It has become evident that coronavirus disease 2019 (COVID-19) has a multi-organ pathology that includes the brain and nervous system. Several studies have also reported acute psychiatric symptoms in COVID-19 patients. An increasing number of studies are suggesting that psychiatric deficits may persist after recovery from the primary infection. In the current systematic review, we provide an overview of the available evidence and supply information on potential risk factors and underlying biological mechanisms behind such psychiatric sequelae. We performed a systematic search for psychiatric sequelae in COVID-19 patients using the databases PubMed and Embase. Included primary studies all contained information on the follow-up period and provided quantitative measures of mental health. The search was performed on June 4th 2021. 1725 unique studies were identified. Of these, 66 met the inclusion criteria and were included. Time to follow-up ranged from immediately after hospital discharge up to 7 months after discharge, and the number of participants spanned 3 to 266,586 participants. Forty studies reported anxiety and/or depression, 20 studies reported symptoms- or diagnoses of post-traumatic stress disorder (PTSD), 27 studies reported cognitive deficits, 32 articles found fatigue at follow-up, and sleep disturbances were found in 23 studies. Highlighted risk factors were disease severity, duration of symptoms, and female sex. One study showed brain abnormalities correlating with cognitive deficits, and several studies reported inflammatory markers to correlate with symptoms. Overall, the results from this review suggest that survivors of COVID-19 are at risk of psychiatric sequelae but that symptoms generally improve over time.

1-[2-(2,4-Dimethylphenyl-sulfanyl)-phenyl]-piperazine (Lu AA21004) is a human (h) serotonin (5-HT) 3A receptor antagonist (K i ϭ 3.7 nM), h5-HT 7 receptor antagonist (K i ϭ 19 nM), h5-HT 1B receptor partial agonist (K i ϭ 33 nM), h5-HT 1A receptor agonist (K i ϭ 15 nM), and a human 5-HT transporter (SERT) inhibitor (K i ϭ 1.6 nM) (J Med Chem 54: 3206 -3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT 1B receptor agonist [EC 50 ϭ 460 nM, intrinsic activity ϭ 22%] using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT 7 receptor antagonist (K i ϭ 200 nM and IC 50 ϭ 2080 nM). In vivo, Lu AA21004 occupies the r5-HT 1B receptor and rSERT (ED 50 ϭ 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT 3 receptor antagonist in the Bezold-Jarisch reflex assay (ED 50 ϭ 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT 3 receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant-and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant-and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.

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Quantitative real-time polymerase chain reaction (qPCR) has become a widely used tool in the search for disease genes. When examining gene expression with qPCR in psychiatric diseases, endogenous reference gene(s) must be used for normalization. Traditionally, genes such as beta-actin (ActB), Gapd, and 18s rRNA, assumed to be stably expressed, have been used for normalization. However, it has become clear that expression of these genes is influenced by different experimental paradigms. Since stable gene expression of houskeeping genes (HKGs), therefore, cannot be expected, alternative strategies are warranted. With the overall aim to inspect the gene expression of three target genes, NMDAR1, SORT, and CREB, in rat hippocampus, we tested a panel of eight HKGs, 18s rRNA, ActB, CycA, Gapd, Hmbs, Hprt1, Rpl13A, and Ywhaz in order to select the most stably expressed gene, using the NormFinder and geNorm software applets. Additionally, we have applied four different normalization approaches for normalization of the three target genes. We found using the NormFinder software that Ywhaz is the most stably expressed gene among the eight tested HKGs. However, the results of the analysis of the target genes are highly dependent on the choice of normalization approach. Moreover, the number of HKGs, used for selection of the most stable HKG, also influences on the result of the gene expression analysis of target genes. These results underline the importance of choosing a proper normalization strategy when analyzing gene expression with qPCR. The strategy should be unbiased and carried out in every specific experimental setting.

Stress-restress-mediated glucocorticoid release activates iNOS, followed by a reactive downregulation of hippocampal NMDA receptors and dysregulation of inhibitory GABA pathways. The role of NO in neuronal toxicity, and its regulation by glutamate and GABA has important implications in stress-related hippocampal degeneration.