Abstract Antipsychotic medication forms the basis of the long-term, even lifelong treatment of schizophrenia. Antipsychotic polypharmacy and adjunctive psychiatric medications are also common treatment strategies. The long-term effects of psychiatric medication, especially on cognition in schizophrenia, are largely unknown. Cognitive impairment is a central, persisting symptomatic feature during the lifespan course of schizophrenia and a key predictor of functional outcome. This naturalistic study aimed to analyse how the lifetime exposure to antipsychotic, benzodiazepine and antidepressant medications, and lifetime trends in antipsychotic use, were associated with cognition in early midlife in schizophrenia. Non-psychotic controls were included as a reference group of normative cognitive performance. The study samples consisted of 40–60 subjects with schizophrenia and 73–191 non-psychotic controls from the Northern Finland Birth Cohort 1966. Data on the lifetime use of medications were collected from medical records, registers and interviews and connected with information from extensive psychiatric and neurocognitive assessments at the ages of 34 and 43 years. Higher cumulative lifetime exposure to antipsychotics was associated with poorer verbal learning and memory at 34 years of age, a decline in verbal learning and memory between the ages of 34 and 43 years and poorer global cognition at the age of 43 years in schizophrenia. A relatively long antipsychotic-free period before the cognitive assessment was associated with better global cognition at 43 years of age. Other lifetime trends in antipsychotic use, antipsychotic polypharmacy or cumulative benzodiazepine or antidepressant exposures were not associated with global cognition. This naturalistic study was the first to report an association between higher cumulative lifetime antipsychotic exposure and poorer cognition in early midlife in schizophrenia, which was not likely confounded by the use of other psychiatric medications or illness-related factors. Though residual confounding is still possible, these results suggest that high-dose long-term antipsychotic treatment may have some influence on the clinical course of schizophrenia, possibly by attenuating cognitive recovery. More research on the long-term effects of psychiatric medications is needed to develop the safe and effective treatment of schizophrenia. / Tiivistelmä Psykoosilääkitys on skitsofrenian pitkäaikaisen, jopa elinikäisen hoidon perusta. Useiden psykoosilääkkeiden yhtäaikaiskäyttö ja muiden psyykenlääkkeiden oheiskäyttö ovat yleisiä hoitostrategioita. Psyykenlääkkeiden pitkäaikaisvaikutuksia etenkin kognitioon skitsofreniassa tunnetaan huonosti. Kognitiiviset puutokset ovat keskeinen, elinaikaisesti pysyvä skitsofrenian oirepiirre ja merkittävimpiä ennustetekijöitä. Tämän naturalistisen tutkimuksen tavoite oli analysoida elinaikaisen psykoosi-, bentsodiatsepiini- ja masennuslääkealtistuksen sekä elinaikaisten psykoosilääkkeiden käytön trendien yhteyttä kognitioon varhaisessa keski-iässä skitsofreniassa. Ei-psykoottiset verrokit toimivat normatiivisen kognitiivisen suorituskyvyn vertailuryhmänä. Tutkimusaineisto koostui Pohjois-Suomen vuoden 1966 syntymäkohorttiin kuuluvista 40 ja 60 henkilöstä, joilla oli skitsofrenia, sekä 73 ja 191 ei-psykoottisesta verrokista. Tiedot psyykenlääkkeiden elinaikaiskäytöstä kerättiin sairauskertomuksista, rekistereistä ja haastatteluista, ja ne yhdistettiin 34 ja 43 vuoden iässä tehtyihin laajoihin psykiatrisiin ja neuropsykologisiin tutkimuksiin. Korkeampi kumulatiivinen elinaikainen psykoosilääkealtistus oli yhteydessä heikompaan kielelliseen muisti- ja oppimissuoriutumiseen 34-vuotiaana ja sen suurempaan laskuun 34 ja 43 ikävuoden välillä sekä heikompaan kognitioon 43-vuotiaana skitsofreniassa. Suhteellisen pitkä psykoosilääketauko ennen neuropsykologista tutkimusta oli yhteydessä parempaan kognitioon 43-vuotiaana. Muut elinaikaisen psykoosilääkityksen käytön trendit, psykoosilääkkeiden yhtäaikaiskäyttö tai elinaikainen kumulatiivinen bentsodiatsepiini- tai masennuslääkealtistus eivät olleet yhteydessä kognitioon. Tämä naturalistinen tutkimus kuvasi ensimmäisenä yhteyden suuremman kumulatiivisen elinaikaisen psykoosilääkealtistuksen ja heikomman kognition välillä varhaisessa keski-iässä skitsofreniassa. Muiden psyykenlääkkeiden käyttö tai sairauteen liittyvät tekijät eivät näyttäneet sekoittavan tätä yhteyttä. Vaikka on mahdollista, että kaikkia sekoittavia tekijöitä ei pystytty huomioimaan, tulosten perusteella korkea-annoksinen, pitkäaikainen psykoosilääkitys saattaa vaikuttaa skitsofrenian taudinkulkuun heikentämällä kognitiivista toipumista. Lisätutkimusta psyykenlääkityksen pitkäaikaisvaikutuksista tarvitaan skitsofrenian turvallisen ja tehokkaan hoidon kehittämiseksi.

Background: It is unclear whether antidepressants can prevent suicides or suicide attempts, particularly during longterm use. Methods: We carried out a comprehensive review of long-term studies of antidepressants (relapse prevention). Sources were obtained from 5 review articles and by searches of MEDLINE, PubMed Central and a hand search of bibliographies. We meta-analyzed placebo-controlled antidepressant RCTs of at least 3 months’ duration and calculated suicide and suicide attempt incidence rates, incidence rate ratios and Peto odds ratios (ORs). Results: Out of 807 studies screened 29 were included, covering 6,934 patients (5,529 patient-years). In total, 1.45 suicides and 2.76 suicide attempts per 1,000 patient-years were reported. Seven out of 8 suicides and 13 out of 14 suicide attempts occurred in antidepressant arms, resulting in incidence rate ratios of 5.03 (0.78–114.1; p = 0.102) for suicides and of 9.02 (1.58–193.6; p = 0.007) for suicide attempts. Peto ORs were 2.6 (0.6–11.2; nonsignificant) and 3.4 (1.1–11.0; p = 0.04), respectively. Dropouts due to unknown reasons were similar in the antidepressant and placebo arms (9.6 vs. 9.9%). The majority of suicides and suicide attempts originated from 1 study, accounting for a fifth of all patient-years in this meta-analysis. Leaving out this study resulted in a nonsignificant incidence rate ratio for suicide attempts of 3.83 (0.53–91.01). Conclusions: Therapists should be aware of the lack of proof from RCTs that antidepressants prevent suicides and suicide attempts. We cannot conclude with certainty whether antidepressants increase the risk for suicide or suicide attempts. Researchers must report all suicides and suicide attempts in RCTs.

In der Pathophysiologie der Depression könnte das Zusammenspiel von Immun- und Nervensystem eine zentrale Rolle spielen. In den Krankheitsepisoden zeigen depressive Patienten eine gesteigerte Produktion pro-inflammatorischer Zytokine wie z. B. Interleukin (IL)-1β und dem Tumornekrosefaktor (TNF)-α. Es gibt nur begrenzte Informationen bezüglich der Effekte von Antidepressiva auf Zytokine. Die meisten Studien berichten nur über die Veränderungen einzelner Zytokine und keine hat bis jetzt über Effekte von Antidepressiva auf IL-22 berichtet. Wir haben systematisch die Wirkung von drei Antidepressiva, nämlich Citalopram, Escitalopram und Mirtazapin auf die Sekretion der Zytokine IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 und TNF-α in einem Vollblutverfahren in-vitro untersucht. Als Immunstimulanzien wurden der gegen humanes CD3 gerichtete monoklonale Antikörper OKT3 und der gegen CD40 gerichtete monoklonale Antikörper 5C3 verwendet. Es zeigte sich, dass es unter Citalopram zu einer erhöhten IL-1β, I-6, IL-22 und TNF-α-Produktion und unter Mirtazapin zu einer erhöhten Produktion von IL-1β, IL-22 und TNF-α gegenüber der Kontrollbedingung, in der keine Antidepressiva zugesetzt wurden, kam. Unter Escitalopram kam es zu einer gegenüber der Kontrollbedingung verringerten IL-17-Produktion. Der Einfluss der Antidepressiva auf IL-2 und IL-4 war für alle drei Psychopharmaka nicht signifikant. Verglichen mit Escitalopram führte Citalopram zu höheren IL-1β-, IL-6-, IL-17- und IL-22-Konzentrationen und Mirtazapin führte zu einer höheren IL-1β-, IL-17-, IL-22- und TNF-α-Produktion. Möglicherweise besteht ein Bezug zwischen dem Profil der Zytokinproduktion eines Antidepressivums und seinen therapeutischen Effekten, Nebenwirkungen und seinem Rückfallrisiko. Zur Überprüfung dieser Hypothese sind jedoch in-vivo Studien notwendig.:1. Bibliografische Zusammenfassung 3 2. Abkürzungsverzeichnis 4 3. Einführung 6 3.1. Einleitung 6 3.2. Ziel der vorliegenden Arbeit und Fragestellung 10 3.3. Materialien und Methoden 11 3.4. Ergebnisse 14 3.4.1. Einfluss der Antidepressiva auf die Zytokinproduktion 14 3.4.2. Vergleich der Antidepressiva 16 3.5. Diskussion 17 4. Publikation 20 5. Zusammenfassung 35 6. Literaturverzeichnis 37 7. Anlagen 44 7.1. Erklärung über die eigenständige Abfassung der Arbeit 44 7.2. Publikationen 45 7.3. Danksagung 46 / The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively.Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.:1. Bibliografische Zusammenfassung 3 2. Abkürzungsverzeichnis 4 3. Einführung 6 3.1. Einleitung 6 3.2. Ziel der vorliegenden Arbeit und Fragestellung 10 3.3. Materialien und Methoden 11 3.4. Ergebnisse 14 3.4.1. Einfluss der Antidepressiva auf die Zytokinproduktion 14 3.4.2. Vergleich der Antidepressiva 16 3.5. Diskussion 17 4. Publikation 20 5. Zusammenfassung 35 6. Literaturverzeichnis 37 7. Anlagen 44 7.1. Erklärung über die eigenständige Abfassung der Arbeit 44 7.2. Publikationen 45 7.3. Danksagung 46

ithium is an important psychopharmacologi- cal agent for the treatment of unipolar as well as bipolar affective disorders. Lithium has a number of side effects such as hypothyroidism and aggravation of psoriasis. On the other hand, lithium has pro-inflammatory effects, which appear beneficial in some disorders associated with immunological deficits, such as human immunodeficiency virus (HIV) infection and systemic lupus erythematosus (SLE). Therefore, immunological characteristics of lithium may be an important consideration in individualized ther- apeutic decisions. We measured the levels of the cytokines interleukin (IL)-1ß, IL-2, IL-4, IL-6, IL-22, IL-17 and tumour necrosis factor (TNF)-a in the stimulated blood of thirty healthy subjects supplemented with lithium alone, the antidepressants citalopram, escitalopram or mirtazapine alone, the combination of each antidepressant with lithium, and a no drug control. These drugs were tested under three blood stimulant conditions: murine anti-human CD3 monoclonal antibody OKT3 and the 5C3 monoclonal antibody (OKT3/5C3), phytohemagglutinin (PHA), and unstimulated blood. Lithium, alone and in combination with any of the tested antidepressants, led to a consistent increase of IL-1ß, IL-6 and TNF-a levels in the unstimulated as well as the stimulated blood. In the OKT3/ 5C3- and PHA-stimulated blood, IL-17 production was significantly enhanced by lithium. Lithium additionally increased IL-2 concentrations significantly in PHA-stimu- lated blood. The data support the view that lithium has pro- inflammatory properties. These immunological character- istics may contribute to side effects of lithium, but may also explain its beneficial effects in patients suffering from HIV infection or SLE.

Syftet med den här studien är att utreda om det finns något samband mellan den psykiska ohälsan och konjunkturcykeln i Sverige. Relationen är viktig att undersöka på grund av att en försämring av psykisk hälsa som ett resultat av ekonomiska kriser, skulle kunna leda till ytterligare kostnader såsom förlorad produktion. För att kunna sätta in relevanta insatser och eventuellt lindra negativa effekter, studeras det också om det finns skillnader mellan män och kvinnor. Indikatorer för psykisk ohälsa som används för att besvara syftet är förekomsten av suicid, användning av antidepressiva, depression samt psykiatriska tillstånd. Som konjunkturmått används bruttoregionprodukt och arbetslöshet. Ytterligare kontrollvariabler som andel utrikesfödda, befolkningstäthet och andel av befolkningen med högre utbildning inkluderas också. Regressionsanalyser görs på två olika modeller, där modell 1 fångar upp sambandet mellan ohälsa och konjunkturförändringar och modell 2 fångar upp skillnaden mellan könen. Resultatet är att under lågkonjunktur minskar användningen av antidepressiva, men ingen förändring för depression eller psykiatriska tillstånd observeras. Resultatet angående suicid är att under lågkonjunktur minskar suicidgraden mer för kvinnor än för män. Detta innebär att det delvis finns ett samband mellan konjunkturförändringar och psykisk ohälsa i Sverige. / The purpose of this study is to investigate if mental health in Sweden is connected to the business cycle. The relationship is important to investigate since deterioration of mental health, due to economic crises, could lead to additional costs in the form of losses in production. To be able to make relevant decisions to mitigate any negative effects, the question of whether there is a difference between men and women is also studied. The four different indicators that are used to describe mental illness are: suicide, antidepressants, depression, and psychiatric conditions. Gross regional product and unemployment are used as economic indicators. Additional control variables such as the share of foreign-born individuals, population density, and the share of individuals with tertiary degrees are also included. Furthermore, the regression analyses are made based on two types of models. Model number one captures the relation between mental illness and changes in business cycle, while model number two captures the difference in mental illness between genders. The results show that during recessions the consumption of antidepressants decreases while there is no change in depression and psychiatric conditions. Whereas results regarding suicide show that during recessions suicide for women decrease more than for men. This means that there is a partial relationship between cyclical changes and mental illness in Sweden.

No description available.

This study set out to review and analyse aspects of antidepressant prescribing in children and adolescents in a section of the private health care sector of South Africa. The research was conducted in two phases, namely a literature review and an empirical investigation. The aim of the literature review was to provide background to the study by conceptualising antidepressants. The empirical review followed a retrospective, descriptive, observational design. The data employed in the study was obtained from the medicine claims database of a South African Pharmaceutical Benefit Management (PBM) company. The study population consisted of 3 611 children and adolescents receiving ≥1 antidepressants from 1 January 2010 to 31 December 2010. Basic descriptive statistics, such as frequency, prevalence, average, weighted average, standard deviation, weighted standard deviation, median, effect sizes, prescribed daily dosages and DU95% methodology were used to characterise the study sample, and were calculated using the Statistical Analysis System SAS® for Windows 9.3® program. The data were used to determine the prescribing patterns of antidepressants with regard to age, gender, geographic area, type of prescriber, the comparison of prescribed daily dosages vs. recommended daily dosages, and the prevalence of potential drug-drug interactions. Potential drug-drug interactions were identified and compiled by using various interaction compendia, whereas recommended daily dosages were identified by cross-referencing various dosage compendia. The study population consisted of 1 850 girls and 1 761 boys. The mean age of girls was 13.7 ± 3.9 years, vs. 12.3 ± 3.8 years for boys (d = 0.4). A total of 11 735 prescriptions containing 12 272 antidepressants were documented in 2010. Results of the study furthermore showed that the average number of prescriptions claimed per patient increased with age, from an average of 1.0 ± 0.28 among those up to the age of 2 years, to an average of 3.4 ± 3.21 among those 16 to 18 years of age. Prescribing with regard to age groups differed, rising gradually from birth and peaking at middle childhood for boys, whereas antidepressant use in girls increased from birth up to 6 years of age, reaching a plateau and increases again from age 13 and onward. Approximately 25% (n = 12 272) of antidepressants prescribed were either not indicated in children, or the dosages were deemed too high. More than 50% (n = 12 272) of antidepressants prescribed were in the Gauteng province. The SSRIs (selective serotonin re-uptake inhibitors) and the TCAs (tricyclic antidepressants) were the most prescribed antidepressants in both gender groups. The male-to-female ratio for the selective serotonin re-uptake inhibitors was 0.9, compared to 1.2 for the tricyclic antidepressants. The top three antidepressants prescribed were imipramine (21.8%), citalopram (15.3%) and escitalopram (14.7%, n = 12 272). Potential DDIs were observed on 284 (2.4%) (n = 11 743) prescriptions. The drug pairs with potential drug-drug interactions prescribed most, were imipramine with methylphenidate [43 cases (15.1%)] and valproic acid [38 cases (13.4%)], and followed by methylphenidate in combination with fluoxetine and sertraline [both documenting 32 cases (11.3%), respectively. The TCAs accounted for 182 (64.1%) cases of possible DDIs (drug-drug interactions), whereas combination therapy of SSRIs and TCAs accounted for 21.4% of potential DDIs. In conclusion, this study determined that there were a number of differences with regard to antidepressant prescribing in children and adolescents. Recommendations for future studies were made. / MPharm (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

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

This study set out to review and analyse aspects of antidepressant prescribing in children and adolescents in a section of the private health care sector of South Africa. The research was conducted in two phases, namely a literature review and an empirical investigation. The aim of the literature review was to provide background to the study by conceptualising antidepressants. The empirical review followed a retrospective, descriptive, observational design. The data employed in the study was obtained from the medicine claims database of a South African Pharmaceutical Benefit Management (PBM) company. The study population consisted of 3 611 children and adolescents receiving ≥1 antidepressants from 1 January 2010 to 31 December 2010. Basic descriptive statistics, such as frequency, prevalence, average, weighted average, standard deviation, weighted standard deviation, median, effect sizes, prescribed daily dosages and DU95% methodology were used to characterise the study sample, and were calculated using the Statistical Analysis System SAS® for Windows 9.3® program. The data were used to determine the prescribing patterns of antidepressants with regard to age, gender, geographic area, type of prescriber, the comparison of prescribed daily dosages vs. recommended daily dosages, and the prevalence of potential drug-drug interactions. Potential drug-drug interactions were identified and compiled by using various interaction compendia, whereas recommended daily dosages were identified by cross-referencing various dosage compendia. The study population consisted of 1 850 girls and 1 761 boys. The mean age of girls was 13.7 ± 3.9 years, vs. 12.3 ± 3.8 years for boys (d = 0.4). A total of 11 735 prescriptions containing 12 272 antidepressants were documented in 2010. Results of the study furthermore showed that the average number of prescriptions claimed per patient increased with age, from an average of 1.0 ± 0.28 among those up to the age of 2 years, to an average of 3.4 ± 3.21 among those 16 to 18 years of age. Prescribing with regard to age groups differed, rising gradually from birth and peaking at middle childhood for boys, whereas antidepressant use in girls increased from birth up to 6 years of age, reaching a plateau and increases again from age 13 and onward. Approximately 25% (n = 12 272) of antidepressants prescribed were either not indicated in children, or the dosages were deemed too high. More than 50% (n = 12 272) of antidepressants prescribed were in the Gauteng province. The SSRIs (selective serotonin re-uptake inhibitors) and the TCAs (tricyclic antidepressants) were the most prescribed antidepressants in both gender groups. The male-to-female ratio for the selective serotonin re-uptake inhibitors was 0.9, compared to 1.2 for the tricyclic antidepressants. The top three antidepressants prescribed were imipramine (21.8%), citalopram (15.3%) and escitalopram (14.7%, n = 12 272). Potential DDIs were observed on 284 (2.4%) (n = 11 743) prescriptions. The drug pairs with potential drug-drug interactions prescribed most, were imipramine with methylphenidate [43 cases (15.1%)] and valproic acid [38 cases (13.4%)], and followed by methylphenidate in combination with fluoxetine and sertraline [both documenting 32 cases (11.3%), respectively. The TCAs accounted for 182 (64.1%) cases of possible DDIs (drug-drug interactions), whereas combination therapy of SSRIs and TCAs accounted for 21.4% of potential DDIs. In conclusion, this study determined that there were a number of differences with regard to antidepressant prescribing in children and adolescents. Recommendations for future studies were made. / MPharm (Pharmacy Practice), North-West University, Potchefstroom Campus, 2014

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