In Chapter 2, results of a study are reported in which remitted depressed patients are compared to healthy controls to investigate possible residual cognitive impairments that persist into the... Show moreIn Chapter 2, results of a study are reported in which remitted depressed patients are compared to healthy controls to investigate possible residual cognitive impairments that persist into the euthymic phase. Chapter 3 will describe the effects of an alpha-lactalbumin enriched diet on cognitive performance in unmedicated recovered depressed patients and healthy controls. In Chapter 4 the effects of alpha-lactalbumin on mood and stress-induced cortisol response in unmedicated recovered depressed patients and healthy controls are reported. Chapter 5 describes the effects of low-dose and high-dose ATD on mood and neutral as well as emotional information processing in medicated remitted depressed patients. In Chapter 6, the effects of low-dose and high-dose tryptophan depletion on individual plasma tryptophan levels and the ratio tryptophan/LNAA will be discussed. In Chapter 7 the effects of ATD on heart rate variability in medicated remitted depressed patients are reported. A literature overview of studies investigating the effects of serotonin manipulations on emotional information processing and mood is given in Chapter 8. Also, evidence for a possible sequential link between serotonin induced changes in emotional information processing and mood is evaluated. Chapter 9 contains a summary and integration of the main findings, as well as methodological strengths and limitations, directions for future research and clinical implications of the findings reported in this thesis Show less
The main objective of the investigations was to explore the PK/PD correlations of fluvoxamine, as a prototype for the Selective Serotonin Reuptake Inhibitors (SSRIs). In the various investigations,... Show moreThe main objective of the investigations was to explore the PK/PD correlations of fluvoxamine, as a prototype for the Selective Serotonin Reuptake Inhibitors (SSRIs). In the various investigations, a spectrum of different biomarkers was used, each reflecting a specific process on the causal path between drug administration and response. The effects of fluvoxamine have been explored in six investigation steps; from the relatively simple description of the pharmacokinetics of fluvoxamine in plasma and brain to the more complex relationships with the effects on SERT occupancy, 5-HT and 5-HIAA levels and REM sleep. In the PCA study, a categorical PK/PD model was proposed for the effects of fluvoxamine on PCA induced behavioral effects as a kind of intermediary biomarker. There appeared to be important aspects in the PK/PD relationships of fluvoxamine, which was already indicated in the well-known delayed therapeutic effect of SSRIs. The cascading PK/PD model enables the prediction of the effects of functional adaptation upon long-term administration. For SSRIs, adaptation may occur at various levels in the biological system. The various studied biomarkers provide a basis to determine at which level of the biological system functional adaptation occurs (i.e. target site distribution, target expression, turnover of neurotransmitters, transduction mechanisms). Show less
