Effects of inflammation modulation on tryptophan and kynurenine pathway regulation in treatment resistant bipolar depression

Q3 Medicine Neurology Psychiatry and Brain Research Pub Date : 2019-09-01 DOI:10.1016/j.npbr.2019.07.001

Stephen Murata , Monica Feliz R. Castillo , Michael Murphy , Markus Schwarz , Natalie Moll , Brendan Martin , Elif Weidinger , Bianka Leitner , Norbert Mueller , Angelos Halaris

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引用次数: 6

Abstract

Background

Adjunctive immune-modulation can be safe and effective for treatment-resistant bipolar depression (TRBDD), but molecular work is needed to further characterize the safety and efficacy involved in treatment response and the reversal of treatment resistance. Here we profiled the kynurenine pathway (KP) for biomarkers associated with TRBDD and treatment response to celecoxib (CBX)-augmentation.

Methods

47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg twice daily) + CBX (200 mg twice daily), or ESC (10 mg twice daily) + placebo (PBO) (twice daily). Plasma kynurenine pathway (KP) metabolite levels were measured at baseline, week 4, and week 8, and in a healthy control (HC) group of subjects (N = 35) once.

Results

Patients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT=3, and 15.300 greater odds of remitting (p < 0.001) with NNT=2, compared with ESC + PBO patients. Study patients exhibited elevated baseline tryptophan (p < 0.001), low kynurenine/tryptophan (p < 0.001), elevated 3-hydryoxykynurenine/kynurenine (adj-p*<0.001), low kynurenic acid/3-hydroxykynurenine, and low picolinic acid/quinolinic acid (p < 0.001) compared to healthy controls. Treatment responders exhibited tryptophan depletion (p = 0.020) without a concomitant change in kynurenine/tryptophan ratio by week 8 (p = 0.163).

Conclusion

Clinical response to CBX augmentation is not associated with altered neurotoxic or neuroprotective indices within the time frame of this study. TRBDD revealed alterations in neuroprotective and neurotoxic indices, in the context of low kynurenine/tryptophan and high tryptophan. Treatment responders revealed a depletion in tryptophan by week 8, without concomitant kynurenine pathway (KP) activation.

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治疗难治性双相抑郁症中炎症调节对色氨酸和犬尿氨酸通路调节的影响

结合免疫调节治疗难治性双相抑郁症(TRBDD)是安全有效的，但需要进一步的分子研究来确定治疗反应和治疗耐药逆转的安全性和有效性。在这里，我们分析了与TRBDD相关的生物标志物的犬尿氨酸途径(KP)和对塞来昔布(CBX)增强的治疗反应。方法47例HAMD-17评分为中重度的TRBDD患者随机接受依西酞普兰(ESC)(10 mg每日2次)+ CBX(200 mg每日2次)或ESC(10 mg每日2次)+安慰剂(PBO)(每日2次)治疗。在基线、第4周和第8周以及健康对照(HC)组(N = 35)中测量一次血浆犬尿氨酸途径(KP)代谢物水平。结果与ESC + PBO患者相比，接受ESC + CBX治疗的患者，当NNT=3时，缓解的几率增加4.278 (p = 0.021)，当NNT=2时，缓解的几率增加15.300 (p < 0.001)。与健康对照相比，研究患者表现出基线色氨酸升高(p < 0.001)、低犬尿氨酸/色氨酸(p < 0.001)、3-羟基犬尿氨酸/犬尿氨酸升高(j-p*<0.001)、低犬尿氨酸/3-羟基犬尿氨酸和低吡啶酸/喹啉酸(p < 0.001)。治疗应答者表现出色氨酸耗损(p = 0.020)，但在第8周时犬尿氨酸/色氨酸比值没有随之变化(p = 0.163)。结论在本研究的时间框架内，CBX增强的临床反应与神经毒性或神经保护指标的改变无关。在低犬尿氨酸/色氨酸和高色氨酸的情况下，TRBDD显示神经保护和神经毒性指标的改变。治疗应答者在第8周发现色氨酸减少，没有伴随犬尿氨酸途径(KP)激活。

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Neurology Psychiatry and Brain Research 医学-精神病学

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期刊介绍： Neurology, Psychiatry & Brain Research publishes original papers and reviews in biological psychiatry, brain research, neurology, neuropsychiatry, neuropsychoimmunology, psychopathology, psychotherapy. The journal has a focus on international and interdisciplinary basic research with clinical relevance. Translational research is particularly appreciated. Authors are allowed to submit their manuscript in their native language as supplemental data to the English version. Neurology, Psychiatry & Brain Research is related to the oldest German speaking journal in this field, the Centralblatt fur Nervenheilkunde, Psychiatrie und gerichtliche Psychopathologie, founded in 1878. The tradition and idea of previous famous editors (Alois Alzheimer and Kurt Schneider among others) was continued in modernized form with Neurology, Psychiatry & Brain Research. Centralblatt was a journal of broad scope and relevance, now Neurology, Psychiatry & Brain Research represents a journal with translational and interdisciplinary perspective, focusing on clinically oriented research in psychiatry, neurology and neighboring fields of neurosciences and psychology/psychotherapy with a preference for biologically oriented research including basic research. Preference is given for papers from newly emerging fields, like clinical psychoimmunology/neuroimmunology, and ideas.