新型抗精神病药对躁狂发作的辅助治疗

目的:研究利培酮与奥氮平合并碳酸锂治疗双相障碍躁狂发作的疗效与安全性.方法:66例双相障碍躁狂发作患者随机分为两组,使用碳酸锂治疗,分别合用利培酮或奥氮平,疗程6周.以Bech-Rafaelsen躁狂量表(BRMS)、大体评定量表(GAS)、疗效总评量表病情严重程度(CGI-SI)、副反应量表(TESS)进行评价.结果:利培酮组与奥氮平组疗效相仿,不良反应有不同.结论:利培酮与奥氮平可作为治疗躁狂症的辅助药物.     

Novel antipsychotics in bipolar and schizoaffective mania

OBJECTIVE: Novel antipsychotics are increasingly used in the treatment of bipolar and schizoaffective mania. This paper presents an overview of the controlled studies in this field. METHOD: Using cross-references, a computerized search was performed on MEDLINE and EMBASE psychiatry covering the period 1990-2002. RESULTS: Olanzapine and risperidone, added to mood stabilizers, and olanzapine as monotherapy enjoy the most evidential support in terms of efficacy and side-effect profile for their use in acute bipolar mania. The use of modern antipsychotics in bipolar prophylaxis and in both the short- and long-term treatment of schizomania has not been widely studied yet. CONCLUSION: More controlled trials are still needed comparing modern antipsychotics as monotherapy and adjunctive to mood stabilizers with conventional antipsychotics, lithium, anticonvulsants and with each other in short-term and, especially, maintenance treatment of (schizo)mania. Partly based on controlled studies, olanzapine, risperidone and other modern antipsychotics could become preferable for these indications.     

Risperidone in the treatment of bipolar mania

Atypical antipsychotic medications have assumed growing importance for the treatment of bipolar disorder, an illness that affects approximately 1.2%–3.7% of the general population in a given year. Current practice guidelines for the treatment of bipolar mania support the use of atypical antipsychotic medications as monotherapy or as a component of polytherapy, and in clinical settings the use of atypical antipsychotics to treat bipolar disorder is widespread. Risperidone is an atypical antipsychotic, sometimes referred to as a second-generation antipsychotic. The receptor-binding profile of risperidone, which includes potent antagonism of the serotonin 5-HT2_A, dopamine D₂, and alpha-adrenergic receptors, is believed to be related to positive effects on mood. The FDA-approved bipolar indications for risperidone include: 1) monotherapy for short-term treatment of acute manic or mixed episodes associated with bipolar I disorder and 2) combination therapy with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. This review of risperidone for bipolar mania will address the chemistry, pharmacodynamics, pharmacokinetics, and metabolism of risperidone, use with concomitant medications, clinical trials in bipolar mania, as well as safety and tolerability issues. Finally, dosing and administration are addressed as well as use for bipolar mania in geriatric, child, or adolescent patients.     

利培酮与氯氮平辅助治疗老年躁狂症研究

目的：观察利培酮与氯氮平分别合并碳酸锂治疗老年躁狂症的疗效和不良反应。方法：将62例老年躁狂症随机分为两组,在服用碳酸锂的基础上分别合并利培酮或氯氮平治疗。疗程6周,采用躁狂量表（BRMS）评定疗效,采用治疗中出现的症状量表（TESS）评定不良反应。结果：利培酮与氯氮平疗效相当,利培酮起效时间迟于氯氮平,但不良反应较轻,依从性好。结论：利培酮合并碳酸锂与氯氮平合并碳酸锂治疗躁狂症总体疗效相当,但安全性较高。     

Drug treatment of mania: a critical review

While lithium is generally considered to be a first-line treatment for mania, the position of the anticonvulsants and the antipsychotics in the treatment of this disorder is currently under debate. For that reason, this paper reviews the original literature, in particular addressing the randomized controlled trials (RCTS) on lithium, anticonvulsants and antipsychotics, and the methodological limitations therein. As the treatment of mania needs to anticipate the future course of the illness, the data on prophylaxis will also be reviewed, albeit briefly. It is concluded that antipsychotics are powerful antimanics, which are particularly beneficial for some clinical presentations of severe mania. However, in general their use should not be prolonged into the maintenance phase. Lithium is still to be considered the mood-stabilizing drug par excellence, although it may be insufficient in mixed states and severe mania. The evidence for antimanic efficacy of valproate, in particular for mixed states, seems more convincing than that for carbamazepine, while the evidence for a prophylactic action of carbamazepine still exceeds that for valproate. Adjunctive treatment with benzodiazepines is often useful. Small sample sizes, highly selected study populations and high drop-out rates seem to be the most important limitations of the RCTS on mania. Quasi-experimental, naturalistic studies on unselected populations are needed to investigate how the various treatments work in clinical practice. Based on the available evidence, summary guidelines for treatment are proposed.     

A pilot study of rapid lithium administration in the treatment of acute mania

Objectives: The use of rapid lithium dosage administration, a strategy that could lead to rapid improvement in mania, has been largely unexamined. In this open-label, pilot, acute-treatment study, we sought to determine the safety and tolerability of lithium administered at 20 mg/kg/day. A secondary aim was to provide preliminary data regarding the efficacy of this strategy in ameliorating manic, depressive, and psychotic symptoms. Methods: Fifteen patients hospitalized with DSM-IV bipolar disorder, manic or mixed, and who provided written informed consent, received lithium 20 mg/kg/day for up to 10 days. Patients were evaluated for adverse effects daily. Lithium levels were obtained on days 2, 3, 4, 5, 7, and 10 or at study termination. Electrocardiograms (EKGs) were performed at baseline and on days 1–5, 7, and 10 or at study termination. Symptomatic improvement was assessed daily using the Young Mania Rating Scale, 24-item Hamilton Depression Rating Scale, and the Scale for Assessment of Positive Symptoms (SAPS). Results: Five of the 15 patients completed the 10-day study period. Two patients dropped out due to adverse events. Seven patients did not complete the inpatient trial because of improvement sufficient to allow hospital discharge. All patients achieved serum lithium concentrations ≥0.6 mEq/L after 1 day of treatment; the mean±SD concentration on day 5 was 1.1 (±0.1) mEq/L on day 5. There were significant reductions from baseline to endpoint on all rating scales, except the SAPS bizarre behavior subscale. Conclusions: These pilot data suggest that lithium 20 mg/kg/day was well tolerated and that this strategy may produce rapid improvement in affective and psychotic symptoms. These impressions require confirmation in double-blind, randomized trials.     

奥氮平单药与联合碳酸锂治疗双相障碍躁狂发作患者的对照研究

目的:比较奥氮平单药与奥氮平联合碳酸锂治疗双相躁狂或混合发作患者的疗效与安全性. 方法:60例双相障碍Ⅰ型躁狂发作或混合性发作患者随机分为单用药组29例和合用药组31例.分别给予奥氮平单药和奥氮平联合碳酸锂治疗.疗程4周.于基线时,治疗l,2,3和4周,分别采用临床总体印象量表-双相障碍版、Young躁狂量表(YMR...     

The impact of response to previous mood stabilizer therapy on response to olanzapine versus placebo for acute mania

Objectives: A clinically important question for any new treatment for bipolar disorder is whether its efficacy extends to patients who have both responded and failed to respond to other mood stabilizers. In this secondary analysis of a placebo-controlled trial demonstrating olanzapine's efficacy for acute mania, we explore whether its usefulness extends to those patients with a history of poor response to other mood stabilizers.

Methods: This 4-week, double-blind, placebo-controlled trial studied olanzapine monotherapy 5–20 mg/day for hospitalized patients in acute manic or mixed bipolar episodes. The primary outcome variable was beginning to endpoint change in the Young-Mania Rating Scale (Y-MRS) total score. We investigated whether prospectively identified history of recent failure to respond to other mood stabilizers predicted response to olanzapine.

Results: As previously reported, olanzapine-treated patients experienced significantly greater improvement in Y-MRS total score and higher remission rates relative to placebo-treated patients. The current analysis compared these outcome parameters in patients with known poor prior response to lithium and/or valproate with all other patients and found no significant group by treatment interactions, i.e., treatment effects were not significantly diminished in non-responders to older mood stabilizing agents.

Conclusions: Olanzapine has been shown to be superior to placebo for the treatment of mania. This secondary analysis suggests that olanzapine monotherapy is similarly effective for patients whether or not they previously have failed to respond to another mood stabilizer for mania. A study limitation is that response to lithium or valproate was determined retrospectively.     

Pharmacotherapy patterns in the treatment of bipolar disorder

Objectives:  To assess medication use patterns of patients with bipolar disorder, and, through multivariate analysis, to elucidate the role of selected demographic and clinical factors on medication choice and use patterns.
Methods:  Patients were privately insured individuals aged 18–64, continuously enrolled in a health plan for 15 months or longer during the years 1994–1998, and either diagnosed with bipolar disorder or prescribed lithium or valproate at least 90 days after the start of the study period. Medical and pharmacy claims data were used to analyze medication therapy over a 12-month period.
Results:  First-generation antipsychotics were used by 16.4% of patients and second-generation agents by 12.4%. Patients starting on antipsychotics tended to stay with them for 12 months or longer, while patients starting on anticonvulsants or antidepressants were more likely to stop therapy or to switch to another medication class. Patients treated with olanzapine appeared to have more psychiatric comorbidities and more psychiatric hospitalizations than users of first-generation agents.
Conclusions:  Although mood stabilizers and anticonvulsant agents are widely used to treat bipolar disorder, antipsychotic agents are also present in the treatment regimens of bipolar patients. Demographic and clinical factors were significant predictors of the choice of initial medication therapy and subsequent use patterns. In particular, patient gender and the number of psychiatric and physical comorbidities were significantly related to the course of medication therapy.     

Asenapine versus olanzapine in acute mania: a double‐blind extension study

Objective: To assess the efficacy and tolerability of asenapine versus olanzapine in the extended treatment of bipolar mania. Methods: Patients with bipolar I disorder experiencing acute manic or mixed episodes who completed either of two 3‐week, double‐blind trials with asenapine 5 or 10 mg twice daily, olanzapine 5 to 20 mg once daily, or placebo were eligible for this 9‐week, double‐blind extension study. Patients receiving active medication in the 3‐week trials continued the same regimen; those who had received placebo were blindly switched to asenapine but were assessed for safety outcomes only. The primary efficacy measure was the change from baseline to day 84 on the Young Mania Rating Scale (YMRS) total score in the per‐protocol population. Results on the primary efficacy outcome were used to determine the noninferiority of asenapine versus olanzapine. Results: A total of 504 patients (placebo/asenapine, n = 94; asenapine, n = 181; olanzapine, n = 229) were enrolled in the extension study. At day 84, the mean (SD) change from baseline in YMRS total score was ?24.4 (8.7) for asenapine and ?23.9 (7.9) for olanzapine. Prespecified statistical analysis for noninferiority indicated no significant difference between asenapine and olanzapine. The overall incidence of treatment‐emergent adverse events was similar across treatment groups (77% placebo/asenapine, 77% asenapine, 78% olanzapine). Clinically significant weight gain occurred in 10%, 19%, and 31% of the placebo/asenapine, asenapine, and olanzapine groups, respectively. Conclusions: Asenapine was efficacious, showed noninferiority to olanzapine, and was well tolerated in the extended treatment of patients experiencing manic symptoms associated with bipolar I disorder.     

利培酮治疗躁狂症对照观察

目的:了解利培酮对躁狂症患者的疗效及不良反应。方法:对90例躁狂症患者随机分为单用利培酮组30例,利培酮合并碳酸锂组30例及氯氮平合并碳酸锂组30例,在治疗前及治疗第1、2、4、6、8周末分别评定Young氏躁狂量表(YMRS)、阳性与阴性症状量表(PANSS)及治疗中出现的症状量表(TESS),以了解疗效及不良反应。结果:单用利培酮组、利培酮合并碳酸锂组及氯氮平合并碳酸锂组治疗第2、4、6、8周末YMRS、PANSS总分均显著下降(P<0.01),但3组间比较差异无显著性(P>0.05)。治疗第4、6、8周末TESS总分3组间比较差异有显著性(P<0.01)。利培酮合并碳酸锂组及氯氮平合并碳酸锂组不良反应较单用利培酮组明显增多,尤其是氯氮平合并碳酸锂组更甚。结论:单用利培酮治疗躁狂症有效,而且不良反应更小。     

抗精神病药对躁狂症的治疗作用：利培酮治疗躁狂症对照观察

目的：了解利培酮对躁狂症患者的疗效及不良反应。方法：对90例躁狂症患者随机分为单用利培酮组30例,利培酮合并碳酸锂组30例及氯氮平合并碳酸锂组30例,在治疗前及治疗第1、2、4、6、8周末分别评定Young氏躁狂量表（YMRS）、阳性与阴性症状量表（PANSS）及治疗中出现的症状量表（TESS）,以了解疗效及不良反应。结果：单用利培酮组、利培酮合并碳酸锂组及氯氮平合并碳酸锂组治疗第2、4、6、8周末YMRS、PANSS总分均显著下降（P〈0.01）,但3组间比较差异无显著性（P〉0.05）。治疗第4、6、8周末TESS总分3组间比较差异有显著性（P〈0.01）。利培酮合并碳酸锂组及氯氮平合并碳酸锂组不良反应较单用利培酮组明显增多,尤其是氯氮平合并碳酸锂组更甚。结论：单用利培酮治疗躁狂症有效,而且不良反应更小。     

Olanzapine vs. other antipsychotics in actual out-patient settings: six months tolerability results from the European Schizophrenia Out-patient Health Outcomes study

OBJECTIVE: The European Schizophrenia Out-patient Health Outcomes study is an observational study investigating treatment in schizophrenia. We report treatment-emergent adverse events during the first 6 months of treatment. METHOD: The rate of extrapyramidal symptoms (EPS), anticholinergic use, weight gain and sexual related dysfunctions were assessed in 8,400 out-patients. RESULTS: Patients typical antipsychotics and risperidone experienced significantly more EPS and anticholinergic use than patients in the clozapine, olanzapine, and quetiapine cohorts. Patients treated with amisulpride, typical antipsychotics and risperidone were significantly more likely to have sexual related dysfunctions and/or amenorrhea. Increases in weight and body mass index occurred in all cohorts, but were significantly greater in the olanzapine and clozapine cohorts. CONCLUSION: Patients treated with olanzapine, quetiapine and clozapine had better tolerability outcomes regarding EPS and sexual related dysfunctions compared with patients receiving risperidone, amisulpride and typicals. Patients treated with olanzapine and clozapine had higher weight increases than patients treated with risperidone, quetiapine and typicals.     

Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind, placebo-controlled study

Objectives:  To evaluate the efficacy, safety, and tolerability of risperidone monotherapy for the treatment of an acute mixed or manic episode in children and adolescents with bipolar I disorder.
Methods:  This randomized, placebo-controlled, double-blind, 3-arm study (N = 169) included children and adolescents (ages 10–17 years) with a DSM-IV diagnosis of bipolar I disorder, experiencing a manic or mixed episode. Study participants were randomized to placebo (n = 58), risperidone 0.5–2.5 mg/day (n = 50), or risperidone 3–6 mg/day (n = 61) for 3 weeks. The primary efficacy measure was change in Young Mania Rating Scale (YMRS) total score from baseline to end point. Safety assessments included adverse event (AE) monitoring and scores on extrapyramidal symptom rating scales.
Results:  Improvement in mean YMRS total score was significantly greater in risperidone-treated subjects than in placebo-treated subjects [mean change (SD) −9.1 (11.0) for placebo; −18.5 (9.7) for risperidone 0.5–2.5 mg (p < 0.001); −16.5 (10.3) for risperidone 3–6 mg (p < 0.001)]. The most common risperidone-associated AEs were somnolence, headache, and fatigue. Mean (SD) weight gain was 0.7 (1.9) kg, 1.9 (1.7) kg, and 1.4 (2.4) kg in the placebo, risperidone 0.5–2.5 mg, and risperidone 3–6 mg groups, respectively, during this 3-week study.
Conclusions:  At daily doses of 0.5–2.5 mg and 3–6 mg, risperidone was effective and well tolerated in children and adolescents experiencing acute manic or mixed episodes of bipolar I disorder. Results indicate that risperidone 0.5–2.5 mg has a better benefit–risk profile than risperidone 3–6 mg.     

Recovery and functional outcomes following olanzapine treatment for bipolar I mania

BACKGROUND: Typical experimental categorizations of treatment responses in bipolar disorder (BPD) patients may have limited relationship to clinical recovery or functional status, and there is inadequate research on such clinically important outcomes. METHODS: We analyzed data from a study of open continuation of olanzapine treatment following a 3-week placebo-controlled trial involving initially hospitalized adult subjects with DSM-IV BP-I mania to estimate rates and times to symptomatic remission (low scores on standardized symptomatic assessments) and clinical recovery (remission sustained>or=8 weeks), associated clinical factors, and functional outcomes. RESULTS: During treatment with olanzapine for 27.9+/-20.1 weeks, symptomatic remission was attained by 70% of subjects, half by 8 weeks (95% CI 6-10) weeks, and later lost by 82% of remitted subjects; remitted (versus non-remitted) subjects had slightly lower baseline clinical global impression scores and greater trial-completion. Sustained clinical recovery was attained by only 40 of 113 (35%) of subjects, half by 36 (95% CI 20-40) weeks, and later lost by 45%. Subjects with above-median (>12) initial Hamilton-Depression rating scale depression scores were half as likely to recover (p=0.016) and did so much later (36 versus 12 weeks) than those with lower scores. At final assessment, self-rated well being (SF-36 psychosocial functioning scores) improved substantially more among recovered versus non-recovered subjects (mean changes: 87% versus 23%), and two-thirds of recovered subjects remained unemployed-for-pay while half received disability-compensation. CONCLUSIONS: Clinically meaningful symptomatic remission and recovery in relatively severely ill adult bipolar I manic patients were achieved slowly and sustained by only some patients within an average of 7 months of continuous treatment. These clinically relevant outcomes were worse with relatively high initial dysphoria ratings. Well-being was rated higher by recovered subjects, but their ability to work and live independently were markedly impaired. These findings underscore the emerging view that BPD can often be severe, slow to remit, and disabling, particularly in association with prominent depression-dysphoria symptoms. Improved treatments for BPD are needed, guided by longitudinal assessments of clinically meaningful measures of symptomatic recovery and functional outcome.     

A 3-week, randomized, placebo-controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states

Objective:  Asenapine is approved for bipolar disorder and schizophrenia. This was a 3-week, randomized, double-blind, placebo-controlled trial of asenapine for treating acute bipolar mania.
Methods:  After a single-blind placebo run-in period, adults (n = 488) experiencing manic or mixed episodes were randomized to flexible-dose sublingual asenapine (10 mg BID on day 1; 5 or 10 mg BID thereafter; n = 194), placebo (n = 104), or oral olanzapine (15 mg BID on day 1; 5–20 mg QD thereafter; n = 191). Primary efficacy, change in Young Mania Rating Scale (YMRS) total score from baseline to day 21, was assessed using analysis of covariance with last observation carried forward [(LOCF); primary analysis]. A mixed model for repeated measures [(MMRM); prespecified secondary analysis] was also used to assess efficacy. Tolerability and safety assessments included adverse events, physical examinations, extrapyramidal symptom ratings, and laboratory values.
Results:  Mean daily dosages were asenapine 18.2 mg and olanzapine 15.8 mg. Significantly greater least squares (LS) mean ± SE changes in YMRS scores were observed on day 2 with asenapine (−3.0 ± 0.4) and olanzapine (−3.4 ± 0.4) versus placebo (−1.5 ± 0.5, both p < 0.01) and were maintained until day 21 (−10.8 ± 0.8 with asenapine, −12.6 ± 0.8 with olanzapine; both p ≤ 0.0001 versus placebo, −5.5 ± 1.1) with LOCF. The results of MMRM analyses were consistent with those of LOCF. Asenapine had a modest impact on weight and metabolic measures.
Conclusions:  These results indicate that asenapine is rapidly acting, efficacious, and well tolerated for patients with bipolar I disorder experiencing an acute manic episode.     

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.