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. 2018 Apr 1;75(4):370-378.
doi: 10.1001/jamapsychiatry.2017.4595.

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

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Free PMC article

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

Donald C Goff et al. JAMA Psychiatry. .
Free PMC article

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: In the past 3 years, Dr Goff reported receiving research support from the National Institute of Mental Health, Stanley Medical Research Institute, and Avanir Pharmaceuticals. Dr Fan reported receiving research support from the National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, the Stanley Medical Research Institute, the Baer Foundation, the Shine Foundation, the Vanguard Group, Janssen, Avanir Pharmaceuticals, Neurocrine, and Alkermes; and reported receiving honoraria for serving on an advisory board for Allergen. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Duration of Untreated Psychosis (DUP) and Annualized Percentage Change in Left Hippocampal Volumetric Integrity (LHVI) From Baseline to Follow-up in Participants With First-Episode Psychosis
The solid line represents the association between ranked values for LHVI and DUP. Spearman rank correlation coefficient is shown.
Figure 2.
Figure 2.. Change From Baseline to Follow-up in Left Hippocampal Volumetric Integrity (LHVI) by Time Since Onset of Psychosis in Participants With First-Episode Psychosis (FEP)
The solid lines indicate individual participants with FEP; HC indicates the median LHVI value for healthy controls. Hippocampal volumetric integrity, defined as the parenchymal fraction of a standardized volume of interest that is expected to encompass the hippocampus in a healthy brain, was calculated using a fully automated procedure in which the volume of interest is estimated for each hemisphere using automatically detected landmarks and the tissue fraction is estimated by histogram analysis.

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