Effects of aripiprazole vs. haloperidol on brain activity in healthy volunteers
Year: 2016
Type: dissertation
Abstract: Schizophrenia is a disorder characterized by positive symptoms, such as hallucinations and delusions, and negative symptoms, such as affect flatness and social withdrawal, in addition to cognitive impairment. Many of these symptoms have been associated with dopamine system disturbances. Schizophrenia is primarily treated with antipsychotic drugs, which are based on either dopamine D2 receptor antagonism (typicals), or dopamine D2 receptor antagonism in combination with other pharmacological properties (atypicals). Antipsychotics are relatively efficacious in treatment of positive symptoms, but are less effective treating negative and cognitive symptoms, and therefore new strategies are needed in drug development. One such strategy is based on partial agonism to the dopamine D2 receptor, and aripiprazole is a drug that belongs to this category.\nThe goal of this thesis was to examine possible alterations in behavior and brain activation resulting from single dose treatment of aripiprazole or haloperidol, a typical antipsychotic drug, compared to placebo. Two brain functions shown to be disturbed in psychosis were of particular interest: Handling of incentive salient stimuli by the motivational system (Study 2) and executive functioning (Study 3). Before performing the drug challenge study we aimed to design a reliable task to target the mesolimbic motivational system, and examine cortico-striatal connectivity (Study 1).\nFirst, we designed a task inspired by the conditioned avoidance response (CAR) animal model, for use with functional magnetic resonance imaging (fMRI) with bloodoxygen- level-dependent (BOLD) contrast. Then, this task, targeting incentive motivational salience, was applied without drug intervention. We showed that salient cues predicting aversive events were associated with stronger activations in the mesolimbic system, in particular the ventral striatum (VS), and with stronger connectivity between the VS and the frontal cortex (Study 1). Further, when participants doing this task were given haloperidol, the VS activation was diminished, while after aripiprazole the mesolimbic activation was intermediate of placebo and haloperidol (Study 2). In almost the same sample, when targeting executive functioning with the Tower of London problem-solving task, there were no significant differences in activation in the frontal cortex between participants given haloperidol and participants given aripiprazole (study 3). These results show that BOLD-fMRI is sensitive to changes from pharmacological manipulation. Further, the group difference in Study 2 implies different effects of haloperidol and aripiprazole, probably related to dopamine transmission.\nTaken together, these results indicate that pharmacological fMRI studies add knowledge about current pharmacological treatment strategies, and that pharmacological fMRI may be a useful tool for facilitating drug development for schizophrenia as well as other mental disorders.
Author: Ingeborg Bolstad
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2512801633