Antidepressant Effects on Serotonin Plateau at the Minimum Recommended Dose

腦成像研究表明，增加抗抑鬱藥劑量並支持雙曲線減量停藥幾乎沒有益處。
Brain imaging studies show little benefit to increasing antidepressant doses and support hyperbolic tapering for discontinuation.
彼得·西蒙斯-2021 年 9 月 27 日

分子精神病學的一項新研究探討了抗抑鬱藥物對血清素轉運蛋白 (SERT) 佔用的影響。研究結果支持在停藥期間使用雙曲線逐漸變細——在完全停藥之前將劑量減少到非常小的量。如果藥物不起作用，他們還挑戰增加劑量的概念。
A new study in Molecular Psychiatry explores the effects of antidepressant drugs on serotonin transporter (SERT) occupancy. The findings support the use of hyperbolic tapering during withdrawal—decreasing the dose to a very small amount before entirely discontinuing. They also challenge the notion of increasing the dose if the drug doesn’t work.

該研究由北歐科克倫中心的 Anders Sørensen 領導，包括 Henricus G. Ruhé 和 Klaus Munkholm。他們的分析使用了來自 17 項不同腦成像研究的數據，這些研究涉及 SSRI、SNRI 和 5-羥色胺調節劑藥物的影響。他們觀察了被不同劑量藥物阻斷的血清素神經遞質受體 (SERT) 的百分比。據研究人員稱：
The research was led by Anders Sørensen at the Nordic Cochrane Center and included Henricus G. Ruhé and Klaus Munkholm. Their analysis used data from 17 different brain imaging studies of the effects of SSRI, SNRI, and serotonin modulator drugs. They looked at the percentage of the serotonin neurotransmitter receptors (SERT) blocked by the drugs at different doses. According to the researchers:

“SERT 佔用率隨著劑量的增加呈雙曲線關係增加，在較低劑量下佔用率迅速增加，並在通常的最低推薦劑量下達到約 80% 的平台期。”
“SERT occupancy increased with a higher dose in a hyperbolic relationship, with occupancy increasing rapidly at lower doses and reaching a plateau at approximately 80% at the usual minimum recommended dose.”

這有兩個含義。首先是即使在最低推薦劑量（低於正常處方劑量）下，藥物對血清素系統的影響也已達到平穩狀態（約佔 SERT 的 80%）。因此，即使藥物處於最低推薦水平，增加劑量的生物學益處也很小。這意味著，如果抗抑鬱作用是由神經化學驅動的，那麼較低劑量應該提供與較高劑量大致相同的益處——因此即使藥物似乎不起作用，增加劑量也幾乎沒有益處。
This has two implications. The first is that even at the minimum recommended dose (below the normal prescribed dose), the drugs’ effects on the serotonin system have plateaued (occupying about 80% of SERT). Thus, there is minimal biological benefit to increasing the dose, even when the drug is at the minimum recommended level. This means that if antidepressant effects were driven by neurochemistry, lower doses should provide about the same benefit as higher ones—so there would be little benefit to increasing the dose, even if the drug doesn’t seem to work.

研究人員寫道：
The researchers write:

“雙曲線劑量-佔用關係可能提供與抗抑鬱治療中劑量遞增的有限臨床益處和可能出現的戒斷症狀相關的機制見解。”
“The hyperbolic dose-occupancy relationship may provide mechanistic insight of relevance to the limited clinical benefit of dose-escalation in antidepressant treatment and the potential emergence of withdrawal symptoms.”

該研究的第二個含義是，在低劑量下，即使是非常小的劑量變化也會對血清素水平產生很大影響。因此，在低劑量時小劑量增加可以產生巨大的差異，而在高劑量時即使大劑量增加也不會產生太大影響。
The second implication of the study is that at low doses, even very small shifts in the dose have a large impact on serotonin levels. Thus, a small dose increase while at a low dose can make a huge difference, while even large increases once already at a high dose don’t have much of an impact.

逐漸減少藥物也是如此——從高劑量大幅減少對實際血清素水平幾乎沒有影響。但是一旦劑量變小，即使是微小的劑量調整也會對血清素水平產生巨大的影響。
And the same goes for tapering off the medication—a large decrease from a high dose will have little effect on actual serotonin levels. But once the dose becomes smaller, even tiny dose adjustments can have outsized effects on serotonin levels.

下面的氟西汀（百憂解）圖表是典型的例子。低劑量血清素受體 (SERT) 佔用率的急劇增加在約 5 mg 時開始趨於平穩（約 65% 佔用率）。20 mg 處的垂直虛線代表最小推薦劑量。該圖表表明，即使是 10 毫克的一半劑量，其血清素受體的百分比（略高於 70%）與 20 毫克（略低於 80%）幾乎相同——因此它應該具有大致相同的生物學效應。更高的劑量產生的影響甚至更小，60 毫克的 SERT 比 20 毫克多不到 5%。
The chart below for fluoxetine (Prozac) is the quintessential example. The steep increase in serotonin receptor (SERT) occupancy at low doses begins to level off at about 5 mg (about 65% occupancy). The dotted vertical line at 20 mg represents the minimum recommended dose. The chart demonstrates that even half that dose, 10 mg, occupies almost the same percentage (a little over 70%) of serotonin receptors as 20 mg (a little less than 80%)—so it should have about the same biological effect. Higher doses make even less of a difference, with 60 mg occupying less than 5% more SERT than 20 mg.

這種與 SERT 佔用率的雙曲線關係也解釋了為什麼研究發現在最終停藥之前的幾個月內逐漸減量越來越小的劑量可能是必要的，以盡量減少戒斷影響。（研究人員寫道，“大約一半的患者停止或減少抗抑鬱藥的劑量會出現戒斷症狀，其中可能包括流感樣症狀、焦慮、情緒不穩定、情緒低落和易怒。”）
This hyperbolic relationship with SERT occupancy also explains why studies have found that tapering to smaller and smaller doses over months before eventually discontinuing the drug may be necessary in order to minimize withdrawal effects. (The researchers write that “approximately half of the patients stopping or reducing the dose of antidepressants experience withdrawal symptoms, which, among others, may include flu-like symptoms, anxiety, emotional lability, lowering of mood, and irritability.”)

另一個令人驚訝的發現是血清素受體佔有率與臨床效果之間沒有關係。
Another surprising finding was that there was no relationship between serotonin receptor occupancy and clinical effect.

作者寫道，“本綜述中包含的測量臨床效果和 SERT 佔用率之間關係的研究沒有發現顯著的相關性。”
The authors write, “the studies included in the present review that measured the relationship between clinical effect and SERT occupancy did not find significant correlations.”

也就是說，藥物阻斷5-羥色胺受體的百分比與人們的抑鬱症是否改善無關。這進一步挑戰了長期被揭穿的化學失衡神話。
That is, the percentage of serotonin receptors blocked by the drugs had no correlation with whether people’s depression improved. This further challenges the long-debunked chemical imbalance myth.

最後，研究人員還指出，關於該主題的證據有限，並且方法問題困擾著研究文獻。
Finally, the researchers also note that the evidence on this topic is limited and that methodological problems plague the research literature.

“證據受到不透明報告、缺乏標準化方法、樣本量小和治療持續時間短的限制。未來的研究應該標準化成像和報告程序，以較低的抗抑鬱劑量測量佔用率，並研究劑量-佔用率關係的調節因素。”
“The evidence is limited by non-transparent reporting, lack of standardized methods, small sample sizes, and short treatment duration. Future studies should standardize the imaging and reporting procedures, measure occupancy at lower antidepressant doses, and investigate the moderators of the dose-occupancy relationship.”

****

Sørensen, A.、Ruhé, HG 和 Munkholm, K. (2021)。抗抑鬱藥劑量與血清素轉運蛋白佔有率之間的關係——系統評價。分子精神病學。發佈時間：2021 年 9 月 21 日。https://doi.org/10.1038/s41380-021-01285-w （鏈接）
Sørensen, A., Ruhé, H. G., & Munkholm, K. (2021). The relationship between dose and serotonin transporter occupancy of antidepressants—A systematic review. Molecular Psychiatry. Published: on September 21, 2021. https://doi.org/10.1038/s41380-021-01285-w (Link)

文章來源:
https://www.madinamerica.com/2021/09/antidepressant-effects-serotonin-plateau-minimum-recommended-dose/