P300 amplitude reduction is associated with early-onset and late-onset pathological substance use in a prospectively studied cohort of 14-year-old adolescents

Four decades of research have provided evidence that P300 amplitude reduction (P3AR), or a reduced component of the third positive peak in the visual event-related potential (ERP) waveform generated in an oddball task, is associated with an increased liability to engage in alcohol and drug misuse (Iacono, Malone et al. 2003). P3AR has been found to correlate with use of a variety of drugs, including alcohol (Porjesz, Begleiter et al. 1980; Begleiter, Porjesz et al. 1984; Iacono, Carlson et al. 2002), cocaine (Bauer 1997), marijuana (Kempel, Lampe et al. 2003), opiods (Singh, Basu et al. 2009), and tobacco (Anokhin, Vedeniapin et al. 2000). A recent meta-analysis estimated that individuals with a positive history of a substance use disorder (SUD) differ from individuals without a positive history of a SUD by about half a standard deviation in P300 amplitude (d = 0.51; Euser, Arends et al. 2012). Additional lines of evidence support the notion that P3AR indexes a familial liability that emerges prior to the onset of substance abuse. For example, P3AR has been found to manifest in unaffected biological offspring of individuals with substance use problems (for a recent meta-analysis, see Euser, Arends et al. 2012; d = 0.28). Moreover, in longitudinal studies of youth P3AR has been found to correlate with substance use outcomes years later, including a factor-analysis-derived composite of substance use habits, (Berman, Whipple et al. 1993), age of onset of substance use (Hill, Shen et al. 2000), and the development of a SUD (Hill, Shen et al. 2000; Iacono, Carlson et al. 2002; Carlson, Iacono et al. 2004; Habeych, Charles et al. 2005; Carlson, McLarnon et al. 2007; Hill, Steinhauer et al. 2009). Contributions of the Current Study The present investigation used data from over 1100 adolescents from a longitudinal community-based study. We examined several features of the association between P3AR recorded at age 14 years and pathological substance use (PSU), where PSU is operationalized as evidencing any symptom of substance abuse or dependence for a DSM-IIIR or DSM-IV SUD. Specifically, we examined the association between P3AR and the timing of PSU onset for three drug classes (e.g. PSU-Nicotine, PSU-Alcohol, and PSU Illicit), the effect of PSU-comorbidity (i.e. meeting criteria for PSU in more than one drug class), and gender differences. Different PSU drug classes and comorbidity A primary objective of the present investigation was to clarify whether P3AR recorded at age 14 is a marker of risk for PSU generally (Iacono, Malone et al. 2008), or is specific to risk for misuse of certain kinds of drugs. To accomplish this objective, we assigned adolescents to three mutually-inclusive PSU groups based on the substances for which they manifested criteria: PSU-Nicotine, PSU-Alcohol, and PSU-Illicit; the latter includes various illicit substances, such as cannabis and cocaine. A fourth group was comprised of individuals who did not meet criteria for PSU within the developmental time frame of our study (“Controls”). Prior studies from our laboratory examined the specificity of P3AR to single versus multiple drug classes using an older cohort of twins. Across several studies, P3AR recorded from 18 year-olds adolescents was found to be associated with general risk for substance use (non-specific) instead of with only one drug class (Iacono, Carlson et al. 2002; Yoon, Iacono et al. 2006). These findings, as well as similar findings from other laboratories examining several outcomes (Hill, Steinhauer et al. 2009), contributed to the hypothesis that P3AR indexes an underlying neurobiological risk factor for the development of PSU that is not specific to any class of drug. The current study is of the same theme but is unique in that it examines a different, younger twin cohort than the late adolescent sample used in our prior studies. Use of these younger participants made it possible to focus on the early appearance of symptoms from mid (age 14) to late (age 18) adolescence rather than on the development of manifest psychiatric disorder. We also examined the association between P3AR and degree of PSU drug class comorbidity (i.e., meeting criteria for PSU in more than one drug class). Finding that P3AR is greater in those with PSU comorbidity would contradict the notion that P3AR is marker of risk for one particular drug. In contrast, finding that P3AR was associated with only one PSU drug class and not associated with comorbidity would provide evidence for drug specificity. Timing of PSU onset A second aim of the present investigation was to examine P3AR as a function of the timing of PSU onset. Within each of the three PSU drug class groups, adolescents were segregated based on whether PSU manifested before age 14 (“Early Adolescent Onset”) or between age 14 and age 18 (“Late Adolescent Onset”). This provided an opportunity to test two independent predictions reported in the literature regarding the association between P3AR and PSU. The first prediction was that P3AR distinguishes adolescents who have already developed PSU from unaffected adolescents (Euser, Arends et al. 2012). This prediction was tested by comparing Controls to each Early Adolescent Onset PSU group. The second prediction was that P3AR distinguishes adolescents who will develop PSU at a later time point from adolescents who remain unaffected. This prediction was tested by comparing Controls to each Late Adolescent Onset PSU group. Gender and sample size in prospective P3AR studies A third aim of this study was to examine gender differences in P3AR. Cross-sectional studies have provided evidence that P3AR indexes risk for PSU for males more effectively than among females (Euser, Arends et al. 2012). However, the relationship of P3AR with PSU has not been examined in a longitudinal analysis with adequate sample size to detect subtle gender differences. Previous prospective analyses examined either an exclusively male cohort (Berman, Whipple et al. 1993; Iacono, Carlson et al. 2002; Carlson, McLarnon et al. 2007), a mixed gender sample including a relatively small cohort of females (Hill, Steinhauer et al. 1995; Hill, Shen et al. 2000) or a mixed gender sample including approximately 200 females (Carlson, Iacono et al. 2004; Hill, Steinhauer et al. 2009). To our knowledge, the current study examines the largest cohort of female adolescents in a prospective design to date (n = 619). Furthermore, while two prospective studies have examined a large cohort of about 500 18 year-old males (Iacono, Carlson et al. 2002; Carlson, McLarnon et al. 2007), the current study examines 593 14 year-old males. This is, to our knowledge, the first prospective study of P3AR and substance use in adolescents younger than age 18 to examine large samples of both boys and girls. Hypotheses Based on the literature, we hypothesized that P3AR recorded at age 14 reflects a premorbid risk factor for all three drug classes of PSU rather than any single class of drug. Thus, we predicted that P3AR would be evident in those with (a.) Early Adolescent Onset PSU in each drug class and comorbidity, and (b.) Late Adolescent Onset PSU in each drug class and comorbidity. Furthermore, we expected the hypothesized effects to be stronger in males than females.