对精神分裂症患者补充叶酸需考虑基因型

《美国医学会杂志·精神病学》发表的一项研究显示，补充叶酸和维生素B₁₂可能改善精神分裂症的阴性症状，但仅限于携带影响叶酸代谢的基因变异的患者(2013 March 6 [doi: 10.1001/jamapsychiatry.2013.900])。

已知叶酸缺乏症是精神分裂症的一项危险因素，并且研究中纳入的所有4种基因变异均与精神分裂症的阴性症状(如冷漠、社交退缩和感情表达缺陷)相关。这项双盲、安慰剂对照研究共纳入140例精神分裂症门诊患者，尽管这些患者均经过抗精神病药物治疗，症状却仍然持续存在。随机给予患者每日叶酸2 mg和维生素B₁₂ 400 mcg或安慰剂治疗16周。患者年龄为18~68岁，已接受抗精神病药物治疗至少6个月，接受稳定剂量治疗至少6周，且阳性和阴性综合征评分≥60分。

结果显示，当考虑基因型时，与安慰剂组相比，接受叶酸+维生素治疗者的阴性症状评估量表(SANS)评分显著改善[组间差异为每周评分改变–0.33；95%置信区间(CI)为–0.62~–0.05]。高功能性FOLH1(484T)变异与补充治疗获益相关，而FOLH1(484C)低功能性变异或MTHFR、MTR或COMT基因型患者接受补充治疗的效益未达到统计学意义。在484T等位基因[叶酸水解酶1(FOLH1)基因的一种变异]为纯合子的患者中，补充叶酸和维生素B₁₂的获益更为显著(SANS评分每周改变–0.59；95%CI为–0.99~–0.18)。尽管治疗效应仅为中度，但研究者指出，鉴于与阴性症状相关的残疾、缺乏针对这些症状的治疗，以及补充维生素的副作用很小，故即使很小的效应也具有临床意义。

研究者总结认为，仅T等位基因纯合子患者在接受16周的叶酸补充治疗后可改善阴性症状。

该研究由国立精神卫生研究所和哈佛Hughes医学研究所的奖金资助，并得到哈佛大学医学院临床与转化科学研究中心的支持。研究者披露接受了多个医药公司和研究组织的支持和资助。

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By: BIANCA NOGRADY, Cardiology News Digital Network

Folate and vitamin B12 supplements may improve the negative symptoms of schizophrenia but only in patients with a genetic variant that influences folate metabolism, a study has shown.

"Although four such variants have previously been associated with negative symptom severity, the genotype that contributed most strongly to treatment response was FOLH1 484T>C," wrote Dr. Joshua L. Roffman, of the psychiatry department at Massachusetts General Hospital, Boston, and his colleagues.
 
Patients treated with folate plus vitamin B12 showed significant improvement on the Scale for the Assessment of Negative Symptoms (SANS), compared with placebo (group difference, –0.33 change in score per week; 95% confidence interval, –0.62 to –0.05), when genotype was taken into account.

Among patients homozygous for the 484T allele – a genetic variant in the folate hydrolase 1 (FOLH1) gene – the benefits of folate and vitamin B12 supplements were even greater (–0.59 change in SANS score per week; 95% CI, –0.99 to –0.18), according to results published in JAMA Psychiatry (formerly Archives of General Psychiatry) (2013 March 6 [doi: 10.1001/jamapsychiatry.2013.900]).

The double-blind, placebo-controlled study randomized 140 outpatients with schizophrenia, who had persistent symptoms despite treatment with antipsychotics, to 2 mg of folic acid and 400 mcg of vitamin B12 daily for 16 weeks or placebo. The patients were 18-68 years old, had been treated with an antipsychotic for at least 6 months, and were at a stable dose for at least 6 weeks. They also had to have scored at least 60 on the Positive and Negative Syndrome Scale.

The study found that only the high-functioning variant of FOLH1 (484T) was associated with a benefit from supplementation, while the effects of supplementation did not reach significance for either the low-functioning variant of FOLH1 (484C) or the MTHFR, MTR, or COMT genotypes.

While the treatment effects were modest, the researchers noted that even small effects could be clinically meaningful given the disability associated with negative symptoms, the paucity of available treatments for these symptoms, and the minimal side effects of vitamin supplements.

Folate deficiency is known to be a risk factor for schizophrenia, and all four genetic variants included in the study have been associated with increased severity of negative symptoms such as apathy, social withdrawal, and loss of emotional expressiveness.

"Thus, the finding that only patients homozygous for the T allele exhibited improvement in negative symptoms after 16 weeks of folate supplementation could reflect diminished folate absorption, and briefer exposure to higher folate levels, among C allele carriers," the researchers wrote.

The authors suggested that the findings could have implications for other health conditions associated with reduced folate and elevated homocysteine concentrations, such as stroke, cardiovascular disease, and dementia. "The current results suggest that individual differences in folate metabolism related to the presence of common functional genetic variants may have a bearing on treatment outcomes in these other disorders, as well as negative symptoms of schizophrenia," Dr. Roffman and his colleagues noted.

The research was funded by the National Institute of Mental Health and an award from the Howard Hughes Medical Institute, with support from Harvard Catalyst. The investigators disclosed receiving support and grants from a number of pharmaceutical companies and research organizations.