Alpha-5/alpha-3 nicotinic receptor subunit alleles increase risk for heavy smoking.

Twin studies indicate that additive genetic effects explain most of the variance in nicotine dependence (ND), a construct emphasizing habitual heavy smoking despite adverse consequences, tolerance and withdrawal. To detect ND alleles, we assessed cigarettes per day (CPD) regularly smoked, in two European populations via whole genome association techniques. In these approximately 7500 persons, a common haplotype in the CHRNA3-CHRNA5 nicotinic receptor subunit gene cluster was associated with CPD (nominal P=6.9 x 10(-5)). In a third set of European populations (n= approximately 7500) which had been genotyped for approximately 6000 SNPs in approximately 2000 genes, an allele in the same haplotype was associated with CPD (nominal P=2.6 x 10(-6)). These results (in three independent populations of European origin, totaling approximately 15 000 individuals) suggest that a common haplotype in the CHRNA5/CHRNA3 gene cluster on chromosome 15 contains alleles, which predispose to ND.

Understanding the patterns and distribution of opioid analgesic dependence symptoms using a latent empirical approach.

Prevalence of extramedical opioid analgesic use in the US is rising, yet little is known about the nature and extent of problems of dependence related to the use of these drugs. This study uses Latent Class Analysis to empirically define classes of past-year extramedical opioid analgesic users based on observed clustering of DSM-IV defined clinical dependence features; multinomial logistic regression is used to describe differences across these groups. The 2002-2003 public data-files of the National Survey on Drug Use and Health were used to identify 7810 extramedical opioid analgesic users in the past-year. The best-fitting four-class model identified classes that differed quantitatively and qualitatively, with 2% of the users in Class 4 (most severe) and 84% in Class 1 (least severe). Classes 2 and 3 had parallel symptom profiles, but those in Class 3 reported additional problems. Adolescents (12-17 year olds) were at higher odds of being in Class 3 versus older age groups; females were two times as likely to be in Classes 2 and 4, and those with mental health problems were at higher odds of belonging to the more severe classes. Differences by type of past year opioid users were also detected. This study sheds light on the classification and distribution of extramedical opioid analgesic dependence symptoms in the US general population, identifying subgroups that warrant immediate attention.

The effect of an abuse-deterrent opioid formulation (OxyContin) on opioid abuse-related outcomes in the postmarketing setting.

An extended-release opioid analgesic (OxyContin, OC) was reformulated with abuse-deterrent properties to deter abuse. This report examines changes in abuse through oral and nonoral routes, doctor-shopping, and fatalities in 10 studies 3.5 years after reformulation. Changes in OC abuse from 1 year before to 3 years after OC reformulation were calculated, adjusted for prescription changes. Abuse of OC decreased 48% in national poison center surveillance systems, decreased 32% in a national drug treatment system, and decreased 27% among individuals prescribed OC in claims databases. Doctor-shopping for OC decreased 50%. Overdose fatalities reported to the manufacturer decreased 65%. Abuse of other opioids without abuse-deterrent properties decreased 2 years later than OC and with less magnitude, suggesting OC decreases were not due to broader opioid interventions. Consistent with the formulation, decreases were larger for nonoral than oral abuse. Abuse-deterrent opioids may mitigate abuse and overdose risks among chronic pain patients.

Posttraumatic stress disorder and drug disorders: testing causal pathways.

BACKGROUND: Although there is a high degree of comorbidity between posttraumatic stress disorder (PTSD) and drug use disorders, little is known about causal relationships between PTSD, exposure to traumatic events, and drug use disorders. METHODS: In a longitudinal study in southeast Michigan, 1007 adults aged 21 to 30 years were initially assessed in 1989 and were followed up 3 and 5 years later, in 1992 and 1994. Psychiatric disorders according to DSM-III-R criteria were measured by the National Institute of Mental Health Diagnostic Interview Schedule. To take into account temporal sequencing, the associations between PTSD, traumatic events, and drug use disorders were analyzed by using Cox proportional hazards models with time-dependent covariates. RESULTS: Posttraumatic stress disorder signaled an increased risk of drug abuse or dependence (hazards ratio, 4.5; 95% confidence interval, 2.6-7.6, adjusted for sex), whereas exposure to traumatic events in the absence of PTSD did not increase the risk of drug abuse or dependence. The risk for abuse or dependence was the highest for prescribed psychoactive drugs (hazards ratio, 13.0; 95% confidence interval, 5.3-32.0). There was no evidence that preexisting drug abuse or dependence increased the risk of subsequent exposure to traumatic events or the risk of PTSD after traumatic exposure. CONCLUSION: The results suggest that drug abuse or dependence in persons with PTSD might be the inadvertent result of efforts to medicate symptoms, although the possibility of shared vulnerability to PTSD and drug use disorders cannot be ruled out.

Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma.

BACKGROUND: The study estimates the relative importance of specific types of traumas experienced in the community in terms of their prevalence and risk of leading to posttraumatic stress disorder (PTSD). METHODS: A representative sample of 2181 persons in the Detroit area aged 18 to 45 years were interviewed by telephone to assess the lifetime history of traumatic events and PTSD, according to DSM-IV. Posttraumatic stress disorder was assessed with respect to a randomly selected trauma from the list of traumas reported by each respondent, using a modified version of the Diagnostic Interview Schedule, Version IV, and the World Health Organization Composite International Diagnostic Interview. RESULTS: The conditional risk of PTSD following exposure to trauma was 9.2%. The highest risk of PTSD was associated with assaultive violence (20.9%). The trauma most often reported as the precipitating event among persons with PTSD (31% of all PTSD cases) was sudden unexpected death of a loved one, an event experienced by 60% of the sample, and with a moderate risk of PTSD (14.3%). Women were at higher risk of PTSD than men, controlling for type of trauma. CONCLUSIONS: The risk of PTSD associated with a representative sample of traumas is less than previously estimated. Previous studies have overestimated the conditional risk of PTSD by focusing on the worst events the respondents had ever experienced. Although recent research has focused on combat, rape, and other assaultive violence as causes of PTSD, sudden unexpected death of a loved one is a far more important cause of PTSD in the community, accounting for nearly one third of PTSD cases.

Major depression and stages of smoking. A longitudinal investigation.

BACKGROUND: Epidemiologic studies have reported an association between major depression and smoking. This prospective study examines the role of depression in smoking progression and cessation, and the role of smoking in first-onset major depression. METHODS: Data are from a 5-year longitudinal epidemiologic study of 1007 young adults. Incidence and odds ratios (ORs) are based on the prospective data. Hazards ratios are based on the combined lifetime data and estimated in Cox proportional hazards models with time-dependent covariates. RESULTS: Based on the prospective data, history of major depression at baseline increased significantly the risk for progression to daily smoking (OR, 3.0; 95% confidence interval, 1.1-8.2), but did not decrease significantly smokers' rate of quitting (OR, 0.8; 95% confidence interval, 0.4-1.6). History of daily smoking at baseline increased significantly the risk for major depression (OR, 1.9; 95% confidence interval, 1.1-3.4). These estimates were reduced somewhat when history of early (ie, before age 15 years) conduct problems was controlled. Estimates based on lifetime data were consistent with these results. CONCLUSIONS: The observed influences from major depression to subsequent daily smoking and smoking to major depression support the plausibility of shared etiologies. Separate causal mechanisms in each direction might also operate, including self-medication of depressed mood as a factor in smoking progression and neuropharmacologic effects of nicotine and other smoke substances on neurotransmitter systems linked to depression.

Psychiatric sequelae of low birth weight at 11 years of age.

BACKGROUND: We examined the relationship between low birth weight (LBW) and psychiatric problems at age 11 years. METHODS: Random samples of 6-year-old LBW and normal birth weight (NBW) children from two socioeconomically disparate communities were identified, traced, and assessed. We targeted the 1983-1985 cohort of newborns who reached age 6 in 1990-1992, the scheduled period of fieldwork. Of the 1,095 in the target sample, 823 (75%) were assessed. Five years later, the sample was reassessed. Behavior problems were evaluated by standardized behavior problems scales rated by mothers and teachers. A multiple regression application that combines data from multiple informants was used. Prospective data were used to estimate the incidence of severe attention problems during the follow-up period. RESULTS: Information from mothers and teachers revealed that LBW was associated with an excess of attention problems at age 11 in the urban but not in the suburban children. In the urban setting, LBW children had a higher incidence of clinically significant attention problems than NBW children. Although LBW children scored higher than NBW children on externalizing problems, the effect was accounted for in large part by maternal smoking in pregnancy. CONCLUSIONS: The LBW-attention problems association observed in the urban community suggests an interaction between biologic vulnerability associated with premature birth and environmental risk associated with social disadvantage. Further research and replication are called for.

Low birth weight and neurocognitive status at six years of age.

We examined the relationship between low birth weight (LBW) (< or = 2500 g) and specific neurocognitive abilities at 6 years of age in a large-scale nonconcurrent prospective study. In 1990-1992, we randomly selected and evaluated LBW and normal birth weight (NBW) children from the 1983-1985 newborn lists of two major hospitals in southeast Michigan, one serving an urban and the other a suburban population. LBW children (n = 473) scored significantly lower than NBW children (n = 350) on tests measuring language, spatial, fine motor, tactile, and attention abilities, controlling for population site, race, maternal IQ, and education. Gradient relationships were observed across levels of LBW with language, spatial, tactile, and attention tests. Exploratory analysis, using general additive models, revealed that test performance varied within birth weight levels and that performance continued to improve with increased birth weight well above 3000 g. Follow-up assessments as the children mature will shed light on the persistence of these associations and their implications for learning disorders.

Neurologic soft signs and low birthweight: their association and neuropsychiatric implications.

BACKGROUND: We examine the relationship between neurologic soft signs and cognitive deficits, learning disorders, and psychiatric problems in low birthweight (LBW) and normal birthweight (NBW) children. METHODS: Representative samples of LBW and NBW children were selected from the 1983-1985 newborn discharges of two major hospitals in Michigan. Eight hundred-twenty three children (75% of the target sample) were evaluated at ages 6 and 11. A standardized neurologic evaluation was used by neurologists to measure neurologic soft signs at age 6 (children with frank neurologic impairment were excluded). IQ was measured by WISC-R and behavior problem lists were rated by mothers and teachers. Standard tests of academic achievement were used to identify learning disorders. All assessments were blind to LBW status. Using multiple regression analysis, applying generalized estimating equations (GEE), we estimated the effects of soft signs on 3 behavioral domains, based on information from multiple informants and times of assessment. RESULTS: LBW was associated with a two-fold increased risk for soft signs. Soft signs increased the risk for subnormal IQ and for learning disorders in children with normal IQ. Soft signs were associated with excess internalizing problems in LBW and NBW children, and with attention and externalizing problems in LBW children; the excess in externalizing problems in LBW children was observed only at age 6. CONCLUSIONS: Soft signs are a marker of high risk for cognitive and psychiatric problems. Of particular concern is their presence in LBW children, in whom they are associated with more severe cognitive deficits and more pervasive psychiatric problems.

Previous exposure to trauma and PTSD effects of subsequent trauma: results from the Detroit Area Survey of Trauma.

OBJECTIVE: With the exception of a few reports of higher rates of childhood trauma in Vietnam veterans with posttraumatic stress disorder (PTSD), little is known about the influence of previous exposure to trauma on the PTSD effects of subsequent trauma. The authors examine interrelated questions about the effects of previous exposure to trauma. METHOD: A representative sample of 2,181 individuals in southeast Michigan were interviewed by telephone to record lifetime history of traumatic events specified in DSM-IV as potentially leading to PTSD. PTSD was assessed with respect to a randomly selected index trauma from the list of events reported by each respondent. RESULTS: History of any previous exposure to traumatic events was associated with a greater risk of PTSD from the index trauma. Multiple previous events had a stronger effect than a single previous event. The effect of previous assaultive violence persisted over time with little change. When they examined several features of the previous exposure to trauma, the authors found that subjects who experienced multiple events involving assaultive violence in childhood were more likely to experience PTSD from trauma in adulthood. Furthermore, previous events involving assaultive violence--single or multiple, in childhood or later on--were associated with a higher risk of PTSD in adulthood. CONCLUSIONS: Previous exposure to trauma signals a greater risk of PTSD from subsequent trauma. Although these results are consistent with a sensitization hypothesis, like the results from previous research on PTSD, they do not address the mechanism of increased responsivity to trauma. Long-term observational studies can further elucidate these observations.

Further evidence on the link between migraine and neuroticism.

Epidemiologic studies have demonstrated an association between migraine and neuroticism. In this report, we examine prospectively whether higher levels of neuroticism, measured at baseline by the Eysenck Personality Questionnaire, signaled increased risk for first incidence of migraine during a 5-year follow-up interval. The sample was randomly selected from the list of young adult members of a large Health Maintenance Organization in southeast Michigan. Follow-up data were available on 972 subjects, 97.2% of the initial sample. Neuroticism predicted the first incidence of migraine in females. The relative risk for migraine in females scoring in the highest quartile of the neuroticism scales versus the lowest quartile was 4.0 (95% CI 1.6, 10.3). Controlling for history of major depression and anxiety disorders at baseline reduced the estimate to 2.9 (95% CI 1.1, 7.7). Neuroticism did not predict migraine in males, although the results in males were limited greatly by the small number of incidence cases. Neuroticism might be causally related to migraine, or alternatively, might be an early correlate with shared etiologies.

Does psychiatric history bias mothers' reports? An application of a new analytic approach.

OBJECTIVE: To evaluate whether mothers' psychiatric history biases reports of their children's behavior problems, mothers' and teachers' reports of children's behavior problems were compared using a recently developed statistical approach. METHOD: Child Behavior Checklists and Teacher's Report Forms were completed by mothers and teachers, respectively, about 801 six-year-old children. Mother's history of major depression, anxiety disorders, and substance use disorder was assessed by using the National Institute of Mental Health Diagnostic Interview Schedule. Generalized estimating equations were used for data analysis. RESULTS: According to both teachers and mothers, maternal history of major depression was associated with more internalizing problems; the association was significantly stronger when mothers were the informants. Mothers with history of any psychiatric disorder reported more externalizing problems in their children than expected, whereas teachers' reports of externalizing behaviors were unrelated to maternal psychiatric history. These findings could not be explained by variations in children's behaviors across settings. CONCLUSION: The generalized estimating equation models enabled simultaneous examination of whether children of depressed mothers have excess behavior problems and whether depressed mothers overreport behavior problems in their children. The results indicate that children of depressed mothers have more internalizing problems. In addition, depressed mothers overstate and overgeneralize their offspring's behavior problems. This study broadens the concerns with reporting bias beyond maternal depression to include other psychiatric problems. The results emphasize the potential for bias in family history studies that rely on informants.

Impact of parent monitoring on initiation of drug use through late childhood.

OBJECTIVE: To examine whether parental supervision and monitoring in middle childhood might have a sustained impact on risk of drug use later in childhood and adolescence. METHOD: An epidemiological sample of 926 urban-dwelling youths were individually interviewed annually, beginning in 1989 when the children were 8 to 10 years old, continuing through 1992. Standardized questions measured drug use, parenting behaviors, and other suspected determinants of drug use. RESULTS: Survival analysis estimates indicated that children in the lowest quartile of parent monitoring initiated drug use at earlier ages. The contrast in risk of initiating alcohol, tobacco, or other drug use across levels of parent monitoring was greatest when children were under 11 years old; at older ages there was no difference in risk. However, in analyses focused specifically on marijuana, cocaine, and inhalant drugs, we observed a sustained higher risk of starting to use these drugs among youths who had been monitored at the lowest levels in middle childhood. CONCLUSION: These results add to the chain of inference that effective supervision and monitoring in middle childhood by parents or guardians might induce a delay or prevent onset of drug use among youths living in urban areas, a hypothesis that now ought to be tested in rigorous field experiments.

Pathways from ADHD to early drug use.

OBJECTIVE: This study tests whether attention-deficit hyperactivity disorder (ADHD) increases the risk of early drug use. METHOD: A community-based sample of 412 low birth weight and 305 normal birth weight children and their mothers initially were assessed when the children were 6 years old with a follow-up assessment at age 11. RESULTS: The relationship of ADHD with drug use varied by level of externalizing problems. Regardless of ADHD status, children with a low level of externalizing problems had a low risk of drug use, and those with the highest level of externalizing problems had a high risk. At the middle level of externalizing problems, ADHD increased the incidence of drug use to the magnitude observed at the high level of externalizing problems, and children with ADHD were at significantly higher risk than those without ADHD (odds ratio = 2.1, p = .03). Findings were similar for low and normal birth weight children. Low parent monitoring and high peer drug use signaled increased risk of drug use for children, independent of ADHD status. Psychostimulant treatment for ADHD was unrelated to risk of drug use. CONCLUSIONS: Risk for early drug use in children with ADHD depends on level of associated externalizing problems. Parent monitoring and peer drug use appear to be potential targets for drug prevention for children with ADHD, as well as children in general.

Potential barriers to parent monitoring: social disadvantage, marital status, and maternal psychiatric disorder.

OBJECTIVE: To test whether social disadvantage, marital status, and history of psychiatric disorder might impair mothers' monitoring and supervision of their children. METHOD: An epidemiological sample of 673 mothers of 8- through 11-year-old children, who had been participants in a longitudinal study of children's development, completed standardized telephone interviews about their monitoring and supervision of children. Indicators of social disadvantage also were collected in the telephone interview, and maternal history of psychiatric disorder had been assessed using the National Institute of Mental Health Diagnostic Interview Schedule, administered when the children were 6 years old. RESULTS: Mothers who were never married were twice as likely to be in the lowest quintile of parent monitoring as those who were married (31% versus 16%, p = .001); a similar distribution was found for mothers who did not complete high school compared with those who attended college (31% versus 15%, respectively, p = .001). Mother's history of substance use disorder, anxiety disorder, or major depression was also linked to lower levels of monitoring. Mothers of girls reported higher levels of monitoring than mothers of boys (p < .001). CONCLUSIONS: This study indicates that social disadvantage and maternal psychiatric disorder could have a negative influence on mothers' monitoring behaviors. Although the causal role of these factors is still unclear, interventions that target parenting behaviors should be designed to take them into account.

Age-specific patterns of hallucinogen use in the US population: an analysis using generalized additive models.

Although there has been growing concern in recent years about an escalation in the use of LSD and other hallucinogens, little is known about the distribution of the use of these drugs in the United States population. In order to fill this gap, we used generalized additive models to analyze data from the 1988, 1990, and 1992 National Household Survey on Drug Abuse, to compare the age-specific prevalence of hallucinogen use by level of socio-economic indicators. In addition, we used survival analysis to compare patterns in the onset of use. Use of hallucinogens in the past year was highest at the age of 19 years for each of the NHSDA surveys, but use was not linked to enrollment in school at this age. Past year prevalence was highest among whites and respondents with high family income. The onset of hallucinogen use was most likely to occur between ages 15-19 years, regardless of birth cohort. These results indicate a stable pattern since hallucinogens were made widely available in the late 1960s, in which the transition from adolescence to adulthood has been the period of highest risk for hallucinogen use.

Low power? Use two-dimensional confidence regions as a graphical method for depicting uncertainty.

Prospective studies of rare outcomes, such as HIV seroconversion or obsessive-compulsive disorder, can often result in small sample sizes with limited power for detecting associations. For this reason, it is useful to develop graphical procedures that enable researchers to depict uncertainty around parameter estimates and examine the direction of association when statistical power is low. Classical procedures include the reporting of confidence intervals, which typically are derived from asymptotic normality of parameters estimated using large samples. In this paper, we present a likelihood-based procedure for the estimation of the confidence region of two parameters from a conditional logistic regression of a nested case-control study with a relatively small number of cases. Graphical depiction of the confidence regions provides an easily comprehensible procedure to quantify the uncertainty of the estimation based on small samples.

Post-traumatic stress disorder and somatization symptoms: a prospective study.

The objective of this study is to determine whether persons with a history of post-traumatic stress disorder (PTSD) are at increased risk for somatization symptoms. Using the NIMH Diagnostic Interview Schedule, 1007 21-30-year-old members of a large health maintenance organization in south-east Michigan were interviewed initially in 1989, with follow-up interviews conducted in 1992 and 1994. Prevalence of somatization syndrome and number of somatization symptoms in the 5-year follow-up period were compared in relation to PTSD status at baseline, using logistic regression. History of PTSD was associated with significantly more symptoms in each of the somatic symptom groups, except pain. In addition, persons with PTSD were more likely to report each of the symptoms of somatization, compared to those with other psychiatric disorders. Prospectively, baseline history of PTSD signaled an increased risk of pain (OR = 2.1) and conversion symptoms (OR = 2.3) in the follow-up interval, relative to those with no disorder. PTSD increased the risk of somatization symptoms beyond that expected by the presence of comorbid psychiatric disorders. The excess of somatization symptoms in persons with history of PTSD might be attributable to PTSD per se, or to the greater severity of the associated comorbidity, compared to persons with disorders other than PTSD.

Trouble sleeping and anxiety/depression in childhood.

The purpose of this report was to estimate the association between children's trouble sleeping and anxiety/depression at ages 6 and 11, cross-sectionally and prospectively. Data come from a study of the psychiatric sequelae of low birth weight (LBW: <2500 g). LBW and normal birth weight children were randomly selected from the 1983-1985 newborn lists of an urban and a suburban hospital. Eight hundred and twenty-three children participated at age 6 and, of those, 717 (87.1%) participated at age 11. Achenbach's Child Behavior Checklist (CBCL) and the Teacher Report Form (TRF) were used to obtain ratings of psychiatric problems. The CBCL asked if the child had trouble sleeping during the past 6 months. Children with trouble sleeping had significantly increased odds of anxiety/depression based on mothers' reports (OR=6.9, 95% CI 4.1-11. 4) but not teachers' reports (OR=1.1, 95% CI 0.4-2.7). There was a greater association between sleep and depression at age 11 than at age 6, and among suburban than among urban children. These findings remained when adjusted for birthweight, sex, and mother's history of major depressive disorder. Profile analysis indicated a stronger association of trouble sleeping with anxiety/depression than other psychiatric problems. The association of trouble sleeping at age 6 with incidence of depression at age 11 was not statistically significant (suburban children RR=2.22, 95% CI 0.53-9.23; urban children RR=0.92, 95% CI 0.20-4.18).

Alcohol disorders in young adulthood: effects of transitions into adult roles.

Using data gathered prospectively, the authors examined whether transitions in two major adult social roles, marriage and parenthood, influence the risk of developing (1) DSM-III-R alcohol disorder and (2) symptoms of alcohol disorder. Additionally, the potential impact of these transitions on persistence of alcohol disorder was examined. In the study, 1,007 members (21 to 30 years old) of a large health maintenance organization located in southeast Michigan were interviewed initially in 1989, 979 of whom were reinterviewed in 1992. Incidence of alcohol disorder symptoms was significantly higher among those who remained single (RR = 2.1) or became divorced (RR = 6.0) during the follow-up period, compared to those getting or staying married. Those who were never parents through the follow-up were also at increased risk (RR = 2.5), relative to those who became parents for the first time. Similar results were obtained for the incidence and persistence of an alcohol disorder. Transitions into adult roles, such as marriage and parenthood, appear to reduce the risk of developing alcohol disorder or related symptoms in young adulthood. These transitions also reduce the likelihood that an existing alcohol disorder will persist.