- Title
- Factors contributing to serotonin toxicity
- Creator
- Cooper, Joyce
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Serotonin toxicity is caused by an excess of the chemical serotonin (5-hydroxytryptamine (5-HT) in the synaptic cleft. The signs and symptoms of toxicity result from the action of serotonin on the receptors, particularly the 5-HT2A receptors, and manifest as a triad of clinical effects that include neuromuscular and autonomic instability and changes in mental state. Following an overdose of a serotonergic drug it is unclear why some patients present with few or mild symptoms, whilst others may show more marked signs of toxicity. The broad aim of this work was to investigate the factors that may influence the occurrence of serotonin toxicity following an overdose of a serotonergic antidepressant. The main factors considered were the pharmacokinetic and pharmacodynamic relationships of the drugs and patients, and how these influenced the outcome of serotonin toxicity. Identifying patients from a large database of antidepressant overdoses allowed the investigation of patient genetics, in particular the serotonin receptor genes. Using timed blood concentration data allowed investigation of pharmacokinetic parameters and the effect of decontamination. Examining desvenlafaxine (the major active metabolite of venlafaxine) in overdose provided a useful comparison to venlafaxine, where the incidence of toxicity is thought to be higher than with SSRIs. Finally, performing a regression analysis on almost two-thousand cases of SSRI/SNRI overdose allowed prediction of the probability of serotonin toxicity based on age, sex, type of antidepressant and presence of co-ingestants. The results provide a much clearer picture of factors that can influence the outcome of serotonin toxicity with implications for clinical management. Polymorphism at the 5-HT2A receptor was not associated with increased incidence of toxicity however, other polymorphisms require investigation. Charcoal decontamination may be of benefit up to four hours post overdose with sertraline; and overdose of desvenlafaxine causes only low incidence of serotonin toxicity compared to venlafaxine. A regression analysis of SSRI/SNRI overdoses showed a protective effect on serotonin toxicity from co-ingestants that included the 5-HT2A antagonists olanzapine and risperidone, however moclobemide markedly increased the probability of serotonin toxicity.
- Subject
- serotonin; toxicity; antidepressant; overdose; SSRI; SNRI; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1388144
- Identifier
- uon:32719
- Rights
- Copyright 2018 Joyce Cooper
- Language
- eng
- Full Text
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| View Details Download | ATTACHMENT01 | Thesis | 3 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 694 KB | Adobe Acrobat PDF | View Details Download |