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Journal of Neurology Jul 2023Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system... (Review)
Review
Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system areas and networks. A growing increase in the understanding of migraine pathophysiology in recent years has facilitated translation of that knowledge into novel treatments, which are currently becoming available to patients in many parts of the world and are substantially changing the clinical approach to the disease. In the first part of this review, we will provide an up to date overview of migraine pathophysiology by analyzing the anatomy and function of the main regions involved in the disease, focusing on how these give rise to the plethora of symptoms characterizing the attacks and overall disease. The second part of the paper will discuss the novel therapeutic agents that have emerged for the treatment of migraine, including molecules targeting calcitonin gene-related peptide (gepants and monoclonal antibodies), serotonin 5-HT receptor agonists (ditans) and non-invasive neuromodulation, as well as providing a brief overview of new evidence for classic migraine treatments.
Topics: Humans; Migraine Disorders; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Receptors, Calcitonin Gene-Related Peptide; Migraine with Aura
PubMed: 37029836
DOI: 10.1007/s00415-023-11706-1 -
Molecular Psychiatry Aug 2023The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin... (Meta-Analysis)
Meta-Analysis
The serotonin hypothesis of depression is still influential. We aimed to synthesise and evaluate evidence on whether depression is associated with lowered serotonin concentration or activity in a systematic umbrella review of the principal relevant areas of research. PubMed, EMBASE and PsycINFO were searched using terms appropriate to each area of research, from their inception until December 2020. Systematic reviews, meta-analyses and large data-set analyses in the following areas were identified: serotonin and serotonin metabolite, 5-HIAA, concentrations in body fluids; serotonin 5-HT receptor binding; serotonin transporter (SERT) levels measured by imaging or at post-mortem; tryptophan depletion studies; SERT gene associations and SERT gene-environment interactions. Studies of depression associated with physical conditions and specific subtypes of depression (e.g. bipolar depression) were excluded. Two independent reviewers extracted the data and assessed the quality of included studies using the AMSTAR-2, an adapted AMSTAR-2, or the STREGA for a large genetic study. The certainty of study results was assessed using a modified version of the GRADE. We did not synthesise results of individual meta-analyses because they included overlapping studies. The review was registered with PROSPERO (CRD42020207203). 17 studies were included: 12 systematic reviews and meta-analyses, 1 collaborative meta-analysis, 1 meta-analysis of large cohort studies, 1 systematic review and narrative synthesis, 1 genetic association study and 1 umbrella review. Quality of reviews was variable with some genetic studies of high quality. Two meta-analyses of overlapping studies examining the serotonin metabolite, 5-HIAA, showed no association with depression (largest n = 1002). One meta-analysis of cohort studies of plasma serotonin showed no relationship with depression, and evidence that lowered serotonin concentration was associated with antidepressant use (n = 1869). Two meta-analyses of overlapping studies examining the 5-HT receptor (largest n = 561), and three meta-analyses of overlapping studies examining SERT binding (largest n = 1845) showed weak and inconsistent evidence of reduced binding in some areas, which would be consistent with increased synaptic availability of serotonin in people with depression, if this was the original, causal abnormaly. However, effects of prior antidepressant use were not reliably excluded. One meta-analysis of tryptophan depletion studies found no effect in most healthy volunteers (n = 566), but weak evidence of an effect in those with a family history of depression (n = 75). Another systematic review (n = 342) and a sample of ten subsequent studies (n = 407) found no effect in volunteers. No systematic review of tryptophan depletion studies has been performed since 2007. The two largest and highest quality studies of the SERT gene, one genetic association study (n = 115,257) and one collaborative meta-analysis (n = 43,165), revealed no evidence of an association with depression, or of an interaction between genotype, stress and depression. The main areas of serotonin research provide no consistent evidence of there being an association between serotonin and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations. Some evidence was consistent with the possibility that long-term antidepressant use reduces serotonin concentration.
Topics: Humans; Depression; Serotonin; Receptor, Serotonin, 5-HT1A; Tryptophan; Hydroxyindoleacetic Acid; Antidepressive Agents; Serotonin Plasma Membrane Transport Proteins
PubMed: 35854107
DOI: 10.1038/s41380-022-01661-0 -
Anesthesiology Oct 2023Chronic pain is a public health concern that affects approximately 1.5 billion people globally. Conventional therapeutic agents including opioid and non-opioid... (Review)
Review
Chronic pain is a public health concern that affects approximately 1.5 billion people globally. Conventional therapeutic agents including opioid and non-opioid analgesics have been associated with adverse side effects, issues with addiction, and ineffective analgesia. Novel agents repurposed to treat pain via different mechanisms are needed to fill the therapeutic gap in chronic pain management. Psychedelics such as lysergic acid diethylamide and psilocybin (the active ingredient in psychedelic mushrooms) are thought to alter pain perception through direct serotonin receptor agonism, anti-inflammatory effects, and synaptic remodeling. This scoping review was conducted to identify human studies in which psychedelic agents were used for the treatment of pain. Twenty-one articles that assessed the effects of psychedelics in treating various pain states were included. The present scarcity of clinical trials and small sample sizes limit their application for clinical use. Overall, psychedelics appear to show promise for analgesia in patients with certain headache disorders and cancer pain diagnoses. Future studies must aim to examine the combined effects of psychotherapy and psychedelics on chronic pain.
Topics: Humans; Hallucinogens; Chronic Pain; Pain Management; Pain Perception; Analgesia; Drug-Related Side Effects and Adverse Reactions
PubMed: 37698433
DOI: 10.1097/ALN.0000000000004673 -
Cell Jun 2023Serotonin influences many aspects of animal behavior. But how serotonin acts on its diverse receptors across the brain to modulate global activity and behavior is...
Serotonin influences many aspects of animal behavior. But how serotonin acts on its diverse receptors across the brain to modulate global activity and behavior is unknown. Here, we examine how serotonin release in C. elegans alters brain-wide activity to induce foraging behaviors, like slow locomotion and increased feeding. Comprehensive genetic analyses identify three core serotonin receptors (MOD-1, SER-4, and LGC-50) that induce slow locomotion upon serotonin release and others (SER-1, SER-5, and SER-7) that interact with them to modulate this behavior. SER-4 induces behavioral responses to sudden increases in serotonin release, whereas MOD-1 induces responses to persistent release. Whole-brain imaging reveals widespread serotonin-associated brain dynamics, spanning many behavioral networks. We map all sites of serotonin receptor expression in the connectome, which, together with synaptic connectivity, helps predict which neurons show serotonin-associated activity. These results reveal how serotonin acts at defined sites across a connectome to modulate brain-wide activity and behavior.
Topics: Animals; Caenorhabditis elegans; Serotonin; Caenorhabditis elegans Proteins; Receptors, Serotonin; Behavior, Animal; Brain
PubMed: 37192620
DOI: 10.1016/j.cell.2023.04.023