Duration of Untreated Psychosis Correlates With Brain Connectivity and Morphology in Medication-Naïve Patients With First-Episode Psychosis

Biol Psychiatry Cogn Neurosci Neuroimaging. 2020 Feb;5(2):231-238. doi: 10.1016/j.bpsc.2019.10.014. Epub 2019 Nov 9.


Background: In the United States, the average duration of untreated psychosis (DUP) is 21 months, and it remains unknown how longer DUP may affect brain functioning in antipsychotic-naïve patients with first-episode psychosis. The objective was to determine the effects of DUP on functional connectivity and brain morphology measured with resting-state functional and structural magnetic resonance imaging.

Methods: Medication-naïve patients with first-episode psychosis were referred from various clinical settings. After accounting for exclusion criteria, attrition, and data quality, final analyses included 55 patients (35 male and 20 female; mean age, 24.18 years). Patients with first-episode psychosis were subjected to a 16-week trial of risperidone, a commonly used antipsychotic drug. Treatment response was calculated as change in the psychosis subscale of the Brief Psychiatric Rating Scale between baseline and 16 weeks. Resting-state functional connectivity magnetic resonance imaging and brain morphology (surface area and cortical thickness) were assessed.

Results: Longer DUP was associated with worse treatment response and reduced functional connectivity-more specifically in the default, salience, and executive networks. Moreover, longer DUP was associated with reduced surface area in the salience and executive networks and with increased cortical thickness in the default mode and salience networks. When the functional connectivity of the default mode network was added as a mediator, the relationship between DUP and treatment response was no longer significant.

Conclusions: These data suggest that several neurobiological alterations in the form of reduced functional connectivity and surface area and increased cortical thickness underpin the effect of prolonged DUP.

Trial registration: ClinicalTrials.gov NCT03442101 NCT02034253.

Keywords: Brain networks; Duration of untreated psychosis; Functional connectivity; Morphology; Resting state; Treatment response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use
  • Brain / diagnostic imaging
  • Depressive Disorder, Major* / drug therapy
  • Depressive Disorder, Major* / physiopathology
  • Female
  • Humans
  • Magnetic Resonance Imaging
  • Male
  • Psychotic Disorders* / drug therapy
  • Risperidone / therapeutic use
  • Schizophrenia* / drug therapy
  • Young Adult


  • Antipsychotic Agents
  • Risperidone

Associated data

  • ClinicalTrials.gov/NCT03442101
  • ClinicalTrials.gov/NCT02034253