Functional dysconnectivity 'widespread' in antipsychotic-naive first-episode psychosis

Antipsychotic-naive patients with first-episode psychosis exhibited widespread functional dysconnectivity at baseline, according to results of a secondary analysis of a randomized clinical trial published in JAMA Psychiatry.

“To our knowledge, no prior study has compared longitudinal [functional connectivity] changes in patients who were medicated and nonmedicated, making it impossible to disentangle [functional connectivity] changes attributable to antipsychotic medication vs. other factors, such as the natural course of the illness or adjunct interventions,” Sidhant Chopra, BSc, of the Turner Institute for Brain and Mental Health at Monash University School of Psychological Sciences in Australia, and colleagues wrote. “This comparison can be done only through a randomized placebo-controlled study of antipsychotic-naive patients. We recently used such a design to show, using a noninferiority design, that the placebo group had comparable clinical and functional outcomes to the medicated group and that patients who were medicated and unmedicated show different trajectories of gray matter volume, with antipsychotics normalizing basal ganglia volume in early illness stages.”

In the current secondary analysis of a triple-blind, randomized clinical trial with a 5-year recruitment period between April 2008 and December 2016, the researchers aimed to investigate longitudinal functional connectivity changes in antipsychotic-naive and antipsychotic-treated patients with first-episode psychosis. They analyzed data of 59 antipsychotic-naive patients with first-episode psychosis receiving either a second-generation antipsychotic or a placebo pill over 6 months of treatment. Eligibility criteria included low suicidality and aggression, having a duration of untreated psychosis of less than 6 months and to be living in stable accommodations with social support. Both first-episode psychosis groups received intensive psychosocial therapy. The researchers also recruited a healthy control group of 27 individuals. At baseline, 3 months and 12 months, participants completed resting state functional MRI, with data analysis between May 2019 and August 2020.

Results showed widespread functional dysconnectivity among patients vs. controls at baseline. Reductions mostly affected interactions between the default mode network, limbic systems and the rest of the brain. Those who received placebo exhibited increased functional connective principally within the same systems from baseline to 3 months, with some of these changes correlating with improved clinical outcomes. The researchers noted an association between antipsychotic exposure and increased functional connectivity primarily between the thalamus and the rest of the brain.

“Future work may extend our approach to include more rigorous monitoring of patients with a higher risk and evaluate the extent to which our findings generalize to that [first-episode psychosis] subgroup,” Chopra and colleagues wrote. “We also note that, although rates of substance and tobacco use did not differ between the treatment groups, use of these substances was not controlled for in our analyses.”