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Title: Adverse effects of antidepressants in central white matter
Author: Fryer, Kirsty Laura
ISNI:       0000 0004 6346 7978
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2016
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Major depressive disorder (depression) is a significant, recurrent disorder, affecting over 350 million people worldwide. Often having a detrimental effect on quality of life, daily functioning, medical morbidity, and mortality it is one of the leading causes of disability worldwide. Depression pathology is little understood, and so treatments are often a 'stab in the dark'. Currently the most widely prescribed pharmacological treatment for depression is a group of antidepressants named the SSRIs (Selective Serotonin Reuptake Inhibitors), however their effectiveness over placebo is hotly debated. It may be that these drugs give a sense of hope where there was once hopelessness. Patients may be prescribed these drugs over decades, but no longitudinal studies on their prolonged side effects have been undertaken. With an aging population disturbing research on elderly patients taking these drugs showed an increase in white matter lesions compared to drug naive patients. White matter lesions have been indicated in various degenerative disorders, but as yet no studies have discussed the potential mechanism(s) of the SSRIs on white matter. This thesis explores the effect of various SSRIs, in particular fluoxetine (Prozac), on white matter using the rodent optic nerve (ON) as a model. Acute fluoxetine application had a concentration dependant effect, attenuating the compound action potential (CAP) evoked from the ON. These effects caused both decrease in peak area at high concentrations, and increased peak latency at lower concentrations. Similar effects were seen with other SSRIs, but not with a novel antidepressant, tianeptine, of the selective serotonin reuptake enhancer (SSRE) class. Chronic fluoxetine application caused a decreased CAP area, and a loss of the smallest and fastest conducting axons in the ON. Morphologically, fluoxetine has a clear effect on both myelin and the axons within the ON, causing damage similar to that seen during metabolic insult. Further exploration of the effects of fluoxetine show it is clearly a pharmacologically 'dirty drug', most likely acting on ion channels and oxidative metabolism; effects unrelated to its action as a SSRI. This study is a novel exploration into unchartered territory, where little prior research is available, but the findings encourage further exploration into SSRIs and their potential short and long term effects in white matter.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available