80 patients (43 BD I, 33 BD II, 4 BD NOS, mean±SD age 46±14 years, 63.7% female) were assessed. Demographic and clinical characteristics are shown in . Patients were seen in the clinic on average every 58±38 days, were taking 3.7±1.9 prescription psychotropic medications, and had MPY-CGI-BP-OS score of 3.1±0.9. Although approximately half (51.2%) of enrolled patients had experienced a syndromal mood episode in the prior year, at enrollment only 25.0% of patients had current syndromal or subsyndromal mood symptoms, consistent with efforts to enroll patients when euthymic in order to reduce the likelihood of mood disturbance confounding recollection of stressful life events.
Sample Description: Overall Group
BDNF val66met genotype
37.5% of patients were BDNF met allele carriers (7.5% met/met, 30.0% val/met), and 62.5% were non-met allele carriers (val/val). These genotype frequencies were all within 6% of those reported for the U.S. population (Shimizu et al., 2004
), and were in Hardy-Weinberg equilibrium (Chi-Square=1.56, df=1, p>0.05).
Early life stress
31.3% of patients reported a history of CTQ-sexual, while 28.8% reported a history of CTQ-physical, and 13.8% reported a history of both types of abuse. Rates of CTQ-sexual and CTQ-physical were statistically similar in BDNF met allele carriers compared to non-met allele carriers.
Relationships between BDNF met allele carrier genotype, early life stress, and bipolar illness severity and chronicity
BDNF met allele carriers (but not non-met allele carriers) with compared to without CTQ-sexual had 21% higher MPY-CGI-BP-OS scores (), whereas BDNF genotype and CTQ-sexual status considered individually had no significant effect upon MPY-CGI-BP-OS. However, a multiple regression model of MPY-CGI-BP-OS as a function of BDNF met allele carrier genotype, CTQ-sexual, and BDNF met allele carrier genotype × CTQ-sexual, including age and gender as covariates, yielded a non-significant G × E interaction term (β=0.69, s.e.=0.42, p=0.110). Nevertheless, in this model the effect of current age on MPY-CGI-BP-OS score was significant (β=0.02, s.e.=0.01, p=0.029). Analogous between-group comparisons using CTQ-physical (rather than CTQ-sexual) considered individually and stratified by BDNF met allele carrier genotype yielded all non-significant results.
Childhood Sexual Abuse Associated with Greater Bipolar Illness Severity and Chronicity in BDNF Met Allele Carriers
Patients with (n=20) compared to without (n=60) syndromal/subsyndromal mood symptoms at study enrollment (at which time the CTQ was completed) reported statistically similar rates of CSA (40.0% in symptomatic compared to 28.3% in euthymic patients, p=0.406) and CPA (35.0% in symptomatic compared to 26.7% in euthymic patients, p=0.570), and had similar rates of BDNF met allele carrier genotype (40.0% in symptomatic compared to 36.7% in euthymic patients, p=0.796). Including mood state at enrollment (syndromal/subsyndromal mood symptoms=−0.5, euthymic=0.5) as a covariate in the regression analysis improved the fit of the overall model (F change=32.30, p<0.001). Mood state was a significant predictor of MPY-CGI-BP-OS (β=−1.08, s.e.=0.19, p<0.001), while age became non-significant (p = .087), and BDNF × CSA remained non-significant (p=.129).
Chi-square analysis demonstrated no statistically significant difference in proportion of met versus non-met allele carriers across racial/ethnic categories (p=0.113). Nevertheless, we included dummy variables for Asian versus non-Asian, black versus non-black, Hispanic versus non-Hispanic, and other/unspecified versus non-other/unspecified as covariates in the regression analysis (with Caucasian race serving as the reference category), which neither improved the fit of the model (F change=1.47, p=0.222) nor changed the overall pattern of findings: age remained a significant predictor of MPY-CGI-BP-OS (β=0.017, s.e.=0.007, p=0.021), and BDNF × CSA remained non-significant (p=0.124). Main effect of black versus non-black race (black=0.5, non-black=−0.5) was significant (β=1.79, s.e.=0.86, p=0.041), whereas effects of other racial/ethnic categories were non-significant in the regression model.
In a more comprehensive regression model evaluating MPY-CGI-BP-OS as a function of BDNF met allele carrier genotype, CSA, BDNF × CSA, age, gender, mood state at enrollment, and race/ethnicity, adding mood state at enrollment (F change=32.30, p<0.001) but not race/ethnicity (F change=0.76, p=0.556) improved the model fit. Mood state at enrollment was the only significant predictor of MPY-CGI-BP-OS (p<0.001), while all other terms were non-significant.
Relationships between BDNF met allele carrier genotype, early life stress, and clinical and demographic characteristics
BDNF met allele carriers (but not BDNF non-met allele carriers) with compared to without CTQ-sexual had 35% earlier bipolar onset age (), and were more likely to have a personality disorder (27.3% versus 0.0%, Chi-Square=5.5, df=1, p=0.045), whereas analogous between-group comparisons using CTQ-physical (rather than CTQ-sexual) yielded non-significant results. Conversely, BDNF non-met allele carriers (but not BDNF met allele carriers) with compared to without CTQ-sexual had less education (64.3% versus 14.3% had only some college, Chi-square=12.3, df=1, Fisher’s exact p=0.001) and older current age (51.1±13.6 versus 42.6±11.2 years, t=−2.3, df=48, p=0.028), and with compared to without CTQ-physical had longer illness duration (30.9±16.0 versus 22.2±10.8 years, t=−2.3, df=48, p=0.027), higher rate of prior psychiatric hospitalization (88.2% versus 45.5%, Chi-square=8.6, df=1, Fisher’s exact p=0.005), and less education (52.9% versus 15.6% had only some college, Chi-square=7.6, df=1, Fisher’s exact p=0.009).
Childhood Sexual Abuse Associated with Earlier Bipolar Onset Age in BDNF Met Allele Carriers
CTQ-sexual more than CTQ-physical and BDNF genotype status, when considered individually, was associated with clinical characteristics and demographic features potentially related to poorer outcomes. Thus, patients with compared to without CTQ-sexual had a 30% earlier bipolar onset age (15.9±7.8 versus 21.6±9.6 years, t=2.6, df=77, p=0.01), longer bipolar illness duration (35.9±14.7 versus 22.5±13.3 years, t=−4.0, df=77, p<0.001), higher rate of personality disorder (12.0% versus 0.0%, Chi-square=6.7, df=1, Fisher’s exact p=0.03), older current age (51.8±13.5 versus 43.9±13.6 years, t=−2.4, df=78, p=0.02), and less education (60.0% versus 17.0% had only some college, Chi-square=14.8, df=1, Fisher’s exact p=0.0002; and 12.0% versus 41.5% had a college degree, Chi-square=6.8, df=1, Fisher’s exact p=0.01), but were otherwise similar with respect to the clinical and demographic characteristic parameters in . Patients with compared to without CTQ-physical also had longer bipolar illness duration (32.5±16.0 versus 24.5±14.2 years, t=−2.2, df=77, p=0.03), and less education (54.5% versus 21.4% had only some college, Chi-square=8.1, df=1, Fisher’s exact p=0.007; and 13.6% versus 39.3% had a graduate degree, Chi-square=4.8, df=1, Fisher’s exact p=0.03). BDNF met allele carriers compared to non-met allele carriers had a higher rate of personality disorder (10.3% versus 0.0%, Chi-Square=5.4, df=1, p<0.05).
Rates of current treatment with mood stabilizers, second-generation antipsychotics, sedative-hypnotics, antidepressants, or other psychotropic medications (including pramipexole, modafinil, and anticonvulsants not approved by the United States Food and Drug Administration for management of BD) were statistically similar in BDNF met allele carriers compared to non-met allele carriers, and in patients with compared to without CTQ-sexual/CTQ-physical. Just over half (52.5%) of the patients were not employed (i.e. unemployed/student/homemaker, disabled, or retired), and this group compared to employed individuals had a significantly higher MPY-CGI-BP-OS (3.4±0.9 versus 2.9±0.9, t=−2.8, df=78, p=0.007), but statistically similar rates of ELS and BDNF met allele carrier genotype.