使用methylphenidate對注意力不足過動症患童發生精神疾病之影響

Abstract

研究背景：注意力不足過動症（ADHD）為常見的早發型兒童神經精神疾患之一，主要的治療藥物為中樞神經興奮劑（stimulants），其中使用最廣泛的是methylphenidate（MPH）。臨床上ADHD病患常見伴有其它神經精神疾病，因此也會使用神經精神藥物作治療。雖然MPH的療效已獲得證實，但近幾年對其引起物質濫用或精神性相關的副作用有多起報導。然而目前國內尚無神經精神藥物在ADHD患童及青少年的使用情形之研究，且缺乏ADHD病患長期使用MPH的相關研究報告，因此本研究希望可提供這方面的資料，作為臨床用藥之參考。 研究目的：針對小於18歲的ADHD病患，分析近十年來神經精神藥物的使用趨勢，並探討長期使用MPH對日後發生其他神經精神疾病的影響。 研究方法：本研究為藥物流行病學之分析，使用台灣健保資料庫2005年100萬人承保抽樣歸人檔（LHID2005）為研究材料。第一部份將1997-2007年門診就醫診斷有ADHD之小於18歲病患的紀錄取出，計算ADHD患童的治療盛行率，及其在性別、年齡、年代的分佈情形，並探討神經精神藥物及MPH在近十年來的使用趨勢。第二部份為回溯性世代追蹤研究，以1999-2003年新診斷有ADHD之病患為研究對象（ADHD組），依研究追蹤期間有無使用過MPH作治療，分成ADHD-M和ADHD-N兩組，由年齡及性別以1：4比例配對找出1997-2007年無ADHD也無使用過MPH之病患為non-ADHD組。主要研究終點事件為雙極性躁鬱症（BP）事件之發生，次研究終點事件為憂鬱症、低落性情感疾患、焦慮症、行為規範障礙（CD）和對立反抗性疾患（ODD）之發生，探討MPH的使用對研究終點事件的影響。以time dependent Cox proportional hazard regression model進行存活分析，以單變項分析結果，將有可能成為干擾因子之變項納入多變項迴歸模式進行統計校正。 研究結果：第一部分研究：自1997-2007年ADHD病患在門診的治療盛行率由0.05%上升至1.27%（β =0.25，p<.0001），有逐年上升之趨勢，男性對女性的比例約2.6：1至5：1，平均年齡在7.2-8.9歲之間。不同年齡層族群的治療盛行率皆呈現逐年上升之趨勢，其中以6-9歲族群之治療盛行率最高且增加幅度最大。MPH（β =0.08，p<.0001）在ADHD門診的使用人次比例位居歷年之冠，近十年來由40%增加為60%，呈現逐年上升之趨勢。其中短效劑型的MPH （β = -0.04，p<.0001）之使用人次比例逐年下降，相反的長效劑型的MPH（β = 0.46，p<.0001；β = 0.85，p<.0001），自2004年到2007年呈現顯著逐年遞增之趨勢。1997-2007年，ADHD病患於門診就醫中除MPH以外，使用最多的神經精神藥物為抗憂鬱劑（4.4%-8.2%），其次為抗精神病藥物（3.9%-5.2%），其中SSRIs（β =0.11，p<.0001）的使用人次比例由0.34%上升至2.7%有逐年上升之趨勢，而TCAs（β = -0.16，p<.0001）的使用人次比例由4.3%下降至1.1%有逐年下降之趨勢；第一代抗精神病藥物（β = -0.1，p<.0001）的使用人次比例由4.2%下降至0.99%有逐年下降之趨勢，而第二代抗精神病藥物（β =0.18，p<.0001）的使用人次比例由0.34%-3.0%有逐年上升之趨勢。第二部分研究：從1999年至2003年新診斷ADHD病患有2109人（ADHD組），平均年齡為7.3歲，男性佔79.8%；non-ADHD組共8414人，平均年齡7.2歲，男性占78.7%。ADHD-M組病人曾有過行為治療之比例高達75％，亦高於ADHD-N組病人之50％。ADHD-M組比上ADHD-N組之勝算比，在BP、憂鬱症、低落性情感疾患、焦慮症、CD和ODD等精神疾病有較顯著之差異。經多變項分析後之結果顯示，在ADHD病患，長期使用MPH對BP和ODD的發生，校正可能之干擾因子後，MPH的使用依然達p<0.05之顯著水準。 結論：在1997-2007年期間，小於18歲的ADHD病患之治療盛行率呈現逐年增加的趨勢，表示國人對ADHD認知的提升。各類神經精神藥物中，MPH在ADHD病患的使用率最高且隨著年代而上升，然而隨著長效劑型的MPH在台灣上市，短效劑型MPH的使用人次有下降之趨勢。在回溯性世代追蹤的結果顯示，ADHD病人長期使用MPH與病人發生BP和ODD具有相關性。雖其機轉尚未明確，但於臨床使用仍需注意。

Background: Attention deficit/hyperactivity disorder (ADHD) is the most common developmental neuropsychiatric disease in children. CNS stimulants especially methylphenidate (MPH) are major therapeutic agents for ADHD. ADHD often occurs with other psychiatric illness therefore the treatment with neuropsychotropic agents is common. Although numerous studies strongly support the efficacy of MPH in symptom reduction, its role in the risks for substance use or occurring psychiatric adverse events has been the interesting topics for MPH. Up to now; there have been no information about the long-term use of neuropsychotropic agents to children with ADHD in Taiwan. The pharmacoepidemiology data for ADHD patients is important for clinical practice and medical policy. Objectives: To describe the trends of neuropsychotropic agents used to treat children with ADHD over 10 years of time and to investigate the impact of long-term effect of MPH use on coming up other psychiatric disorder with ADHD. Methods: This study was a pharmacoepidemiology study. The medical claim from outpatient settings with a diagnosis of ADHD and patients’ age under 18 years old were retrieved from a subset database of National Health Insurance database (NHIRD), i.e., the LHID2005, from 1997 to 2007. Descriptive analysis on the treated prevalence rate and the trend in the use of neuropsychotropic agents especially MPH for ADHD patients was conducted. The second part of our study was a retrospective cohort study. Children with new onset of ADHD from 1999 to 2003 were included as ADHD group; they were further divided into two subset group (ADHD-M and ADHD-N) according to the MPH usage in the observation period. The non-ADHD group of the same age range and sex to the ADHD group was retrieved from LHID2005 of patients other than the ADHD group. Time to bipolar disorder come up was the primary endpoint of this study, and time to depression, dysthymia, anxiety, conduct disorder and oppositional defiant disorder come up were secondary endpoint. Survival analysis was conducted by using time dependent Cox proportional hazard regression model to evaluate potential confounding factors by univariate analysis. Potential confounding factors were used to adjust hazard ratio of MPH use model in multivariate analysis. Results: The rate of outpatient services for ADHD increased from 0.05% in 1997 to 1.27% in 2007 (β =0.25，p<.0001). The male to female ratios for patients in the retrieved ADHD medical records were in the range of 2.6:1 to 5:1 over the years, and the mean age of patients in the medical records was 8.5±3.2 years old. The rate of outpatient services in all age groups for ADHD increased from 1997 to 2007, and 6-9 age group increased at most. The most commonly used neuropsychotropic agents was methylphenidate (MPH), the prescription rate of MPH increased significantly (β= 0.078, p<0.0001) from 42.6 to 64 per 100 medical records from 1997 to 2007. ADHD patients in 12-15 age group had the highest prescription rate of MPH. Percentage of patients under MPH treatment in male ADHD patients was higher than those in female ADHD patients. The prescription rate of immediate-release (IR) MPH (β = -0.04, p<.0001) decreased with a significantly increased from 2004 to 2007 in osmotic release oral system (OROS) MPH (β = 0.46, p<.0001；β = 0.85, p<.0001). Other than MPH, antidepressants (4.4%-8.2%) were the highest prescription rate of psychotropic medications and antipsychotics (3.9%-5.2%) were the second. The prescription rate of SSRIs (β= 0.11, p<0.0001) increased from 0.8% to 3.7%, however, significantly decrease in the prescription rate of TCAs (β= -0.16, p<0.0001) from 4.4% to 1.1% was found in the same period. The prescription rate of atypical antipsychotics (β= 0.18, p<0.0001) increased significantly (0% to 3%) with a decrease (4.1% to 1.0%) in typical antipsychotics (β = -0.10, p<0.0001) from 1997 to 2007. A total of 2109 new onset ADHD patients from 1999 to 2003 were identified and 8414 matched controls were randomly selected. The ADHD group had a mean age of 7.3 year old and 79.8% were males. There were higher risk of occurring bipolar disorder, depression, dysthymia, anxiety, conduct disorder and oppositional defiant disorder in group of ADHD-M to ADHD-N by calculating the odds ratio. After multivariate analysis and adjusted by univariate, MPH (p<0.05) use had a relationship with bipolar disorder and oppositional defiant disorder in ADHD patients. Conclusions: Results of this study indicated that not only the rate of outpatient services for ADHD patients but also the rate of medication therapy in ADHD patients in Taiwan increased significantly from 1997 to 2007. MPH was the most used neuropsychotropic agents to children with ADHD in Taiwan as expected. The impact of long-term effect of MPH use on coming up bipolar disorder and oppositional defiant disorder is truly existed. Although the mechanism of this effect still unknown, it should be used cautiously on clinical practice.