Evidence in primates supporting the use of chemogenetics for the treatment of human refractory neuropsychiatric disorders

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奎的平与氯氮平治疗精神分裂症疗效比较研究

目的探讨奎的平与氯氮平治疗精神分裂症的疗效和安全性。方法将68例精神分裂症患者随机分为研究组（奎的平治疗）与对照组（氯氮平治疗）各34例。治疗期间研究组脱落1例，实际完成33例，对照组脱落2例，实际完成32例。两组疗程均为8w。于治疗前及治疗第2、4、8w末采用阳性与阴性症状量表评定临床疗效，副反应量表评定不良反应，并进行对比分析。结果研究组显效率69．7％，有效率93．9％；对照组显效率68．8％，有效率93．8％，两组间比较均无显著性差异（P〉0.05）。研究组不良反应较对照组少且轻。结论奎的平治疗精神分裂症疗效确切，不良反应少，服药依从性好。     

氯氮平、阿立哌唑对精神分裂症患者血浆神经肽Y、瘦素水平的影响及其与体质量变化的关系

目的:探讨氯氮平和阿立哌唑对精神分裂症患者血浆神经肽Y、瘦素水平的影响及其与体质量变化的关系。方法:60例精神分裂症患者随机分为氯氮平组和阿立哌唑组各30例,分别接受氯氮平和阿立哌唑治疗6周。于治疗前及治疗3周和6周后分别测定两组血浆神经肽Y、瘦素水平及体质量,并进行治疗前后的比较及回归分析。结果:重复测量方差分析显示,血浆神经肽Y、瘦素水平及体质量存在交互效应(F=11.203,P=0.000;F=5.981,P=0.033;F=7.523,P=0.003)和组别主效应(F=6.772,P=0.023;F=37.771,P=0.000;F=5.674,P=0.039)。治疗3周和6周时,氯氮平组血浆神经肽Y水平(F=30.764,P=0.000;F=59.963,P=0.000)、体质量(F=5.424,P=0.042;F=11.423,P=0.000)均高于治疗前;治疗6周时,血浆瘦素水平显著高于治疗前(F=10.132,P=0.004)。阿立哌唑组血浆神经肽Y(F=0.143,P=0.708;F=0.293,P=0.593)、瘦素水平(F=1.343,P=0.256;F=1.030,P=0.326)、体质量(F=2.743,P=0.113;F=0.132,P=0.722)与治疗前比较差异无统计学意义。逐步回归分析显示,治疗3周和6周时神经肽Y变化值可以解释同期体质量变化值变异的41.9%和21.8%。结论:与阿立哌唑比较,氯氮平可显著增加精神分裂症患者血浆神经肽Y、瘦素水平;神经肽Y水平增高可能是氯氮平导致患者体质量增加的内因之一。     

Cannabidiol Attenuates Sensorimotor Gating Disruption and Molecular Changes Induced by Chronic Antagonism of NMDA receptors in Mice

Background:

Preclinical and clinical data suggest that cannabidiol (CBD), a major non-psychotomimetic compound from Cannabis sativa, induces antipsychotic-like effects. However, the antipsychotic properties of repeated CBD treatment have been poorly investigated. Behavioral changes induced by repeated treatment with glutamate N-methyl-D-aspartate receptor (NMDAR) antagonists have been proposed as an animal model of schizophrenia-like signs. In the present study, we evaluated if repeated treatment with CBD would attenuate the behavioral and molecular modifications induced by chronic administration of one of these antagonists, MK-801.

Methods:

Male C57BL/6J mice received daily i.p. injections of MK-801 (0.1, 0.5, or 1mg/kg) for 14, 21, or 28 days. Twenty-four hours after the last injection, animals were submitted to the prepulse inhibition (PPI) test. After that, we investigated if repeated treatment with CBD (15, 30, and 60mg/kg) would attenuate the PPI impairment induced by chronic treatment with MK-801 (1mg/kg; 28 days). CBD treatment began on the 6th day after the start of MK-801 administration and continued until the end of the treatment. Immediately after the PPI, the mice brains were removed and processed to evaluate the molecular changes. We measured changes in FosB/ΔFosB and parvalbumin (PV) expression, a marker of neuronal activity and a calcium-binding protein expressed in a subclass of GABAergic interneurons, respectively. Changes in mRNA expression of the NMDAR GluN1 subunit gene (GRN1) were also evaluated. CBD effects were compared to those induced by the atypical antipsychotic clozapine.

Results:

MK-801 administration at the dose of 1mg/kg for 28 days impaired PPI responses. Chronic treatment with CBD (30 and 60mg/kg) attenuated PPI impairment. MK-801 treatment increased FosB/ΔFosB expression and decreased PV expression in the medial prefrontal cortex. A decreased mRNA level of GRN1 in the hippocampus was also observed. All the molecular changes were attenuated by CBD. CBD by itself did not induce any effect. Moreover, CBD effects were similar to those induced by repeated clozapine treatment.

Conclusions:

These results indicate that repeated treatment with CBD, similar to clozapine, reverses the psychotomimetic-like effects and attenuates molecular changes observed after chronic administration of an NMDAR antagonist. These data support the view that CBD may have antipsychotic properties.     

Weight gain and antipsychotics: a drug safety review

Introduction: Second-generation antipsychotics (SGAs) are widely used in several psychiatric disease entities and exert to a different extent a risk for antipsychotic-induced weight gain (AIWG). As AIWG is associated with an increase in metabolic syndrome or cardiovascular events, knowledge of these risks is crucial for further monitoring and the initiation of counteractive measures.

Areas covered: We searched PubMed and Web of Sciences for randomized-controlled trials and naturalistic observational studies published between 2010 and 2014 with sample sizes exceeding 100, including all marketed SGAs apart from zotepine, and providing data on weight increase. We also summarized relevant systematic reviews and meta-analyses of head-to-head comparisons.

Expert opinion: Recently published data still support the hierarchical ranking of SGAs already proposed in previous reviews ranking clozapine and olanzapine as having the highest risk, followed by amisulpride, asenapine, iloperidone, paliperidone, quetiapine, risperidone and sertindole in the middle, and aripiprazole, lurasidone and ziprasidone with the lowest risk. Number needed to harm varied considerably in our meta-analysis. Younger patients and patients with a lower baseline body mass index are most vulnerable. The greatest amount of weight gain occurs within the first weeks of treatment. AIWG occurs in all diagnostic groups and is also common in treatment with first-generation antipsychotics; therefore, awareness of this adverse event is essential for anyone prescribing antipsychotics.