The main aim of the thesis was to measure antidepressant (AD) non-compliance, to determine which factors are closely associated with AD non-compliance and the consequences of prolonged AD non-compliance in the private health sector of South Africa. The empirical study followed an observational, prospective, cohort study using longitudinal medicine claims data provided by a nationally representative Pharmaceutical Benefit Management company (PBM) from 1 January 2006 to 31 December 2011. Failure to respond to AD treatment and achieving remission has severe neurobiological and clinical consequences. The clinical consequences include increased social and functional impairment, higher risk for recurrence and relapse of a depressive episode, a weak treatment outcome, significant increase in treatment cost, over-utilization of health care systems, and ultimately an increased suicide risk. However, the neurobiological consequences are much more far reaching. One of the more serious yet under-recognized neurobiological complications of AD non-compliance is the development of antidepressant discontinuation syndrome (ADS), which is the result of non-compliance or the abrupt discontinuation of AD treatment. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. After the first four months only 34% (n=12 397) of patients were compliant. What’s more a statistically significant association was found between active ingredient consumed and compliance (p < 0.0001). Only 26.2% of patients who received amitriptyline-containing products were complaint compared to 38.8% and 38.7% in the cases of venlafaxine and duloxetine, respectively. The current study found that females have a significantly higher prevalence of MDD and HIV/AIDS when compared to males. The co-morbidity between HIV/AIDS and major depressive disorder (MDD) had a significant effect on AD treatment compliance as patients diagnosed with both HIV/AIDS and MDD (74.43. ± 32.03, 95%Cl: 71.51-77.34) displayed a lower compliance vs. MDD patients (80.94% ± 29.44, 95%Cl: 80.56-81.33). Noteworthy, observations were that 75% (p < 0.0217; Cramer’s V = 0.0388) of venlafaxine and 28.6% (p < 0.0197; Cramer’s V = -0.0705) of the paroxetine items were compliant in patients diagnosed with both HIV/AIDS and MDD. The overall compliance (35.19% acceptable compliance; n = 42 869) of patients taking both ADs and GDs was weak. In the group receiving both AD and GDs, an increased AD treatment period was associated with a significant increase (p < 0.0001) in AD compliance (406.60 days; 95%Cl: 403.20 – 409.90 vs. 252.70 days; 95%Cl: 250.20 – 255.20). In this cohort amitriptyline (29.57%), mirtazapine (31.36%) and fluoxetine (32.29%) were associated with the lowest levels of compliance, while duloxetine (40.67%) was found to have the highest compliance. Lastly, ADs with highest non-compliance were associated with an increase use in GDs. Alprazolam (n = 10 201) and zolpidem (n = 9 312) were the most frequently dispensed GDs in combination with AD treatment. In conclusion the current study confirms that AD non-compliance is as big an obstacle in developing countries as it is in developed countries. Antidepressant treatment non-compliance has far reaching consequences especially with the development of ADS which further complicates MDD and might be a precursor for the development of TRD. Several factors were found to be closely associated with AD treatment non-compliance which include; pharmacological class of AD, gender, chronic co-morbid illnesses and a short treatment period. / PhD (Pharmacy Practice), North-West University, Potchefstroom Campus, 2015

The main aim of the thesis was to measure antidepressant (AD) non-compliance, to determine which factors are closely associated with AD non-compliance and the consequences of prolonged AD non-compliance in the private health sector of South Africa. The empirical study followed an observational, prospective, cohort study using longitudinal medicine claims data provided by a nationally representative Pharmaceutical Benefit Management company (PBM) from 1 January 2006 to 31 December 2011. Failure to respond to AD treatment and achieving remission has severe neurobiological and clinical consequences. The clinical consequences include increased social and functional impairment, higher risk for recurrence and relapse of a depressive episode, a weak treatment outcome, significant increase in treatment cost, over-utilization of health care systems, and ultimately an increased suicide risk. However, the neurobiological consequences are much more far reaching. One of the more serious yet under-recognized neurobiological complications of AD non-compliance is the development of antidepressant discontinuation syndrome (ADS), which is the result of non-compliance or the abrupt discontinuation of AD treatment. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. After the first four months only 34% (n=12 397) of patients were compliant. What’s more a statistically significant association was found between active ingredient consumed and compliance (p < 0.0001). Only 26.2% of patients who received amitriptyline-containing products were complaint compared to 38.8% and 38.7% in the cases of venlafaxine and duloxetine, respectively. The current study found that females have a significantly higher prevalence of MDD and HIV/AIDS when compared to males. The co-morbidity between HIV/AIDS and major depressive disorder (MDD) had a significant effect on AD treatment compliance as patients diagnosed with both HIV/AIDS and MDD (74.43. ± 32.03, 95%Cl: 71.51-77.34) displayed a lower compliance vs. MDD patients (80.94% ± 29.44, 95%Cl: 80.56-81.33). Noteworthy, observations were that 75% (p < 0.0217; Cramer’s V = 0.0388) of venlafaxine and 28.6% (p < 0.0197; Cramer’s V = -0.0705) of the paroxetine items were compliant in patients diagnosed with both HIV/AIDS and MDD. The overall compliance (35.19% acceptable compliance; n = 42 869) of patients taking both ADs and GDs was weak. In the group receiving both AD and GDs, an increased AD treatment period was associated with a significant increase (p < 0.0001) in AD compliance (406.60 days; 95%Cl: 403.20 – 409.90 vs. 252.70 days; 95%Cl: 250.20 – 255.20). In this cohort amitriptyline (29.57%), mirtazapine (31.36%) and fluoxetine (32.29%) were associated with the lowest levels of compliance, while duloxetine (40.67%) was found to have the highest compliance. Lastly, ADs with highest non-compliance were associated with an increase use in GDs. Alprazolam (n = 10 201) and zolpidem (n = 9 312) were the most frequently dispensed GDs in combination with AD treatment. In conclusion the current study confirms that AD non-compliance is as big an obstacle in developing countries as it is in developed countries. Antidepressant treatment non-compliance has far reaching consequences especially with the development of ADS which further complicates MDD and might be a precursor for the development of TRD. Several factors were found to be closely associated with AD treatment non-compliance which include; pharmacological class of AD, gender, chronic co-morbid illnesses and a short treatment period. / PhD (Pharmacy Practice), North-West University, Potchefstroom Campus, 2015

Hippokampale Sharp Wave-Ripples (SWRs) sind elektrografische Ereignisse, die für die Konsolidierung von Erinnerungen eine Rolle spielen. Eine SWR ist durch eine schnelle Oszillation (>90 Hz, ''ripple'') charakterisiert, die sich mit der langsameren ''sharp wave'' ( / Hippocampal sharp wave-ripples (SWRs) are electrographic events that have been implicated in memory consolidation. A SWR is characterized by a fast (> 90 Hz) oscillation, the ripple, superimposed on a slow (< 30 Hz) sharp wave. In vivo, the fast component can express frequencies either in the ripple range (140-200 Hz) or fast-gamma range (90-140 Hz). Episodes in both bands exhibit intra-ripple frequency accommodation (IFA). In vitro, ripples are frequency-resistant to GABA modulators. These features constrain the type of mechanisms underlying the generation of the fast component. A prominent hypothesis proposes that a recurrent network of parvalbumin-immunoreactive basket cells (PV+BC) is responsible of setting the ripple frequency. The focus of the present thesis is on testing to which extent the PV+BC network can account for the aforementioned features of SWRs, which remain unexplained. Here, I simulated and analyzed a physiologically constrained in silico model of the PV+BC network in CA1 under different conditions of excitatory drive. The response of the network to transient excitation exhibits both IFA in the ripple band and frequency resistance to GABA modulators. The expression of IFA in the fast gamma band requires the involvement of pyramidal cells in a closed loop with the PV+BC network. The model predicts a peculiar relationship between the instantaneous frequency of ripples and the time course of the excitatory input to CA1. This prediction was confirmed in an in vitro model of SWRs. Additionally, I study the involvement of oriens lacunosum-moleculare interneurons (O-LM) during SWRs in vitro. I characterize the excitatory currents received by O-LM cells during SWRs and investigate the factors that determine their recruitment.