, Ed Bullmore
, William Soni, Malini Varatheesan, Steve Williams
, Tonmoy SharmaSection of Cognitive Psychopharmacology, Institute of Psychiatry, London, UK.
Department of Psychological Medicine, Institute of Psychiatry
Department of Clinical Neurosciences, Institute of Psychiatry
INTRODUCTION Compared to ‘typical’ antipsychotics, novel ‘atypical’ drugs have been shown to be more effective in treating negative signs of schizophrenia, and have been associated with improved performance on cognitive tasks dependent on frontal lobe function. These therapeutic and cognitive benefits of atypical antipsychotic treatment have been attributed to the relative selectivity of D2 antagonism mediated by these drugs. In animal models, atypical antipsychotics produce less potent blockade than typical drugs of the mesocortical dopaminergic projection from ventral tegmentum to prefrontal cortex. Indeed, atypical anti-psychotics have been shown to augment prefrontal dopaminergic activity in animal models. It has been suggested that negative symptoms and cognitive deficits associated with schizophrenia may reflect impaired prefrontal cortical function, due to reduced dopaminergic drive to the prefrontal cortex via the mesocortical projection, and accordingly this may explain improvement in cognitive and negative symptoms following treatment with atypical antipsychotics. However, there is as yet no direct evidence from human studies that, compared to typical antipsychotics, atypical drugs do indeed enhance prefrontal function. This study used functional magnetic resonance imaging (fMRI) to examine the effect of atypical anti-psychotics on prefrontal function. We predicted that substitution of risperidone for typical antipsychotic drugs in the treatment of patients with schizophrenia would be associated with enhanced functional activation during the performance of a verbal working memory task, hypothetically due to relatively increased dopaminergic drive to the prefrontal cortex.
METHODS We used multislice echoplanar functional MRI and a verbal working memory task in two groups of schizophrenic patients at baseline and 6 weeks later. One group was treated with typical antipsychotic drugs throughout. Risperidone was substituted for typical antipsychotics after baseline assessment in the second group. The assignment of patients to atypical or typical treatments was clinically determined. On each assessment, patients were also symptomatically assessed using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). A matched group of healthy volunteers were also studied on a single occasion. Images were acquired over a 5 minute period at 1.5 Tesla. We used a blocked periodic design to activate verbal working memory systems, using the n-back task. Generic brain activation (GBAM) maps were constructed from individual images by sinusoid regression analysis. To test the interactive effect of treatment by time on power of functional response, the power maps observed at 6 weeks were subtracted from the corresponding maps observed at baseline, representing the difference in experimentally determined power over time at each voxel. An analysis of variance model was then fitted at each voxel that was generically activated in one or more of the 4 GBAMs previously generated from the two patient subgroups:
RESULTS The patients switched to risperidone treatment had higher scores on positive, negative and global psychopathology scales at both assessments than patients who continued on typical antipsychotic drug treatment, though the risperidone-treated group showed a non-significant trend towards improvement on all three subscales of the PANNS. All subjects were able to perform the working memory task with a high degree of accuracy. There were no significant changes in accuracy or reaction time between baseline and 6 weeks in either treatment group, although the risperidone-treated group showed a trend towards improvement in reaction time. The working memory task activated a network of fronto-parietal brain regions in controls. Activation was relatively attenuated in both patient groups at baseline, and in the typically-treated group at 6 weeks. The risperidone-treated group had significantly greater response at 6 weeks in dorsolateral prefrontal cortex, supplementary motor area and parietal cortex (p< 0.005) (see Figure 1).
DISCUSSION These data provide the first direct evidence for enhanced prefrontal cortical function in schizophrenic patients following substitution of risperidone for typical antipsychotic drugs. The precise mechanism by which substitution of risperidone might enhance prefrontal function remains hypothetical. It is possible that the 5HT2A antagonist properties of risperidone might increase dopaminergic effects on PFC by blocking the inhibitory effects of serotonin on presynaptic dopamine release. This is supported by evidence of serotonergic modulation of prefrontal dopamine in animal models using 5-HT2 antagonists. These data also indicate the potential value of fMRI as a tool for longitudinal assessment of psychopharmacological effects on cerebral physiology.
