A multi-centre,randomised, double-blind,placebo-controlled clinical trial of methylphenidate in the initial treatment of acute mania (MEMAP study)

Based on many clinical and preclinical findings the ‘vigilance regulation model of mania’ postulates that an unstable regulation of wakefulness is a pathogenetic factor in both mania and Attention Deficit Hyperactivity Disorder (ADHD) and induces hyperactivity and sensation seeking as an autoregulatory attempt to stabilize wakefulness. Accordingly, stimulant medications with their vigilance stabilizing properties could have rapid antimanic effects similar to their beneficial effects in ADHD. The MEMAP study – a multi-center, double-blind, placebo-controlled and randomized clinical trial (RCT) – assessed the antimanic efficacy and safety of a 2.5-day treatment with methylphenidate (20–40 mg/day). Of 157 screened patients with acute mania, 42 were randomly assigned to receive 20–40 mg per day of methylphenidate in one or two applications, or placebo. The primary outcome was the change in Young Mania Rating Scale (YMRS) sum scores from baseline to day 2.5 in the methylphenidate group compared to the placebo group. A group sequential design was chosen to justify early RCT termination based on efficacy or futility at an interim analysis after inclusion of 40 patients. In the interim analysis, the change from baseline in the YMRS total score at day 2.5 was not significantly different between both groups (F(1,37)=0.23; p=0.64). Thus, futility was declared for methylphenidate and the RCT was stopped. In summary, although methylphenidate was well tolerated and safe in the full analysis set, it failed to show efficacy in the treatment of acute mania. Trial registration: clinicaltrials.gov (URL: http://www.clinicaltrials.gov; registration number: NCT01541605).     

喹硫平、氯氮平联合碳酸锂治疗女性躁狂症的随机对照研究

目的探讨使用喹硫平或氯氮平合并碳酸锂治疗女性躁狂发作的临床疗效。方法将符合《国际疾病分类(第10版)》(ICD-10)情感障碍中"躁狂发作"或"双相障碍目前为躁狂发作"诊断标准的64例女性躁狂症患者采用分段随机分组法分为两组,分别予喹硫平和氯氮平联合碳酸锂治疗6周。采用Bech-Rafaelsen躁狂量表(BRMS)评价药物的总体有效性,采用副反应量表(TESS)和血、尿常规、生化、心电图、脑电图检查评价安全性及不良反应,并用成本-效果分析计算药物的经济性。结果两组有效率比较差异无统计学意义(P0.05),但两组在不良反应头晕、嗜睡、心电图、便秘、流涎、血糖异常、体质量增加等方面比较差异有统计学意义(P0.05),喹硫平组副反应率低于氯氮平组,差异有统计学意义(P0.05)。结论两药物组的临床疗效相当,但喹硫平组副反应率低于氯氮平组。喹硫平合并碳酸锂可能更适用于治疗女性躁狂发作。     

Distinct profiles of behavioral inhibition and activation system sensitivity in unipolar vs. bipolar mood disorders

Psychiatric outpatients with mood disorders (n=275) and community controls (n=733) completed a measure of Behavioral Inhibition System (BIS) and Behavioral Activation System (BAS) sensitivity; psychiatric outpatients also completed measures of mood symptom severity. All patients scored higher on BIS compared to controls; patients with bipolar disorders scored higher on BAS scales compared to patients with depressive disorders. BIS and BAS demonstrated unique patterns of association with mood symptoms. Results support the clinical utility of the BIS/BAS.     

The effects of n-acetylcysteine and/or deferoxamine on manic-like behavior and brain oxidative damage in mice submitted to the paradoxal sleep deprivation model of mania

Bipolar disorder (BD) is a severe psychiatric disorder associated with social and functional impairment. Some studies have strongly suggested the involvement of oxidative stress in the pathophysiology of BD. Paradoxal sleep deprivation (PSD) in mice has been considered a good animal model of mania because it induces similar manic-like behavior, as well as producing the neurochemical alterations which have been observed in bipolar patients. Thus, the objective of the present study was to evaluate the effects of the antioxidant agent's n-acetylcysteine (Nac) and/or deferoxamine (DFX) on behavior and the oxidative stress parameters in the brains of mice submitted to the animal model of mania induced by PSD. The mice were treated for a period of seven days with saline solution (SAL), Nac, DFX or Nac plus DFX. The animals were subject to the PSD protocol for 36 h. Locomotor activity was then evaluated using the open-field test, and the oxidative stress parameters were subsequently evaluated in the hippocampus and frontal cortex of mice. The results showed PSD induced hyperactivity in mice, which is considered a manic-like behavior. In addition to this, PSD increased lipid peroxidation and oxidative damage to proteins, as well as causing alterations to antioxidant enzymes in the frontal cortex and hippocampus of mice. The Nac plus DFX adjunctive treatment prevented both the manic-like behavior and oxidative damage induced by PSD. Improving our understanding relating to oxidative damage in biomolecules, and the antioxidant mechanisms presented in the animal models of mania are important in helping to improve our knowledge concerning the pathophysiology and development of new therapeutical treatments for BD.     

Bipolar disorder and antibodies against the N-methyl-d-aspartate receptor: A gate to the involvement of autoimmunity in the pathophysiology of bipolar illness

The high prevalence of comorbidity between bipolar disorder (BD) and other medical conditions, including autoimmune diseases, supports the hypothesis of the nature of BD as a biological illness category. Hence, an immune dysregulation process may play an important role in the development of at least certain subtypes of BD. Increasing evidence also suggests that the N-methyl-d-aspartate receptor (NMDAR) may be relevant in the pathophysiology of BD. A possible key mechanism underlying the physiopathology of certain autoimmune diseases that may present with affective symptoms might be the production of anti-NMDAR auto-antibodies (auto-Abs). The best characterized autoimmune anti-NMDAR disease is the anti-NMDAR encephalitis. It has been found that 4% of these patients present isolated, mostly affective, psychiatric manifestations during their illness. An interesting suggestion emerged from this overview is that the same mechanisms that trigger affective symptoms in patients with increased anti-NMDAR auto-Abs levels could be involved in the physiopathology of at least a subgroup of BD. Future studies are needed to characterize the relationship between anti-NMDAR auto-Abs and BD.     

Delirium with manic and psychotic features associated with amantadine

While clinicians are familiar with psychosis as a complication in the long-term treatment with amantadine, rapid psychiatric complications are of much less concern. In the case presented, severe decompensation in mental status occurred within 48 h of initiation of standard doses of amantadine hydrochloride. Clinicians should be alert not only for delayed complications but also for early-onset mental decompensation in elderly patients with influenza A treated with amantadine.     

Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models

Over the past 20 years there has been a growing interest in the neural underpinnings of cost/benefit decision-making. Recent studies with animal models have made considerable advances in our understanding of how different prefrontal, striatal, limbic and monoaminergic circuits interact to promote efficient risk/reward decision-making, and how dysfunction in these circuits underlies aberrant decision-making observed in numerous psychiatric disorders. This review will highlight recent findings from studies exploring these questions using a variety of behavioral assays, as well as molecular, pharmacological, neurophysiological, and translational approaches. We begin with a discussion of how neural systems related to decision subcomponents may interact to generate more complex decisions involving risk and uncertainty. This is followed by an overview of interactions between prefrontal-amygdala-dopamine and habenular circuits in regulating choice between certain and uncertain rewards and how different modes of dopamine transmission may contribute to these processes. These data will be compared with results from other studies investigating the contribution of some of these systems to guiding decision-making related to rewards vs. punishment. Lastly, we provide a brief summary of impairments in risk-related decision-making associated with psychiatric disorders, highlighting recent translational studies in laboratory animals.