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Original Investigation
April 2018

Association of Hippocampal Atrophy With Duration of Untreated Psychosis and Molecular Biomarkers During Initial Antipsychotic Treatment of First-Episode Psychosis

Author Affiliations
  • 1Department of Psychiatry, New York University Langone Medical Center, New York
  • 2Nathan Kline Institute for Psychiatric Research, Orangeburg, New York
  • 3Department of Psychiatry, Qingdao Mental Health Center, Qingdao, China
  • 4Department of Psychiatry, Stony Brook School of Medicine, Stony Brook, New York
  • 5Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China
  • 6Department of Psychiatry, University of Massachusetts Medical Center, Worcester
  • 7Mindstrong Health, Palo Alto, California
  • 8Department of Population Health, Division of Biostatistics, New York University School of Medicine, New York
JAMA Psychiatry. 2018;75(4):370-378. doi:10.1001/jamapsychiatry.2017.4595
Key Points

Question  Does hippocampal volume loss occur during initial antipsychotic treatment and is it associated with duration of untreated psychosis?

Findings  In this longitudinal case-control study of individuals with first-episode nonaffective psychosis before and after initiation of antipsychotic medication, patients had significantly greater hippocampal atrophy compared with healthy controls at baseline. Moreover, at 8-week follow-up, hippocampal atrophy increased to a greater extent in patients compared with healthy controls, and the rate of progression of left hippocampal atrophy was significantly correlated with the duration of untreated psychosis.

Meaning  Early hippocampal volume loss may play a role in mediating the association between duration of untreated psychosis and poor outcomes in schizophrenia.


Importance  Duration of untreated psychosis (DUP) has been associated with poor outcomes in schizophrenia, but the mechanism responsible for this association is not known.

Objectives  To determine whether hippocampal volume loss occurs during the initial 8 weeks of antipsychotic treatment and whether it is associated with DUP, and to examine molecular biomarkers in association with hippocampal volume loss and DUP.

Design, Setting, and Participants  A naturalistic longitudinal study with matched healthy controls was conducted at Shanghai Mental Health Center. Between March 5, 2013, and October 8, 2014, 71 medication-naive individuals with nonaffective first-episode psychosis (FEP) and 73 age- and sex-matched healthy controls were recruited. After approximately 8 weeks, 31 participants with FEP and 32 controls were reassessed.

Exposures  The participants with FEP were treated according to standard clinical practice with second-generation antipsychotics.

Main Outcomes and Measures  Hippocampal volumetric integrity (HVI) (an automated estimate of the parenchymal fraction in a standardized hippocampal volume of interest), DUP, 13 peripheral molecular biomarkers, and 14 single-nucleotide polymorphisms from 12 candidate genes were determined.

Results  The full sample consisted of 71 individuals with FEP (39 women and 32 men; mean [SD] age, 25.2 [7.7] years) and 73 healthy controls (40 women and 33 men; mean [SD] age, 23.9 [6.4] years). Baseline median left HVI was lower in the FEP group (n = 57) compared with the controls (n = 54) (0.9275 vs 0.9512; difference in point estimate, −0.020 [95% CI, −0.029 to −0.010]; P = .001). During approximately 8 weeks of antipsychotic treatment, left HVI decreased in 24 participants with FEP at a median annualized rate of −.03791 (–4.1% annualized change from baseline) compared with an increase of 0.00115 (0.13% annualized change from baseline) in 31 controls (difference in point estimate, −0.0424 [95% CI, −0.0707 to −0.0164]; P = .001). The change in left HVI was inversely associated with DUP (r = −0.61; P = .002). Similar results were found for right HVI, although the association between change in right HVI and DUP did not achieve statistical significance (r = −0.35; P = .10). Exploratory analyses restricted to the left HVI revealed an association between left HVI and markers of inflammation, oxidative stress, brain-derived neurotrophic factor, glial injury, and markers reflecting dopaminergic and glutamatergic transmission.

Conclusions and Relevance  An association between longer DUP and accelerated hippocampal atrophy during initial treatment suggests that psychosis may have persistent, possibly deleterious, effects on brain structure. Additional studies are needed to replicate these exploratory findings of molecular mechanisms by which untreated psychosis may affect hippocampal volume and to determine whether these effects account for the known association between longer DUP and poor outcome.