Functional Connectivity in Antipsychotic-Treated and Antipsychotic-Naive Patients With First-Episode Psychosis and Low Risk of Self-harm or Aggression: A Secondary Analysis of a Randomized Clinical Trial

JAMA Psychiatry. 2021 Sep 1;78(9):994-1004. doi: 10.1001/jamapsychiatry.2021.1422.


Importance: Altered functional connectivity (FC) is a common finding in resting-state functional magnetic resonance imaging (rs-fMRI) studies of people with psychosis, yet how FC disturbances evolve in the early stages of illness, and how antipsychotic treatment influences these disturbances, remains unknown.

Objective: To investigate longitudinal FC changes in antipsychotic-naive and antipsychotic-treated patients with first-episode psychosis (FEP).

Design, setting, and participants: This secondary analysis of a triple-blind, randomized clinical trial was conducted over a 5-year recruitment period between April 2008 and December 2016 with 59 antipsychotic-naive patients with FEP receiving either a second-generation antipsychotic or a placebo pill over a treatment period of 6 months. Participants were required to have low suicidality and aggression, to have a duration of untreated psychosis of less than 6 months, and to be living in stable accommodations with social support. Both FEP groups received intensive psychosocial therapy. A healthy control group was also recruited. Participants completed rs-fMRI scans at baseline, 3 months, and 12 months. Data were analyzed from May 2019 to August 2020.

Interventions: Resting-state functional MRI was used to probe brain FC. Patients received either a second-generation antipsychotic or a matched placebo tablet. Both patient groups received a manualized psychosocial intervention.

Main outcomes and measures: The primary outcomes of this analysis were to investigate (1) FC differences between patients and controls at baseline; (2) FC changes in medicated and unmedicated patients between baseline and 3 months; and (3) associations between longitudinal FC changes and clinical outcomes. An additional aim was to investigate long-term FC changes at 12 months after baseline. These outcomes were not preregistered.

Results: Data were analyzed for 59 patients (antipsychotic medication plus psychosocial treatment: 28 [47.5%]; mean [SD] age, 19.5 [3.0] years; 15 men [53.6%]; placebo plus psychosocial treatment: 31 [52.5%]; mean [SD] age, 18.8 [2.7]; 16 men [51.6%]) and 27 control individuals (mean [SD] age, 21.9 [1.9] years). At baseline, patients showed widespread functional dysconnectivity compared with controls, with reductions predominantly affecting interactions between the default mode network, limbic systems, and the rest of the brain. From baseline to 3 months, patients receiving placebo showed increased FC principally within the same systems; some of these changes correlated with improved clinical outcomes (canonical correlation analysis R = 0.901; familywise error-corrected P = .005). Antipsychotic exposure was associated with increased FC primarily between the thalamus and the rest of the brain.

Conclusions and relevance: In this secondary analysis of a clinical trial, antipsychotic-naive patients with FEP showed widespread functional dysconnectivity at baseline, followed by an early normalization of default mode network and cortical limbic dysfunction in patients receiving placebo and psychosocial intervention. Antipsychotic exposure was associated with FC changes concentrated on thalamocortical networks.

Trial registration: ACTRN12607000608460.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aggression / physiology
  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / pharmacology*
  • Brain* / diagnostic imaging
  • Brain* / drug effects
  • Brain* / physiopathology
  • Connectome*
  • Default Mode Network* / diagnostic imaging
  • Default Mode Network* / drug effects
  • Default Mode Network* / physiopathology
  • Double-Blind Method
  • Female
  • Humans
  • Limbic System / diagnostic imaging
  • Limbic System / drug effects
  • Limbic System / physiopathology
  • Longitudinal Studies
  • Magnetic Resonance Imaging
  • Male
  • Nerve Net* / diagnostic imaging
  • Nerve Net* / drug effects
  • Nerve Net* / physiopathology
  • Outcome Assessment, Health Care
  • Psychotic Disorders* / diagnostic imaging
  • Psychotic Disorders* / drug therapy
  • Psychotic Disorders* / physiopathology
  • Risk
  • Self-Injurious Behavior / physiopathology
  • Young Adult


  • Antipsychotic Agents

Associated data

  • ANZCTR/ACTRN12607000608460