건강한 인간 뇌의 시냅스 밀도에 대한 에스시탈로프람의 효과(2023)

Abstract Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram (n = 17) or a placebo (n = 15). After an intervention period of 3–5 weeks, participants underwent a [11C]UCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24–38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between [11C]UCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3–5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs. Similar content being viewed by others Introduction Drugs targeting the serotonin system, specifically the serotonin transporter, have long been the primary pharmacological treatment for affective and anxiety-related disorders [1]. The most widely used group is the selective serotonin reuptake inhibitors (SSRIs), presumed to work by increasing serotonergic neurotransmission [2]. Serotonin plays an important modulatory role in the brain, including regulation of mood, sleep, cognition, and behaviour, and in the early development of the central nervous system [3, 4]. Further, years of preclinical studies have established a link between the serotonin system and cellular processes such as cytoskeletal rearrangements, long-term potentiation, and neuronal firing – processes that collectively are regarded as forms of neuroplasticity [2, 5]. Functionally, neuroplasticity can be thought of as the ability of the brain to change and adapt to physiological or psychological stimuli to uphold homeostasis [6]. Despite years of research, the question of how inhibition of the serotonin transporter leads to symptom relief in neuropsychiatric conditions, remains unresolved. Major depressive disorder (MDD) is a vastly heterogeneous syndrome [7] and up to 35% of patients treated with SSRIs do not reach a state of remission [8]. Thus, a deeper understanding of the neurobiological effects of SSRIs, together with better patient stratification [9], is needed to tailor treatment to individual patients and pursue other treatment strategies for patients who are unlikely to benefit from SSRIs. One hypothesis for the mechanism of action in neuropsychiatric disorders is that strengthened serotonergic neurotransmission induces neuroplasticity and, in turn, improves cognitive and emotion processing [10,11,12]. Neuroplastic effects have foremost been demonstrated for the visual system; in adult rats, chronic treatment with the SSRI fluoxetine has been shown to reactivate a critical period-like plasticity in the visual cortex [13, 14]. However, whether neuroplasticity is central to the effects of SSRIs in humans has been difficult to investigate, mainly due to the lack of specific biomarkers. A suggested proxy is a change in cortical thickness or brain volume, as measured with MRI, in response to, e.g., learning new skills or tasks, such as juggling [15]. However, by using PET, it is possible to non-invasively quantify molecular biomarkers that more specifically reflect plasticity in vivo. Here, we use the PET radioligand [11C]UCB-J that binds to the Synaptic Vesicle glycoprotein 2A (SV2A), which enables visualization and quantification of pre-synaptic density [16], as a proxy for synaptic plasticity. PET studies on several neuropsychiatric disorders linked to synaptic dysfunction, including depression, have found lower cerebral SV2A density in patients compared to healthy individuals [17,18,19,20,21,22]. So far, the only investigation of a pharmacological intervention on SV2A density in humans is a study that examined the acute effect of a single administration of the rapid-acting antidepressant ketamine, and they found no changes for healthy participants and psychiatric patie