氯胺酮 (Ketamine) 與減少自殺念頭、抑鬱、焦慮有關

資料來源：寶琳.安德森/ 2022年9月14日/ Medscape / 財團法人台灣紅絲帶基金會編譯

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新的研究表明，氯胺酮 (Ketamine ) 輸注有助於減輕難治性抑鬱症 (treatment-resistant depression,  TRD) 患者的自殺意念、抑鬱和焦慮症狀。

包括 400 多名難治性抑鬱症 (TRD) 參與者在內的醫療記錄回顧性分析結果顯示，氯胺酮在現實世界的患者群體中是一種安全且快速的治療方法，主要作者維吉尼亞州李奇盟心寧平和診所 (MindPeace Clinics) 創始人兼醫療主任醫學博士 Patrick A. Oliver，告訴 Medscape 醫學新聞。

他說，這種效果在減少自殺意念方面可能最為顯著。

「在 2 週內，我們可以讓某人從自殺變為非自殺。這完全改變了遊戲規則」，奧利弗補充道。

調查人員指出，在美國，每年約有 1,200 萬人想到自殺，320 萬人計劃自殺，超過 46,000 人成功。

該研究結果於 9 月 12 日於線上發表在《臨床精神病學雜誌》上。

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分子混合物

氯胺酮主要用作醫院的麻醉劑，也被非法用作娛樂性藥物。使用者的目標可能是強烈的興奮感或分離感，或出體式的體驗。

氯胺酮是兩種鏡像分子的混合物。這些分子之一艾氯胺酮 (esketamine)的鼻內版本已被美國食品和藥物管理局批准用於難治性抑鬱症。艾氯胺酮和氯胺酮都被認為會增加神經營養訊號影響突觸的功能。

該研究包括 424 名患有重度抑鬱症或其他情緒障礙的患者（平均年齡 41.7 歲），他們在專科診所接受了至少一次氯胺酮輸注。大多數參與者之前的藥物試驗都失敗了。

研究中的患者通常開始使用 0.5 mg/kg 的氯胺酮，劑量效價逐漸增加以達到部分解離的症狀。滴定後給藥的中位劑量為 40 分鐘內 0.93 mg/kg。

70% 的患者完成了 21 天內至少 6 次輸注的主要治療過程。

在每次門診就診時，所有參與者都完成了患者健康問卷-9 (the Patient Health Questionnaire-9, PHQ-9) 和廣泛性焦慮症- 7 (the Generalized Anxiety Disorder-7, GAD-7)。

主要結果是 PHQ-9 總分，研究人員查看了七個時間段：1 週、2-3 週、4-6 週、7-12 週、13-24 週、25-51 周和 52+週。

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《把它從水裡吹出來》

結果顯示 PHQ-9 總分在整個治療過程中下降了 50%，大部分改善在 4-6 週內獲得。第 1 周和所有後期（所有 P 值 < .001）之間以及第 2 周和第 3 周和所有後期（所有 P 值 < .001）之間存在顯著差異。

其他措施包括治療反應（定義為 PHQ-9 至少改善 50%）和抑鬱緩解（定義為 PHQ-9 評分低於 5）。在 3 次輸注後，14% 的患者有反應，7% 的患者有反應在緩解。 10 次輸注後，72% 有反應，38% 處於緩解狀態。

奧利弗說，這些結果與其他抑鬱症治療相比是有利的。老實說，除了 ECT [電休克療法]，這一切都將它從水中吹走了」，他補充道。

Oliver 指出，重複經顱磁刺激 (repetitive transcranial magnetic stimulation) 的成功率為 40%-60%，具體取決於方式；對於選擇性血清素再攝取抑製劑 (selective serotonin reuptake inhibitors)，成功率「介於 20 到 30% 之間」。

另一個結果的衡量標準是 PHQ-9 問卷中的自殘/自殺意念項目，該項目詢問「你最好還是死了，或以某種方式傷害自己的想法」。大約 22% 的研究參與者在 3 次輸注後不再報告有自殺意念，50% 透過 6 次輸注，75% 透過 10 次輸注。

透過 15 次輸注，85% 的人不再報告這些想法。「沒有其他任何東西可以證明這一點」，奧利弗說。

廣泛性焦慮的症狀也得到了顯著改善。治療期間 GAD-7 評分降低了約 30%，而且大部分反應發生在 4-6 週。

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研究限制

性別、年齡和其他人口統計特徵不能預測反應或緩解，但自殺計畫趨向於更高的反應率 (P = .083)。研究人員指出，這顯示更抑鬱的亞組可以從治療中獲得比症狀較少的患者更大的益處。

精神病史也傾向於對治療有更好的反應（P = .086），但沒有緩解。

研究人員指出，研究的局限性包括它是回顧性的，缺乏對照組，並且不需要患者住院——因此研究樣本的病情可能沒有其他研究那麼嚴重。

此外，大多數患者每次輸注以 495 美元的價格自付費用，並且他們自我報告了自己的症狀。

同樣，研究人員沒有評估不良事件，儘管護士對患者進行了追縱。 Oliver 指出，氯胺酮最常見的副作用是噁心、嘔吐和焦慮。

奧利弗說，以前的研究顯示，氯胺酮治療與長期副作用無關，例如性功能障礙、體重增加、嗜睡或認知問題。

研究人員指出，另一個研究限制是缺乏詳細的人口統計信息，例如種族、收入和教育，這可能會影響其普遍性。

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疑慮和問題

瑞典隆德大學精神病學高級顧問和研究員 Pouya Movahed Rad 醫學博士在評論 Medscape 醫學新聞 時指出了一些擔憂，包括用氯胺酮治療研究參與者的診所從中受益。

他還推測了誰能負擔得起治療費用，因為研究中只有少數患者透過保險獲得了核銷。

Movahed Rad 沒有參與當前的研究，但他是最近一項將靜脈注射氯胺酮與 ECT 進行比較的研究的首席研究員。

他質疑新研究中的患者群體是否真的是「真實世界」。他說，精心設計的隨機對照試驗是在「自然主義的環境中進行的，[這]更接近現實生活中的患者」。

他還指出，臨床醫生滴定後的中位劑量（0.93 mg/kg/40 m）「可能被認為非常高」。

關於效價劑量以達到部分解離症狀，「據我所知，沒有明顯的證據顯示患者需要出現解離症狀才能產生抗抑鬱作用」，Movahed Rad 說。

最後，他指出，28% 的參與者使用非法藥物的發現「令人擔憂」，並想知道他們正在服用什麼藥物；他還質疑為什麼 81% 的研究人群需要服用抗抑鬱藥。

該研究沒有獲得外部資助。 Oliver 是心寧平和診所 (MindPeace Clinics) 的創始人，該診所專門從事氯胺酮治療。 Movahed Rad 報告沒有相關的財務關係。

 

 

 

 

 

Ketamine Linked to Reduced Suicidal Thoughts, Depression, Anxiety

Pauline Anderson / September 14, 2022 / Medscape

 

Ketamine infusions can help reduce symptoms of suicidal ideation, depression, and anxiety in patients with treatment-resistant depression (TRD), new research suggests.

Results from a retrospective chart review analysis, which included more than 400 participants with TRD, illustrate that ketamine is a safe and rapid treatment in a real-world patient population, lead author Patrick A. Oliver, MD, founder and medical director, MindPeace Clinics, Richmond, Virginia, told Medscape Medical News.

The effect was perhaps most notable for reducing suicidal ideation, he said.

“In 2 weeks, we can take somebody from being suicidal to non-suicidal. It’s a total game changer,” Oliver added.

Every year in the United States, about 12 million individuals think about suicide, 3.2 million make a plan to kill themselves, and more than 46,000 succeed, the investigators note.

The findings were published online September 12 in The Journal of Clinical Psychiatry.

Molecule Mixture

Primarily used as an anesthetic in hospitals, ketamine is also taken illegally as a recreational drug. Users may aim for an intense high or feeling of dissociation, or an out-of-body–type experience.

Ketamine is a mixture of two mirror-image molecules. An intranasal version of one of these molecules (esketamine) is approved by the US Food and Drug Administration for TRD. Both esketamine and ketamine are believed to increase neurotrophic signalling that affects synaptic function.

The study included 424 patients (mean age, 41.7 years) with major depressive disorder or another mood disorder and who received at least one ketamine infusion at a specialty clinic. Most participants had failed prior medication trials.

Patients in the study were typically started on 0.5 mg/kg of ketamine, with the dose titrated to achieve symptoms of partial dissociation. The median dose administered after titration was 0.93 mg/kg over 40 minutes.

The main treatment course of at least six infusions within 21 days was completed by 70% of the patients.

At each clinic visit, all participants completed the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7).

The primary outcome was PHQ-9 total scores, for which researchers looked at seven time periods: 1 week, 2-3 weeks, 4-6 weeks, 7-12 weeks, 13-24 weeks, 25-51 weeks, and 52+ weeks.

“Blows It Out of the Water”

Results showed PHQ-9 total scores declined by 50% throughout the course of treatment, with much of the improvement gained within 4-6 weeks. There was a significant difference between week 1 and all later time periods (all P values < .001) and between weeks 2 and 3 and all later periods (all P values < .001).

Other measures included treatment response, defined as at least a 50% improvement on the PHQ-9, and depression remission, defined as a PHQ-9 score of less than 5. After three infusions, 14% of the patients responded and 7% were in remission. After 10 infusions, 72% responded and 38% were in remission.

These results compare favorably to other depression treatments, said Oliver. “Truthfully, with the exception of ECT [electroconvulsive therapy], this blows it all out of the water,” he added.

Oliver noted that the success rate for repetitive transcranial magnetic stimulation is 40%-60% depending on the modality; and for selective serotonin reuptake inhibitors, the success rate “is somewhere between the mid-20s and low-30s percent range.”

Another outcome measure was the self-harm/suicidal ideation item of the PHQ-9 questionnaire, which asks about “thoughts that you would be better off dead, or of hurting yourself in some way.” About 22% of the study participants no longer reported suicidal ideation after three infusions, 50% by six infusions, and 75% by 10 infusions.

By 15 infusions, 85% no longer reported these thoughts. “Nothing else has shown that, ever,” said Oliver.

Symptoms of generalized anxiety were also substantially improved. There was about a 30% reduction in the GAD-7 score during treatment and, again, most of the response occurred by 4-6 weeks.

Study Limitations

Sex, age, and other demographic characteristics did not predict response or remission, but suicide planning trended toward higher response rates (P = .083). This suggests that a more depressed subgroup can achieve greater benefit from the treatment than can less symptomatic patients, the investigators note.

A history of psychosis also trended toward better response to treatment (P = .086) but not remission.

The researchers note that study limitations include that it was retrospective, lacked a control group, and did not require patients to be hospitalized — so the study sample may have been less severely ill than in other studies.

In addition, most patients paid out of pocket for the treatment at $495 per infusion, and they self-reported their symptoms.

As well, the researchers did not assess adverse events, although nurses made follow-up calls to patients. Oliver noted the most common side effects of ketamine are nausea, vomiting, and anxiety.

Previous research has suggested that ketamine therapy is not linked to long-term side effects, such as sexual dysfunction, weight gain, lethargy, or cognitive issues, said Oliver.

The investigators point out another study limitation was lack of detailed demographic information, such as race, income, and education, which might affect its generalizability.

Concerns and Questions

Commenting for Medscape Medical News, Pouya Movahed Rad, MD, PhD, senior consultant and researcher in psychiatry, Lund University, Sweden, noted several concerns, including that the clinics treating the study participants with ketamine profited from it.

He also speculated about who can afford the treatment because only a few patients in the study were reimbursed through insurance.

Movahed Rad was not involved with the current research but was principal investigator for a recent study that compared intravenous ketamine to ECT.

He questioned whether the patient population in the new study really was “real world.” Well-designed randomized controlled trials have been carried out in a “naturalistic setting, [which] get closer to real life patients,” he said.

He also noted that the median dose after clinician titration (0.93 mg/kg/40 m) “may be considered very high.”

With regard to doses being titrated to achieve symptoms of partial dissociation, “there is no obvious evidence to my knowledge that patients need to develop dissociative symptoms in order to have antidepressant effect,” said Movahed Rad.

Finally, he noted that the finding that 28% of the participants were using illegal drugs “is worrying” and wondered what drugs they were taking; he also questioned why 81% of the study population needed to take antidepressants.

The study did not receive outside funding. Oliver is the founder of MindPeace Clinics, which specialize in ketamine therapeutics. Movahed Rad has reported no relevant financial relationships.

J Clin Psychiatry. Published online September 12, 2022. Abstract

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