Whale, W.R.; (2005) The assessment of serotonin function in major depression. Doctoral thesis , University of London.

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Abstract

The serotonergic system has been implicated in the aetiology and treatment of depression by a wealth of preclinical and clinical evidence. This includes findings that drug increasing serotonin neurotransmission have antidepressant action and inhibition of serotonin synthesis (via tryptophan depletion) can induce relapse of symptoms in depressed patients. Neuroendocrine challenges are an established method of indirectly examining brain serotonergic function, utilising changes in the secretion of pituitary hormones influenced by tonic serotonergic activity at the level of the hypothalamus. This thesis describes the development of two such neuroendocrine challenge tests, using the selective serotonertic probes, zolmitriptan and citalopram. Orally administered zolmitriptan, licensed for the treatment of migraine, clearly elevated plasma growth hormone in healthy subjects. This growth hormone response was antagonised by ketanserin suggesting mediation by postsynaptic 5-HT1D receptors. The response to zolmitriptan was attenuated in melancholic depressed subjects, and further reduced following antidepressant treatment. This implies a dysfunction of postsynaptic 5-HT1D receptor function in melancholia, and further 5-HT1D functional downregulation following antidepressant treatment. Citalopram, a selective serotonin reuptake inhibitor, administered at low dose intravenously was associated with an increase in plasma prolactin and cortisol in healthy subjects. The postsynaptic serotonin receptor subtype mediating these responses was not clearly elucidated from experiments using available 5-HT2 and 5-HT1A ligands. Depressed subjects demonstrated an attenuated prolactin response to citalopram suggesting impaired presynpatic 5-HT neuron function. These findings confirm impaired 5-HT function is depressed patients and assist in more clearly defining the nature of this impairment.

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