奥氮平使用者体重增加可能缘于大脑改变

《普通精神病学文献》(Archives of General Psychiatry)8月刊发的一项研究显示，奥氮平可明显改变大脑期望食物和体验饮食奖赏的方式，这种改变可导致用药者易于出现快速体重增加(doi:10.1001/archgenpsychiatry.2012.934)。

这项研究由圣路易斯华盛顿大学的Jose Mathews博士及其同事进行，共纳入19例平均体重指数为25.78 kg/m2的年轻受试者(平均27岁)。受试者在第1个晚上使用5 mg奥氮平，之后6天每晚使用10 mg。

所有受试者每晚均在研究中心住宿。每天早上进行功能性磁共振成像(fMRI)扫描，在此期间让受试者观看巧克力奶、番茄汁或水的图片，让其选取自己青睐的饮料，然后让受试者通过吸管品尝少量其青睐的饮料，并采用5分制Likert量表来评价他们所选的饮料(非常愉快、愉快、中性、不愉快、非常不愉快)。在扫描后，让受试者饮用其所选的饮料早餐，直至不再感到饥饿，然后再次进行扫描。

 

结果显示，第7天时平均摄入的早餐量为32盎司(约合907 g)，相对于基线摄入量(25盎司，约合709 g)显著增加。受试者的体重在第1周内平均增加1.1 kg。

此外，受试者的三因素饮食问卷脱抑制饮食分量表评分也显著增加。然而，受试者的饥饿感和对早餐的愉快感并未发生显著改变。

颅脑扫描显示，参与期望和奖赏的脑区发生明确改变。奥氮平治疗后，在尾状核和壳核观察到奖赏性味道体验反应增加，但对水的反应降低。奥氮平还影响下额叶皮质、纹状体和扣带回前部。所有这些区域在奥氮平治疗后均对奖赏性饮料图片的反应增强，但对水的图片的反应降低。在参与饱腹感的外侧眶额叶皮质也观察到反应降低。这些fMRI改变表明，对食物的预期渴望增加、奖赏性饮食体验增加和饱腹感相关机制受损。这些改变可能是奥氮平治疗后体重增加的原因。

该研究存在一些局限性，如未设安慰剂对照组，因此无法证明所观察到的改变与奥氮平治疗相关。另外，未用药扫描总是先于用药后扫描，这意味着习惯化效应可能与奥氮平效应相互混杂。

研究者表示，尽管存在这些局限性，但该研究结果仍将有助于研发既能降低增高的奖赏性饮食体验感，又可强化控制饮食摄入的抑制性回路的靶向治疗。

该研究获美国国立精神分裂症与抑郁症研究联盟及国立卫生研究院资助。Mathews博士曾是杨森制药公司和百时美施贵宝公司的讲师，但目前与药企无利益关系。

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By: MICHELE G. SULLIVAN, Clinical Neurology News Digital Network

Olanzapine apparently alters the way the brain anticipates food and experiences the reward of eating – changes that might predispose patients taking the drug to rapid weight gain, a study has shown.

Healthy, normal-weight volunteers who took the drug for a week gained a mean of 1 kg – a significant change from baseline. Brain imaging showed altered activity in areas involved with anticipation, reward response, and satiety, Dr. Jose Mathews and his colleagues reported in the August issue of Archives of General Psychiatry (doi:10.1001/archgenpsychiatry.2012.934).


"Interestingly, subjects’ perception of hunger did not change significantly after olanzapine treatment nor did their perception of the pleasantness," of morning food intake, wrote Dr. Mathews of Washington University in St Louis and his coauthors. "These findings contrast to the actual behavior of the subjects ... as they consumed significantly more breakfast and gained weight after treatment with olanzapine."

The study comprised 19 young people (mean age, 27 years) with a mean body mass index of 25.78 kg/m2. On the first night, they took 5 mg of olanzapine. They took 10 mg each night for the next 6 nights.

Each night, all of the volunteers stayed at the investigation site. Every morning, they had a functional magnetic resonance imaging session during which they saw images of chocolate milk, tomato juice, or water. After identifying which drink they preferred, they received a small portion through a tube, then rated their choices (very pleasant, pleasant, neutral, unpleasant, and very unpleasant) on a 5-point Likert scale.

After the scan, they consumed a breakfast of the liquid they had chosen and were instructed to drink until they were no longer hungry. Then all were rescanned.

A significant increase was found in the mean amount of breakfast consumed, from about 25 ounces at baseline to about 32 ounces by day 7. The subjects gained a mean of 1.1 kg over the course of the 1-week study.

They also showed a significant increase in the disinhibited eating subscale of the Three-Factor Eating Questionnaire. However, no changes were found in their feeling of hunger or in how pleasant they perceived their drink to be.

Brain imaging, however, showed definite changes in regions involved with anticipation and reward, the authors said.

"In the caudate and putamen, activation to the experience of rewarding taste increased after olanzapine treatment while the response to [water] decreased," the investigators wrote. The drug also affected the inferior frontal cortex, striatum, and anterior cingulate. "All these regions showed enhanced responses to cues predicting rewarding liquids after olanzapine, while there was a decrease in activation elicited by the picture of the [water]."

They also observed decreased activity in the lateral orbital frontal cortex, a region involved in satiety. "These fMRI changes suggested an enhanced anticipatory desire for food, an enhanced reward experience of [eating], and a compromised satiety-related mechanism. This pattern of change after treatment with olanzapine provides a plausible set of mechanisms that may contribute to the weight gain commonly associated with this medication."

The investigators cited several limitations of the study. The absence of a placebo control group limited their ability to show conclusively that the observed changes were tied to olanzapine treatment. Also, the subjects’ unmedicated scan always came before the scan with olanzapine, which means "it is possible that habituation effects could be confounded with the olanzapine effects."

Despite these limitations, Dr. Mathews and his colleagues said they think their findings might "pave the way for targeted treatments that may help dial down the enhanced reward value of food while strengthening the inhibitory circuits that control food intake."

The study was sponsored by the National Alliance for Research on Schizophrenia and Depression, and the National Institutes of Health. Dr. Mathews has been on the speakers bureaus of Janssen Pharmaceuticals and Bristol-Myers Squibb, but had no current financial disclosures.