A pilot study of adjunctive atomoxetine treatment to second-generation antipsychotics for cognitive impairment in schizophrenia

Relationships between altered prefrontal cortical dopamine, norepinephrine, and some of the cognitive impairments of schizophrenia support an approach for pharmacological remediation of cognitive symptoms through manipulations of prefrontal cortical dopamine and norepinephrine. Atomoxetine, a selective norepinephrine reuptake inhibitor, produces a widespread increase in brain norepinephrine and a secondary and selective increase in prefrontal dopamine. Given this, we evaluated atomoxetine's cognitive effects in a pilot placebo-controlled trial in patients with schizophrenia. Moreover, a functional magnetic resonance imaging investigation was undertaken to assess the neural mechanisms underlying the cognitive effects of atomoxetine. Twenty participants with schizophrenia were randomized to treatment with placebo or atomoxetine 80 mg daily for an 8-week parallel-designed treatment trial. Cognitive performance was assessed with the Brief Assessment of Cognition in Schizophrenia. No significant cognitive improvement was associated with atomoxetine treatment. However, atomoxetine treatment was associated with significantly greater increases in working memory-related activation of the left dorsolateral prefrontal and left posterior cingulate cortices. The negative results of this study conflict with the effectiveness of amphetamine in enhancing the cognitive abilities of schizophrenic patients and may be related to the differential pattern of cortical activation and deactivation produced by amphetamine.     

缺陷型与非缺陷型精神分裂症患者的精神症状及认知功能损害的研究

目的分析缺陷型与非缺陷型精神分裂症患者的精神症状及认知功能损害的临床特征。方法选择2013年1月~2015年12月期间于北京市大兴区心康医院就诊的77例稳定期精神分裂症患者,根据中文版缺陷型精神分裂症诊断量表分为缺陷型(24例)和非缺陷型(53例),同时选择社区及广告募集的志愿者50例为对照组。分析三组研究对象的精神症状、认知功能损害的情况。结果缺陷组与非缺陷组患者在总病程、起病年龄、发作次数、吸烟量、一般精神病理评分、简明精神病量表(BPRS)总分、阳性和阴性症状量表(PANSS)总分、阳性症状量表(SAPS)评分以及抗精神病药用量比较,差异均无统计学意义(P>0.05);而缺陷型组的阴性症状量表(SANS)评分明显高于非缺陷型组(P<0.05)。缺陷型组、非缺陷型组的重复性成套神经心理状态测验(RBANS)测验在注意、语言、视觉广度、即刻记忆、延迟记忆的5个认知领域评分以及总分均明显低于正常对照组(均P<0.05),且缺陷型组的RBANS测验在注意、语言、视觉广度、即刻记忆、延迟记忆的5个认知领域评分以及总分均明显低于非缺陷型组(均P<0.05)。缺陷型组、非缺陷型组的Stroop色词测验、听觉惊跳反射指标知觉空间融合前脉冲抑制(PSC-PPI)、知觉空间分离前脉冲抑制(PSS-PPI)和感知空间分离-知觉空间融合(PSS-PSC)评分均明显低于正常对照组(均P<0.05),且缺陷型组的Stroop色词测验、听觉惊跳反射指标PSCPPI、SS-PPI、PSS-PSC评分均明显低于非缺陷型组(均P<0.05)。结论缺陷型精神分裂症患者的听觉惊跳反射以及认知功能方面明显较非缺陷型严重,而缺陷型与非缺陷型精神分裂症患者的精神症状、阳阴性症状无明显差异,提示缺陷型精神分裂症患者的认知功能损害的更严重。     

奥氮平与喹硫平治疗以阴性症状为主精神分裂症的对照研究

目的评价国产奥氮平治疗以阴性症状为主的精神分裂症的疗效和安全性。方法将80例符合DSM-Ⅳ精神分裂症患者随机分为2组,分别给予奥氮平和喹硫平治疗,疗程共8周,用阳性症状与阴性症状量表(PANSS)、临床疗效总评量表(CGI)评定疗效,药物副反应量表(TESS)评定不良反应。结果奥氮平组显效率87.2%、喹硫平组显效率为81.1%,两药对阴性症状的疗效无显著性差异(P>0.05)。2组在治疗过程中出现较多的不良反应是嗜睡、体质量增加,但两者之间无显著性差异(P>0.05)。结论奥氮平对以阴性症状为主的精神分裂症有较好的疗效,与喹硫平的疗效和不良反应相当。     

A double-blind, placebo controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia

Although there have been several case reports suggesting the beneficial effect of acetylcholinesterase inhibitors in the cognitive deficits seen in schizophrenia, controlled studies have revealed contradictory results. The aim of this study was to investigate if donepezil could improve cognitive functions in schizophrenia. Twelve schizophrenic patients, who were diagnosed according to DSM-IV criteria and who had been on a stable dose of a high-potency typical antipsychotic for a minimum period of 3 months, participated in this 12-wk double-blind, placebo controlled, cross-over study of donepezil adjunctive treatment. Patients were randomly assigned under double-blind conditions to receive 5 mg/d donepezil or placebo for 6 wk, and then were crossed over to the alternate condition for 6 additional weeks. At baseline, 6 and 12 wk, patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, the Wechsler Memory Scale Revised (WMS-R), a test for Verbal Fluency, Trail Making Test, Parts A and B, and Wisconsin Card Sorting Test (WCST). Treatment effect was not significant in any of the cognitive measures. There were also no significant changes in the PANSS and depression scores. Nicotinic receptor desensitization may cause non-responsiveness to acetylcholine as previously suggested, but the most likely explanation appears to be that defects in other neurotransmitter systems account for the cognitive deficits seen in schizophrenic patients.     

喹硫平治疗精神分裂症伴抑郁症状的疗效

目的 :观察喹硫平治疗精神分裂症伴抑郁的疗效 ,并与利培酮作对照。方法 :对 5 2例精神分裂症伴抑郁病人分成喹硫平组与利培酮组 ,其中喹硫平组 2 7例 ,给予喹硫平 30 0～ 70 0mg·d- 1治疗。利培酮组 2 5例 ,给予利培酮 2～ 5mg·d- 1治疗。观察时间 6wk ,采用PANSS ,HAMD ,CGI等量表 ,分别于治疗前及治疗后wk 1,2 ,4 ,6末评定疗效 ,用TESS观察不良反应。结果 :经 6wk治疗后 ,喹硫平组与利培酮组疗效比较 ,经Ridit分析 ,差异无显著意义 (P >0 .0 5 )。但HAMD评分 ,喹硫平组治疗后减分率大于利培酮组 ,差异有非常显著意义 (P <0 .0 1)。结论 :喹硫平治疗精神分裂症伴抑郁与利培酮疗效相似 ,提示喹硫平除了具有抗精神病性症状作用外 ,还可能具有情感稳定的作用     

文拉法辛联合喹硫平治疗精神分裂症阴性症状的临床研究

目的：考查莫昔沙星文拉法辛缓释剂联合喹硫平治疗精神分裂症阴性症状的疗效和不良反应。方法：采用人院顺序分层随机法,将80例慢性精神分裂症患者分为观察组（文拉法辛缓释剂联合喹硫平）和对照组（喹硫平）,在治疗前和治疗第4、8、12周末以阳性和阴性症状量表（PNASS）总分及阴性因子分和不良反应量表（TESS）评定疗效和不良反应。结果：治疗12周末,观察组PANSS总分为（64．8±14．7）,阴性因子分（30．2±3．2）,与治疗前相比有统计学意义（P〈0．01）;对照组分别为（75．4±14．3）和（36．8±4．5）,与治疗前比较有统计学意义（P〈0．05）,观察组阴性因子各项症状评分均低于对照组。两组患者出现药物不良反应差异无统计学意义（P〉0．05）。结论：喹硫平治疗精神分裂症安全有效,协同文拉法辛治疗精神分裂症阴性症状可增加疗效。     

喹硫平与舒必利改善精神分裂症患者认知功能的比较研究

目的：观察喹硫平与舒必利对精神分裂症患者认知功能的改善情况。方法：将50例初诊或经典抗精神病药物治疗疗效不显著或无法耐受不良反应的精神分裂症患者分为喹硫平（n=25）与舒必利（n=25）两组,进行为期3个月的治疗。治疗前后应用PANSS、MMES分别评定精神症状与认知功能。结果：共39例患者完成3个月的治疗（喹硫平=19,舒必利=20）。与基线比较,喹硫平与舒必利都能明显改善精神分裂症患者的精神症状与认知功能,但两组间精神症状与认知功能改善程度并无差异。结论：喹硫平与舒必利都能明显改善精神分裂症患者的认知障碍,疗效无差异。     

Adjunct mirtazapine for negative symptoms of schizophrenia

Negative symptoms of schizophrenia are characterized by affective flattening, alogia, avolition, and anhedonia and are often nonresponsive to antipsychotic therapy. Because negative symptoms are predictive of poor occupational and social functioning, as well as poor global outcomes, numerous studies evaluating adjunct therapy to antipsychotics have been conducted. This review focuses on the use of the antidepressant mirtazapine as adjunct therapy to antipsychotics for the treatment of negative symptoms of schizophrenia. A literature search of the MEDLINE database (from inception-March 2011) identified eight relevant articles: six were randomized, double-blind, placebo-controlled trials, and two were open-label trials. Of the six randomized trials reviewed, four studies assessed add-on mirtazapine to second-generation antipsychotics, whereas two studies examined add-on mirtazapine to first-generation antipsychotics. Five of the six randomized trials supported the use of mirtazapine for negative symptoms of schizophrenia. Of the two open-label trials, one naturalistic study demonstrated that mirtazapine add-on therapy to clozapine was not associated with improvements in negative symptoms; however, this study focused primarily on improvements in cognition, not negative symptoms. An open-label extension phase to a randomized controlled trial showed that mirtazapine continued to produce significant improvement in negative symptoms over a longer duration of time, when added to first-generation antipsychotic therapy. Overall, mirtazapine appears to be well tolerated and associated with few drug interactions. Although adjunct mirtazapine to antipsychotics has been shown to be effective at doses of 30 mg/day in most of the trials, limitations of these studies include short study duration and small sample sizes. To improve generalizability, larger multicenter studies with broader inclusion criteria should be conducted. In addition, studies of longer duration that use different mirtazapine dosages are needed to further assess the benefits of mirtazapine for negative symptoms of schizophrenia.     

Amphetamine and negative symptoms of schizophrenia

The purpose of this study was to assess further the effect of amphetamine on negative symptoms of schizophrenia. Thirty-seven schizophrenic males meeting DSM-III criteria were rated with the Brief Psychiatric Rating Scale, the Abrams and Taylor Scale, and the Abnormal Involuntary Movements Scale before and after double-blind administration of either amphetamine (n=26) or placebo (n=11). Our results indicated that amphetamine administration generally did not improve negative symptoms, even when accounting for changes in positive symptoms. However, greater baseline negative symptoms were associated with a modest diminution after amphetamine treatment. Therefore, amphetamine may modestly improve negative symptoms in those schizophrenics in whom this symptomatology is more severe.     

Dextro-amphetamine diminishes negative symptoms in schizophrenia

Thirty schizophrenic patients received intravenous dextro-amphetamine while on and off pimozide. The results provide evidence that negative symptoms and depressed mood in schizophrenia respond in part to intravenous challenges of dextro-amphetamine. Improvement in negative symptoms while on d-amphetamine correlated significantly with subsequent improvement in the same negative symptoms while on pimozide. These results do not support the Type II model of irreversible negative symptoms in schizophrenia in our patient sample. Changes in negative symptoms may be related to state dependent changes in the dopamine system, but noradrenergic mechanisms cannot be excluded either.     

Maintenance treatment for schizophrenia with quetiapine

With the majority of current information being derived from short-term clinical trials, the impact of atypical antipsychotics during maintenance treatment of schizophrenia is of considerable interest, although only limited data are available at present. The present report is an analysis of data that are available up to 156 weeks after the start of an open-label extension (OLE) phase of three, double-blind randomized trials in quetiapine-treated patients who responded to an initial 6-week treatment period. The mean daily quetiapine dose (range 150-750 mg) was 439.5 mg for patients included in the brief psychiatric rating scale (BPRS) and 438.5 mg for patients included in the clinical global impression (CGI) analyses. The initial mean acute phase BPRS total score (40.67; n=258) and CGI severity of illness score (4.81; n=259) were reduced at the start of the OLE to 13.94 and 3.00, respectively. After 156 weeks, endpoint scores were 9.04 for BPRS and 2.43 for CGI severity of illness. Although limited by patient attrition, these OLE data suggest that an initial beneficial response with quetiapine treatment can be maintained over a long-term period.     

The treatment of cognitive impairment in schizophrenia

Cognitive deficits are major contributors to disability in schizophrenia. Many pharmacologic targets have been identified for cognitive enhancing agents, including receptors involved in dopaminergic, glutamatergic, GABAergic, serotonergic and cholinergic neurotransmission. In addition, new approaches to drug development have been directed towards neuroprotection and the facilitation of neuroplasticity. While several pharmacologic agents and cognitive remediation have shown promise in early trials, no treatment has yet demonstrated efficacy in large replication trials. The experience with different pharmacologic targets is reviewed and methodologic issues are discussed with recommendations for future research.     

Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia

RATIONALE: Schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia. OBJECTIVE: We examined the involvement of the glycine coagonist site on the N-methyl-D: -aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice. MATERIALS AND METHODS: Behavioral phenotypes relevant to schizophrenia were assessed in Grin1(D481N) mice that have reduced NMDAR glycine affinity. RESULTS: Grin1(D481N) mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, D: -serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, Grin1(D481N) mutant animals showed reduced social approach behaviors that were normalized by D: -serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by D: -serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the Grin1(D481N) mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty. CONCLUSIONS: Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms.     

Differential effect of quetiapine on depressive symptoms in patients with partially responsive schizophrenia

While atypical antipsychotics appear to be effective in reducing depressive symptoms in the acute phase of schizophrenia, little is known about their efficacy in patients with ongoing symptoms. The present study assessed whether quetiapine (Seroquel) is more effective than haloperidol in treating depressive symptoms in patients with persistent positive symptoms, and investigated whether this effect is independent, or secondary to, reductions in other symptoms such as positive, negative or extrapyramidal symptoms. Patients with schizophrenia and a history of partial refractoriness to conventional antipsychotics who had not responded to 4 weeks of fluphenazine treatment (20 mg/day) were randomized to receive either quetiapine (600 mg/day) or haloperidol (20 mg/day) for a further 8 weeks. Change in the Positive and Negative Syndrome Scale depression factor score from baseline to endpoint was calculated and path analyses were performed on data from 269 patients. Quetiapine produced a greater reduction in depressive scores than haloperidol (-1.60 versus -0.54; p = 0.006). The path analyses indicated that this was a direct effect on depressive symptoms. These findings extend the evidence for an antidepressant effect for the novel antipsychotics in schizophrenia, and suggest that this is not limited to acutely psychotic patients.     

Extrapyramidal symptoms related to adjunctive nizatidine therapy in an adolescent receiving quetiapine and paroxetine

Weight gain is a serious problem with recently introduced atypical antipsychotic agents. Nizatidine, a histamine2 (H2)-receptor antagonist, may help reduce this weight gain. To our knowledge, no adverse effects have been reported when nizatidine is given at recommended doses with atypical antipyschotic agents. We describe, however, an adolescent who was receiving quetiapine and paroxetine for schizophrenia and depression, and developed extrapyramidal symptoms (EPS; parkinsonism and akathisia) after taking nizatidine for weight loss. Based on a report of another patient who developed EPS after taking higher-than-recommended doses of nizatidine, we reviewed the literature on treatment with H2-receptor antagonists for weight gain and on central nervous system adverse effects of nizatidine. Nizatidine may be effective for reducing weight gain associated with both medical and psychiatric conditions. Its safety profile is usually benign, although some patients may develop serious adverse effects, such as EPS and delirium. Therefore, the drug is recommended for short-term management of weight gain associated with atypical antipsychotic agents. Patients receiving nizatidine therapy should be monitored closely for development of EPS, particularly when high doses are prescribed.