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美國食物及藥物管理局 (USFDA)不良事件通報系統 (AERS)數據庫的結果顯示, 病人併用血清素能的精神科藥物與屬於可逆性單胺氧化酶抑制劑的亞甲藍 (methylene blue)和linezolid (Zyvox®)作治療時, 可能會導致嚴重的中樞神經系統反應。Methylene blue用於高鐵血紅蛋白血症﹑血管麻痺綜合症﹑ifosfamide引起的腦病變以及氰化物中毒, 也可作為治療和診斷的染色劑。Linezolid是抗感染藥物, 用於治療由耐藥菌株引起的肺炎﹑皮膚感染和其他感染。雖然並不清楚這些藥物之間相互作用的確切原因和機制, 但上述兩種藥物都會抑制負責降解腦部血清素的單酶氧化酶A的作用, 導致腦部血清素積聚, 而引起稱為血清素綜合症 (Serotonin Syndrome)的毒性反應。在停止服用半衰期長的血清素能精神科藥物時, 也可能會出現上述潛在的藥物相互作用。血清素綜合症引起的嚴重中樞神經系統反應的症狀包括神智改變(意識混亂﹑過度活躍和記憶問題)﹑肌肉痙攣﹑過度出汗﹑發顫或抖動﹑腹瀉﹑協調障礙和發熱。基於上述原因, 建議醫生﹑藥劑師及其他衛生專業人士：
- 除非認為效益高於風險, 否則methylene blue和linezolid都不應用於正在服用血清素能精神科藥物的病人。
- 如methylene blue或linezolid需立即用於正在服用血清素能精神科藥物的病人, 以控制危及生命的症狀時, 必須立即停用血清素能藥物, 其後兩個星期需密切監測病人中樞神經系統的急性症狀 (fluoxetine需5個星期)。
- 如正在服用血清素能精神科藥物的病人需安排使用methylene blue或linezolid治療, 大部分的血清素能藥物應至少在治療前兩個星期(fluoxetine需5個星期)停用。
- 教導病人認識上述血清素綜合症的中樞神經毒性症狀, 如在服用血清素能精神科藥物﹑methylene blue或linezolid期間出現上述症狀, 需立即求診。
- 告知正在服用血清素能精神科藥物的病人不要在未經醫生同意下, 自行停止服用藥物。
- 熟悉下列具有血清素能作用的精神科藥物：
- 選擇性血清素再吸收抑制劑 (SSRIs)：citalopram﹑escitalopram﹑fluvoxamine﹑fluoxetine, paroxetine和sertraline;
- 血清素-去甲腎上腺素再吸收抑制劑 (SNRIs)：desvenlafaxine和venlafaxine;
- 三環類抗抑鬱藥 (TCAs)：amitriptyline﹑clomipramine﹑doxepin﹑imipramine﹑nortriptyline和trimipramine;
- 單胺氧化酶抑制劑 (MAOIs)：selegiline;
- 其他精神藥物：bupropion﹑buspirone﹑maprotiline﹑mirtazapine﹑nefazodone和trazodone。
Results on the United States Food and Drug Administration (USFDA) Adverse Events Reporting System (AERS) database indicated that concomitant treatments of serotonergic acting psychiatric medications with either one of the reversible monoamine-oxidase-inhibitors (MAOIs) namely methylene blue and linezolid (Zyvox®), may lead to serious central nervous system (CNS) reactions in patients. Methylene blue is indicated in methemoglobinemia, vasoplegic syndrome, ifosfamide-induced encephalopathy, cyanide poisoning and can also be used as a dye in therapeutic and diagnostic applications. As an anti-infective, linezolid, is used to treat pneumonia, skin infections and other infections caused by resistant bacteria. Although the exact cause and mechanism on how these drugs interaction with one another is unknown, both of them inhibit the action of monoamine-oxidase-A-enzyme, which is responsible for breaking down serotonin in the brain leading to the subsequent build-up in the brain, causing toxicity known as Serotonin Syndrome. It appears that this potential drug interaction can also occur following the discontinuation of serotonergic psychiatric medications with long half-lives. Observable signs and symptoms for serious central nervous system (CNS) effect due to Serotonin Syndrome include mental changes (confusion, hyperactivity and memory problems), muscle twitching, excessive sweating, shivering or shaking, diarrhea, trouble with coordination and fever. In light of the above, it is advised that physicians, pharmacists and other health professionals:
- neither methylene blue nor linezolid should be given to patients taking serotonergic psychiatric drugs unless the benefit is deemed to outweigh the risk.
- if methylene blue or linezolid must be administered immediately to a patient receiving a serotonergic psychiatric drug to treat life-threatening symptoms, the serotonergic drug must be immediately stopped and the patient should be closely monitored for emergent symptoms of CNS toxicity for two weeks (five weeks for fluoxetine).
- when methylene blue or linezolid treatment is scheduled for a patient taking a serotonergic psychiatric medicine, most of the serotonergic medication should be stopped at least 2 weeks in advance of treatment (five weeks for fluoxetine).
- educate patients to recognize the symptoms of serotonin toxicity or CNS toxicity and advise them to contact a healthcare professional immediately if they experience any symptoms while taking serotonergic psychiatric medications, methylene blue or linezolid.
- inform patients not to stop taking their serotonergic psychiatric medicine without first talking to their physician.
- familiarize with the following list of psychiatric medications with serotonergic activity:
- Selective Serotonin Reuptake Inhibitors (SSRIs): citalopram, escitalopram, fluvoxamine, fluoxetine, paroxetine and sertraline;
- Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): desvenlafaxine and venlafaxine;
- Tricyclic Antidepressants (TCAs): amitriptyline, clomipramine, doxepin, imipramine, nortriptyline and trimipramine;
- Monoamine Oxidase Inhibitors (MAOIs): selegiline;
- Other Psychiatric Medications: bupropion, buspirone, maprotiline, mirtazapine, nefazodone and trazodone.
參考資料/References and websites：
https://www.fda.gov/Drugs/DrugSafety/ucm263190.htm#data
https://www.fda.gov/Drugs/DrugSafety/ucm265305.htm