Effect of Intranasal Oxytocin on Resting-state Effective Connectivity in Schizophrenia

Abstract

Objectives Evidence from several lines of research suggests the critical role of neuropeptide oxytocin in social cognition and social behavior. Though a few studies have examined the effect of oxytocin on clinical symptoms of schizophrenia, the underlying neurobiological changes are underexamined. Hence, in this study, we examined the effect of oxytocin on the brain’s effective connectivity in schizophrenia. Methods 31 male patients with schizophrenia (SCZ) and 21 healthy male volunteers (HV) underwent resting functional magnetic resonance imaging scans with intra-nasal oxytocin (24 IU) and placebo administered in counterbalanced order. We conducted a whole-brain effective connectivity analysis using a multivariate vector autoregressive granger causality model. We performed a conjunction analysis to control for spurious changes and canonical correlation analysis between changes in connectivity and clinical and demographic variables. Results Three connections, sourced from the left caudate survived the FDR correction threshold with the conjunction analysis; connections to the left supplementary motor area, left precentral gyrus, and left frontal inferior triangular gyrus. At baseline, SCZ patients had significantly weaker connectivity from caudate to these three regions. Oxytocin, but not placebo, significantly increased the strength of connectivity in these connections. Better cognitive insight and lower negative symptoms were associated with a greater increase in connectivity with oxytocin. Conclusions These findings provide a preliminary mechanistic understanding of the effect of oxytocin on brain connectivity in schizophrenia. The study findings provide the rationale to examine the potential utility of oxytocin for social cognitive deficits in schizophrenia.

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“…In a controlled clinical trial involving individuals with schizophrenia, participants were administered nasal OXT (24 IU) or saline via a spray bottle. Subsequent magnetic resonance imaging (MRI) scans revealed improved social cognitive functioning following OXT application [ 59 ]. Notably, OXT comprises only nine amino acids, which may partially account for its extensive research focus [ 60 ].…”

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“…This is a secondary data analysis of three studies conducted between 2013 and 2019 that included 87 patients with SCZ and 70 healthy volunteers (HV) in the age range of 18 to 50. [ 32 33 34 ] The eligibility criteria for the sample in the three studies are given in Supplementary Table S1 . All the studies were approved by the Institutional Ethics Committee (approval numbers: study 1 NIMHANS/85 th IEC/2013, dated May 17, 2013; study 2 NIMHANS/105 th IEC/2016, dated Jul 02, 2016; study 3 NIMHANS/105 th IEC/2016, dated Jul 02, 2016).…”

“…We administered Structured Clinical Interview for DSM-IV Disorders,[ 37 ] the Calgary Depression Scale for Schizophrenia,[ 38 ] and the Clinical Global Impression Scale,[ 39 ] to assess clinical symptoms. In two studies,[ 33 34 ] we used the Positive and Negative Syndrome Scale (PANSS), and in one study,[ 32 ] we used the Brief Psychiatric Rating Scale (BPRS) [ Supplementary Table 1 ]. Hence, we computed equipercentile scores of the PANSS using a validated method.…”

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“…Likewise, exogenous sublingual OXT administration, in addition to clozapine treatment, reduced negative symptoms and maintained low positive symptoms in young adult patients with treatment-resistant schizophrenia [ 62 ]. Meanwhile, a single dose of intranasal OXT increased functional connectivity between the amygdala and left middle temporal gyrus (MTG), superior temporal sulcus (STS), and angular gyrus (AngG), associated with a reduction in negative symptoms, as well as the caudate and left supplementary motor area, precentral gyrus, and frontal inferior triangular gyrus, associated with greater cognitive insight and lower negative symptoms [ 63 , 64 ].…”