Abstract
Schizophrenia may develop from disruptions in functional connectivity regulated by neurotransmitters such as dopamine and acetylcholine. The modulatory effects of these neurotransmitters might explain how antipsychotics attenuate symptoms of schizophrenia and account for the variable response to antipsychotics observed in clinical practice. Based on the putative mechanisms of antipsychotics and evidence of disrupted connectivity in schizophrenia, we hypothesised that functional network connectivity, as assessed using network-based statistics, would exhibit differences between treatment response subtypes of schizophrenia and healthy controls. Resting-state functional MRI data were obtained from 17 healthy controls as well as individuals with schizophrenia who responded well to first-line atypical antipsychotics (first-line responders; FLR, n=18), had failed at least two trials of antipsychotics but responded to clozapine (treatment-resistant schizophrenia; TRS, n=18), or failed at least two trials of antipsychotics and a trial of clozapine (ultra-treatment-resistant schizophrenia; UTRS, n=16). Data were pre-processed using the Advanced Normalization Toolkit and BrainWavelet Toolbox. Network connectivity was assessed using the Network-Based Statistics toolbox in Matlab. ANOVA revealed a significant difference in functional connectivity between groups that extended between cerebellar and parietal regions to the frontal cortex (p<0.05). Post-hoc t-tests revealed weaker network connectivity in individuals with UTRS compared with healthy controls but no other differences between groups. Results demonstrated distinct differences in functional connectivity between individuals with UTRS and healthy controls. Future work must determine whether these changes occur prior to the onset of treatment and if they can be used to predict resistance to antipsychotics during first-episode psychosis.
Highlights
What we observe is a division of schizophrenia into different response subtypes, with first- and second-generation antipsychotics providing relief for ~70% of individuals (Agid et al, 2011) and clozapine providing relief for only 30%-70% of its recipients (Elkis, 2007; Essali et al, 2009; Kane and Correll, 2016; Kane et al, 1988)
Participants were enrolled into one of three study arms. Those who were responding well to first-line atypical antipsychotic monotherapy were assigned to the “first-line responder” (FLR) group; response to treatment was assessed by the treating psychiatrist, based on an improvement of positive symptoms and according to standard practice and current treatment guidelines for schizophrenia (Lehman et al, 2004; McGorry, 2005). Those who had failed at least two previous sixto-eight-week trials of atypical antipsychotics and were receiving clozapine were assigned to the “treatment-resistant” (TRS) group and participants who had failed at least two previous six-toeight-week trials of atypical antipsychotics and had failed an adequate trial of clozapine monotherapy (at least 8 weeks post titration (Mouaffak et al, 2006)) were assigned to the “ultratreatment-resistant” (UTRS) group
Post-hoc Ttests revealed significantly weaker network connectivity in individuals with UTRS compared to healthy controls (p
Summary
Post-mortem and in vivo studies have provided overwhelming evidence of aberrant functional connectivity in schizophrenia (Friston et al, 2016; Kanaan et al, 2005; Karbasforoushan and Woodward, 2012; Lynall et al, 2010; Menon, 2011; Zhou et al, 2007), supporting a role for dysconnection in the aetiology of the disorder (Stephan et al, 2009). Farooq and colleagues proposed subtyping schizophrenia according to treatment response, suggesting that division into subgroups, especially within the scope of research and drug development, could help us better understand and thereby treat this often disabling disorder (Farooq et al, 2013; Lee et al, 2015). This concept is supported by work demonstrating differences in dopaminergic and glutamatergic transmission between first-line responders (FLR) and individuals who fail to respond to treatment (Demjaha et al, 2014; Goldstein et al, 2015; Howes et al, 2015)
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