Adding lithium carbonate to carbamazepine: antimanic efficacy in treatment-resistant mania

Although lithium and carbamazepine used alone are effective in treating acute mania, some patients do not respond adequately to either of these medications used alone. We assessed, under double-blind conditions, a potential synergism between carbamazepine and lithium in the acute treatment of mania. Six of 7 manic patients who had previously been largely refractory to lithium alone, and who still showed substantial mania after several weeks of double-blind treatment with carbamazepine, improved following the blind addition of lithium. The clinical and theoretical implications of the response to this combination treatment are discussed.     

Topiramate monotherapy in the management of acute mania: results of four double-blind placebo-controlled trials

OBJECTIVE: To evaluate the efficacy and tolerability of topiramate monotherapy in adults with acute manic or mixed episodes of bipolar I disorder. METHODS: In four trials, adults hospitalized with acute mania, a diagnosis of bipolar I disorder, history of > or =1 previous manic or mixed episodes, and > or =20 Young Mania Rating Scale (YMRS) score were randomized to double-blind treatment with topiramate (target doses: 200, 400, or 600 mg/day) or placebo; two trials included an active comparator (lithium, 1500 mg/day). The core study duration in all trials was 3 weeks; three trials also had 9-week double-blind extensions. The primary efficacy variable was mean change from baseline in YMRS in the core 3-week study. RESULTS: Changes in YMRS score during 3 weeks were not significantly different for topiramate versus placebo (mean YMRS reductions, -5.1 to -8.4). Mean YMRS reductions in lithium-treated groups were significantly greater (p < or = 0.001 versus placebo and topiramate). A similar pattern was observed after 12 weeks of double-blind treatment in studies with double-blind extensions. Paresthesia, appetite decrease, dry mouth, and weight loss were more frequently associated with topiramate than with placebo. CONCLUSIONS: These studies do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder. Topiramate was not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression. Lithium was confirmed as an effective therapy in this population.     

Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study

OBJECTIVE: Evaluate the efficacy and tolerability of quetiapine (QTP) combined with lithium (Li) or divalproex (DVP) in the treatment of acute mania. METHODS: Patients were randomized to 21 days of double-blind treatment with QTP plus Li/DVP, or placebo (PBO) plus Li/DVP. QTP was rapidly dosed up to a maximum of 800 mg/day; Li was dosed to 0.7-1.0 mEq/L; or DVP to 50-100 microg/mL. RESULTS: Fifty-six of 91 (61.5%) individuals in the QTP + Li/DVP group compared with 49 of 100 (49%) taking PBO + Li/DVP completed the study. A significantly greater mean reduction in total Young Mania Rating Scale (YMRS) score was observed at end-point in patients receiving QTP + Li/DVP compared with those in the PBO + Li/DVP group (-13.76 versus -9.93; p = 0.021). The response rate (> or =50% YMRS improvement) was significantly higher in the QTP + Li/DVP group than in PBO + Li/DVP-treated patients (54.3% versus 32.6%; p = 0.005), as was the proportion of patients achieving clinical remission (YMRS < 12) (45.7% versus 25.8%; p = 0.007). Patients receiving QTP + Li/DVP also had a significantly greater improvement in Clinical Global Impressions-Bipolar (CGI-BP) Severity of Illness scores (-1.38 versus -0.78; p = 0.001). The mean last-week dose of QTP was 584 mg/day in patients meeting response criteria. Common adverse events (at least 10% and twice the rate of Li/DVP) in the QTP + Li/DVP group included somnolence, dry mouth, asthenia, and postural hypotension. CONCLUSIONS: Quetiapine combined with either Li or DVP has superior efficacy compared with Li or DVP monotherapy for treating patients with bipolar mania. Combination therapy was well-tolerated and most adverse events were mild, withdrawal because of adverse events being only 5% compared with 6% on Li or DVP monotherapy.     

A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Down syndrome and Alzheimer's disease--pilot study

BACKGROUND: Donepezil Hydrochloride (Aricept) is a selective anticholinesterase inhibitor developed for the treatment of Alzheimer's disease (AD). This study investigated the safety and efficacy of the drug to treat Down syndrome (DS) adults with mild to moderate AD. METHOD: This was a 24-week, double blind, placebo controlled, parallel-group trial. Patients were randomized to receive placebo or donepezil (5 mg per day during the first four weeks, and then 10 mg per day thereafter). Primary efficacy was measured using the Dementia Scale for Mentally Retarded Persons (DMR), and secondary efficacy was measured using the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI) and by the Adaptive Behavior Scale (ABS). RESULTS: A total of 30 DS patients with AD entered the study of which 27 were included in the subsequent data analysis. The donepezil group had non-statistically significant reduction in deterioration in DMR, SIB, and ABS mean scores relative to the placebo group. However NPI scores showed less improvement in the donepezil group when compared to the placebo group. Fifty percent of subjects in the donepezil group showed improvement in mean DMR scores at the end point compared to baseline, when compared to 31% on placebo. There were no life threatening adverse effects associated with treating adults with DS with donepezil. A number of side-effects did occur including diarrhoea, insomnia, fatigue, and nausea. CONCLUSION: Donepezil Hydrochloride administered once a day appears to be generally well tolerated and safe in DS adults who have AD. There is some possible efficacy in the treatment of symptoms of mild to moderate Alzheimer's disease in this population, although the sample size of this study was too small for statistical significance. It is recommended that donepezil, with the appropriate precautions, should be considered for the treatment of AD in adults with DS as deemed by a specialist.     

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.     

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.     

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.     

Amisulpride plus valproate vs haloperidol plus valproate in the treatment of acute mania of bipolar I patients: a multicenter, open-label, randomized, comparative trial

The primary objective of this study was to compare the effectiveness of combination treatment of valproate and amisulpride with that of valproate and haloperidol in bipolar I disorder. Adult inpatients with a current manic episode fulfilling DSM-IV-TR diagnostic criteria for bipolar type I disorder were included. Patients were randomized to amisulpride (400-800 mg/day) or haloperidol (5-15 mg/day) for 3 months and all received valproate. The primary effectiveness criterion was the percentage of responders (defined by a decrease of >/=50% of the Y-MRS) in patients completing the study. Safety was evaluated by adverse event reporting, determination of extrapyramidal function and clinical examination. Sixty-two patients were randomized to receive valproate-amisulpride, and 61 to receive valproate-haloperidol. At study end, responder rates were 72.6% in the amisulpride group and 65.5% in the haloperidol group. Remission rates were 83.9% and 89.7%, respectively. At study end, neither response rates nor remission rates differed significantly between groups. Treatment-emergent adverse events occurred significantly (p = 0.009) more frequently in the haloperidol group (86.4%) than in the amisulpride group (66.1%). In conclusion, the valproate-amisulpride combination was as effective as the valproate - haloperidol combination in bipolar I patients, with a better safety profile.     

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...     

A randomized, double-blind, placebo-controlled clinical trial of acamprosate in alcohol-dependent individuals with bipolar disorder: a preliminary report

Tolliver BK, DeSantis SM, Brown DG, Prisciandaro JJ, Brady KT. A randomized, double‐blind, placebo‐controlled clinical trial of acamprosate in alcohol‐dependent individuals with bipolar disorder: a preliminary report. Bipolar Disord 2012: 14: 54–63. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Background: Alcohol use disorders commonly co‐occur with bipolar disorder and are associated with a more severe course of bipolar illness, yet treatment research in this important clinical population is scarce. The current study assessed the effects of acamprosate on alcohol use and mood symptoms in subjects with co‐occurring bipolar disorder and active alcohol dependence. Methods: Thirty‐three adults meeting criteria for bipolar I or bipolar II disorder and current alcohol dependence were randomized to receive add‐on acamprosate (1998 mg/day) or placebo while concurrently maintained on mood stabilizing medications. Participants were assessed weekly for frequency and quantity of alcohol consumption and general clinical severity for eight weeks. Depressive symptoms, manic symptoms, and alcohol craving were assessed biweekly. Biomarkers of alcohol use were assessed at study baseline and endpoint. Results: Of the 33 subjects randomized, 23 (69.7%) completed all active phase visits. Over the trial as a whole, no statistically significant treatment differences were detected in drinking outcomes. Post‐hoc analysis revealed lower Clinical Global Impression scores of substance use severity in acamprosate‐treated participants in weeks 7–8 of the trial. No significant differences in depressive symptoms, manic symptoms, or adverse events were observed between groups. Conclusions: Acamprosate was well‐tolerated, with no worsening of depressive or manic symptoms, and appeared to confer some clinical benefit in study completers in the last two weeks of the trial. Larger studies of longer duration are required to fully explore the utility of acamprosate in this population.     

Is preadolescent mania the same condition as adult mania? A British perspective.

Until relatively recently, the prevailing view was that mania was uncommon in preadolescent children. In the past 15 years, however, there has been increasing interest in the idea that mania may be much more common at younger ages than previously recognized. This article is concerned with the issue of whether preadolescent mania represents the same kind of problem as adult mania. It reviews concepts of bipolar disorder and mania in adults and preadolescents, some of the issue that arise in diagnosing mania in children, and the evidence for continuities between preadolescent and adult mania. The diagnosis of mania in preadolescent children often requires that inferences are made about the meaning of some symptoms but it is not always clear that these inferences are valid. It is concluded that the extant evidence does not provide a clear conclusion about the links between preadolescent and adult mania. More work is needed on the phenomenology and diagnosis of mania in children, on its natural history and on its familial correlates.     

A double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia.

BACKGROUND: Despite the beneficial effects of atypical antipsychotics on cognition, these improvements will not return most schizophrenic patients to normative standards of cognitive functioning. Therefore, other treatments need to be considered. Subtle changes in cholinergic function in schizophrenic patients provide the rationale to test the effectiveness of cholinesterase inhibitors in treating cognitive impairment in schizophrenia. METHODS: Given this, a 12-week, double-blind, placebo-controlled trial of donepezil (5 mg and 10 mg) as adjunctive treatment to risperidone was conducted in a total of 36 schizophrenic patients. RESULTS: Neither the 5-mg nor 10-mg dose of donepezil produced significant improvements in any cognitive measure compared with placebo. CONCLUSIONS: It is possible that nicotinic receptor desensitization produced by chronic tobacco use in these patients rendered their nicotinic receptors refractory to the effects of increased agonist activity produced by donepezil. An alternative treatment is the allosterically potentiating ligands, which enhance the activity of (sensitize) nicotinic receptors in the presence of acetylcholine.     

A randomized, double-blind, placebo-controlled trial of donepezil to improve memory in epilepsy

PURPOSE: To determine whether an acetylcholinesterase inhibitor, such as donepezil, would improve memory or other cognitive/psychological functions in epilepsy patients with subjective memory complaints. METHODS: Twenty-three epilepsy patients with subjective memory difficulty were randomized to either 3 months of donepezil (10 mg/day) or 3 months of placebo treatment, and then crossed over to the other treatment arm. Patients and physicians were blinded to treatment phase throughout data acquisition. Assessment of memory and other cognitive functions, subjective memory, mood, and self-rated quality of life (QOL) and social functioning was performed at baseline and following completion of both treatment phases. Seizure frequency and severity as well as treatment emergent adverse effects were also monitored. RESULTS: Donepezil treatment was not associated with improvement in memory or other cognitive functions, mood, social functioning or QOL. Comparable increases in self-rated memory functioning relative to baseline were evident during donepezil and placebo phases. Donepezil treatment was not associated with increased seizure frequency or severity. Similar to group results, analysis of change within individual patients as a function of treatment phase also showed neither significant benefit nor detriment associated with donepezil. CONCLUSION: This study found no benefit on memory or other cognitive/psychological functions in a heterogeneous group of epilepsy patients with subjective memory difficulty. Further investigation would be required to determine whether individual patients, or those with particular epilepsy syndromes, might benefit from donepezil or other acetylcholinesterase inhibitors, or if a higher dosage might be effective.     

Does EEG Predict Response to Valproate Versus Lithium in Patients with Mania?

A number of factors may suggest that a patient with mania may respond to valproate or to lithium. However, prediction of which patients will respond to either medication remains difficult. In this study nonepileptiform EEG abnormalities in responders to each medication were investigated. Six of 20 patients (30%) responsive to lithium but not to valproate had nonepileptiform EEG abnormalities while 14 of 20 patients (70%) responsive to valproate but not to lithium had nonepileptiform EEG abnormalities. Patients presenting with mania and EEG abnormalities, particularly sharp activity, are statistically more likely (₂ = 4.9, df = 1, p = .027) to respond to valproate than to lithium. Whether such a finding will also hold true for other anticonvulsants used to treat mania remains to be seen.     

丙戌酸镁与安慰剂治疗锂盐难治性躁狂症的双盲对照研究

本研究用丙戊酸镁与安慰剂治疗锂盐难治性躁狂症进行双盲对照研究。结果显示，丙戊酸镁组显效率为６０．０％，安慰剂组为６．７％，二组间疗效有极显著差异。说明丙戌酸镁对锂盐难治性躁狂症有显著疗效。