P300 amplitude, externalizing psychopathology, and earlier-versus later-onset substance-use disorder

Acknowledgement: This research was supported by National Institute on Drug Abuse Grant DA 05147 and National Institute of Alcohol Abuse and Alcoholism Grants AA 00175 and AA 09367.

P300 amplitude reduction has long been considered a candidate event-related potential marker of risk for alcoholism and other substance-use disorders (e.g., Begleiter, Porjesz, Bilhari, & Kissin, 1984; Hesselbrock, Begleiter, Porjesz, O'Connor, & Bauer, 2001; Hill, Steinhauer, & Zubin, 1987; Iacono, Malone, & McGue, 2003; Polich, Pollock, & Bloom, 1994; Porjesz et al., 1998, 2005; Steinhauer, Hill, & Zubin, 1987). A key set of findings supporting P300 indexing vulnerability, rather than solely being a consequence of substance use, is that smaller P300 predicts the initiation of alcohol use (Hill, Shen, Lowers, & Locke, 2000) and precedes the development of substance problems (Berman, Whipple, Fitch, & Noble, 1993; Carlson, Iacono, & McGue, 2004; Habeych, Charles, Sclabassi, Kirisci, & Tarter, 2005; Hill, Steinhauer, Lowers, & Locke, 1995; Iacono, Carlson, Malone, & McGue, 2002). These studies have so far evalutated P300 before the age of 18 years with assessment of substance use or disorder at no later than 21 years of age. Substance-use disorders that start before adulthood are associated with more types of psychoactive substance abuse (Dom, Hulstijin, & Sabbe, 2006; Irwin, Schuckit, & Smith, 1990; Watson et al., 1997), greater co-occurrence of antisocial behavior (Bakken, Landheim, & Vaglum, 2004; Bennett, Tolman, Rogalski, & Srinivasaraghavan, 1994; Clark, Kirisci, & Tarter, 1998; Franken & Hendriks, 2000; Fulwiler, Grossman, Forbes, & Ruthazer, 1997; Irwin et al., 1990; Stabenau, 1984; Vaillant, 1994; Watson et al., 1997), and stronger familial loading in men (Dom, Hulstijin, & Sabbe, 2006; McGue, Slutske, Taylor, & Iacono, 1997; Windle, 1996) than are later-onset substance problems. At present, it is unclear if amplitude reduction in adolescence is associated with substance problems, regardless of their age of onset, or if it is only predictive of early-onset problems.

Rather than reflecting risk specific to substance-use disorders, P300 amplitude appears to reflect vulnerability for a spectrum of so-called “externalizing” disorders involving poor behavioral constraint (Hicks et al., 2007; Iacono et al., 2003; Patrick et al., 2006). In addition to substance abuse and dependence, the externalizing spectrum includes attention-deficit/hyperactivity (ADHD), oppositional defiant (ODD), and conduct (CD) disorders, as well as the adult symptoms of antisocial personality disorder (i.e., the adult antisocial behavior [AAB] syndrome). Twin studies of the covariance among substance and other externalizing disorders suggest a considerable genetic vulnerability common to these phenotypes (Krueger et al., 2002; Young, Stallings, Corley, Krauter, & Hewitt, 2000). The idea that P300 amplitude reflects this general vulnerability is supported by a growing body of empirical evidence (Hicks et al., 2007; Iacono et al., 2003). Consistent with P300 being a genetic marker, individual differences in P300 amplitude are substantially influenced by genetic differences among people (see van Beijsterveldt & van Baal, 2002, for a meta-analysis), particularly in young men (van Beijsterveldt, van Baal, Molenaar, Boomsma, & de Geus, 2001; Yoon, Iacono, Malone, & McGue, 2006). Further, reduced amplitude appears to be associated with genetic factors related to risk (Carlson, Iacono, & McGue, 2002; Hicks et al., 2007; Hill, Yuan, & Locke, 1999).

A recent comparison of latent class and trait models suggested that comorbidity among substance and antisocial behavior disorders was due to this underlying externalizing dimension, rather than reflecting a categorically distinct antisocial subtype of substance disorder (Krueger, Markon, Patrick, & Iacono, 2005). In this conceptualization, individual disorders are indicators that vary in how well they discriminate the severity of the underlying externalizing dimension. For adults, alcohol dependence was a relatively weak indicator, meaning that a less severe level of externalizing was needed for people to meet criteria for this diagnosis. In contrast, AAB was a stronger indicator of externalizing in adults. In general, the less socially sanctioned a substance, the more indicative dependence on it was of the severe end of the externalizing dimension. In the United States, the law largely prohibits use of alcohol before age 21 and tobacco prior to age 18. Because underage use of these substances necessitates committing an illegal activity, disorders involving these substances may be better indicators of externalizing at younger ages than they are in adulthood. We propose that earlier-onset substance problems represent a more severe level of an externalizing dimension than do later-onset disorders and are therefore more strongly associated with reduced P300 in adolescence.

In addition to being related to risk for substance abuse and dependence, P300 amplitude is also associated with nonsubstance externalizing disorders. Adolescents with elevated levels of CD symptoms (Bauer & Hesselbrock, 1999a, 1999b; Kim, Kim, & Kwon, 2001) and adults with antisocial personality disorder (ASPD; Bauer, 1997; Bauer, O'Connor, & Hesselbrock, 1994; Costa et al., 2000) have reduced P300. This effect is not merely due to comorbid substance disorders. Smaller amplitude has been seen in “pure” cases of CD and ODD in the absence of other externalizing or substance-use disorders (Iacono et al., 2002). In addition, among adult substance abusers, P300 amplitude is inversely correlated with other externalizing characteristics, such as impulsive personality traits (Moeller et al., 2004) and the number of childhood CD symptoms (Bauer, 1997). Mediational studies indicate that, at least for men, constructs derived in part from externalizing-disorder symptoms account for the relationship between P300 amplitude and early-onset alcohol problems (Justus, Finn, & Steinmetz, 2001) or substance disorders more broadly construed (Habeych et al., 2005).

These studies suggest that there may be no unique relationship between P300 and early-onset substance disorders independent of their comorbidity with other externalizing problems. Iacono et al. (2002), however, reported that P300 amplitude at age 17 was reduced among individuals at low familial risk who were free of substance-use or externalizing disorders at the time of their P300 recording and went on to develop a disorder by age 20. Reduced amplitude at age 17 was also seen in individuals without a disorder at age 17 or 20 who had a twin who was unaffected at age 17 but developed an alcohol disorder by age 20 (Carlson et al., 2004). These individuals had reduced amplitude at age 17 even in the absence of other conventional indicators of familial risk or externalizing problems at that age. Early-onset substance disorders may be relatively good indicators of externalizing, even in the absence of other disinhibited disorders. Most supportive of P300 being related to a broad externalizing dimension that includes substance disorders is Patrick et al.'s (2006) report that P300 amplitude in adolescence is related to the shared variance across CD, AAB, alcohol, drug and nicotine dependence, but not to the unique variance of any individual disorder.

Smaller P300 amplitude is found in persons with an earlier, rather than later, age at first use of a psychoactive substance (Iacono & McGue, 2006; McGue, Iacono, Legrand, Malone, & Elkins, 2001). Although age at first use is not synonymous with an early-onset substance-use disorder, this finding supports greater prominence of P300 reduction in earlier-onset, compared with later-onset substance problems. An early age at first drink is associated with earlier alcohol-disorder onset (DeWit et al., 2000; Grant & Dawson, 1997; Grant, Stinson, & Harford, 2001; McGue et al., 2001), more nicotine and drug-use disorders (McGue et al., 2001; Schuckit & Russell, 1983), higher rates of antisocial behavior disorders, and elevated levels of disinhibited personality traits (McGue et al., 2001). Moreover, early use of any substance and early behavior indicative of social deviance show similar patterns of associations (McGue & Iacono, 2005). These outcomes are not exclusively the consequence of precocious alcohol ingestion, because age at first drink itself is preceded by disruptive behavior (Clark, 2004; McGue et al., 2001). Hill et al. (2000) found that P300 amplitude contributed significantly to the prospective prediction of the age of drinking initiation. Further, Benegal, Jain, Subbukrishna, & Channabassavanna (1995) found no difference in amplitude between the siblings of late-onset alcoholics with a low familial loading and control subjects, but they did find reduced amplitude in the siblings of early-onset alcoholics with a high familial loading. Taken together, these findings suggest that P300 amplitude reduction may be associated more strongly with an earlier-onset substance-use disorder than with a later-onset one.

In the present study, P300 was measured in a community-representative sample of young men at the age of approximately 17 years. Subjects were assessed for psychopathology at that time and twice more at 3- to 4-year intervals. They were subdivided on the basis of development of their first substance-use disorder by the second assessment (i.e., roughly 20 years old), between the second and third assessments (i.e., ages 20–24 years), or not at all by the third assessment. Nonsubstance externalizing syndromes were also assessed. Although this sample has been used to investigate P300 differences at age 17 between subjects who retrospectively reported an age at first drink before or after age 14 (McGue et al., 2001), to our knowledge, this is the first study investigating P300 amplitude in young men with substance-use disorders defined explicitly by onset age. Unlike in the McGue et al. (2001) study, we also have followed up with these young men through their mid 20s and can differentiate those who developed a new substance-use disorder by age 20 from those who developed their first disorder later. These two groups can be further contrasted with young men who had yet to manifest a substance use disorder by age 24. Consistent with early-onset substance problems being associated with more severe levels of an externalizing dimension related to P300 amplitude, we hypothesize that P300 will be reduced, and the prevalence of nonsubstance externalizing disorders will be greater, in subjects with an earlier-onset disorder than in those who do not develop a substance disorder. Consistent with an intermediate level of severity on the externalizing dimension, later-onset subjects are predicted to have levels of P300 amplitude and nonsubstance externalizing disorders intermediate between the early-onset and disorder-free subjects.

In this study, we also compare subjects with earlier-onset substance disorders who did not have any disorder by the time of P300 recording to men with a later-onset substance disorder. Because the substance disorder in this subset of the earlier-onset group developed between the first and second assessments, P300 differences at age 17 between these and the later-onset subjects cannot be attributed to the effects of a pre-existing substance disorder. Because P300 amplitude is thought to be associated with vulnerability to, rather than the effects of, early-onset substance problems, we predict that the earlier-onset group with no substance disorder at age 17 will show reduced amplitude relative to the later-onset group.

It might be argued that the association between the shared variance across externalizing disorders and P300 in Patrick et al.'s (2006) study could be due to substance problems making subsequent antisocial behaviors more likely to occur. Antisocial behavior, however, typically precedes substance problems (e.g., Clark, 2004; McGue et al., 2001; Vaillant, 1994). We predict reduced amplitude in subjects with externalizing problems, regardless of whether or not they develop a substance disorder by age 24. A past study with this sample reported associations at age 17 between externalizing disorders in the absence of comorbidity (Iacono et al., 2002). However, the current study is the first to evaluate both individuals with an externalizing disorder who do not develop a substance disorder by their mid 20s (i.e., past the point when an early-onset substance disorder would develop) and those who develop an earlier-onset substance-use disorder but show no indication of other externalizing disorders up through age 24 (i.e., past a point when AAB symptoms are likely to first appear). As such, this is the first study to test our hypothesis that earlier-onset substance problems and nonsubstance externalizing disorders act as alternate indicators of an externalizing phenotype, both of which reflect P300 amplitude reductions.

The subjects of this investigation were 502 young men from the Minnesota Twin Family Study (MTFS; Iacono & McGue, 2002). Subjects were identified from publicly available birth records as members of same-sex twin pairs born in the state of Minnesota during the years 1972–1978. Families agreeing to participate were initially assessed when the young men were approximately 17 years of age (M = 17.48 years, SD = 0.39). Details regarding sampling and recruitment were provided in Iacono, Carlson, Taylor, Elkins, & McGue (1999). More than 95% of the subjects were Caucasian, a demographic profile corresponding to that of Minnesota at the time of the subjects' births. Census data from 1990 suggested that these participants were broadly representative of Minnesota residents in terms of key demographic factors (Holdcraft & Iacono, 2004). Assessments were carried out on two further occasions at approximately 3- to 4-year intervals. The mean ages at these assessments were 20.66 years (SD = 0.52) and 24.23 years (SD = 1.01), respectively. Subjects aged 18 years and older provided written informed consent at all assessments. Written assent was obtained from younger subjects at the first assessment, with consent provided by a custodial parent. The present study involves only male subjects. Because our recruitment of female twins began several years after the male study, their data for the second follow-up assessment at age 24 were not available for this report.

At the initiation of the MTFS, the nosology in the United States was the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; DSM–III–R; American Psychiatric Association, 1987). For the sake of consistency, its criteria were used for each wave of assessment. Structured interviews were administered by trained staff. Teams of at least two graduate students with advanced training in the diagnosis of mental disorders reviewed all interviews and reached consensus on the status of each symptom. To be consistent with previous MTFS P300 studies (e.g., Carlson et al., 2002, 2004; Carlson, Katsanis, Iacono, & Mertz, 1999; Iacono et al., 2002), we categorized a disorder as present if the diagnosis was met at the “definite” (i.e., DSM–III–R threshold met or exceeded) or “probable” (i.e., all but one required symptom present) level of certainty. An exception was substance abuse, for which one symptom is sufficient for a positive diagnosis. Otherwise, disorders were considered absent.

At the initial assessment, the subjects were assessed for ADHD and ODD with the Diagnostic Interview for Children and Adolescents (DICA–R; Reich, 2000; Welner, Reich, Herjanic, Jung, & Amado, 1987), revised slightly to include additional probes (Iacono et al., 1999). CD and ASPD were assessed with an adaptation of the Structured Clinical Interview for DSM–III–R Axis II Disorders (SCID–II; First, Spitzer, Gibbon, & Williams, 1995). This allowed for a “diagnosis” of AAB if subjects had enough post-age-15 ASPD symptoms to qualify for the adult subsyndrome of ASPD. Although AAB is not a clinical diagnosis, individuals with this syndrome in the absence of childhood CD resemble those with ASPD in personality, psychopathology, substance-use, and offspring psychopathology (Elkins, Iacono, Doyle, & McGue, 1997; Herndon & Iacono, 2005; Marmorstein & Iacono, 2005). To avoid mandatory reporting in this community sample, we did not assess the CD symptom involving forced sexual activity.

Lifetime alcohol and illicit-drug abuse or dependence, as well as nicotine dependence, were assessed with the expanded Substance Abuse Module (SAM; Robins, Babor, & Cottler, 1987) of the Composite International Diagnostic Interview. Illicit substances considered were as follows: amphetamines, cannabis, cocaine, hallucinogens, inhalants, opiates (including heroin), phencyclidine, and sedatives/hypnotics. Subjects also answered several quantitative questions regarding substance use.

Because adolescents tend to underreport symptoms of some externalizing disorders (Hope et al., 1999), at the first assessment, the primary caretaker (usually the mother) was interviewed about her sons with a modified version of the DICA–R—Parent Version (Reich, 2000), which covered all syndromes except AAB. To reduce false negatives common to nontreatment samples (Leckman, Sholomskas, Thompson, Belanger, & Weissman, 1982), we considered a symptom present if either informant reported it and absent if both denied it. This diagnostic approach results in diagnoses with good to excellent reliability (Iacono et al., 1999). Kappa reliability coefficients for externalizing disorders ranged from .71 for ODD to .95 for AAB and were greater than .91 for substance-use disorders.

Only the young men provided diagnostic information at later assessments. The SAM and modified SCID–II were administered at each occasion. For the second assessment, subjects again reported on the lifetime history of substance-use disorders, CD, and AAB. For the third assessment, they reported on substance-use disorders since their most immediate previous interview and lifetime occurrence of CD and AAB.

Subjects were identified as having a diagnosis of a nonsubstance externalizing disorder if they had a lifetime diagnosis of ADHD, ODD, CD or AAB by the final assessment. They were classified into three groups on the basis of their substance-disorder history. If they never had a diagnosis of alcohol abuse or dependence, illicit drug abuse or dependence, or nicotine dependence they were classified as “substance-disorder-free” subjects. If they had at least one of these disorders at the first or second assessment (i.e., by the age-20 assessment), they were classified as “earlier-onset” substance-use-disorder subjects. Finally, subjects free of these disorders at the first two assessments, but who developed at least one between the age 20 and final assessments, were designated “later-onset” subjects. We use the relative terms “earlier” and “later” to acknowledge that some investigators consider onset after adolescence to be relatively late (e.g., Bakken et al., 2004; Clark et al., 1998), and others consider a disorder occurring before age 25 to be of early onset (e.g., Dom, D'haene, Hulstijn, & Sabbe, 2006; Watson et al., 1997). We have previously shown that reduced amplitude at age 17 precedes new substance disorder at the age-20 assessment (Carlson et al., 2004; Iacono et al., 2002), and so we use this as our cutoff.

Diagnoses for the young men at the first assessment were largely complete. Of the 502 subjects, only 1 was missing information for a single diagnosis at the first assessment (i.e., 1 AAB diagnosis) and 68 (13.5%) were missing later diagnostic information needed to determine an externalizing or substance-use disorder diagnosis. Of this latter group, 58 were missing a nonsubstance externalizing diagnosis. Thirty-one of the 68 subjects missing diagnoses were missing a substance-disorder outcome. We were able to still provide an outcome classification for some subjects missing data for a single substance-use disorder diagnosis, because they had a positive outcome for another substance disorder. For example, some men missing diagnostic data for illegal drug abuse from the second follow-up could still be classified as having a later-onset substance-use disorder, because they had a new diagnosis of alcohol dependence between ages 20 and 24. A similar situation allowed us to classify some young men as having a nonsubstance externalizing disorder, despite missing diagnostic information for a single disorder (i.e., AAB) at a follow-up assessment. As such, we were able to form an outcome diagnosis regarding the presence of substance-use or externalizing disorders for all but 49 men. This resulted in a final sample of 433 men.

Electrophysiological data were collected with the Grass Systems Model 12 Neurodata Acquisition System (Grass Instruments, Quincy, MA). Electroencephalographic (EEG) and electrooculographic (EOG) signals were recorded with 1/2 amplitude low- and high-frequency filter settings at 0.01 Hz and 30 Hz, respectively. EEG activity was recorded at electrode sites Pz, P3, and P4, referenced to linked ear lobes. Data are presented only from Pz, the site that has received the most attention in the P300-alcoholism literature. A ground electrode was placed on the right shin. EOG sensors were located above and to the side of one eye. Impedance was below 10 kΩ for the ground and EOG and 5 kΩ for the EEG electrodes. Data were sampled at a rate of 256 Hz during a 2,000-ms epoch with a 500-ms baseline period. We made corrections for the effects of blinks and other ocular activity on the EEG using the method of Gratton, Coles, and Donchin (1983). A lowpass 7.5-Hz digital filter was further applied to reduce high-frequency artifact.

The “rotated heads” task (Begleiter et al., 1984) was used to elicit P300. This task was used in the first study to demonstrate reduced P300 amplitude in the unaffected sons of alcoholic fathers without using an alcohol-challenge manipulation (Begleiter et al., 1984). During the late 1980s, when the MTFS was initiated, the procedure used in this highly influential study was a reasonable one to replicate. A subsequent meta-analysis supported the view that challenging visual tasks such as this one are associated with greater differences between adolescents with and without a family history of alcoholism (Polich et al., 1994). P300 amplitude from this task is also substantially influenced by genes (e.g., heritability of 60%–80% in men; Carlson & Iacono, 2006; Katsanis, Iacono, McGue, & Carlson, 1997; Yoon et al., 2006), making this procedure a good one for eliciting a candidate marker of genetic risk.

Subjects viewed a computer screen that displayed either an oval depicting a superior view of a human head or a plain oval every few seconds. When the head appeared, it had a nose pointing toward either the top or bottom of the monitor screen. An ear appeared on one side of the head, and the subject was required to press one of two buttons corresponding to the side of the head on which the ear appeared. The target trials in which the nose pointed up were considered the “easy” cases, and those in which the nose pointed down were considered “difficult.” No response was required for the neutral ovals. Subjects practiced the task to ensure that they understood it. They were instructed to respond as quickly and accurately as possible. A total of 240 trials was presented, of which 160 were in the neutral condition. There were 40 trials each of the easy and difficult conditions. Stimuli were presented for 98 ms in a pseudorandom order, with an intertrial interval varying randomly between 1 s and 2 s.

EEG waveforms were averaged across target conditions, because amplitude from these conditions is highly correlated (Iacono et al., 2002), and there is no apparent interaction between condition and externalizing (Patrick et al., 2006). A computer program identified the maximum voltage occurring 200–800 ms following stimulus onset. A rater blind to the subject's diagnoses corrected misidentified peaks (as detailed in Carlson et al., 1999). Amplitude was the voltage difference between the prestimulus baseline mean and the peak. The test–retest reliability of this procedure is .71–.79 over 3 years (Carlson & Iacono, 2006). In this report, only P300 from the first assessment is described.

As indicated previously, some subjects' diagnostic classifications were lost because of attrition. Subjects for whom a diagnosis could not be conclusively confirmed or ruled out were excluded from the study. This may have caused the results to be biased such that the rates of disorders may be slightly elevated. The nonsubstance externalizing disorders assessed in this study, with the exception of AAB, typically first occur prior to age 17. The diagnostic information, however, was largely complete at this age. Subjects who did not have a diagnosis of a nonsubstance externalizing disorder at age 17 were unlikely to have developed such a disorder by the second or third assessments, but because follow-up data on new possible cases of AAB were missing, they could not be included in the analysis. Thus, the group excluded because of attrition would likely have a low incidence of externalizing disorders. When calculating proportions of subjects with an externalizing disorder in each substance-outcome group, the overall total was reduced because of exclusion of subjects with missing data, whereas the number of subjects with a disorder is unlikely to have been as affected. As such, the prevalence rates reported could be slightly exaggerated.

Analyses were carried out to evaluate whether P300 amplitude differed between subjects with complete data and those who remained unclassified. We fit a mixed model with subjects nested within families using SAS Proc Mixed (SAS Institute, 1998) with full maximum-likelihood estimation. It indicated that the 49 subjects missing an outcome did not differ significantly in P300 amplitude from the 433 with complete data, F(1, 486) = 0.21, p = .650. This multilevel model accounts for the nonindependence of subjects because of multiple subjects originating from the same family.

Further supportive of the results not being substantially biased is the finding that whether or not a subject had enough diagnostic information to make a substance-outcome classification at age 24 was unrelated to their ADHD, χ2(1, N = 502) = 0.26, p = .613; ODD, χ2(1, N = 502) = 0.03, p = .855; CD, χ2(1, N = 502) = 2.46, p = .117; or AAB, χ2(1, N = 501) = 1.68, p = .195, diagnosis at the first assessment. Similarly, absence of a nonsubstance externalizing-disorder classification was not related to alcohol-disorder diagnosis, χ2(1, N = 502) = 1.72, p = .190; drug-disorder diagnosis, χ2(1, N = 502) = 1.37, p = .243; or nicotine-disorder diagnosis, χ2(1, N = 502) = 1.45, p = .228, at the first assessment.

Differences in prevalence of subjects' diagnoses between the substance-disorder groups were evaluated with the chi-square test of independence. The varying sample sizes provided below reflect missing lifetime diagnostic information for some individual disorders. An alcohol-use disorder was the most common diagnosis in both affected substance-use-disorder groups, with 85.8% of the earlier-onset and 76.0% of the later-onset subjects having alcohol abuse or dependence. This difference in prevalence was not statistically significant, χ2(1, N = 289) = 1.45, p = .229. A significantly greater proportion of the earlier-onset men had illicit drug abuse or dependence (52.6% vs. 7.5 %), χ2(1, N = 283) = 35.47, p < .001, and nicotine dependence (68.8% vs. 18.9%), χ2(1, N = 290) = 44.83, p < .001, compared with the later-onset individuals.

The percentage of subjects in each substance-disorder group with a given nonsubstance externalizing disorder is provided in Figure 1. As expected, there was a significant relationship between substance-use and externalizing disorder outcomes, χ2(2, N = 433) = 62.72, p < .001. About three quarters (75.8%) of the men with an earlier-onset substance-use disorder also had at least one nonsubstance externalizing disorder. This was a significantly greater proportion than for men with a later-onset substance disorder (53.3%), χ2(1, N = 304) = 11.92, p = .001, or for those without a substance disorder by the final assessment (34.1%), χ2(1, N = 373) = 61.94, p < .001. The later-onset substance-disorder group also had a significantly higher percentage of individuals with any nonsubstance externalizing disorder than did the substance-disorder-free group, χ2(1, N = 189) = 6.30, p = .012.

The substance-disorder outcome groups differed in rates of ADHD, χ2(2, N = 433) = 10.23, p = .006; ODD, χ2(2, N = 433) = 17.37, p < .001; CD, χ2(2, N = 430) = 39.08, p < .001; AAB, χ2(2, N = 407) = 92.36, p < .001; and ASPD, χ2(2, N = 405) = 77.04, p < .001. In each case, the earlier-onset group had a higher rate of the disorder than did the substance-disorder-free men (ps ≤ .012). For almost all of these disorders, a significantly higher proportion of the earlier-onset subjects had the disorder than did the later-onset group (ps ≤ .023). The exception was ODD (p = .154). The later-onset group had significantly greater rates of CD, χ2(1, N = 188) = 4.29, p = .038, and AAB, χ2(1, N = 179) = 8.58, p = .003, than did the substance-disorder-free group. No other differences were statistically significant.

To evaluate differences in P300 in adolescence among the outcome groups, we fit a multilevel model using SAS Proc Mixed with full maximum-likelihood estimation. This model tested all main and interaction-fixed effects, as in an analysis of variance for Substance-Disorder Outcome Status (no disorder, later-onset, earlier-onset) × Nonsubstance Externalizing Disorder Status (absent vs. present), with a random effect for model intercept varying across families. The Satterthwaite method for determining residual degrees of freedom was used. Table 1 provides the descriptive statistics for observed P300 amplitude and behavioral data. The upper half of Figure 2 depicts the event-related-potential waveforms for each substance-disorder outcome group, subdivided by the absence (Figure 2A) or presence (Figure 2B) of a nonsubstance externalizing disorder.

There was a significant difference in adolescent P300 amplitude across the substance-disorder outcome groups, F(2, 415) = 3.24, p = .040. Follow-up t tests using least-squares approximation of group means indicated that the earlier-onset men had significantly smaller P300 than did the substance-disorder-free subjects, t(431) = 2.47, p = .014. On average, the later-onset subjects did not differ significantly from either the men with an earlier-onset substance disorder, t(394) = 1.40, p = .162, or those without a substance disorder, t(398) = 0.60, p = .549.

Men with nonsubstance externalizing disorders had smaller P300 in adolescence than did those who did not develop an externalizing disorder, F(1, 418) = 6.56, p = .002. Differences in amplitude across substance-disorder and nonsubstance externalizing groups must be interpreted in the context of a significant interaction between these two variables, F(2, 371) = 3.64, p = .027. This interaction is illustrated in Figure 3. Men with an earlier-onset substance disorder had significantly smaller amplitude than did either those with a later-onset substance disorder, t(390) = 2.62, p = .009, or those with no substance disorder, t(425) = 2.58, p = .010, if an externalizing disorder was absent, but had comparably small amplitude across the substance-disorder groups if an externalizing disorder was present. For men with a nonsubstance externalizing disorder, the earlier-onset substance-disorder group did not differ significantly from the later-onset, t(362) = 0.97, p = .333, or substance-disorder-free, t(408) = 0.96, p = .337, groups. The later-onset men did not differ significantly from the substance-disorder-free subjects, whether a nonsubstance externalizing disorder was present, t(342) = 1.53, p = .126, or absent, t(408) = 0.69, p = .489.

Similar multilevel models were fit to manual reaction time to stimuli. There were no significant main or interaction effects. Task performance was generally good, resulting in a markedly skewed distribution of error rates. The rank of performance error rate, both to targets and false positives to neutrals, was evaluated across substance-outcome groups at both levels of nonsubstance externalizing with the Kruskal–Wallis test, and differences because of externalizing were evaluated at each level of substance outcome with the Wilcoxon signed-ranks test. No differences were statistically significant (ps > .079).

To evaluate the expectation that P300 amplitude reductions are related to risk and not merely concurrent psychopathology, we examined further the externalizing-disorder-free subjects who did not have a substance-use disorder at the time of P300 measurement. We screened out of the analyses subjects who reported using any caffeine on the day of the assessment, alcohol during the previous year, tobacco during the previous month, or illicit drugs ever, to reduce the possibility that reduced amplitude in the earlier-onset subjects was due to greater substance use prior to the P300 recording. To reduce the possibility that P300 differences were affected by differences in depression history, we also screened out subjects with a major depressive disorder by age 17, as assessed with subject reports on the Structured Clinical Interview for DSM–III–R (SCID; Spitzer, Williams, Gibbon, & First, 1992) and parent report on the DICA–R—Parent Version.

This resulted in groups that were parallel to the previously reported substance-disorder groups but were free of an externalizing or substance disorder and had minimal recent substance use at the time of the P300 recording. In this analysis, the earlier-onset group was composed of individuals who did not have a disorder at the intake assessment but who developed a substance-use disorder by the first follow-up at age 20. The event-related potential waveforms for these substance-disorder outcome groups are depicted in Figure 2C.

We fit a multilevel model to evaluate differences across these groups. There was a significant difference in amplitude across these outcome groups, F(2, 110) = 3.49. p = .034. The earlier-onset subjects without a disorder at the time of the P300 recording had significantly smaller P300 amplitude (n = 19, M = 22.04 μV, SD = 7.53) than did either the later-onset (n = 23, M = 28.35 μV, SD = 8.07), t(112) = 2.41, p = .018; or the substance-disorder-free (n = 70, M = 27.50 μV, SD = 8.50), t(112) = 2.37, p = .020, men. As before, the later-onset and disorder-free subjects did not differ significantly, t(102) = 0.55, p = .581. There were no significant group differences in manual reaction time, target error, or false-positive rate (ps ≥ .119).

We recorded visual P300 amplitude at approximately age 17 in a community-representative sample of young men differing in the onset age of substance-use disorders and the presence of nonsubstance externalizing disorders by age 24. Consistent with our expectation that earlier-onset substance problems are associated with more severe levels of an externalizing dimension related to P300 amplitude, we found both smaller P300 amplitude and a higher prevalence of nonsubstance externalizing disorders in earlier-onset subjects relative to those who had not developed a substance disorder by the final assessment. The later-onset subjects were intermediate in terms of P300 amplitude in the entire sample, although they did not differ significantly from either of the other substance-disorder outcome groups.

Men with a later-onset substance-use disorder had rates of most nonsubstance externalizing disorders in between those of the earlier-onset and substance-disorder-free subjects, consistent with an intermediate level of an underlying externalizing dimension. This was especially true for AAB, the syndrome that best distinguishes severe externalizing from less severe levels in adults (Krueger et al., 2005) and has the highest loading on a highly heritable externalizing factor, as assessed in adolescence (Krueger et al., 2002). Although the earlier- and later-onset disorder groups did not differ in the presence of alcohol abuse or dependence by the final assessment, those with an earlier-developing problem were more likely to have a disorder involving illicit drugs and to be nicotine dependent than were men with a later-developing problem. Taken together, these findings underscore the greater social deviance associated with substance disorders originating by the very early 20s than with later-onset substance problems.

As predicted, the reduced amplitude at age 17 was not due exclusively to the effects of having a disorder or high levels of substance use prior to the time of recording. Group differences associated with substance-disorder onset remained after removing subjects with any nonsubstance externalizing disorder and those with a substance-use disorder or recent substance use at the time of the P300 measurement. These subjects were unlikely to have an undiagnosed substance problem or even extreme substance-use histories at the time of P300 recording. Not only were men required to be at least two symptoms below threshold for most disorders, as reported by two informants at the time of their P300 recording, but they also reported no history of illicit substance use, no alcohol consumption in the previous year, and no tobacco use in the previous month. Furthermore, although there have been reports of P300 amplitude reductions associated with internalizing as well as externalizing disorders in offspring of alcoholic fathers (e.g., Hill & Shen, 2002; van der Stelt, 1999), in the present study, the amplitude reductions seen in men with early-onset substance disorder were not due to a diagnosis of current or past major depressive disorder (a prevalent internalizing disorder).

P300 amplitude reductions are associated with the variance shared by substance-use and antisocial behavior disorders, rather than with a specific disorder in adolescence (Patrick et al., 2006). The results of the present study are consistent with P300 amplitude being linked to risk for a latent externalizing phenotype, with early-onset substance-use and nonsubstance externalizing disorders being alternate indicators. As we hypothesized, the amplitude reduction reported was not present exclusively in the early-onset subjects, as it was seen in those with a nonsubstance externalizing disorder, regardless of substance-disorder status. This finding is inconsistent with P300 reflecting risk for a strict “early-onset subtype.” Similarly, the amplitude reduction is not present only in those with a substance-use and comorbid antisocial behavior disorder, as one might expect from association with an “antisocial subtype” of substance disorder. Our findings are also inconsistent with the idea that the relationship between substance-use disorders and P300 amplitude reduction is an epiphenomenon that is due to comorbid antisocial behavior disorders (c.f. Bauer, 1997; Bauer & Hesselbrock, 1999a, 1999b), as subjects with an early-onset substance disorder but no nonsubstance externalizing disorders (including CD and ASPD) by age 24 had reduced amplitudes.

Although it is not universally supported, various studies suggest that there are differences in potential etiological factors among alcoholism groups characterized by varying onset age. These include differences in personality traits related to impulsivity, novelty or sensation seeking, and aggression (Basiaux et al., 2001; Cloninger, 1987; Dom, D'haene, et al., 2006; Dom, Hulstijn, & Sabbe, 2006; Howard, Kivlahan, & Walker, 1997; Lykouras, Moussas, & Botis, 2004; McGue et al., 1997); laboratory measures of impulsivity (Bjork, Hommer, Grant, & Danube, 2004; Dom, D'haene, et al., 2006); prefrontal cortex anatomy (De Bellis et al., 2005; Laakso et al., 2000); indicators of monoamine neurotransmitter functioning (Buydens-Branchey, Branchey, Noumair, & Lieber, 1989; Demɨr et al., 2002; Fils-Aime et al., 1996; George et al., 1997; Hallman, von Knorring, & Oreland, 1996; Johnson, 2004); and gene associations (Dahmen, Völp, Singer, Hiemke, & Szegedi, 2005; Mottagui-Tabar et al., 2005; Wernicke et al., 2003).

A common theme in research that attempts to make sense of this type of heterogeneity is a distinction between a developmental course associated with both early-onset substance problems and antisocial personality and at least one other pathway involving different etiological factors (e.g., Babor et al., 1992; Cloninger, 1987; Cloninger, Sigvardsson, & Bohman, 1996; Sher, 1991; Tarter et al., 1999; Zucker, Ellis, Fitzgerald, & Bingham, 1996; Zucker, Fitzgerald, & Moses, 1995). A similar distinction has been made between an antisocial and a nonantisocial subtype of drug dependence (Ball, Kranzler, Tennen, Poling, & Rounsaville, 1998; Feingold, Ball, Kranzler, & Rounsaville, 1996). Sher and Slutske (2003) described four nonexclusive “metamodels” in their review of possible mediators and moderators of a family history of alcoholism. One model, involving deviance proneness, described neuropsychological deficits and personality traits related to impulsivity that, under the influence of relevant environmental risk factors, can lead to a variety of socially deviant outcomes including early-onset alcohol problems, illegal drug use, and antisocial behavior. Both the deviance-proneness models of early-onset alcoholism (Sher, 1991) and models of an early-onset, life-course-persistent subtype of antisocial behavior (e.g., Moffitt, 2003) include many of the same risk factors (e.g., verbal and executive cognitive deficits leading to impulsive behavior). This deviance-proneness pathway may reflect the development and manifestation of the externalizing dimension. Etiological influences on later-onset alcoholism may be largely mediated by one or more of the other three pathways described by Sher and Slutske (i.e., problems coping with negative emotions, greater susceptibility to the appetitive aspects of substance use, or differences in pharmacological sensitivity).

Rather than reflecting etiologically distinct pathways, however, differences between individuals with early- and late-onset substance-use disorders are also consistent with affected individuals being located at varying levels of severity on the same underlying dimension of externalizing (Krueger et al., 2005). The same etiological factors may be relevant but differ only in the degree to which they are present. The present study does not directly provide insight into whether later-onset substance-use disorders are largely etiologically distinct from earlier-onset substance problems or differ primarily in the severity of a common underlying vulnerability. The latent-trait model of a single dimension, however, has received empirical support from studies of alcoholism (Krueger et al., 2004) and a broader array of externalizing problems (Krueger et al., 2005). The current finding of an intermediate level of nonsubstance externalizing syndromes, especially AAB, is consistent with this group being at an intermediate level of the externalizing dimension. Further developmental research using dimensional measures of substance involvement, externalizing tendencies, and potential etiological factors is needed to help resolve whether or not there are common or distinct etiological pathways to early- and late-onset substance-use disorders.

Because this study only involved men, generalizations to women are not appropriate. The relationship between P300 amplitude and family history of alcoholism (Reese & Polich, 2002) or the presence of social deviance (Justus et al., 2001) appears to differ by sex. Genetic influences on P300 in adolescence may be less important contributors to variability in visual amplitude in women than in men (van Beijsterveldt et al., 2001; Yoon et al., 2006). Further, the modality of P300 amplitude may interact with sex in predicting future substance problems, with auditory P300 being more predictive for girls than for boys (Hill et al., 2000).

The relationship between P300 amplitude, externalizing, and earlier-onset substance problems would likely not extend to P300 recorded at very different ages. Visual P300 amplitude at parietal scalp sites decreases in males from childhood and adolescence to early adulthood (Carlson & Iacono, 2006; Hill, Shen, et al., 1999). The processes underlying change may be related to vulnerability for alcoholism, with family-history group differences being attenuated by the early 20s (Hill, Shen, et al., 1999; Hill & Shen, 2002). P300 amplitude at parietal sites assessed later than adolescence may not be as strong an indicator of the externalizing spectrum. Bauer and Hesselbrock (1999a) found a maximal difference between subjects with and without conduct-disorder problems at posterior scalp sites in subjects under the median age of 16.5 years but a maximum difference located more frontally in older individuals. Studies of adults with antisocial personality disorder (Bauer, 1997; Bauer et al., 1994; Costa et al., 2000) or early-onset substance problems (Justus et al., 2001) suggest a greater association between externalizing characteristics at frontal scalp sites relative to parietal ones. Frontal scalp sites are likely more appropriate for assessing relationships between P300 amplitude and externalizing characteristics in adult subjects.

P300 amplitude reductions are not specific to externalizing disorders and have been related to familial risk for schizophrenia (Friedman, Cornblatt, Vaughan, & Erlenmeyer-Kimling, 1986; Saitoh et al., 1984; Schreiber, Stolzborn, Kornhuber, & Born, 1992; Weisbrod, Hill, Niethammer, & Sauer, 1999). Meta-analyses, however, suggest a greater relationship between alcoholism risk and visual, rather than auditory, P300 (Polich et al., 1994), whereas the opposite is true for schizophrenia (Jeon & Polich, 2003). It is possible that P300 is reduced in these two types of disorder through a common mechanism (e.g., prefrontal cortex dysfunction affecting a common cognitive risk factor) or through different processes that can be differentiated through refinement of measurement tasks (e.g., specialized auditory tasks tapping a cognitive vulnerability specific to schizophrenia and visual tasks targeted to processes involved in externalizing). Which is the case remains to be empirically demonstrated.

The development of a substance-use disorder by the early 20s is associated with a wider variety of substances of abuse, greater comorbidity with nonsubstance externalizing disorders, and more attenuation of P300 amplitude in adolescence, compared with later-onset substance disorders. P300 amplitude may reflect risk for a dimension of externalizing psychopathology, with earlier-onset substance disorders being indicators of more severe externalizing than are later-onset disorders. Researchers on the etiology of severe substance use or antisocial disorders occurring at different levels of analysis (e.g., vulnerability-gene identification, neurocognitive processes, personality traits) would likely benefit by focusing on the externalizing dimension underlying these disorders as the target phenotype. Taken together, the findings of this study suggest that earlier-onset substance disorders are more socially malignant than later-onset ones and warrant special attention in studies of etiology, prevention, and intervention.

1  The nonindependence of subject sampling because of multiple subjects coming from the same family violates an assumption of the chi-square test of independence. To correct for this, we randomly assigned subjects to one of two unrelated subsamples. In all comparisons involving the entire sample and in comparisons of the earlier-onset with the substance-disorder-free group, differences in illicit drug abuse or dependence, nicotine dependence, ODD, CD, AAB, ASPD, and the presence of any nonsubstance externalizing disorder were replicated in each subsample. This was also true for significant differences in diagnoses between the earlier- and later-onset groups, except for CD and ADHD. For these comparisons, significant differences were detected in one subsample, but a nonsignificant difference was present in the other subsample. For most comparisons between the later-onset and substance-disorder-free subjects, where there was a significant difference in the entire sample, the difference was significant in only one subsample. The exception was for AAB, where the difference was replicated in both subsamples. Differences in the entire sample not borne out in both subsamples of unrelated subjects must be accepted with caution.

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Submitted: October 23, 2006 Revised: February 19, 2007 Accepted: March 5, 2007