Clinical Pharmacy & Pharmacogenomics Life

代謝症候群 (metabolic syndrome, MeS) 是一種涵蓋了許多臨床與生化風險因子的疾病，這些病人可能正被心血管疾病、糖尿病與過早死亡等問題侵蝕著。
The metabolic syndrome (MeS) is a collection of clinical and biochemical risk factors that predispose affected individuals to cardiovascular disease (CVD), diabetes mellitus, and premature mortality (Med Clin North Am. 2006;90 (4): 573-591).

代謝症候群最主要的潛在風險因子是腹部肥胖 (abdominal obesity) 與胰島素阻抗性 (insulin resistance)。此外，不好活動者、年長者與荷爾蒙失衡也被認為是代謝症候群的病理性因子。其他被認為與代謝症候群相關的狀況包括非酒精性脂肪肝、多發性卵巢症候群、睡眠呼吸中止症，以及脂肪萎縮症。
The major underlying risk factors for MeS are abdominal obesity and insulin resistance. Habitual inactivity, aging, and hormonal imbalances are also considered to be pathogenic factors for MeS (J Am Coll Cardiol. 2005;44 (3): 720-732). Other conditions associated with MeS are non-alcoholic fatty liver disease, polycystic ovarian syndrome, sleep apnea, and lipodystrophies (Bipolar Disord. 2005;7 (3): 246-259).

雖然有幾個協會皆有對代謝症候群進行定義，但目前最廣為被引用的，係屬美國國家膽固醇教育計畫 (NCEP) 檢測、評估與治療成人高血脂症之專家會議的第三次報告中所發表之定義。
Although several definitional schemas have been proposed for MeS, the Third Report of the US National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]) is the most often cited definition.

其中各個協會制定的定義中皆強調，肥胖與胰島素阻抗性是代謝症候群典型的生理進程。
The commonalities across the various schemas for defining MeS emphasize obesity and insulin resistance as paradigmatic physiological processes.

近來有許多流病學與臨床研究指出，在某些精神官能症，如重度憂鬱症 (major depressive disorder, MDD) 患者，其罹患代謝症候群的風險會較一般人高。
The increased risk for MeS in individuals with psychotic as well as major depressive disorders has been well documented in both epidemiological and clinical studies (McEvoy et al., 2005).

此外，也有文獻指出，罹患精神分裂症合併代謝症候群的高風險群為較年長者、白種人、女性，以及具有較高的 Short Form (SF) 12量表分數者。
Individuals with comorbid schizophrenia and MeS were more likely to be older, white and female and to have higher scores on the Short Form (SF)12 (Physical score). (Meyer et al., 2005).

實驗方法 (Methods)

簡略來說，作者去 Pubmed 用 metabolic syndrome, bipolar disorder, mania, manic-depression 等關鍵字，撈了從 2005 年 1 月到 2009年 7 月的英文論文，以期探討代謝症候群與躁鬱症病患族群的相關性。
We conducted a PubMed search of all English-language articles published between January 2005 and July 2009 with the following search terms: metabolic syndrome and bipolar disorder, mania and manic-depression.

統合與概要 (Synthesis and synopsis)

作者將這些從12個國家來的研究進行整合：
首先，各個研究中對躁鬱症病患是否有符合代謝症候群的標準，會依照其所參照的各個協會有不同的定義。
Taken together, there are several themes that emanate from the extant data reviewed herein from twelve countries. Firstly, it is well established that individuals with BD are differentially affected by NCEP-III- and IDF-defined MeS.

其次，代謝症候群患者在患病定義中的各項標準於各個研究中幾乎都是增加的，其中所有研究皆一致地顯現腰圍異常的狀況。
Secondly, each component of the MeS is abnormal in most studies with increased waist circumference as the most consistently reported abnormality.

三者，發生代謝症候群與躁鬱症的病患，與較複雜的病況表現 (自殺行為)，對治療反應較差，以及不良的疾病進程與治療成效有較高度的相關性。
Thirdly, the co-occurrence of MeS and BD is associated with a more complex illness presentation, less favorable response to treatment, and adverse course and outcome.

第四，這些合併產生代謝症候群與躁鬱症的患者，幾乎都有使用會引起體重增加之抗精神分裂症藥物。
雖然以現有的文獻並無法去確切的評估這些精神科藥物對於引起代謝症候群的傷害揪竟有多大，但可以確信的是，其影響是顯著的。
Fourthly, the co-occurence of MeS and BD is very often associated with exposure to weight-gain promoting psychotropic agents.
As such, the precise extent to which psychotropic agents account for the hazard for MeS in this population cannot be precisely estimated but appears to be significant.

作者也提到，在整合這些研究中，因為研究方法的缺陷等問題因此讓研究結果有所缺陷。
1) 各個研究的病患組成、內容，以及對躁鬱症與代謝症候群診斷標準或定義不一所造成的異質性
2) 幾乎都來自於回溯型橫斷性研究
3) 在收納的病患中並沒有提到對於代謝症候群患者在發病前的治療資料
There are several methodological deficiencies that limit inferences and interpretations of the data. They include, but are not limited to:
1) heterogeneity in sample size, diagnostic criteria for BD and MeS, sample composition
2) a reliance on largely cross-sectional retrospective studies
3) insufficient pre-treatment information on MeS in enrolled subjects.

臨床建議 (Clinical Recommendations)

臨床醫師應仔細的評估每一位躁鬱症患者，並適切的回顧病史、用藥史和家族史，注意其是否具有可能與代謝症候群相關的風險因子。
Clinicians should carefully screen all BD patients for risk factors related to MeS as well as comprehensively review medical and family history.

腰圍已被證實是用來觀測腹部肥胖良好的參數，此外我們也可以藉由觀測腰圍的變化，來探知病患在基礎值 (baseline) 乃至治療期間的趨勢曲線。
Waist circumference has been demonstrated to be a surrogate for abdominal obesity and can easily be measured at baseline and during ongoing surveillance of a patient (Bosello and Zamboni, 2000; Yusuf et al., 2005).

從美國糖尿病／美國精神病／協會與國際躁鬱症安全性評估準則指引一致建議：

※ 接受第二代抗精神分裂症藥物 (second-generation antipsychotic agents, SGAs) 治療之躁鬱症患者，應在 baseline 與開始服藥或換藥後之第 4, 8, 12 週測量其體重與BMI值，並於每季進行例行性追蹤。
Extrapolating from the American Diabetes/American Psychiatric/Association Consensus recommendations as well as the International Society for Bipolar Disorder Guidelines on the safety monitoring of the bipolar patient, BD patients receiving SGAs should have their weight and BMI evaluated at baseline and assessed at 4, 8, and 12 weeks after initiating or changing SGA and quarterly thereafter at the time of routine visits (American Diabetes Association, 2004; Ng et al., 2009).
 

※ 在開始服用抗精神分裂症藥物三個月後，應追蹤其空腹血糖值、血脂濃度與血壓值。
※ 之後，應每年定期檢查血壓和血糖值，而在某些 baseline 就顯示為糖尿病或高血壓高風險群的病人，應更頻繁的進行監測。
Fasting plasma glucose, lipid levels, and blood pressure should also be assessed 3 months after initiation of antipsychotic medications. Thereafter, blood pressure and plasma glucose values should be obtained annually or more frequently in those who have a higher baseline risk for the development of diabetes or hypertension.

※ 在接受治療後三個月內血脂數據呈現正常的病患，應每三年接受血脂檢驗，如臨床上有需要，可更頻繁的追蹤。
In patients with a normal lipid profile at 3 months, repeat testing should be performed at 3-year intervals or more frequently if clinically indicated.

治療 (Treatment)

非典型抗精神分裂症藥物 (SGAs) 目前已知會顯著的造成體重增加與肥胖，並可能加速糖尿病的進程。對於躁鬱症病患而言，合併使用 SGAs 與 mood stabilizers 可能會造成更大的肥胖風險。此外，與使用 SGAs 單一治療相較，病患使用抗精神病藥的多重治療會有較高的比率罹患代謝症候群與胰島素阻抗性。
Treatment with atypical antipsychotics is well known to be associated with significant weight gain and obesity, as well as with hyperglycemia, exacerbation of pre-existing diabetes, or development of type 2 diabetes (Henderson, 2008). The combination of atypical antipsychotics and mood stabilizers may result in additional risk for obesity in patients with BD (Kim et al., 2008). Compared with antipsychotic monotherapy, patients receiving antipsychotic polytherapy were shown to have higher rates of MeS and insulin resistance (Correll et al., 2007)

SGAs: clozapine, olanzapine, risperidone and quetiapine et al.

Mood stabilizers: lithium, valproate et al.

Adapted from Journal of Affective Disorder 2010; 126: 366-367

Bipolar disorder and metabolic syndrome: an international perspective.

McIntyre RS, Danilewitz M, Liauw SS, Kemp DE, Nguyen HT, Kahn LS, Kucyi A, Soczynska JK, Woldeyohannes HO, Lachowski A, Kim B, Nathanson J, Alsuwaidan M, Taylor VH.

Link: http://www.ncbi.nlm.nih.gov/pubmed/20541810 
　

Wind Wei-Lun Chang

11 Nov. 2011