Effects of acute antipsychotic treatment on brain activation in first episode psychosis: An fMRI study

Abstract

This study aimed to assess the neurophysiological effects of acute atypical antipsychotic treatment on cognitive functioning in subjects presenting with a first episode of psychosis. We used functional MRI to examine the modulatory effects of acute psychopharmacological intervention on brain activation during four different cognitive tasks: overt verbal fluency, random movement generation, n-back and a spatial object memory task. Treatment with atypical antipsychotics was associated with alterations in regional activation during each task and also when task demands were manipulated within paradigms. The initial treatment of psychosis with atypical antipsychotics thus appears to be associated with modifications of the neurofunctional correlates of executive and mnemonic functions. These effects need to be considered when interpreting group differences in activation between medicated patients and controls.

Introduction

Cognitive function is impaired in schizophrenia, particularly in the domains of executive functions and working memory (Addington and Addington, 2002, Fusar-Poli et al., in press). According to the neurodegenerative model of psychosis (Heydebrand et al., 2004; Fusar-Poli, 2007; Broome et al., 2005), early treatment of psychotic symptoms might not only improve symptomatic outcome (Waddington et al., 1997) but could also act at a more fundamental level, attenuating some active, morbid process underlying the expression of the illness. Since for most patients the extensive decline in cognition must develop during the prodromal period (Jones et al., 1994, Hambrecht et al., 2002), the first psychotic episode (Nopoulos et al., 1994, Saykin et al., 1994), or both (Meltzer and McGurk, 1999), this action should be most evident on the earliest possible effective intervention following the onset of psychosis, before functional deterioration has started (Ruhrmann et al., 2005, Waddington et al., 1997). In fact, as well as reducing the severity of psychotic symptoms, there is evidence that antipsychotic drugs may also ameliorate some of the cognitive impairments (Amminger et al., 2000, Harvey and Keefe, 2001, Meltzer and McGurk, 1999) and exert a neuroprotective action (Ruhrmann et al., 2005). A central question regarding antipsychotic action is also the speed of onset of antipsychotic response (Kapur et al., 2005). Treatment with Risperidone has been reported to have a beneficial effect on perceptual/motor processing, reaction time, executive functions, working memory, verbal learning and memory, and motor function in the short-term (Meltzer and McGurk, 1999) and on episodic memory, verbal fluency, vigilance, executive functioning and visuomotor speed in the long-term (Harvey et al., 2005). Similarly, treatment with Quetiapine has been correlated with improvement on measures of attention, verbal productivity and executive function in the short-term (Good et al., 2002) and with improvements in sustained attention, visuomotor speed and sequencing, verbal fluency and verbal memory in the longer term (Kopala et al., 2006, Velligan et al., 2002). Despite some data suggesting that these beneficial effects on cognition are independent of any effect related to symptoms (Weiser et al., 2000), the physiological mechanism of their early action is still unclear (Malla et al., 2004). While potential pharmacological targets as receptors (especially D1) in the prefrontal cortex (PFC), the serotonin receptors in the PFC and anterior cingulate cortex, the glutamatergic excitatory synapse, the acetylcholine nicotinic receptors in the hippocampus, the acetylcholine muscarinic receptors and the brain gamma-aminobutyric acid (GABA) system are putative targets under research (Tamminga, 2006), the specific cortical regions where cognitive function may be modulated by antipsychotic treatment have yet to be defined.

A few papers, to date, have used functional neuroimaging (fMRI) to investigate the acute physiological effects of atypical antipsychotics on cognitive functions in antipsychotic naive subjects (Snitz et al., 2005). The present study sought to address this issue by using functional MRI to address the correlates of acute treatment in patients with a first episode of schizophrenia. Investigation of cognitive processes in first episode patients provides unprecedented opportunity to minimize specific confounders (Heydebrand et al., 2004): long-term neuroleptic treatment, long-term institutionalisation, progression of the disease itself or a combination of all these factors (Riley et al., 2000).

We predicted that early treatment with atypical antipsychotics would be correlated with physiological changes in regional brain activation (a) during tasks that engaged executive functions and working memory and (b) when cognitive load during such tasks was experimentally manipulated. As well as clarifying the mechanism of action of antipsychotics on symptoms and cognitive functions, we aimed to inform the interpretation of functional imaging studies that compare activation in medicated patients and controls.