Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS

Abstract

Background: Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data.

Methods: Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures.

Results: 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis×test site interaction. HCS>schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures.

Discussion: The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses.

Keywords: Endophenotype; Genetics; Multi-site; Prepulse inhibition; Schizophrenia; Startle.

Conflict of interest statement

Conflict of interest: Drs. Braff, Calkins, Greenwood, Light, Radant, Seidman, Siever, Silverman, Stone, Sugar, DW Tsuang, and MT Tsuang report no financial relationships with commercial interests. Dr. Green reports having been a consultant to Abbott laboratories (AbbVie), Biogen, and Roche, he is a member of the scientific board for Mnemosyne, and he has received research funds from Amgen. Drs. Gur and Turetsky have received unrelated research support for investigator-initiated grants from Pfizer and AstraZeneca. Dr. Nuectherlein has received unrelated research support from Janssen Scientific Affairs, Genentech, and Brain Plasticity, Inc., and has consulted to Genentech, Otsuka, and Brain Plasticity, Inc. Dr. Swerdlow has been a paid Consultant for Neurocrine, Inc.

Copyright © 2013 Elsevier B.V. All rights reserved.

Figures

Figure 1

Startle measures (± SEM) in the interim COGS-2 sample. A. Startle magnitude on pulse-alone trials (PA), EMG activity during nostim trials (NS) and % startle habituation (%HAB), based on % reduction in startle magnitude in block 4 vs. block 1. Data shown are from aggregate group of N = 884 subjects. B. Same variables in “A”, shown by test site. (*) statistically significant effect of group, see text. @ significantly greater than other 4 sites (PA: site 5 HCS and patients > all other sites; NS: site 3 patients > all other sites).

Figure 2

Peak startle latency on PA and 30, 60 and 120 ms prepulse trials in the aggregate sample of N = 884 subjects. B. Same variables in “A”, shown by test site. (*) statistically significant effect of group, see text. Error bars are too small to be visible.

Figure 3

% PPI (± SEM). A. Primary dependent measure: %PPI with 60 ms prepulse intervals shown across all trials (“ALL”) and divided by trial block (B2, B3), among 884 carefully screened HCS and patients. B. Same variables in “A”, shown by test site (! p=0.01; !! p

Figure 4

Medication effects on %PPI (± SEM) in this interim COGS-2 sample. Data shown are %PPI with 60 ms prepulse intervals in HCS vs. 3 subgroups of patients: those taking no antipsychotics (“No Meds”), those taking no second generation antipsychotics (“No SGAs”), and those taking SGA’s (“SGA’s”). (*) statistically significant effect of group, see text.

Figure 5

Reference data (± SEM) on identical measures from published single-site study at UCSD (Swerdlow et al., 2006a), N=169). A. Startle magnitude on PA trials (compare to Figure 1A). B. Peak startle latency (compare to Figure 2A). C. PPI across 30, 60 and 120 ms prepulse intervals (compare to Figures 3C and 3D). (*) statistically significant effect of group. At UCSD, d for 60 ms PPI, HCS vs. patients was 0.24 in (Swerdlow et al., 2006a) and 0.28 in present study (0.39 in Block 2).