A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT_2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT_2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT_2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [³H]UCB-J (SV2A), [³H]MDL100907 (5-HT_2AR antagonist) and [³H]Cimbi-36 (5-HT_2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT_2AR density (−15.21% to −50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [³H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT_2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT_2AR density, which may play a role in psilocybin’s antidepressive effects.

Neuromuscular adverse events following cancer treatment with anti–programmed cell death protein 1 (PD-1) monoclonal antibodies are relatively rare, yet potentially fatal. We performed a systematic review to characterize the clinical presentation, diagnostic workup, and management of neuromuscular disorders (NMDs) in patients treated with nivolumab or pembrolizumab monotherapy or concurrent with other immunologic agents, such as ipilimumab. Sixty-one publications on 85 patients (mean age 66.9 years [range 34–86]; male/female 2.6:1; 59% metastatic melanoma) were identified from selected indexing databases until June 2018. Forty-eight patients had received nivolumab and 39 pembrolizumab. The mean number of PD-1 inhibitor treatment cycles prior to onset of symptoms was 3.6 (range 1–28). Symptoms included oculomotor (47%), respiratory (43%), bulbar (35%), and proximal weakness (35%), as well as muscle pain (28%). Diagnoses were categorized as myasthenia gravis (27%), neuropathy (23%), myopathy (34%), or a combination of these (16%). After a critical review of the data, however, evidence did not support the stated NMD diagnosis in 13% of cases, while up to 25% of patients had signs of additional NMDs. Cardiac complications occurred in more than 30% of patients diagnosed with myasthenia gravis or myositis. Mortality was high in these patients, despite adequate treatment strategies including corticosteroid, IV immunoglobulins, and plasma exchange. The clinical presentation of NMDs associated with PD-1 inhibitors is often atypical, with considerable overlap between myasthenia gravis and myopathy, and cardiac/respiratory complications are common.

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.

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of ‘cold’ cognition (including inhibition, cognitive flexibility, memory) and ‘hot cognition’ including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on ‘cold’ or ‘hot’ cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the ‘blunting’ effect often reported by patients with MDD treated with SSRIs. Trial Registration:NCT04239339.

[¹¹C]Cimbi-36, a 5-HT_2A receptor agonist PET radioligand, contains three methoxy groups amenable to [¹¹C]-labeling. In pigs, [¹¹C]Cimbi-36 yields a polar (M1) and a less polar (M2) radiometabolite fraction, while changing the labeling to [¹¹C]Cimbi-36_5 yields only the M1 fraction. We investigate whether changing the labeling position of [¹¹C]Cimbi-36 eliminates M2 in humans, and if this changes the signal-to-background ratio. Six healthy volunteers each underwent two dynamic PET scans; after injection of [¹¹C]Cimbi-36, both the M1 and M2 fraction appeared in plasma, whereas only the M1 appeared after [¹¹C]Cimbi-36_5 injection. [¹¹C]Cimbi-36_5 generated higher uptake than [¹¹C]Cimbi-36 in both neocortex and cerebellum. With the simplified reference tissue model mean neocortical non-displaceable binding potential for [¹¹C]Cimbi-36 was 1.38 ± 0.07, whereas for [¹¹C]Cimbi-36_5, it was 1.18 ± 0.14. This significant difference can be explained by higher non-displaceable binding caused by demethylation products in the M1 fraction such as [¹¹C]formaldehyde and/or [¹¹C]carbon dioxide/bicarbonate. Although often considered without any impact on binding measures, we show that small polar radiometabolites can substantially decrease the signal-to-background ratio of PET radioligands for neuroimaging. Further, we find that [¹¹C]Cimbi-36 has a better signal-to-background ratio than [¹¹C]Cimbi-36_5, and thus will be more sensitive to changes in 5-HT_2A receptor levels in the brain.

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n=6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n=6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.4% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in hippocampus (+9.24%) and PFC (+6.1%) whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin’s antidepressive actions are linked to increased persistent synaptogenesis and possibly also to an acute decrease in 5-HT2AR density.