A neurobiological hypothesis of treatment-resistant depression - mechanisms for selective serotonin reuptake inhibitor non-efficacy.
A neurobiological hypothesis of treatment-resistant depression - mechanisms for selective serotonin reuptake inhibitor non-efficacy.
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DOI：
10.3389/fnbeh.2014.00189
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发表时间：
2014
影响因子：
3
通讯作者：
Berry BR
中科院分区：
文献类型：
--
作者：
Coplan JD;Gopinath S;Abdallah CG;Berry BR
重性抑郁症的一线治疗包括使用选择性5-羟色胺再摄取抑制剂（SSRI），但研究表明，两次SSRI试验后的缓解率<50%。作者研究了“难治性抑郁症（TRD）”潜在的假定生物基质，目的是阐明治疗TRD的新原理。我们研究了临床前和临床文献中的相关文章，并结合TRD患者的临床暴露。一个主要重点是概述病理生理机制，其中血清素系统变得不受SSRI所需的血清素神经传递增强的影响。一个补充的重点是解剖神经递质系统，这有助于抑制背缝。我们建议，基于一个身体的翻译研究，TRD可能不代表一个简单的5-羟色胺赤字状态，而是过量的中脑中缝周围5-羟色胺和随后的赤字在关键的额边缘投射部位，最终妥协，在阿托宁介导的神经可塑性。谷氨酸、5-羟色胺、去甲肾上腺素和组胺被应激激活，并对5-羟色胺流出产生抑制作用，部分原因是5-羟色胺本身“淹没”5-HT 1A自身受体。某些因素可能会加剧这种情况--5-羟色胺转运体基因短臂的存在、早期生活逆境和共病双相情感障碍--每一种都与SSRI治疗抵抗有关。通过利用增量方法，我们提供了一种基于从SSRI诱导的中缝背核停滞状态中拯救5-羟色胺神经传递的策略来治疗TRD患者的系统。这就需要“叠加”干预，如有必要，以SSRI为基础，靶向多巴胺能、肾上腺素能、去甲肾上腺素能和组胺能系统，从而连续消除各自能够对5-羟色胺神经元施加的抑制作用。建议未来的研究来测试这种基于生物学的方法治疗TRD。
First-line treatment of major depression includes administration of a selective serotonin reuptake inhibitor (SSRI), yet studies suggest that remission rates following two trials of an SSRI are <50%. The authors examine the putative biological substrates underlying “treatment resistant depression (TRD)” with the goal of elucidating novel rationales to treat TRD. We look at relevant articles from the preclinical and clinical literature combined with clinical exposure to TRD patients. A major focus was to outline pathophysiological mechanisms whereby the serotonin system becomes impervious to the desired enhancement of serotonin neurotransmission by SSRIs. A complementary focus was to dissect neurotransmitter systems, which serve to inhibit the dorsal raphe. We propose, based on a body of translational studies, TRD may not represent a simple serotonin deficit state but rather an excess of midbrain peri-raphe serotonin and subsequent deficit at key fronto-limbic projection sites, with ultimate compromise in serotonin-mediated neuroplasticity. Glutamate, serotonin, noradrenaline, and histamine are activated by stress and exert an inhibitory effect on serotonin outflow, in part by “flooding” 5-HT1A autoreceptors by serotonin itself. Certain factors putatively exacerbate this scenario – presence of the short arm of the serotonin transporter gene, early-life adversity and comorbid bipolar disorder – each of which has been associated with SSRI-treatment resistance. By utilizing an incremental approach, we provide a system for treating the TRD patient based on a strategy of rescuing serotonin neurotransmission from a state of SSRI-induced dorsal raphe stasis. This calls for “stacked” interventions, with an SSRI base, targeting, if necessary, the glutamatergic, serotonergic, noradrenergic, and histaminergic systems, thereby successively eliminating the inhibitory effects each are capable of exerting on serotonin neurons. Future studies are recommended to test this biologically based approach for treatment of TRD.
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影响因子：
5.3
作者：
Barbee, James G.;Thompson, Thomas R.;Shelton, Richard C.
通讯作者：
Shelton, Richard C.
影响因子：
3.3
作者：
Berman, Robert M.;Fava, Maurizio;Marcus, Ronald N.
通讯作者：
Marcus, Ronald N.
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH
DOI：
10.1176/appi.ajp.2010.09071011
发表时间：
2010-10
期刊：
The American journal of psychiatry
影响因子：
--
作者：
Angst J;Cui L;Swendsen J;Rothen S;Cravchik A;Kessler RC;Merikangas KR
通讯作者：
Merikangas KR
影响因子：
11
作者：
Bortolozzi, A.;Castane, A.;Artigas, F.
通讯作者：
Artigas, F.