Kaddurah-Daouk R, McEvoy J, Baillie R A, Lee D, Yao J K, Doraiswamy P M, Krishnan K R R
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
Mol Psychiatry. 2007 Oct;12(10):934-45. doi: 10.1038/sj.mp.4002000. Epub 2007 Apr 17.
Schizophrenia is associated with impairments in neurotransmitter systems and changes in neuronal membrane phospholipids. Several atypical antipsychotic drugs induce weight gain and hypertriglyceridemia. To date, there has not been a comprehensive evaluation and mapping of global lipid changes in schizophrenia, and upon treatment with antipsychotics. Such mapping could provide novel insights about disease mechanisms and metabolic side effects of therapies used for its treatment. We used a specialized metabolomics platform 'lipidomics' that quantifies over 300 polar and nonpolar lipid metabolites (across seven lipid classes) to evaluate global lipid changes in schizophrenia and upon treatment with three commonly used atypical antipsychotics. Lipid profiles were derived for 50 patients with schizophrenia before and after treatment for 2-3 weeks with olanzapine (n=20), risperidone (n=14) or aripiprazole (n=16). Patients were recruited in two cohorts (study I, n=27 and study II, n=23) to permit an internal replication analyses. The change from baseline to post-treatment was then compared among the three drugs. Olanzapine and risperidone affected a much broader range of lipid classes than aripiprazole. Approximately 50 lipids tended to be increased with both risperidone and olanzapine and concentrations of triacylglycerols increased and free fatty acids decreased with both drugs but not with aripiprazole. Phosphatidylethanolamine concentrations that were suppressed in patients with schizophrenia were raised by all three drugs. Drug specific differences were also detected. A principal component analysis (PCA) identified baseline lipid alterations, which correlated with acute treatment response. A more definitive long-term randomized study of these drugs correlating global lipid changes with clinical outcomes could yield biomarkers that define drug-response phenotypes.
精神分裂症与神经递质系统受损及神经元膜磷脂变化有关。几种非典型抗精神病药物会导致体重增加和高甘油三酯血症。迄今为止，尚未对精神分裂症患者以及使用抗精神病药物治疗后的全球脂质变化进行全面评估和图谱绘制。这样的图谱绘制可以为疾病机制以及用于治疗的疗法的代谢副作用提供新的见解。我们使用了一个专门的代谢组学平台“脂质组学”，该平台可对300多种极性和非极性脂质代谢物（涵盖七种类脂质）进行定量，以评估精神分裂症患者以及使用三种常用非典型抗精神病药物治疗后的全球脂质变化。对50例精神分裂症患者在使用奥氮平（n = 20）、利培酮（n = 14）或阿立哌唑（n = 16）治疗2 - 3周前后的脂质谱进行了分析。患者被招募到两个队列中（研究I，n = 27；研究II，n = 23），以进行内部重复分析。然后比较三种药物从基线到治疗后的变化。奥氮平和利培酮对脂质类别的影响范围比阿立哌唑更广。利培酮和奥氮平都使大约50种脂质趋于增加，两种药物都使甘油三酯浓度升高而游离脂肪酸浓度降低，但阿立哌唑未出现这种情况。三种药物都使精神分裂症患者中被抑制的磷脂酰乙醇胺浓度升高。还检测到了药物特异性差异。主成分分析（PCA）确定了基线脂质改变，其与急性治疗反应相关。对这些药物进行更明确的长期随机研究，将全球脂质变化与临床结果相关联，可能会产生定义药物反应表型的生物标志物。
