstract

Objectives: Self-report measures require less clinician time to administer than clinician-rated assessments. The Internal State Scale (ISS) is a well-validated self-report measure that assesses symptoms of mania and depression in patients with bipolar disorder (BPD). However, the ISS has never been specifically evaluated in patients with BPD and comorbid substance misuse. Substances can induce mood symptoms complicating diagnosis and mood state assessment.

Methods: The ISS was compared with the Hamilton Rating Scale for Depression (HRSD), Young Mania Rating Scale (YMRS), and Brief Psychiatric Rating Scale (BPRS) in 21 patients with BPD and alcohol abuse/dependence at baseline and for up to 16 weeks postbaseline. In addition, ISS-determined mood state was compared to mood state from a structured diagnostic interview.

Results: Significant baseline correlations were observed between the ISS depression subscale and HRSD, ISS activation subscale and YMRS, and ISS perceived conflict subscale and BPRS. Significant correlations of baseline to exit change scores were found between the ISS activation and YMRS, but not ISS depression and HRSD, or ISS perceived conflict and BPRS. All participants had a mixed mood state by structured diagnostic interview. The ISS diagnosed the manic/hypomanic portion of this mood state in 76% of participants but found depression in only 38%.

Conclusions: As in BPD patients without substance abuse, the ISS generally showed correlations with clinician-rated scales at baseline, with less strong correlations observed on change scores. The ISS diagnosis of mania or hypomania appeared to correspond more highly than depression with the findings from a structured diagnostic interview.     

The argument of antidepressant drugs in the treatment of bipolar depression: mixed evidence or mixed states?

Introduction: The role of antidepressant drugs in acute and maintenance treatment of bipolar depression is a matter of debate that cannot be decided from the evidence available in the current literature.

Areas covered: This review includes two sections: in the first, important contributions from the current literature, emphasizing randomized controlled trials (RCTs) and meta-analysis, highlight current controversies and methodological issues; in the second, the impact of mixed depressive features in bipolar depression is evaluated from a psychopathological perspective.

Expert opinion: Methodological issues may complicate evaluation of the evidence from RCTs regarding antidepressants and mixed states. Moreover, nosological constructs may also contribute to the inconclusive findings, by introducing heterogeneity in patient selection and diagnosis. Acknowledging the impact of mixed features in the course of bipolar depression, essentially by the careful reading of classical Kraepelinian contributions, could enhance clinical management. This would in turn allow a more judicious use of antidepressants, ideally helping to shed some light on the much controversial ‘antidepressant-related suicidality', and help to further clarify the reasons for the current literature discordance on this topic.     

喹硫平与丙戊酸钠联合重复经颅磁刺激治疗缓解期双相障碍临床评价

目的探讨喹硫平、丙戊酸钠联合重复经颅磁刺激治疗缓解期双相障碍的临床效果及对患者认知功能障碍的影响。方法选取医院2017年1月至2019年1月收治的缓解期双相障碍患者98例,按奇偶法分为观察组和对照组,各49例。两组患者均予重复经颅磁刺激治疗,观察组患者加服富马酸喹硫平片及丙戊酸钠缓释片(Ⅰ)治疗。两组患者均连续治疗4周。结果观察组总有效率为89.80%,明显高于对照组的73.47%(P<0.05);治疗后,观察组患者抑郁自评量表(SDS)评分、贝克-拉范森躁狂量表(BRMS)评分均明显低于对照组,认知功能筛查量表(CASI)各项(包括注意力、定向力、记忆力、思维流畅性、语言表达力等)评分均明显高于对照组(P<0.05),皮质醇(Cor)、三碘甲状腺原氨酸(T3)、促肾上腺皮质激素(ACTH)水平均明显低于对照组(P<0.05);观察组患者不良反应发生率为16.33%,与对照组的10.20%相当(P>0.05)。结论重复经颅磁刺激联合喹硫平、丙戊酸钠治疗缓解期双相障碍,能改善抑郁、躁狂症状,以及认知功能和神经内分泌功能。     

Use of asenapine as add-on therapy in the treatment of bipolar disorder: a comprehensive review and case series

Introduction: Several randomized controlled trials (RCTs), conducted in schizophrenic and bipolar patients, have documented the efficacy and tolerability of asenapine as monotherapy both for short- and long-term treatment. However, evidence on its augmentative use is more limited and related to the manic/mixed phase of bipolar disorder (BD).

Areas covered: The present article reviews augmentative asenapine efficacy and safety/tolerability in the treatment of BD. It also includes some original cases of bipolar patients treated with add-on asenapine in the short- and long-term.

Expert opinion: To date, only a single RCT with manic/mixed patients with partial response to mood-stabilizer monotherapy supports the efficacy and safety/tolerability of augmentative asenapine to lithium/valproate, both in acute and long-term treatment. Additionally, two case reports confirm the overall effectiveness of augmentative asenapine to clozapine and valproate. Our case series, consisting of 4 bipolar patients treated with adjunctive asenapine to mood stabilizers and atypical antipsychotics – with treatment duration ranging from 1 to 14 months – provided clinical results that are consistent with literature data. Taken as a whole, available evidence seems to support the efficacy and safety of adjunctive asenapine in bipolar patients, though additional studies with active comparators are requested to confirm the current body of evidence.