Drug treatments for bipolar disorder: 1--Acute manic or depressive episodes

Bipolar disorder is a severe, chronic mental illness characterised by repeated episodes of mania or hypomania, depression or mixed affective states. Depending on the clinical context, treatment may involve drugs, psychological therapies, social interventions and/or electroconvulsive therapy (ECT). Here we concentrate on the role of drug treatments for acute manic or depressive episodes in adults with bipolar disorder. A second article will consider their role as maintenance and preventive therapy, and in special situations such as pregnancy.     

安非他酮与喹硫平治疗双相情感障碍抑郁发作的临床疗效及安全性

目的探讨安非他酮与喹硫平治疗双相情感障碍抑郁发作的临床疗效及安全性。方法将双相情感障碍抑郁发作患者68例随机分为安非他酮组和喹硫平组,每组34例,分别口服安非他酮与喹硫平治疗。采用汉密顿抑郁量表(HAMD)评定其临床疗效,用生活质量问卷(GQOLI)评定生活质量,应用副反应量表(TESS)评定不良反应。结果治疗后,两组HAMD评分均降低(P<0.05);治疗第1、2、4、6、8周,喹硫平组较安非他酮组降低,差异有统计学意义(P<0.05);喹硫平组显效率高于安非他酮组(P<0.05)。治疗8周后,喹硫平组躯体功能、心理功能、社会功能及GQOLI总分提高(P<0.05)。喹硫平组不良反应发生率、TESS评分低于安非他酮组(P<0.05),差异有统计学意义(P<0.05)。结论喹硫平治疗双相情感障碍抑郁发作疗效显著,患者依从性好,安全性高,可明显提高患者的生活质量,效果优于安非他酮。     

EEG alpha activity increases during transient episodes of ethanol-induced euphoria

The effects of acute ethanol administration were studied in 18 men to determine the electroencephalographic (EEG) correlates of ethanol-induced behavioral changes. Subjects were instructed to operate an instrumental device to indicate changes in their subjective mood state while EEG activity and plasma ethanol levels were continuously measured. Three groups of 6 subjects consumed either placebo, 0.347 g/kg ethanol or 0.695 g/kg ethanol over a 15 min period. EEG and behavioral changes were directly correlated with plasma ethanol levels during the ascending limb of the plasma ethanol curve. Theta EEG activity increased proportionally as plasma ethanol levels increased during the 2 hr recording session. Alpha EEG activity increased during the first hour and then returned to control levels. The increased alpha activity was most prominent when subjects reported feeling intense pleasure or euphoria. Power spectral analysis of discrete samples of EEG activity revealed that transient increases in alpha activity paralleled the onset of ethanol-induced euphoria. These data suggest that ethanol-induced behavioral effects are associated with discrete changes in brain electrical activity.     

Practical guidance for prescribing ziprasidone in acute manic or mixed episodes of bipolar I disorder

INTRODUCTION: Limited information is available on the clinical issues and strategies for optimal clinical usage of ziprasidone in the treatment of adult patients with acute manic or mixed episodes of bipolar disorder. AREAS COVERED: To address those issues, information from clinical trials addressing the efficacy and tolerability of ziprasidone in acute bipolar mania was reviewed and supplemented with the input from an expert faculty of European psychiatrists with extensive experience in treating patients with bipolar mania, both in clinical trials and in everyday clinical practice. EXPERT OPINION: Effective use of oral ziprasidone in the treatment of acute bipolar mania requires rapid titration to doses in the range 120 - 160 mg/day and administration with meals of ≥ 500 kcal. As in the clinical trials, temporary short-term use of benzodiazepines (in particular lorazepam for agitation or temazepam for insomnia) could be advisable. Available evidence from randomized clinical trials in combination with clinical experience supports the use of ziprasidone as one of the first-line effective and safe treatments for acute manic or mixed episodes associated with bipolar I disorder.     

双相抑郁障碍的诊断及治疗

双相抑郁障碍患病率高,且临床上易误诊和漏诊,导致不正确、不合理的药物治疗.因此,早期诊断及合理的治疗策略非常重要.本文对双相抑郁障碍的自身特点、相关特征和药物治疗(锂盐、拉莫三嗪、非典型抗精神病药物、抗抑郁药)作一综述,以供临床工作者参考.     

Novel glutamatergic agents for major depressive disorder and bipolar disorder

Mood disorders such as major depressive disorder (MDD) and bipolar disorder (BPD) are common, chronic, recurrent mental illnesses that affect the lives and functioning of millions of individuals worldwide. Growing evidence suggests that the glutamatergic system is central to the neurobiology and treatment of these disorders. Here, we review data supporting the involvement of the glutamatergic system in the pathophysiology of mood disorders as well as the efficacy of glutamatergic agents as novel therapeutics.     

The role of mitochondrial dysfunction in bipolar disorder

Altered energy metabolism and accumulated mitochondrial DNA (mtDNA) mutations in the brain, associated mtDNA polymorphisms/mutations or nuclear encoded mitochondrial genes, effects of mood stabilizers on mitochondria and comorbidity of mood disorders with mitochondrial disorders, together suggest the role of mitochondrial dysfunction in the pathophysiology of bipolar disorder. Mitochondrial dysfunction may be involved in the calcium signaling abnormality found in bipolar disorder. We recently produced mice accumulating neuron-specific mtDNA deletions. Bipolar disorder-like behavioral phenotypes of these mice supported this hypothesis. Thus, development of new mood stabilizers acting on mitochondrial function might be warranted.     

Increased mitochondrial complex I activity in platelets of schizophrenic patients

It is believed that dopamine and alterations of energy metabolism in cortical and subcortical structures are involved in the pathophysiology of schizophrenia. Recently, we and others have shown that dopamine may affect energy metabolism by interacting with mitochondrial complex I activity in rats both in vivo and in vitro. In this study activity of complexes I and IV was assessed in mitochondria isolated from blood platelet of schizophrenic patients and compared to patients with affective disorders and healthy control subjects. Seventy-seven in-patients who met DSM-IV criteria for schizophrenia (in acute exacerbation), bipolar disorder depressed type (BP), or recurrent major depressive disorder (MDD) and 24 control subjects participated in the study. A highly significant increase (240%, p < 0.001) in complex I activity but not in complex IV, was detected in medicated and unmedicated schizophrenic patients compared to controls. No such change was observed in patients with affective disorders. The data demonstrate a specific and selective, alteration in platelet complex I activity in schizophrenic patients, which is not related to medication. If this abnormality in platelet mitochondria reflects brain alterations, it may further support the relevance of alterations in energy metabolism to the pathophysiology of schizophrenia. Finally in the lack of any clinically relevant biological marker for schizophrenia, complex I activity in platelets might become a useful peripheral marker for this disorder.     

Increased neuroactive steroid concentrations in women with bipolar disorder or major depressive disorder

Changes in the plasma concentrations of neuroactive steroids have been associated with various neuropsychiatric disorders. However, the possible role of neuroactive steroids in bipolar disorder (BD) has remained unknown. We therefore determined the plasma levels of neuroactive steroids during the luteal phase of the menstrual cycle in women with BD or major depressive disorder (MDD). The plasma concentrations of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THPROG), 3alpha,21-dihydroxy-5alpha-pregnan-20-one, progesterone, and cortisol were determined in 17 outpatients with BD, 14 outpatients with MDD, and 16 healthy control subjects. All patients were in a state of well-being and without relapse or recurrence for at least 3 months. Plasma concentrations of progesterone and 3alpha,5alpha-THPROG were significantly greater in patients than in controls, also being higher in BD patients than in MDD patients. Drug-free patients with BD or MDD showed similar differences in steroid concentrations relative to controls, as did drug-treated patients. Comorbidity with panic disorder, obsessive-compulsive disorder, or eating disorder had no effect on the association of mood disorders with steroid concentrations. Women with BD or MDD in a state of well-being showed higher plasma concentrations of progesterone and 3alpha,5alpha-THPROG in the luteal phase than did healthy controls. These differences did not seem to be attributable simply to drug treatment or to comorbidity with other psychiatric conditions in the patients.     

Lithium versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified.

In a randomized clinical trial (MAP study), the prophylactic efficacy of lithium and carbamazepine was compared in a subgroup of patients (n = 57) who presented either a bipolar II disorder or a bipolar disorder not otherwise specified (DSM-IV). During the observation period of 2.5 years, no significant differences between the drugs were found considering hospitalization, recurrences, subclinical recurrences, concomitant medication and severe side-effects.     

Spotlight on olanzapine in bipolar I disorder

Olanzapine is an atypical antipsychotic that is approved in the US and Europe for the oral treatment of acute manic episodes in patients with bipolar I disorder and for maintenance therapy to prevent recurrence in responders. Oral olanzapine is effective in the treatment of bipolar mania, both as single agent therapy and as adjunctive therapy in combination with lithium or valproate semisodium. In the treatment of acute episodes, olanzapine is superior to placebo and at least as effective as lithium, valproate semisodium, haloperidol and risperidone in reducing the symptoms of mania and inducing remission. Additional comparative studies are required to determine the efficacy of olanzapine relative to newer atypical antipsychotics such as quetiapine, ziprasidone and aripiprazole. Olanzapine is also effective at delaying or preventing relapse during long-term maintenance therapy in treatment responders and is currently the only atypical antipsychotic approved for this indication. Current evidence suggests that olanzapine may be more effective than lithium in preventing relapse into mania, but not relapse into depression or relapse overall. Olanzapine is generally well tolerated and, although it is associated with a higher incidence of weight gain than most atypical agents, it has a low incidence of extrapyramidal symptoms. Therefore, oral olanzapine is a useful first-line or adjunctive agent for both the acute treatment of manic episodes and the long-term prevention of relapse into manic, depressive or mixed episodes associated with bipolar I disorder.     

Frequency of hospitalisations and inpatient care costs of manic episodes: in patients with bipolar I disorder in France

BACKGROUND: Bipolar disorder is a chronic illness that may involve multiple relapses and result in substantial psychosocial impairment. However, very few recent studies have investigated the economic burden of the disease. OBJECTIVE: To assess the frequency of hospitalisation and the inpatient care costs associated with manic episodes in patients with bipolar I disorder in France. METHOD: A cost-of-illness study was conducted based on available data using a hospital payer perspective. The lifetime prevalence of manic episodes was estimated from published epidemiological data using a random-effects meta-analysis. Data were obtained by a computerised literature search using the main scientific and medical databases. Additional epidemiological references were identified from published studies and textbooks. Data on frequency of hospitalisation and length of stay were collected from a large psychiatric university hospital. Data on unit costs for inpatient care were obtained from the accounting system of the largest hospital group in Paris, France for the year 1999. RESULTS: Extrapolating from international data on the average prevalence of bipolar I disorder, the proportion of rapid cycling patients and the average cycle duration, we estimated the annual number of manic episodes in patients with bipolar I disorder to be around 265,000 in France. Based on hospital data in Paris, the proportion of manic episodes that require hospitalisation was estimated to be around 63%. The average length of stay was 32.4 days and the hospitalisation-related costs were estimated to be around 8.8 billion French francs (Euro 3 billion) [1999 values]. CONCLUSION: Our study highlights the lack of medical and economic data on the frequency and hospitalisation-related costs of manic episodes in patients with bipolar I disorder in France. As the lifetime prevalence of bipolar I disorder may be as high as 3% among adults, further studies are required in order to provide representative national data and to allow economic evaluations of costs related to bipolar I disorder in France.     

Extended-release carbamazepine capsules : in bipolar I disorder

An extended-release capsule formulation of carbamazepine is approved for use in adult patients experiencing an acute manic or mixed episode associated with bipolar I disorder. A capsule of extended-release carbamazepine contains three types of bead: immediate release, extended release and enteric release, constituting 25%, 40% and 35% of the dose, respectively.black triangle Extended-release carbamazepine capsules 200--1600 mg/day demonstrated superior antimanic efficacy to placebo in two 3-week, well designed trials in adult patients with bipolar I disorder and acute manic or mixed episodes. At study end, reductions from baseline in Young Mania Rating Scale scores were significantly greater with carbamazepine than with placebo (primary endpoint). The active treatment was effective from the end of the first week of treatment (post hoc analysis).black triangle In the 3-week trials and a 6-month extension study, most treatment-emergent adverse events observed with extended-release carbamazepine were of mild or moderate severity. In the 3-week trials, although significantly greater reductions in white blood cell count occurred with extended-release carbamazepine than with placebo, only one case of leukopenia was deemed serious. There were no reports of agranulocytosis or aplastic anaemia with up to 6 months' treatment.     

Lithium augmentation of topiramate for bipolar disorder with comorbid binge eating disorder and obesity

OBJECTIVE: To evaluate the effectiveness of lithium augmentation of topiramate on mood symptoms, binge eating behavior, and body weight in obese bipolar patients with binge eating disorder (BED) seeking weight management. METHOD: We conducted a naturalistic study of 12 consecutive outpatients with bipolar disorders, BED, and obesity who received lithium augmentation for mood instability during the course of topiramate-based pharmacotherapy for obesity and BED. Lithium was added to topiramate (mean dose 514 mg i.d.) and titrated to a mean dose of 1009 mg i.d. (mean plasma concentration 0.7 mmol/L). Treatment response was assessed by comparing changes in clinical severity scales for mood and eating disorders, weekly binge eating frequency, and weight for the 2 months before and the first 2 months during lithium treatment. RESULTS: A statistically significant improvement in global severity of mood symptoms was observed after as compared to before lithium augmentation. Statistically insignificant reductions in weight and in binge frequency and severity were also observed after lithium addition. CONCLUSION: Optimal weight loss treatment in obese patients with comorbid bipolar and BEDs may require stabilization of mood. The combination of lithium and topiramate may have a role in the management of this difficult-to-treat population.     

Tryptophan depletion: a predictor of future depressive episodes in seasonal affective disorder?

Patients with seasonal affective disorder (SAD) do not necessarily experience depressive episodes every winter. We assessed whether the behavioural response to tryptophan depletion in summer when patients are fully remitted and off therapy is capable of predicting a future depressive episode of SAD. In a prospective study design, we followed up 11 consenting SAD patients who had undergone tryptophan depletion during summer. We evaluated how many of these patients would develop a depressive episode in the subsequent fall/winter. Seven out of eight patients who relapsed during tryptophan depletion in summer developed a depressive episode in the subsequent winter. Two out of the three patients who did not relapse during tryptophan depletion remained well during the follow-up period. Our preliminary findings suggest that those SAD patients who develop depressive symptoms during tryptophan depletion when they are fully remitted and off therapy remain at high risk to experience a depressive episode of SAD also in the subsequent winter.     

Routine clinical assessment of cognitive functioning in schizophrenia,major depressive disorder,and bipolar disorder

As more evidence points to the association of cognitive dysfunction with mental health disorders, the assessment of cognitive function in routine clinical care of these disorders is increasingly important. Despite this, it remains unknown how cognitive function is measured in routine clinical practice. The objective of this study was to assess psychiatrists' awareness of cognitive dysfunction in mental health disorders and their methods of cognitive assessment. An online survey was disseminated to psychiatrists in Europe, Asia, Australia and the United States. The survey asked about their perceptions of cognitive dysfunction in several mental health disorders, knowledge of cognitive assessment, method of cognitive assessment, and instruments used to measure cognitive function. Among the 61 respondents, most perceived that schizophrenia was associated with the greatest cognitive dysfunction. Many were unaware whether guidelines were available on cognitive assessment. In schizophrenia, 59% of psychiatrists reportedly used cognitive instruments, while the remainder relied solely on patient history interviews. The use of instruments to assess cognition in major depressive disorder (MDD) and bipolar disorder (BPD) was lower, 38% and 37% respectively. Of the reported instruments used, only a few were actually appropriate for use in the diseases of interest (12% in schizophrenia, 3% in MDD and 0% in BPD). Other instruments reported were clinical measures that did not assess cognition. These findings reveal some inconsistencies in psychiatrists' routine clinical evaluation of cognitive function. There appeared to be low use of true cognitive assessment instruments in clinical practice and confusion regarding what constituted a cognitive assessment instrument.     

齐拉西酮与奎硫平合并碳酸锂治疗双相情感障碍躁狂发作对照研究

目的探讨齐拉西酮合并碳酸锂治疗双相情感障碍躁狂发作的疗效和安全性。方法将80例双相情感障碍躁狂发作患者随机分为齐拉西酮联合碳酸锂治疗组（研究组）和奎硫平联合碳酸锂治疗组（对照组）各40例。观察4周。分别采用杨氏躁狂量表（YMRS）、治疗中出现的症状量表（TESS）评定疗效和不良反应。结果治疗4周,研究组痊愈率为20.00%,总有效率为85.00%;对照组分别为25.00%和87.50%,两组比较,差异无统计学意义（P〉0.05）。两组YMRS评分治疗前差异无统计学意义（P〉0.05）,治疗后各周均有显著下降（P均〈0.01）,两组比较,差异无统计学意义（P〉0.05）。研究组和对照组不良反应发生率分别为42.50%和47.50%,差异无统计学意义（P〉0.05）,研究组静坐不能、肌张力增高的发生率高于对照组（P均〈0.05）,体质量增加发生率低于对照组（P〈0.05）。结论齐拉西酮联合碳酸锂治疗双相情感障碍躁狂发作有良好疗效,不良反应轻微。