Effects of acute antipsychotic treatment on brain activation in first episode psychosis: An fMRI study
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.
Section snippets
Subjects
Patients who had recently presented with a first episode of psychosis (n = 10) were recruited from Lambeth Early Onset (LEO) Services (http://www.slam.nhs.uk/services/). All met ICD-10 criteria (WHO, 2003) for a schizophreniform psychosis at the time of scanning and met OPCRIT criteria (McGuffin et al., 1991) for schizophrenia when subsequently re-assessed 12 months after first presentation. All the subjects lived in the same borough of London (Lambeth), were native speakers of English and were
Sample characteristics
All the patients here enrolled were recruited from specialist first episode service (inpatient service or community service), they were unwell and they were receiving active treatment. Specifically, at the time of the scanning, all patients met OPCRIT (McGuffin et al., 1991) criteria for schizophrenia. These latter are ensembled in a checklist built up of operational criteria defined by a comprehensive glossary and are designed to assign reliable diagnoses from retrospective case notes. Since
Discussion
Cognitive impairment is a major determinant of functional outcome in schizophrenia (Ruhrmann et al., 2005, Fusar-Poli et al., in press). Treatment with antipsychotic medication (i.e. Risperidone or Quetiapine) is associated with improved cognitive performance in first episode psychosis (Harvey et al., 2005, Kopala et al., 2006) but the neural basis of these effects is still unclear (Keefe et al., 2004). In this functional neuroimaging study we tested the hypothesis that acute atypical
Limits
First, although we assume that the acute effects of antipsychotic are effective on the neurocircuits of cognition, we cannot exclude pharmacological confounding effects that have no bearing on cognitive function. Hence the interpretation of the correlation between duration of treatment and activation during cognitive tasks is not straightforward. However, exposure to medication reflects the severity of symptoms since the duration of treatment was correlated with PANSS score. Second, the doses
Conclusions
This study showed that duration of exposure to atypical antipsychotics appears to alter regional brain activation during a range of cognitive tasks in first episode psychosis subjects. Also, we found that this effect was evident after only a few days of treatment and with low doses of medications. Antipsychotics modulated activation in brain areas that are implicated in executive functions and working memory, as well as in the mediation of psychotic symptoms. The effects of antipsychotics on
Role of the funding source
The study was supported by grants from the Mental Health Foundation, Guy's and St Thomas' Charitable Foundation and GSK. These bodies were not involved in the design of the study, the collection and analysis of the data, or the interpretation of the results.
Contributors
PK McGuire, SCR Williams and M Brammer designed the study and wrote the protocol. MR Broome and P Matthiasson collected the data. P Fusar-Poli managed the literature searches and analyses. P Fusar-Poli and MR Broome undertook the statistical analysis, and wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Conflict of interest
‘The author(s) declare that they have no competing interests’.
The corresponding author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non exclusive for government employees) on a worldwide basis to the European Neuropsychopharmacology to permit this article (if accepted) to be published in European Neuropsychopharmacology editions and any other European Neuropsychopharmacology products to exploit all subsidiary rights.
Acknowledgement
The authors would like to thank Dr. Paddy Power and the staff and patients of the Lambeth Early Onset service of the South London and Maudsley NHS trust.
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2018, Schizophrenia ResearchCitation Excerpt :Abbott et al. found that aberrant activation patterns or connectivity in patients with schizophrenia were no longer apparent or were “normalized” after treatment (Abbott et al., 2013). Many studies have attempted to clarify the mechanism of antipsychotic treatment, but results remain inconsistent due to wide range of pharmaceutical treatments and the heterogenous nature of schizophrenia (Fusar-Poli et al., 2007; Goghari et al., 2013; Lui et al., 2010; Sambataro et al., 2010; Sarpal et al., 2015). As for the neural impacts of ECT, several studies have demonstrated relationships between ECT and brain structural and functional changes, but these studies have principally focused on major depressive disorder (MDD) (Biedermann et al., 2012; Kong et al., 2017; Mulders et al., 2016; Perrin et al., 2012; van Waarde et al., 2015).