Genotype (Met/Met=3.4%, Val/Met=34.5%, Val/Val=62.1%) and allele (20.6% Met) frequency distributions were consistent with those expected of Caucasian samples. Met and Val groups did not differ significantly in age, inter-scan interval, or on factors associated with poor outcome in schizophrenia – male gender, early age of illness onset or poor premorbid social adjustment ().
Comparison of sociodemographics, illness characteristics and antipsychotic treatment (Mean (SD) or Number (%)) between 45 BDNF Met-allele carriers and 74 BDNF Val homozygous schizophrenia patients
At baseline scan, 50 subjects were neuroleptic naïve. The proportions of neuroleptic naïve patients in each BDNF genotype grouping did not differ significantly (; χ2=2.46, p=0.12). Being a long-term longitudinal study, antipsychotic treatment during the inter-scan interval was naturalistic. Patients received antipsychotic treatment for much of the time period between scans (Mean=84.9% of the inter-scan interval (SD=27.7)). Non-clozapine atypicals were the predominant class of antipsychotics. Twenty-four patients (20.2%) required clozapine treatment during the inter-scan interval. Mean antipsychotic dose for the sample was 519.8mg chlorpromazine (CPZ)-equivalent/day (SD=472.6). Compliance with antipsychotic treatment was between Good to Excellent (Mean=1.87 (SD=0.86); rated on a 5-point scale with 1 being ‘Excellent’ and 2 being ‘Good’). None of these antipsychotic treatment measures differed significantly between BDNF genotype groupings ().
Longitudinal changes in MRI brain volumes between BDNF genotype groupings
Least square means for MRI brain volumes at baseline and at follow-up assessment are summarized in . There was a significant genotype main effect on within-subject changes in frontal GM volume (F=4.20, dfs=1,113, p=0.05). Met-allele-carriers showed significant reductions in frontal GM volume at follow-up assessment compared to baseline (Mean=−4.83 cc; T=2.08, df=44, p=0.04). Follow-up frontal GM volumes did not differ significantly from baseline among Val homozygotes (Mean=−0.98 cc; T=0.56, df=73, p=0.58). There were no significant genotype main effects on within-subject changes in temporal, parietal or occipital GM volumes (; F≤0.73, dfs=1,113, p≥0.40).
Comparison of longitudinal changes in MRI brain volumes (Least Square Mean (SD) (cc)) between 45 BDNF Met-allele carriers and 74 BDNF Val homozygous schizophrenia patients
Significant genotype main effects were also found on within-subject changes in lateral ventricles and sulcal CSF volumes (; F≥6.55, dfs=1,113, p≤0.01). Compared to baseline, Met-allele-carriers had significant enlargements in lateral ventricles and sulcal CSF volumes at follow-up assessment (Mean=1.30cc or 16.12cc respectively; T≥3.95, df=44, p≤0.0003). Within-subject changes in these CSF volumes were not statistically significant in Val homozygotes (T≤1.67, df=73, p≥0.10). Furthermore, differential changes in sulcal CSF volumes between genotype groupings were restricted to frontal and temporal lobes. Significant genotype main effects were found on within-subject changes in frontal CSF and temporal CSF volumes (F≥6.71, dfs=1,113, p≤0.01), but not in parietal CSF or occipital CSF volumes (F≤1.84, dfs=1,113, p≥0.18). Met-allele-carriers again showed greater frontal CSF (Mean=11.94cc) and temporal CSF (Mean=1.63cc) volume enlargements than Val homozygotes (Mean=4.69cc or −0.47cc respectively).
Antipsychotic treatment during inter-scan interval and its inter-relationships with brain volume changes and BDNF genotype groupings
To examine the inter-relationships between antipsychotic treatment and BDNF genotype on longitudinal MR brain volume changes, antipsychotic exposure during the inter-scan interval (dose years; 1 dose year=100mg CPZ-equivalent/day for 1 year) was included as a covariate in the repeated measures general linear models (). For frontal GM volume changes, antipsychotic treatment main effect approached but did not achieve statistical significance (F=3.22, dfs=1,113, p=0.08). There were no statistically significant antipsychotic treatment main effects on within subject changes in the other MRI brain volume measures either (F≤2.56 dfs=1,113, p≥0.11).
Additionally, for brain regions where there were significant repeated measures within-subject genotype main effects (i.e. frontal GM, lateral ventricles and sulcal CSF), we used regression analyses to explore the effects sizes and relative independent contributions from BDNF genotype and from antipsychotic exposure on variance in longitudinal brain volume changes. Type II squared partial correlations between brain volume changes and genotype grouping and between brain volume changes and treatment are summarized in .
Variance in MRI brain volume changes associated with BDNF genotype status and antipsychotic treatment.
BDNF genotype accounted for 3.4% (T=2.01, dfs=1,118, p=0.05) of the variance in frontal GM volume changes while antipsychotic treatment contributed an additional 2.8% (T=1.79, dfs=1,118, p=0.08) of variance in frontal GM volume changes (). Higher dose years correlated significantly with greater frontal GM volume reductions (Spearman partial r=−0.20, df=117, p=0.03). However, these inter-relationships varied according to antipsychotic treatment status at baseline scan.
For patients who had been neuroleptic naïve at baseline scan, antipsychotic treatment accounted for 6.5% (T=1.75, dfs=1,118, p=0.09) of variance in frontal GM changes while BDNF genotype had no independent contributions (squared partial r=0.00; T=0.05, p=0.96). Higher dose years correlated significantly with greater frontal GM volume reductions (Spearman partial r=−0.32, df=48, p=0.03). Conversely, among patients who had already been receiving antipsychotic treatment at the time of baseline scan, the relative independent contributions to variance in frontal GM volume changes were 9.9% from BDNF genotype (T=2.63, dfs=1,118, p=0.01), and 0.9% from antipsychotic treatment (T=0.76, dfs=1,118, p=0.45).
Variance in lateral ventricle and sulcal CSF volume changes accounted for by BDNF genotype were larger (~6%) than those from antipsychotic treatment (≤2%; ). These inter-relationships did not differ substantially according to antipsychotic treatment status at baseline scan.
Longitudinal changes in neurocognition and symptom severity between BDNF genotype groupings
Least square means for cognitive domain scores and symptom severity at baseline and at follow-up assessment are summarized in . Each of the 5 cognitive domain scores improved significantly at follow-up (within-subject Time main effect; F≥8.19, dfs=1,109 or 1,113, p≤0.005). Negative symptoms at follow-up were also significantly less severe than at baseline (within-subject Time main effect; F=4.18, dfs=1,114, p=0.04). Severity of psychotic and disorganized symptoms declined at follow-up although these approached but did not achieve statistical significance (within-subject Time main effect; F≤3.53, dfs=1,114, p≥0.06).
Comparison of longitudinal changes in cognitive domain scores (Least Square Mean (SD) (z-score)) and symptom severity between 45 BDNF Met-allele carriers and 74 BDNF Val homozygous schizophrenia patients
However, none of these longitudinal changes in neurocognition or in symptom severity differed significantly between genotype groupings. There were no significant genotype main effects on repeated measures within-subject changes in cognitive domain scores (; F≤0.65, dfs=1,109 or 1,113, p≥0.42) or in symptom severity (F≤2.26, dfs=1,114, p≥0.14). Antipsychotic treatment received during the interscan interval had no significant main effects on within-subject changes in symptom severity (F≤0.39, dfs=1,114, p≥0.54) or cognitive performance (F≤1.15, dfs=1,109 or 1,113, p≥0.29) except on Problem Solving and Visuospatial Abilities domain scores (F≥4.67, dfs=1,113, p≤0.03; partial r≥−0.20, df=118, p≤0.03).
There were significant between-subject genotype main effects on Verbal Memory, Problem Solving and Visuospatial Abilities domain scores (F≥4.19, dfs=1,109 or 1,113, p≤0.04). Met allele-carriers had greater impairment than Val homozygotes on these cognitive domains (univariate genotype main effects on baseline Verbal Memory domain score (F=4.65, dfs=1,114, p=0.03), follow-up Verbal Memory (F=6.44, dfs=1,114, p=0.01), baseline Problem Solving (Baseline: F=3.04, dfs=1,117, p=0.08), follow-up Problem Solving (F=2.85, dfs=1,117, p=0.09), baseline Visuospatial Abilities (F=4.53, dfs=1,117, p=0.03), and follow-up Visuospatial Abilities (F=2.49, dfs=1,117, p=0.12)). Between-subject genotype main effects on Speed/Attention and Language domain scores were not statistically significant (F≤0.78, dfs=1,113, p≥0.38). Symptom severity also did not differ significantly between genotype groupings (between-subject genotype main effects; F≤0.63, dfs=1,114, p≥0.43).
Differential effects of BDNF genotype on the relationships between frontal GM volume changes and longitudinal changes in neurocognition
Since Met allele carriers showed greater frontal GM volume reductions, we explored how longitudinal changes in frontal GM volume may be related to changes in neurocognition, and if such relationships differed between genotype groupings. We first tested the overall effect of frontal GM volume change scores on all five cognitive domain change scores in a joint omnibus multivariate regression test. Frontal GM volume change (follow-up volume minus baseline volume) was the independent variable. The 5 cognitive domain change scores were entered simultaneously as dependent variables. Covariates in the joint omnibus test were total brain compartment volume, age at intake scan, inter-scan interval and dose year. A frontal GM volume change-by-genotype interaction term was also entered in the regression model.
In the joint omnibus test, there was a significant overall main effect of frontal GM volume change on longitudinal changes in neurocognition (F=2.70, dfs=5,103, p=0.02). The frontal GM volume change-by-genotype interaction term was also statistically significant (F=3.75, dfs=5,103, p=0.004), which indicated that the relationships between frontal GM volume changes and changes in cognitive domain scores differed between genotype groupings. Pearson partial correlation coefficients for the relationships between frontal GM volume change scores and cognitive domain change scores within each genotype group are summarized in . Among Val homozygotes, enlargements in frontal GM volumes were significantly associated with worsening Verbal Memory performance ( and Supplementary Figure 1a
; Pearson partial r=−0.32, df=69, p=0.007). In Met allele carriers, frontal GM volume reductions correlated with greater decline in Verbal Memory performance although this was not statistically significant (Pearson partial r=0.16, df=42, p=0.31). Post hoc univariate analyses found significant frontal GM volume change-by-genotype interaction effects on Verbal Memory change scores (F=8.52, dfs=1,114, p=0.004).
Relationships between MRI frontal gray matter volume changes and changes in cognitive domain scores across BDNF genotype groupings (Pearson partial ra (p))
Among Val homozygotes, reductions in frontal GM volume correlated significantly with worsening of Visuospatial Abilities ( and Supplementary Figure 1b
; Pearson partial r=0.28, df=71, p=0.02). Although frontal GM volume-visuospatial relationships were weaker among Met allele carriers (Pearson partial r=0.10, df=43, p=0.54), the association was in the same direction as that observed among Val homozygotes. For Speed/Attention, Problem Solving and Language cognitive domains, there were no significant correlations between changes in frontal GM volumes and changes in cognitive domain scores (; Pearson partial
≤0.16, df=43 or 71, p≥0.18).