First episode schizophrenia: functional MRI findings and treatment response

Abstract

The research of this thesis centers on the investigation of first-episode medication-naive and recent onset schizophrenia patients. In part I, functional MRI studies are described, in part II short term treatment effects are compared between ziprasidone and olanzapine. Part I, chapter 2: Differences in the degree of language lateralization in first-episode medication-naﶥ schizophrenia and healthy controls were measured, using three language tasks. Results demonstrated that lateralization was significantly reduced in medication-naive first-episode patients. This reduction was most prominent in the inferior frontal gyrus (part of Broca’s area) and the superior temporal gyrus (part of Wernicke’s area). The level of lateralization was not related to specific symptomatology. We concluded that language lateralization is impaired already in the first episode of the illness and is not a confound of medication use. Part I, chapter 3: Frontal lobe function was compared in first-episode medication-naﶥ schizophrenia and healthy controls. To test frontal lobe function, we applied a modified Sternberg working memory task, which comprised a novel and practiced task. We expected patients to show a limited profit from practice in terms of brain activation, expressing inefficient neuronal processing in schizophrenia. Results indicated that after practice, both groups increased their performance equally. Frontal brain activation was reduced after practice in controls as well as in patients. In patients, this decrease was significantly smaller than in controls in the left dorsolateral prefrontal cortex (DLPFC), in spite of equal improvement in performance. Furthermore, this reduced effect of practice in left DLPFC activation was related to the severity of negative symptoms and conceptual disorganization. Chapter 4 was follow-up study to the study reported in chapter 3, in which subjects were rescanned after 10 weeks. After the baseline scan, patients were started on atypical antipsychotic medication. Results again showed that function of the left DLPFC was significantly impaired. Interestingly, the abnormal left DLPFC function was almost entirely explained for by the subgroup of patients who failed to respond to antipsychotic treatment. In contrast, in patients responding to medical treatment the activation levels after practice were similar to those of the healthy subjects. Responders and non-responders could not be discriminated by their test performance. Furthermore, the antipsychotic treatment that was applied did not alter the function of the DLPFC. Taken together, our results indicate that prefrontal lobe dysfunction reflects a distinct neuropathological substrate in a subgroup of schizophrenia patients that does not respond to treatment with dopamine antagonists. Part II. Describes a study that compares the effects of short-term treatment of ziprasidone and olanzapine on cognitive function (chapter 5) and on symptomatology and tolerability (chapter 6) in recent-onset schizophrenia. The primary outcome measure of the study was the California Verbal Learning Test (CVLT). In addition, a larger cognitive battery consisting of nine neurocognitive tests, for which a composite score was developed, was administered. We found that short term treatment with both ziprasidone and olanzapine has a comparable effect on symptomatology and cognitive function, but that they differ in side effects.