Exploring opportunities for optimizing treatment in psychotic disorders

Abstract

At present, treatment for psychotic disorder patients is suboptimal, as a substantial part of these patients do not sufficiently respond to currently available treatment options. In order to optimize treatment for these patients, there is a large need to explore how treatment can be improved. There are several options to optimize treatment for schizophrenia patients, of which two options are described in this dissertation: 1) novel augmentation therapies (i.e. anti-inflammatory drugs) and 2) improving currently available treatment by including schizophrenia patients with comorbidities in RCTs or by implementing precision medicine (i.e. TDM). In part I of this dissertation, no support for the beneficial effect of anti-inflammatory therapy in schizophrenia was found, which contradicts previous published meta-analyses, but is in line with the most recently published RCTs. It might be that treatment with statins or prednisolone is effective in a subgroup of patients in which low-grade inflammation in the central nerve system is present. Alternatively, it might be that mild anti-inflammatory drugs (e.g. aspirin) are more effective in a population with a high risk to develop psychosis (Ultra-high risk or Clinical High risk individuals), but this is yet to be determined. In part II of this dissertation two studies were presented with options to improve the application of currently available treatment. The first study of part II of this dissertation investigated the effect of excluding first-episode schizophrenia patients with comorbidities (such as suicidal ideation and/SUD). It was found that the exclusion of comorbidity patients did not have an impact on key RCT outcomes (symptomatic remission, premature study discontinuation, symptom severity and social performance) after four weeks of treatment with amisulpride. As first-episode schizophrenia patients with comorbidities are often excluded from efficacy trials, there is a gap in knowledge of the efficacy of antipsychotics in this group. As a result from this lack in knowledge, clinicians currently do not have an extensive scientific bases for treatment decisions in first episode schizophrenia patient.The second study of part II of this thesis examined whether an association could be found between amisulpride blood level and achieving symptomatic remission. Additionally, it was investigated whether there was an association between symptom severity (psychosis symptoms, depressive symptoms and severity of illness), mean dose and amisulpride blood level. It was also examined whether patient characteristics (age, sex, smoking, alchohol use and weight) had an effect on amisulpride blood level. The outcome of this study was that a low amisulpride blood level was significantly associated with a higher probability of going into symptomatic remission. Additionally, a lower blood level was associated with a better outcome; greater improvement in psychosis symptoms and severity of illness. With this study, no evidence was found for the implemention of TDM in amisulpride treatment, which is in contrast to the recommendation in the “Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology 2017” (Hiemke et al., 2017).