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Serotonin Metabolism in Functional Somatic Illness
Published in Peter Manu, The Psychopathology of Functional Somatic Syndromes, 2020
Investigators from St. Bartholomew’s Hospital, London, and Southern General Hospital, Glasgow, Great Britain, also studied the serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome (Dinan et al., 1997). The authors employed a neuroendocrine challenge with ipsapirone, a moderately selective serotonin agonist, in 14 patients with chronic fatigue syndrome and 14 age-, gender-, and weight-matched healthy control subjects. All patients were medication free at the time of the study and had no evidence of past or current psychiatric or endocrinological disorder. Blood samples were collected at baseline and after the oral administration of ipsapirone (20 mg) and assayed for cortisol and adrenocorticotropin hormone levels.
Exercise and Anxiety Disorders
Published in Henning Budde, Mirko Wegner, The Exercise Effect on Mental Health, 2018
Jennifer Mumm, Sophie Bischoff, Andreas Ströhle
There is evidence that patients with panic disorder and/or agoraphobia show increased sensitivity to the selective 5-HT(1A) receptor agonist ipsapirone in comparison to healthy control subjects. Ipsapirone influences serotonergic mechanisms in the brain through binding to 5-HT(1A) receptor subtypes, resulting in decreased serotonergic transmission. The administration of ipsapirone leads to psychological and somatic symptoms and full panic attacks in patients with panic disorder (Broocks et al. 2000).
Designing multi-target drugs for the treatment of major depressive disorder
Published in Expert Opinion on Drug Discovery, 2023
Amit Kumar Halder, Soumya Mitra, Maria Natalia D. S. Cordeiro
Kułaga et al. designed a series of new hexyl arylpiperazine derivatives (C17, cf. Supplemental data, Figure S18) from the saccharin moiety (i.e. 1,1-dioxo-1,2-benzothiazol-3-one). The authors were also interested to explore the LCAPs for the design of MTDLs considering the potential of such structural residues to function as 5-HT1A inhibitors and linked these to saccharin [64]. Note that one of the inspirations of designing saccharin-based compounds came from ipsapirone, a 1,1-dioxo-1,2-benzothiazol-3-one containing compound with dual 5-HT1A/D2 activity. However, the authors increased the 4-carbon linker and explored hexyl alkyl chain. After synthesizing seventeen compounds, one compound (28, Figure 4) was obtained with nanomolar potencies (5-HT1A = 4 nM and D2 = 15 nM) toward both 5-HT1A and D2 receptors. However, when tested against other receptors, this compound was also found to be highly active toward 5-HT7 as well and a Ki value of 21 nM was obtained. Therefore, this compound may be projected as 5-HT1A/5-HT7/D2 ligand. This investigation clearly pointed out that extension of the carbon chain from 4 to 6 atoms lead to 4-fold increase in 5-HT1A activity; a 13-fold increase in 5-HT2A activity and a 16-fold increase in D2 activity. The preliminary in silico parameters of ADME predicted that the ligands have CNS drug-like potential [64].
Is there a role for cannabidiol in psychiatry?
Published in The World Journal of Biological Psychiatry, 2019
Julia Machado Khoury, Maila de Castro Lourenço das Neves, Marco Antônio Valente Roque, Daniela Alves de Brito Queiroz, André Augusto Corrêa de Freitas, Ângelo de Fátima, Fabrício A. Moreira, Frederico Duarte Garcia
Zuardi et al. (1993) also compared the effect of 300 mg of CBD with ipsapirone, diazepam and placebo on subjectively perceived anxiety, measured by a visual analogue mood scale in a double-blind, RCT, using 40 healthy subjects. The authors reported that CBD significantly reduced subjectively perceived anxiety when compared to placebo, without causing sedation like diazepam. The results should be regarded considering the small sample used, a unique use of the medication and the subjective measure of anxiety.
Novel investigational therapeutics for generalized anxiety disorder (GAD)
Published in Expert Opinion on Investigational Drugs, 2019
Bella Schanzer, Ana Maria Rivas-Grajales, Aamir Khan, Sanjay J Mathew
Tandospirone is a novel nonbenzodiazepine anxiolytic derivative of azapirone that is a strong and selective agonist of serotonin 5HT1A receptor. Tandospirone received regulatory approval in China and Japan for GAD in 2003 and 1996, respectively. 5HT1 receptors have long been a focus of study in the mediation of anxiety. Tandospirone is a partial agonist of the 5-HT1A receptor and likely functions through the development of a continuous water channel by mobilizing nearby amino acid residues. It is also highly potent as compared to other partial agonists, such as buspirone or ipsapirone, with a Ki value of 27 ± 5 nM. In addition, it is highly selective to the 5-HT1A receptor, in contrast to the other azapirones that also have a moderate-to-high affinity for the dopamine D2 receptor and alpha1-adrenergic receptors. In addition, it is characterized as a full agonist at the 5-HT1A autoreceptors in the raphe nuclei as well as a partial agonist at postsynaptic 5-HT1A receptors in the forebrain area [57]. It is currently the focus of a Phase IV trial to determine the optimal dose for treatment.Agomelatine is a selective agonist of melatonergic receptors that are found throughout the central and peripheral nervous systems. It has also been found to activate GABA neurons thereby modulating the GABAergic pathway. It is believed that this is potentiated by agomelatine’s antagonism of 5HT2C receptors that are located in the hippocampus, amygdala, and cerebral cortex. Therefore, in addition to being useful for depression, which is what it has been approved for in some countries, there is evidence to support its use in the treatment of comorbid depression and anxiety [58].Vortioxetine is an atypical antidepressant that mediates its response through inhibition of the serotonin transporter (SERT) by binding with high affinity to the transporter leading to selective blockade of serotonin reuptake and by direct modulation of 5-HT receptor activity. Its activity at the 5-HT receptors depends on which receptor subtype as it acts as a weak antagonist at 5-HT3 and 5-HT7 and 5-HT1D but as a partial agonist at 5-HT1B and a full agonist at 5-HT1A. The multi-receptor activity may account for its broad clinical response including both antidepressant and anxiolytic effects [59].